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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
BRAFTOVI safely and effectively. See full prescribing information for
BRAFTOVI.
BRAFTOVI® (encorafenib) capsules, for oral use
Initial U.S. Approval: 2018
---------------------------RECENT MAJOR CHANGES ----------------------
Indications and Usage (1.2)
12/2024
Dosage and Administration (2.1, 2.3)
12/2024
Warnings and Precautions (5.1, 5.4, 5.5, 5.7, 5.10)
12/2024
---------------------------INDICATIONS AND USAGE------------------------
BRAFTOVI is a kinase inhibitor indicated:
Melanoma
•
in combination with binimetinib, for the treatment of patients with
unresectable or metastatic melanoma with a BRAF V600E or V600K
mutation, as detected by an FDA-approved test. (1.1, 2.1)
Colorectal Cancer (CRC)
•
in combination with cetuximab and mFOLFOX6, for the treatment of
patients with metastatic colorectal cancer (mCRC) with a BRAF V600E
mutation, as detected by an FDA-approved test. (1.2, 2.1)
This indication is approved under accelerated approval based on
response rate and durability of response [see Clinical Studies (14.2)].
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory trial(s).
•
in combination with cetuximab, for the treatment of adult patients with
metastatic CRC with a BRAF V600E mutation, as detected by an
FDA-approved test, after prior therapy. (1.2, 2.1)
Non-Small Cell Lung Cancer (NSCLC)
•
in combination with binimetinib, for the treatment of adult patients
with metastatic non-small cell lung cancer (NSCLC) with a BRAF
V600E mutation, as detected by an FDA-approved test. (1.3, 2.1)
Limitations of Use
BRAFTOVI is not indicated for treatment of patients with wild-type BRAF
melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC. (1.4, 5.2)
---------------------DOSAGE AND ADMINISTRATION--------------------
Melanoma
•
Confirm the presence of BRAF V600E or V600K mutation in tumor
specimens prior to the initiation of BRAFTOVI. (2.1)
•
The recommended dose is 450 mg orally once daily in combination
with binimetinib. (2.2)
CRC
•
Confirm the presence of BRAF V600E mutation in plasma or tumor
specimens prior to the initiation of BRAFTOVI. (2.1)
•
The recommended dose is 300 mg orally once daily in combination
with cetuximab. (2.3)
NSCLC
•
Confirm the presence of BRAF V600E mutation in tumor or plasma
specimens prior to initiating BRAFTOVI. (2.1)
•
The recommended dose is 450 mg orally once daily in combination
with binimetinib. (2.2)
Take BRAFTOVI with or without food. (2.4)
--------------------DOSAGE FORMS AND STRENGTHS-------------------
Capsules: 75 mg. (3)
-----------------------------CONTRAINDICATIONS---------------------------
None. (4)
----------------------WARNINGS AND PRECAUTIONS---------------------
•
New Primary Malignancies, cutaneous and noncutaneous: Can occur.
Monitor for malignancies and perform dermatologic evaluations prior
to, while on therapy, and following discontinuation of treatment. (5.1)
•
Tumor Promotion in BRAF Wild-Type Tumors: Increased cell
proliferation can occur with BRAF inhibitors. (5.2)
•
Cardiomyopathy: Assess left ventricular ejection fraction (LVEF)
before initiating treatment with BRAFTOVI and binimetinib, and after
one month of treatment, then every 2 to 3 months thereafter. The safety
of BRAFTOVI in combination with binimetinib has not been
established in patients with LVEF below 50%. (5.3)
•
Hepatotoxicity: Monitor liver function tests before and during
treatment with BRAFTOVI and binimetinib and as clinically indicated.
(5.4)
•
Hemorrhage: Major hemorrhagic events can occur in patients receiving
BRAFTOVI and binimetinib. (5.5)
•
Uveitis: Perform ophthalmologic evaluation at regular intervals and for
any visual disturbances. (5.6)
•
QT Prolongation: Monitor electrolytes before and during treatment.
Correct electrolyte abnormalities and control for cardiac risk factors for
QT prolongation. Withhold BRAFTOVI for QTc of 500 ms or greater.
(5.7)
•
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with
reproductive potential of potential risk to the fetus and to use effective
nonhormonal method of contraception. (5.8, 8.1, 8.3)
•
Risks Associated with BRAFTOVI as a Single Agent: If binimetinib is
temporarily interrupted or permanently discontinued, reduce the dose
of BRAFTOVI as recommended. (5.9)
•
Risks Associated with Combination Treatment: BRAFTOVI is
indicated for use as part of a regimen in combination with binimetinib
or cetuximab. (5.10)
-----------------------------ADVERSE REACTIONS----------------------------
•
Melanoma: Most common adverse reactions (>25%) for BRAFTOVI,
in combination with binimetinib, are fatigue, nausea, vomiting,
abdominal pain, and arthralgia. (6.1)
•
CRC: Most common adverse reactions (≥25%) for BRAFTOVI, in
combination with cetuximab and mFOLFOX6, are peripheral
neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite,
vomiting, hemorrhage, abdominal pain, and pyrexia. (6.1)
Most common adverse reactions (>25%) for BRAFTOVI, in
combination with cetuximab, are fatigue, nausea, diarrhea, dermatitis
acneiform, abdominal pain, decreased appetite, arthralgia, and rash.
(6.1)
•
NSCLC: Most common adverse reactions (≥25%) for BRAFTOVI, in
combination with binimetinib, are fatigue, nausea, diarrhea,
musculoskeletal pain, vomiting, abdominal pain, visual impairment,
constipation, dyspnea, rash, and cough. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.
at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-----------------------------DRUG INTERACTIONS----------------------------
•
Strong or moderate CYP3A4 inhibitors: Avoid coadministration. If
unavoidable, reduce BRAFTOVI dosage. (2.6, 7.1)
•
Strong CYP3A4 inducers: Avoid coadministration. (7.1)
•
Sensitive CYP3A4 substrates: Avoid coadministration with CYP3A4
substrates (including hormonal contraceptives) for which a decrease in
plasma concentration may lead to reduced efficacy of the substrate.
(7.2)
•
Transporters: Dose reductions of drugs that are substrates of
OATP1B1, OATP1B3, or BCRP may be required when used
concomitantly with BRAFTOVI. (7.2, 12.3)
----------------------USE IN SPECIFIC POPULATIONS---------------------
•
Lactation: Advise not to breastfeed. (8.2)
•
Males of Reproductive Potential: BRAFTOVI may impair fertility.
(8.3)
See 17 for PATIENT COUNSELING INFORMATION and
Medication Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 BRAF V600E or V600K Mutation-Positive Unresectable or
Metastatic Melanoma
1.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer
(mCRC)
1.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell
Lung Cancer (NSCLC)
1.4 Limitations of Use
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Dosage for BRAF V600E or V600K
Mutation-Positive Unresectable or Metastatic Melanoma and
for BRAF V600E Mutation-Positive Metastatic Non-Small Cell
Lung Cancer (NSCLC)
1
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2.3 Recommended Dosage for BRAF V600E Mutation-Positive
Metastatic Colorectal Cancer (CRC)
2.4 Administration
2.5 Dosage Modifications for Adverse Reactions
2.6 Dose Modifications for Coadministration with Strong or
Moderate CYP3A4 Inhibitors
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 New Primary Malignancies
5.2 Tumor Promotion in BRAF Wild-Type Tumors
5.3 Cardiomyopathy
5.4 Hepatotoxicity
5.5 Hemorrhage
5.6 Uveitis
5.7 QT Prolongation
5.8 Embryo-Fetal Toxicity
5.9 Risks Associated with BRAFTOVI as a Single Agent
5.10 Risks Associated with Combination Treatment
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on BRAFTOVI
7.2 Effect of BRAFTOVI on Other Drugs
7.3 Drugs That Prolong the QT Interval
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 BRAF V600E or V600K Mutation-Positive Unresectable or
Metastatic Melanoma
14.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer
(mCRC)-BRAFTOVI with Cetuximab and mFOLFOX6
14.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer
(CRC)
14.4 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung
Cancer
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
2
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or
metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test
[see Dosage and Administration (2.1)].
1.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC)
• BRAFTOVI is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients
with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved
test [see Dosage and Administration (2.1)].
o This indication is approved under accelerated approval based on response rate and durability of
response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in a confirmatory trial(s).
• BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC
with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy [see Dosage and
Administration (2.1)].
1.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
BRAFTOVI is indicated, in combination with binimetinib, for the treatment of adult patients with metastatic
non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test [see
Dosage and Administration (2.1)].
1.4 Limitations of Use
BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC,
or wild-type BRAF NSCLC [see Warnings and Precautions (5.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI
[see Warnings and Precautions (5.2), Clinical Studies (14.1)]. Information on FDA-approved tests for the
detection of BRAF V600E and V600K mutations in melanoma is available at:
http://www.fda.gov/CompanionDiagnostics.
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
Confirm the presence of a BRAF V600E mutation in plasma or tumor tissue prior to initiating BRAFTOVI [see
Warnings and Precautions (5.2), Clinical Studies (14.2, 14.3)]. If no mutation is detected in a plasma specimen,
test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in CRC is
available at: http://www.fda.gov/CompanionDiagnostics.
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
Confirm the presence of a BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI
[see Warnings and Precautions (5.2), Clinical Studies (14.4)]. If no mutation is detected in a plasma specimen,
test tumor tissue. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is
available at: http://www.fda.gov/CompanionDiagnostics.
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2.2 Recommended Dosage for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic
Melanoma and for BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer
(NSCLC)
The recommended dosage of BRAFTOVI is 450 mg (six 75 mg capsules) orally once daily in combination with
binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information
for recommended binimetinib dosing information.
2.3 Recommended Dosage for BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
The recommended dosage of BRAFTOVI is 300 mg (four 75 mg capsules) orally once daily in combination
with biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) [see Clinical Studies
(14.2)] or in combination with weekly cetuximab [see Clinical Studies (14.3)] until disease progression or
unacceptable toxicity.
2.4 Administration
BRAFTOVI may be taken with or without food [see Clinical Pharmacology (12.3)]. Do not take a missed dose
of BRAFTOVI within 12 hours of the next dose of BRAFTOVI.
Do not take an additional dose if vomiting occurs after BRAFTOVI administration but continue with the next
scheduled dose.
2.5 Dosage Modifications for Adverse Reactions
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma or BRAF V600E
Mutation-Positive Metastatic NSCLC
If binimetinib is withheld, reduce BRAFTOVI to a maximum dose of 300 mg (four 75 mg capsules) once daily
until binimetinib is resumed [see Warnings and Precautions (5.9)].
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1.
Table 1:
Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – Melanoma or
NSCLC
Action
Recommended Dose
First Dose Reduction
300 mg (four 75 mg capsules) orally once daily
Second Dose Reduction
225 mg (three 75 mg capsules) orally once daily
Subsequent Modification
Permanently discontinue if unable to tolerate BRAFTOVI 225 mg
(three 75 mg capsules) once daily
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
If cetuximab is discontinued, discontinue BRAFTOVI.
Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 2.
Table 2:
Recommended Dose Reductions for BRAFTOVI for Adverse Reactions – CRC
Action
Recommended Dose
First Dose Reduction
225 mg (three 75 mg capsules) orally once daily
Second Dose Reduction
150 mg (two 75 mg capsules) orally once daily
Subsequent Modification
Permanently discontinue if unable to tolerate BRAFTOVI 150 mg
(two 75 mg capsules) once daily
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma, BRAF V600E
Mutation-Positive Metastatic Colorectal Cancer (CRC), or BRAF V600E Mutation-Positive NSCLC
Dosage modifications for adverse reactions associated with BRAFTOVI are presented in Table 3.
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Table 3:
Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions
Severity of Adverse Reactiona
Dose Modification for BRAFTOVI
New Primary Malignancies [see Warnings and Precautions (5.1)]
Noncutaneous RAS Mutation-positive
Malignancies
Permanently discontinue BRAFTOVI.
Cardiomyopathy [see Warnings and Precautions (5.3)]
•
Symptomatic congestive heart
failure or absolute decrease in
LVEF of greater than 20% from
baseline that is also below LLN
Reduce BRAFTOVI by one dose level [see Dosage and Administration
(2.3)].
•
If LVEF improves to at least institutional LLN and absolute decrease
to less than or equal to 10% compared to baseline, continue
BRAFTOVI at the reduced dose [see Dosage and Administration
(2.3)].
•
If no improvement, withhold BRAFTOVI until improves to at least
institutional LLN and absolute decrease to less than or equal to 10%
compared to baseline and then resume at the reduced dose or reduce
dose an additional dose level.
Hepatotoxicity [see Warnings and Precautions (5.4)]
•
Grade 2 AST or ALT increased
Maintain BRAFTOVI dose.
•
If no improvement within 4 weeks, withhold BRAFTOVI until
improves to Grade 0-1 or to pretreatment/baseline levels and then
resume at same dose.
•
Grade 3 or 4 AST or ALT
increased
See Other Adverse Reactions.
Uveitis [see Warnings and Precautions (5.6)]
•
Grade 1-3
If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3
uveitis, withhold BRAFTOVI for up to 6 weeks.
•
If improved, resume at same or reduced dose.
•
If not improved, permanently discontinue BRAFTOVI.
•
Grade 4
Permanently discontinue BRAFTOVI.
QTc Prolongation [see Warnings and Precautions (5.7)]
•
QTcF greater than 500 ms and
less than or equal to 60 ms
increase from baseline
Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at
reduced dose.
•
If more than one recurrence, permanently discontinue BRAFTOVI.
•
QTcF greater than 500 ms and
greater than 60 ms increase from
baseline
Permanently discontinue BRAFTOVI.
Dermatologic [other than Hand-foot Skin Reaction (HFSR)] [see Adverse Reactions (6.1)]
•
Grade 2
If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0-1.
Resume at same dose.
•
Grade 3
Withhold BRAFTOVI until Grade 0-1. Resume at same dose if first
occurrence or reduce dose if recurrent.
•
Grade 4
Permanently discontinue BRAFTOVI.
Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5)] and HFSR [see Adverse
Reactions (6.1)]b
•
Recurrent Grade 2 or
•
First occurrence of any Grade 3
Withhold BRAFTOVI for up to 4 weeks.
•
If improves to Grade 0-1 or to pretreatment/baseline level, resume at
reduced dose.
•
If no improvement, permanently discontinue BRAFTOVI.
5
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Severity of Adverse Reactiona
Dose Modification for BRAFTOVI
•
First occurrence of any Grade 4
Permanently discontinue BRAFTOVI or
Withhold BRAFTOVI for up to 4 weeks.
•
If improves to Grade 0-1 or to pretreatment/baseline level, then
resume at reduced dose.
•
If no improvement, permanently discontinue BRAFTOVI.
•
Recurrent Grade 3
Consider permanently discontinuing BRAFTOVI.
•
Recurrent Grade 4
Permanently discontinue BRAFTOVI.
a.
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
b.
Dose modification of BRAFTOVI when administered with binimetinib or with cetuximab is not recommended for new primary cutaneous
malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; creatine phosphokinase (CPK)
elevation; rhabdomyolysis; and venous thromboembolism.
Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions
associated with each product, as appropriate.
2.6 Dose Modifications for Coadministration with Strong or Moderate CYP3A4 Inhibitors
Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors. If coadministration is
unavoidable, reduce the BRAFTOVI dose according to the recommendations in Table 4. After the inhibitor has
been discontinued for 3 to 5 elimination half-lives, resume the BRAFTOVI dose that was taken prior to
initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration with Strong or
Moderate CYP3A4 Inhibitors
Current Daily Dosea
Dose for Coadministration with Moderate
CYP3A4 Inhibitor
Dose for Coadministration with Strong
CYP3A4 Inhibitor
450 mg
225 mg (three 75 mg capsules)
150 mg (two 75 mg capsules)
300 mg
150 mg (two 75 mg capsules)
75 mg
225 mg
75 mg
75 mg
150 mg
75 mg
75 mgb
a.
Current daily dose refers to recommended dose of BRAFTOVI based on indication or reductions for adverse reactions based on dosing
recommendations in Table 1 (Melanoma) and Table 2 (CRC).
b.
Encorafenib exposure at the 75 mg QD BRAFTOVI dosage when coadministered with a strong CYP3A4 inhibitor is expected to be higher
than at the 150 mg QD dosage in the absence of a CYP3A4 inhibitor and similar to exposure at the 225 mg QD dosage in the absence of a
CYP3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgement when using BRAFTOVI with strong CYP3A4
inhibitors at the 150 mg dose level.
3 DOSAGE FORMS AND STRENGTHS
Capsules: 75 mg, hard gelatin, stylized “A” on beige cap and “LGX 75mg” on white body.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 New Primary Malignancies
New primary malignancies, cutaneous and noncutaneous, have been observed in patients treated with BRAF
inhibitors and can occur with BRAFTOVI.
Cutaneous Malignancies
In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in
2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with
binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months) [see Adverse
Reactions (6.1)].
6
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For patients who received BRAFTOVI as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma
in 1%, and a new primary melanoma in 5% of patients.
In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a new primary melanoma occurred
in 1.4% of patients who received BRAFTOVI in combination with cetuximab.
In PHAROS, cuSCC and skin papilloma, each occurred in 2% of patients who received BRAFTOVI in
combination with binimetinib.
In BREAKWATER, skin papilloma was reported in 2.6%, basal cell carcinoma in 1.3%, squamous cell
carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4% of patients who
received BRAFTOVI in combination with cetuximab and mFOLFOX6.
Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to
6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and
dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies.
Noncutaneous Malignancies
Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS
through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving
BRAFTOVI for signs and symptoms of noncutaneous malignancies. Discontinue BRAFTOVI for RAS
mutation-positive noncutaneous malignancies [see Dosage and Administration (2.5)].
5.2 Tumor Promotion in BRAF Wild-Type Tumors
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell
proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of
BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Indications and Usage (1), Dosage and
Administration (2.1)].
5.3 Cardiomyopathy
Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic
decreases in ejection fraction, has been reported in patients treated with BRAFTOVI in combination with
binimetinib. In COLUMBUS, evidence of cardiomyopathy (decreased in LVEF below the institutional LLN
with an absolute decreased in LVEF ≥10% below baseline as detected by echocardiography or MUGA)
occurred in 7% of patients receiving BRAFTOVI plus binimetinib. Grade 3 left ventricular dysfunction
occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in
patients receiving BRAFTOVI in combination with binimetinib was 3.6 months (range 0 to 21 months).
Cardiomyopathy resolved in 87% of patients receiving BRAFTOVI plus binimetinib.
In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute
decrease in LVEF ≥10% below baseline as detected by echocardiography or MUGA) occurred in 11% of
patients receiving BRAFTOVI in combination with binimetinib. Grade 3 left ventricular dysfunction occurred
in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving BRAFTOVI plus binimetinib.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after
initiating treatment, and every 2 to 3 months during treatment. The safety of BRAFTOVI in combination with
binimetinib has not been established in patients with baseline ejection fraction that is either below 50% or
below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be
monitored closely when treated with BRAFTOVI.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and
Administration (2.3), Adverse Reactions (6.1)].
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5.4 Hepatotoxicity
Hepatotoxicity can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS,
the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in
combination with binimetinib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase
(AST), and 0.5% for alkaline phosphatase. In PHAROS, the incidence of Grade 3 or 4 increases in liver
function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 10% for AST,
9% for ALT, and 3.2% for alkaline phosphatase.
In BREAKWATER, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients
receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.2% for alkaline phosphatase,
1.3% for ALT, and 0.9% for AST.
Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically
indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage
and Administration (2.3), Adverse Reactions (6.1)].
5.5 Hemorrhage
In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with
binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events
were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal
hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred
in 1.6% of patients.
In BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with
cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal
hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%),
hematochezia (2.3%), and rectal hemorrhage (2.3%).
In PHAROS, hemorrhage occurred in 12% of patients receiving BRAFTOVI in combination with binimetinib
including fatal hemorrhage intracranial (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most
frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).
In BREAKWATER, hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with
cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients.
Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and
Administration (2.5), Adverse Reactions (6.1)].
5.6 Uveitis
Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination
with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in
combination with binimetinib was 4%. In PHAROS, the incidence of uveitis among patients treated with
BRAFTOVI in combination with binimetinib was 1%.
Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new
or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce
dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5),
Adverse Reactions (6.1)].
5.7 QT Prolongation
BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see Clinical
Pharmacology (12.2)]. In COLUMBUS, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of
patients who received BRAFTOVI in combination with binimetinib. In PHAROS, an increase in QTcF to
>500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI in combination with binimetinib.
8
Reference ID: 5500726
In BREAKWATER, an increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving
BRAFTOVI in combination with cetuximab and mFOLFOX6.
Monitor patients who already have or who are at significant risk of developing QTc prolongation, including
patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart
failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and
hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently
discontinue for QTc >500 ms [see Dosage and Administration (2.5), Adverse Reactions (6.1)].
5.8 Embryo-Fetal Toxicity
Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman.
Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in
rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in
the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower
doses.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of
reproductive potential to use an effective, nonhormonal method of contraception since BRAFTOVI can render
hormonal contraceptives ineffective, during treatment and for 2 weeks after the last dose of BRAFTOVI [see
Use in Specific Populations (8.1, 8.3)].
5.9 Risks Associated with BRAFTOVI as a Single Agent
BRAFTOVI when used as a single agent is associated with an increased risk of certain adverse reactions
compared to when BRAFTOVI is used in combination with binimetinib. In COLUMBUS, Grades 3 or 4
dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of
patients treated with BRAFTOVI in combination with binimetinib [see Warnings and Precautions (5.1),
Adverse Reactions (6.1)].
If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as
recommended [see Dosage and Administration (2.5)].
5.10 Risks Associated with Combination Treatment
BRAFTOVI is indicated for use as part of a regimen in combination with binimetinib, in combination with
cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for
binimetinib, cetuximab and individual product components of mFOLFOX6 for additional risk information.
6 ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling:
• New Primary Malignancies [see Warnings and Precautions (5.1)]
• Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)]
• Cardiomyopathy [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Hemorrhage [see Warnings and Precautions (5.5)]
• Uveitis [see Warnings and Precautions (5.6)]
• QT Prolongation [see Warnings and Precautions (5.7)]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.8)]
• Risks Associated with BRAFTOVI as a Single Agent [see Warnings and Precautions (5.9)]
• Risks Associated with Combination Treatment [see Warnings and Precautions (5.10)]
9
Reference ID: 5500726
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600
mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in
combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial
(COLUMBUS).
The COLUMBUS trial [see Clinical Studies (14.1)] excluded patients with a history of Gilbert’s syndrome,
abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or
current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients
treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated with vemurafenib.
The most common (>25%) adverse reactions in patients receiving BRAFTOVI in combination with binimetinib
were fatigue, nausea, vomiting, abdominal pain, and arthralgia.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving
BRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%), and
pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patients
receiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%),
and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib
experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common
were hemorrhage in 2% and headache in 1% of patients.
Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in
COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in
adverse reaction rates for BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any
specific adverse reaction listed in Table 5.
Table 5:
Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Binimetinib in COLUMBUSa
Adverse Reaction
BRAFTOVI
with binimetinib
N=192
Vemurafenib
N=186
All Grades
(%)
Grades 3 and 4b
(%)
All Grades
(%)
Grades 3 and 4
(%)
General Disorders and Administration Site Conditions
Fatiguec
43
3
46
6
Pyrexiac
18
4
30
0
Gastrointestinal Disorders
Nausea
41
2
34
2
Vomitingc
30
2
16
1
Abdominal painc
28
4
16
1
Constipation
22
0
6
1
10
Reference ID: 5500726
Table 5:
Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Binimetinib in COLUMBUSa
Adverse Reaction
BRAFTOVI
with binimetinib
N=192
Vemurafenib
N=186
All Grades
(%)
Grades 3 and 4b
(%)
All Grades
(%)
Grades 3 and 4
(%)
Musculoskeletal and Connective Tissue Disorders
Arthralgiac
26
1
46
6
Myopathyc
23
0
22
1
Pain in extremity
11
1
13
1
Skin and Subcutaneous Tissue Disorders
Hyperkeratosisc
23
1
49
1
Rashc
22
1
53
13
Dry skinc
16
0
26
0
Alopeciac
14
0
38
0
Pruritusc
13
1
21
1
Nervous System Disorders
Headachec
22
2
20
1
Dizzinessc
15
3
4
0
Peripheral neuropathyc
12
1
13
2
Vascular Disorders
Hemorrhagec
19
3
9
2
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm.
c.
Represents a composite of multiple, related preferred terms.
BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to
BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a
single agent, the following adverse reactions were observed at a higher rate (≥5%) compared to patients
receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs.
7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%),
alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back
pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%).
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in
combination with binimetinib were:
Nervous system disorders: Facial paresis
Gastrointestinal disorders: Pancreatitis
Skin and subcutaneous tissue disorders: Panniculitis, Photosensitivity
Immune system disorders: Drug hypersensitivity
11
Reference ID: 5500726
Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI
in Combination with Binimetinib in COLUMBUSa
Laboratory Abnormality
BRAFTOVI
with binimetiniba
N=192
Vemurafeniba
N=186
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
Hematology
Anemia
36
3.6
34
2.2
Leukopenia
13
0
10
0.5
Lymphopenia
13
2.1
30
7
Neutropenia
13
3.1
4.8
0.5
Chemistry
Increased Creatinine
93
3.6
92
1.1
Increased Gamma Glutamyl Transferase
45
11
34
4.8
Increased ALT
29
6
27
2.2
Increased AST
27
2.6
24
1.6
Hyperglycemia
28
5
20
2.7
Increased Alkaline Phosphatase
21
0.5
35
2.2
Hyponatremia
18
3.6
15
0.5
Hypermagnesemia
10
1.0
26
0.5
a.
Grades per National Cancer Institute CTCAE v4.03.
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) in combination with Cetuximab and
mFOLFOX6
The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m2 every 2 weeks) and
mFOLFOX6 was evaluated in 231 patients with BRAF V600E mutation-positive metastatic CRC in a
randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2)].
BREAKWATER excluded patients with pancreatitis, leptomeningeal disease, chronic inflammatory bowel
disease requiring medical intervention, as well as clinically significant cardiovascular diseases [e.g., myocardial
infarction, acute coronary syndromes, NYHA Class ≥II congestive heart failure, prolonged QTcF interval
(≥480 ms), history of prolonged QT syndrome] and active infectious conditions.
Among patients who received BRAFTOVI, 54% were exposed for 6 months or longer and 18% were exposed
for one year or longer.
Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with
cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction and
pyrexia (3.5% each).
Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with
cetuximab and mFOLFOX6.
Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 12% of patients. Adverse
reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included increased
lipase.
Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 57% of patients. Adverse reactions
which required dosage interruption in ≥5% included decreased neutrophil count, pyrexia, and anemia.
Dose reductions of BRAFTOVI due to an adverse reaction occurred in 22% of patients. Adverse reactions
leading to dose reductions of BRAFTOVI in ≥2% of patients included increased lipase, nausea, and vomiting.
12
Reference ID: 5500726
The most common (≥25%) adverse reactions of BRAFTOVI when used in combination with cetuximab and
mFOLFOX6 were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting,
hemorrhage, abdominal pain, and pyrexia.
The most common Grade 3 or 4 laboratory abnormalities (≥10%) of BRAFTOVI when used in combination
with cetuximab and mFOLFOX6 were increased lipase, decreased neutrophil count, decreased hemoglobin,
decreased white blood cell count, and increased glucose.
Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in
BREAKWATER.
Table 7: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Cetuximab and mFOLFOX6 in BREAKWATERa
Adverse Reaction
BRAFTOVI
with cetuximab and mFOLFOX6
N=231
mFOLFOX6 ± bevacizumab
or
FOLFOXIRI ± bevacizumab
or
CAPOX ± bevacizumab
N=228
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Nervous System Disorders
Peripheral neuropathyb
62
15
53
6
Headache
13
<1
7
0
Dysgeusia
12
0
14
0
Neurotoxicity
11
5
8
0
Gastrointestinal Disorders
Nausea
51
3
48
3
Diarrhea
34
1
47
4
Vomiting
33
4
21
2
Abdominal painb
26
4
27
1
Constipation
20
<1
19
<1
General Disorders and Administration Site Conditions
Fatigueb
49
7
38
4
Pyrexiab
26
2
14
<1
Metabolism and Nutrition Disorders
Decreased appetite
33
2
25
1
Musculoskeletal and Connective Tissue Disorders
Arthralgiab
23
1
4
0
Myopathyb
14
0
7
<1
Skin and Subcutaneous Tissue Disorders
Rashb
31
1
4
0
Alopecia
21
0
10
0
Dry skinb
17
0
4
0
Dermatitis acneiformb
17
1
1
0
Skin hyperpigmentation
17
0
2
0
Pruritus
11
0
3
<1
13
Reference ID: 5500726
Table 7: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Cetuximab and mFOLFOX6 in BREAKWATERa
Adverse Reaction
BRAFTOVI
with cetuximab and mFOLFOX6
N=231
mFOLFOX6 ± bevacizumab
or
FOLFOXIRI ± bevacizumab
or
CAPOX ± bevacizumab
N=228
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Vascular Disorders
Hemorrhageb
30
3
18
1
Psychiatric Disorder
Insomniab
11
0
7
0
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
Represents multiple related terms.
Table 8:
Laboratory Abnormalities Occurring in ≥20% (All Grades) of Patients Receiving
BRAFTOVI in Combination with Cetuximab and mFOLFOX6 in BREAKWATERa
Laboratory Abnormalityb
BRAFTOVI
with cetuximab and mFOLFOX6
mFOLFOX6 ± bevacizumab
or
FOLFOXIRI ± bevacizumab
or
CAPOX ± bevacizumab
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Hematology
Neutrophil count decreased
63
36
60
34
White blood cell decreased
62
12
54
7
Hemoglobin decreased
60
13
47
5
Platelet count decreased
60
1
50
2
Activated partial thromboplastin time
prolonged
57
3
38
1
INR increased
39
1
20
1
Chemistry
Lipase increased
82
51
54
25
Creatinine increased
64
1
67
1
Glucose increased
49
11
35
2
Alanine aminotransferase increased
38
1
40
2
Albumin decreased
36
0
24
1
Aspartate aminotransferase increased
36
1
35
2
Potassium decreased
33
4
19
4
Alkaline phosphatase increased
31
2
31
1
Calcium decreased
24
4
16
2
Magnesium decreased
23
1
11
1
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
The denominator used to calculate the rate varied from 220 to 227 based on the number of patients with a baseline and at least one
post-treatment value.
14
Reference ID: 5500726
BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (400 mg/m2 initial dose, followed
by 250 mg/m2 weekly) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a
randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies
(14.3)] excluded patients with a history of Gilbert’s syndrome, abnormal left ventricular ejection fraction,
prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion.
The median duration of exposure was 4.4 months for patients treated with BRAFTOVI in combination with
cetuximab and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic
acid (FA)/irinotecan (FOLFIRI) in combination with cetuximab.
The most common (≥25%) adverse reactions in patients receiving BRAFTOVI in combination with cetuximab
were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 33% of patients receiving
BRAFTOVI in combination with cetuximab; the most common were vomiting (4%), fatigue (4%), nausea (4%),
pyrexia (3%), and diarrhea (3%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 9%
of patients receiving BRAFTOVI in combination with cetuximab; the most common were fatigue (2%),
arthralgia (2%), and peripheral neuropathy (2%). Ten percent (10%) of patients receiving BRAFTOVI in
combination with cetuximab experienced an adverse reaction that resulted in permanent discontinuation of
BRAFTOVI. None of the adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in
more than one patient (>0.5%).
Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in
BEACON CRC.
Table 9: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Cetuximab in BEACON CRCa
Adverse Reaction
BRAFTOVI
with cetuximab
N=216
Irinotecan with cetuximab or
FOLFIRI with cetuximab
N=193
All Grades
(%)
≥ Grade 3b
(%)
All Grades
(%)
≥ Grade 3
(%)
General Disorders and Administration Site Conditions
Fatiguec
51
7
50
8
Pyrexiac
17
1
15
1
Gastrointestinal Disorders
Nausea
34
1
41
1
Diarrheac
33
2
48
10
Abdominal painc
30
4
32
5
Vomiting
21
1
29
3
Constipation
15
0
18
1
Metabolism and Nutrition Disorders
Decreased appetite
27
1
27
3
Musculoskeletal and Connective Tissue Disorders
Arthralgiac
27
1
3
0
Myopathyc
15
1
4
0
Pain in extremity
10
0
1
0
15
Reference ID: 5500726
Table 9: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Cetuximab in BEACON CRCa
Adverse Reaction
BRAFTOVI
with cetuximab
N=216
Irinotecan with cetuximab or
FOLFIRI with cetuximab
N=193
All Grades
(%)
≥ Grade 3b
(%)
All Grades
(%)
≥ Grade 3
(%)
Skin and Subcutaneous Tissue Disorders
Dermatitis acneiformc
32
1
43
3
Rashc
26
0
26
2
Pruritusc
14
0
6
0
Melanocytic nevus
14
0
0
0
Dry skinc
13
0
12
1
Nervous System Disorders
Headachec
20
0
3
0
Peripheral neuropathyc
12
1
6
0
Vascular Disorders
Hemorrhagec
19
2
9
0
Psychiatric Disorders
Insomniac
13
0
6
0
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade 5 hemorrhage (n=1).
c.
Represents a composite of multiple, related preferred terms.
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in
combination with cetuximab were:
Gastrointestinal disorders: Pancreatitis
Table 10: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving
BRAFTOVI in Combination with Cetuximab in BEACON CRCa
Laboratory Abnormalityb
BRAFTOVI
with cetuximab
Irinotecan with cetuximab or
FOLFIRI with cetuximab
All Grades
(%)
Grades 3 and 4
(%)
All Grades
(%)
Grades 3 and 4
(%)
Hematology
Anemia
34
4
48
5
Lymphopenia
24
7
35
5
Increased Activated Partial
Thromboplastin Time
13
1
7
1
Chemistry
Hypomagnesemia
19
0
22
1
Increased Alkaline Phosphatase
18
4
30
7
Increased ALT
17
0
29
3
Increased AST
15
1
22
2
Hypokalemia
12
3
32
5
Hyponatremia
11
2
13
2
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
Based on the number of patients with available baseline and at least one on-treatment laboratory test.
16
Reference ID: 5500726
BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)
The safety of BRAFTOVI in combination with binimetinib was evaluated in 98 patients with BRAF V600E
mutation-positive metastatic NSCLC who received BRAFTOVI (450 mg once daily) in combination with
binimetinib (45 mg twice daily) in an open-label, single-arm trial (PHAROS).
The PHAROS trial [see Clinical Studies (14.4)] excluded patients with abnormal left ventricular ejection
fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein
occlusion. The median duration of treatment for BRAFTOVI and binimetinib was 9.2 and 8.4 months, respectively.
The most common (≥25%) adverse reactions in patients receiving BRAFTOVI were fatigue, nausea, diarrhea,
musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.
Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 59% of patients receiving
BRAFTOVI; the most common (≥5%) were diarrhea (17%); nausea (13%); musculoskeletal pain, fatigue (8%
each); AST increased (7%); ALT increased, anemia, hemorrhage, vomiting (6% each); and acute kidney
injury (5%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 30% of patients receiving
BRAFTOVI; the most common (≥5%) were diarrhea, nausea (8% each); AST increased and fatigue (5% each).
A total of 16% of patients receiving BRAFTOVI experienced an adverse reaction that resulted in permanent
discontinuation of BRAFTOVI; the most common (≥2%) were diarrhea, musculoskeletal pain (3.1% each);
fatigue, rash, nausea, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to
permanent discontinuation of BRAFTOVI occurred in more than 1 patient.
Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with
binimetinib. Serious adverse reactions occurring in ≥2% of patients were hemorrhage (6%); diarrhea (4.1%);
anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction,
and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received BRAFTOVI
(450 mg once daily) in combination with binimetinib, including intracranial hemorrhage and myocardial
infarction (1% each).
Table 11 and Table 12 present adverse drug reactions and laboratory abnormalities, respectively, identified in
PHAROS.
Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Binimetinib in PHAROSa
Adverse Reaction
BRAFTOVI
with binimetinib
N=98
All Grades
(%)
Grades 3 and 4b
(%)
General Disorders and Administration Site Conditions
Fatiguec
61
8
Edemad
23
1
Pyrexia
22
0
Gastrointestinal Disorders
Nausea
58
3.1
Diarrheae
52
7
Vomiting
37
1
Abdominal painf
32
1
Constipation
27
0
Eye Disorders
Visual impairmentg
29
2
17
Reference ID: 5500726
Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination
with Binimetinib in PHAROSa
Adverse Reaction
BRAFTOVI
with binimetinib
N=98
All Grades
(%)
Grades 3 and 4b
(%)
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painh
48
4.1
Skin and Subcutaneous Tissue Disorders
Rashi
27
3.1
Pruritisj
16
0
Dry skin
13
0
Alopecia
12
0
Respiratory, Thoracic and Mediastinal Disorders
Dyspneak
27
8
Coughl
26
0
Nervous System Disorders
Dizzinessm
17
1
Headache
11
0
Metabolism and Nutrition Disorders
Decreased appetite
14
1
Vascular Disorders
Hemorrhageb,n
12
4.1
Hypertension
10
5
Cardiac Disorders
Left ventricular dysfunction/cardiomyopathyo
11
1
Investigations
Weight increased
11
1
Psychiatric Disorders
Insomnia
10
0
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
One Grade 5 adverse reaction of hemorrhage occurred.
c.
Fatigue includes fatigue, asthenia.
d.
Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema.
e.
Diarrhea includes diarrhea, colitis.
f.
Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.
g.
Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia.
h.
Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, noncardiac chest pain, neck
pain.
i.
Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar
erythrodysesthesia syndrome, eczema, skin exfoliation.
j.
Pruritis includes pruritus, pruritus genital.
k.
Dyspnea includes dyspnea, dyspnea exertional.
l.
Cough includes cough, productive cough.
m. Dizziness includes dizziness, balance disorder.
n.
Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage
intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage.
o.
Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive.
18
Reference ID: 5500726
Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in
combination with binimetinib were:
Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis
Gastrointestinal disorders: Pancreatitis
Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity
Immune system disorders: Drug hypersensitivity
Table 12: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving
BRAFTOVI with Binimetiniba
Laboratory Abnormalityb
BRAFTOVI with binimetinib
All Grades
(%)
Grades 3 and 4
(%)
Hematology
Anemia
47
11
Lymphopenia
24
6
Thrombocytopenia
20
1.1
Leukopenia
12
0
Neutropenia
12
1.1
Chemistry
Increased creatinine
91
3.2
Hyperglycemia
48
6
Increased creatine kinase
41
3.3
Lipase increased
40
14
Increased ALT
34
9
Hypoalbuminemia
32
0
Increased AST
31
10
Increased alkaline phosphatase
31
3.2
Hyperkalemia
31
2.1
Hyponatremia
26
11
Serum amylase increased
22
1.1
Hypocalcemia
12
2.1
a.
Grades per National Cancer Institute CTCAE v4.03.
b.
Based on the number of patients with available baseline and at least one on-treatment laboratory test.
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on BRAFTOVI
Strong or Moderate CYP3A4 Inhibitors
Coadministration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increases encorafenib plasma
concentrations [see Clinical Pharmacology (12.3)] and may increase encorafenib adverse reactions. Avoid
coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If
coadministration is unavoidable, reduce the BRAFTOVI dose [see Dosage and Administration (2.6)].
Strong CYP3A4 Inducers
Coadministration of BRAFTOVI with a strong CYP3A4 inducer may decrease encorafenib plasma
concentrations [see Clinical Pharmacology (12.3)] and may decrease encorafenib efficacy. Avoid
coadministration of BRAFTOVI with strong CYP3A4 inducers.
19
Reference ID: 5500726
7.2 Effect of BRAFTOVI on Other Drugs
Sensitive CYP3A4 Substrates
BRAFTOVI is a strong CYP3A4 inducer at steady-state. Concomitant use of BRAFTOVI may decrease the
plasma concentrations of CYP3A4 substrates (including hormonal contraceptives), [see Clinical Pharmacology
(12.3)], which may reduce the efficacy of these substrates. Avoid the coadministration of BRAFTOVI with
CYP3A4 substrates for which a decrease in plasma concentration may lead to reduced efficacy of the substrate.
If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.
OATP1B1, OATP1B3, or BCRP Substrates
Coadministration of BRAFTOVI with OATP1B1, OATP1B3, or BCRP substrates can result in increased
concentrations of the substrates, and may increase toxicity of these agents. When used in combination, monitor
patients closely for signs and symptoms of increased exposure and consider adjusting the dose of these
substrates [see Clinical Pharmacology (12.3)].
7.3 Drugs That Prolong the QT Interval
BRAFTOVI is associated with dose-dependent QTc interval prolongation [see Warnings and Precautions (5.7),
Clinical Pharmacology (12.2)]. Avoid coadministration of BRAFTOVI with drugs known to prolong the
QT/QTc interval.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman
[see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of BRAFTOVI during
pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats
and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures
approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg,
with no clear findings at lower doses (see Data). Advise pregnant women and females of reproductive potential
of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis
resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a
dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time
curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of
encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights,
increased incidence of total skeletal variations and increased post-implantation loss, including total loss of
pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the
recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been
performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%,
respectively, of maternal exposure.
20
Reference ID: 5500726
8.2 Lactation
Risk Summary
There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib
on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions
in a breastfed child from BRAFTOVI, advise women not to breastfeed during treatment with BRAFTOVI and
for 2 weeks after the last dose.
8.3 Females and Males of Reproductive Potential
BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations
(8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use in
Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and
for 2 weeks after the last dose. Counsel patients to use a nonhormonal method of contraception since
BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)].
Infertility
Males
Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose,
use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.
8.5 Geriatric Use
Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI in combination with
binimetinib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older
[see Clinical Studies (14.1)].
Of the 231 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in
combination with cetuximab and mFOLFOX6, 83 (36%) were 65 years of age and over and 16 (7%) were
75 years of age and over [see Clinical Studies (14.2)].
Of the 216 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in
combination with cetuximab, 62 (29%) were 65 years of age to up to 75 years of age, while 20 (9%) were
75 years of age and over [see Clinical Studies (14.3)].
Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI with
binimetinib, 62 (63%) were 65 years of age and over and 20 (20%) were 75 years and over [see Clinical Studies
(14.4)].
No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib, BRAFTOVI plus
cetuximab, or BRAFTOVI plus cetuximab and mFOLFOX6 were observed in older patients as compared to
younger patients.
21
Reference ID: 5500726
8.6 Hepatic Impairment
No BRAFTOVI dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh
Class A) [see Clinical Pharmacology (12.3)]. A recommended dosage has not been established in patients with
moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.
8.7 Renal Impairment
No BRAFTOVI dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr
30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. A recommended dosage has not been established in
patients with severe renal impairment (CLcr <30 mL/min).
10 OVERDOSAGE
Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of
overdose with BRAFTOVI.
11 DESCRIPTION
Encorafenib is a kinase inhibitor. The chemical name is methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3
(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate.
The molecular formula is C22H27ClFN7O4S and the molecular weight is 540 daltons. The chemical structure of
encorafenib is shown below:
Cl
H
N
S
O
O
F
N
N
N
N
HN
NH
O
O
Encorafenib is a white to almost white powder. In aqueous media, encorafenib is slightly soluble at pH 1, very
slightly soluble at pH 2, and insoluble at pH 3 and higher.
BRAFTOVI (encorafenib) capsules for oral use contain 75 mg of encorafenib with the following inactive
ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal
silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titanium dioxide, iron
oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide,
propylene glycol).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro
cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as
BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth.
Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2,
MEK4, and STK36 and reduce ligand binding to these kinases at clinically achievable concentrations
(≤0.9 µM).
Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice
implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with
RAF/MEK/ERK pathway suppression.
22
Reference ID: 5500726
Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with
either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity
in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth
inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of
encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma
xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft
model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared
to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing
cessation was also observed with the coadmnistration compared to either drug alone.
In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been
identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents
targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models.
Coadministration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in a
mouse model of colorectal cancer with mutated BRAF V600E.
12.2 Pharmacodynamics
Cardiac Electrophysiology
A dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted.
BRAFTOVI is associated with dose-dependent QTc interval prolongation. Based on a central tendency analysis
of QTc in a study of adult patients with melanoma who received the recommended dose of BRAFTOVI in
combination with binimetinib, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was
18 (14 to 22) ms [see Warnings and Precautions (5.7)].
12.3 Pharmacokinetics
The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including
advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation,
BRAF V600E mutation-positive metastatic CRC. After a single dose, systemic exposure of encorafenib was
dose proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of
450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the
dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was
reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of
AUC ranged from 12% to 69%.
Absorption
The median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed.
Effect of Food
Following administration of a single dose of BRAFTOVI 100 mg (0.2 times the maximum recommended dose
of 450 mg) with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein,
350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration
(Cmax) decreased by 36% and there was no effect on AUC.
Distribution
The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). The protein binding of
encorafenib is 86% in vitro. The blood-to-plasma concentration ratio is 0.58.
Elimination
The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is
14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state at the maximum recommended dose of
450 mg.
23
Reference ID: 5500726
Metabolism
Encorafenib is primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP2C19 (16%) and
CYP2D6 (1%).
Excretion
Following a single radiolabeled dose of 100 mg encorafenib, 47% (5% unchanged) of the administered dose
was recovered in feces and 47% (2% unchanged) in urine.
Specific Populations
No clinically significant differences in the pharmacokinetics of encorafenib were observed based on age
(19 to 94 years), sex, body weight (34 to 168 kg), mild hepatic impairment (Child-Pugh Class A), and mild or
moderate renal impairment (CLcr 30 to <90 mL/min). The effect of race or ethnicity, moderate or severe
hepatic impairment (Child-Pugh Class B or C), and severe renal impairment (CLcr <30 mL/min) on encorafenib
pharmacokinetics have not been studied.
Drug Interaction Studies
Clinical Studies
CYP3A4 Inhibitors: Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate
CYP3A4 inhibitor) increased AUC of encorafenib by 3- and 2-fold, respectively, and increased Cmax by 68%
and 45%, respectively, after a single dose of 50 mg BRAFTOVI (0.1 times the maximum recommended dose of
450 mg).
Strong CYP3A4 Inducers: The effect of a strong CYP3A4 inducer on encorafenib exposure has not been studied
[see Drug Interactions (7.1)].
Moderate CYP3A4 Inducers: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib
45 mg twice daily with modafinil, a moderate CYP3A4 inducer, decreased encorafenib steady-state AUC by
24% and Cmax by 20%, compared to BRAFTOVI alone.
Effect of encorafenib on CYP3A4 Substrates: Repeat dose administration of BRAFTOVI 450 mg once daily and
binimetinib 45 mg twice daily with a single dose of midazolam 2 mg, a sensitive CYP3A4 substrate, decreased
midazolam AUC by 82% and Cmax by 74% relative to midazolam 2 mg alone.
Effect of encorafenib on Other CYP Substrates: There was no clinically significant effect of repeat dose
administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily on the exposure of
substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6.
Proton Pump Inhibitors: No clinically significant differences in encorafenib pharmacokinetics were observed
when coadministered with rabeprazole.
Binimetinib: No clinically significant differences in the pharmacokinetics of binimetinib (UGT1A1 substrate)
were observed when coadministered with BRAFTOVI (UGT1A1 inhibitor).
Cetuximab: No clinically significant differences in the pharmacokinetics of encorafenib or cetuximab were
observed when the recommended BRAFTOVI dose of 300 mg was coadministered with cetuximab.
Transporters: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily
with a single dose of rosuvastatin (a sensitive substrate for OATP1B1, OATP1B3, and BCRP) increased
rosuvastatin Cmax by 2.7-fold and AUC by 1.6-fold.
In Vitro Studies
CYP/UGT Enzymes: Encorafenib is a reversible inhibitor of UGT1A1.
Transporters: Encorafenib is a substrate of P-glycoprotein (P-gp) but not of breast cancer resistance protein
(BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide (OATP1B1,
OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations.
24
Reference ID: 5500726
Encorafenib is an inhibitor of P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and
OATP1B3, but not of OCT1 or MRP2 at clinically relevant plasma concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies
evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone
marrow of rats.
No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats,
decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were
observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No
effects on reproductive organs were observed in either sex in any of the nonhuman primate toxicity studies.
13.2 Animal Toxicology and/or Pharmacology
Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at
encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose
based on AUC) or greater, in both 4 and 13-week studies.
14 CLINICAL STUDIES
14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
BRAFTOVI in combination with binimetinib was evaluated in a randomized, active-controlled, open-label,
multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or
V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™
BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line
of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or
MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC)
Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG)
performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus
no).
Patients were randomized (1:1:1) to receive BRAFTOVI 450 mg once daily in combination with binimetinib
45 mg twice daily (BRAFTOVI in combination with binimetinib), BRAFTOVI 300 mg once daily, or
vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only
the results of the approved dosing (BRAFTOVI 450 mg in combination with binimetinib 45 mg) are described
below.
The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent
central review, to compare BRAFTOVI in combination with binimetinib with vemurafenib. Additional efficacy
outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of
response (DoR) which were assessed by central review.
A total of 577 patients were randomized, 192 to the BRAFTOVI in combination with binimetinib arm, 194 to
the BRAFTOVI arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the BRAFTOVI
in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years),
59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent
(95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1
directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH),
45% had ≥3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized
testing, 100% of patients’ tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF
V600K (11%), or both (<1%).
25
Reference ID: 5500726
BRAFTOVI in combination with binimetinib demonstrated a statistically significant improvement in PFS
compared to vemurafenib. Efficacy results are summarized in Table 13 and Figure 1.
Table 13: Efficacy Results for COLUMBUS
BRAFTOVI
with binimetinib
N=192
Vemurafenib
N=191
Progression-Free Survival
Number of events (%)
98 (51)
106 (55)
Progressive disease
88 (46)
104 (54)
Death
10 (5)
2 (1)
Median PFS, months (95% CI)
14.9 (11.0, 18.5)
7.3 (5.6, 8.2)
HR (95% CI)a
0.54 (0.41, 0.71)
P-valueb
<0.0001
Overall Survivalc
Number of events (%)
139 (72)
147 (77)
Median OS, months (95% CI)
33.6 (24.4, 39.2)
16.9 (14.0, 24.5)
HR (95% CI)a
0.67 (0.53, 0.84)
Overall Response Rate
ORR (95% CI)
63% (56%, 70%)
40% (33%, 48%)
CR
8%
6%
PR
55%
35%
Duration of Response
Median DoR, months (95% CI)
16.6 (12.2, 20.4)
12.3 (6.9, 16.9)
CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NE = Not estimable; ORR = Overall response
rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response.
a.
Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC)
Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1).
b.
Log-rank test adjusted by the same stratification factors.
c.
Based on a cutoff date of 82.4 months after the date of the PFS analysis.
26
Reference ID: 5500726
1.0
0.9
.; 0.8
> 'f
:, 0.7
"' .. e ...
.i
0.6
. . 0.5
e .. e
... 0.4
l
? 0.3
~
~
.c e
... 0.2
0.1
0.0
0
Number of Patients at Rist
BRAFTOVI + binimetinib
192
vemurafenib
19 1
2
171
1 49
4
151
101
6
128
75
8
107
56
10
92
45
BRAFTOVI + binimetinib
12
14
87
36
Months
70
32
16
57
23
18
41
18
20
28
13
-- Vemurafenib
22
1 4
10
24
4
4
26
0
3
Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS
14.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC)-BRAFTOVI with
Cetuximab and mFOLFOX6
BRAFTOVI in combination with cetuximab and mFOLFOX6 was evaluated in a randomized, active-controlled,
open-label, multicenter trial (BREAKWATER CRC; NCT04607421). Eligible patients were required to have
BRAF V600E mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen
BRAF V600E RGQ polymerase chain reaction (PCR) Kit. Other key eligibility criteria included no prior
systemic treatment in the metastatic setting, absence of prior treatment with any selective BRAF inhibitor or
EGFR inhibitor, tumor that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
unless the patient is ineligible to receive immune checkpoint inhibitors, tumor that is not RAS-mutated or for
which RAS mutation status is unknown, and Eastern Cooperative Oncology Group (ECOG) performance status
0-1. Randomization was stratified by ECOG performance status (0 versus 1) and region (US/Canada versus
Europe versus Rest of World).
Patients were initially randomized 1:1:1 to one of the following treatment arms, and then 1:1 after
discontinuation of enrollment of the BRAFTOVI+cetuximab arm (158 patients):
• BRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every
2 weeks (BRAFTOVI+cetuximab arm)
• BRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every
2 weeks and mFOLFOX6 every 2 weeks (BRAFTOVI+cetuximab+mFOLFOX6 arm)
• mFOLFOX6 (every 2 weeks), or FOLFOXIRI (every 2 weeks), or CAPOX (every 3 weeks), each with
or without bevacizumab (administered per prescribing instructions)
mFOLFOX6 consisted of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 IV bolus, then 5-FU
2400 mg/m2 continuous IV infusion over 46-48 hours; CAPOX consisted of oxaliplatin 130 mg/m2 IV infusion
27
Reference ID: 5500726
and capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14; FOLFOXIRI consisted of irinotecan
165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 or 3200 mg/m2 (per local standard of care)
continuous IV infusion over 46-48 hours.
Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up,
or death. Only the results of the approved regimen (BRAFTOVI in combination with cetuximab and
mFOLFOX6) are described below.
The major efficacy outcome measure was confirmed objective response rate (ORR) as assessed by BICR and
was evaluated in the first 110 participants randomized in each arm. An additional efficacy outcome measure
included duration of response (DoR) as assessed by BICR.
A total of 236 patients were randomized to the BRAFTOVI+cetuximab+mFOLFOX6 arm and 243 to the
control arm. Of these patients, the median age was 61 years, 50% were female, 60% were White, 37% were
Asian, 0.4% were Multiracial, 0.2% were Black or African American, and 2.5% were not reported. Twelve
percent (12%) were Hispanic or Latino, 81% were not Hispanic or Latino, and 7% were not reported. Fifty-four
percent (54%) had baseline ECOG performance status of 0.
BRAFTOVI in combination with cetuximab and mFOLFOX6 demonstrated a statistically significant
improvement in ORR compared to the active comparator. Efficacy results are summarized in Table 14 below.
Table 14:
Efficacy Results for BREAKWATER
Efficacy Parameter
BRAFTOVI
with cetuximab and mFOLFOX6
N=110
mFOLFOX6 ± bevacizumab
or
FOLFOXIRI ± bevacizumab
or
CAPOX ± bevacizumab
N=110
Objective Response Rate (per BICR)
ORR (95% CI)
61% (52%, 70%)
40% (31%, 49%)
CR
2.7%
1.8%
PR
58%
38%
P-valuea
0.0008
Duration of Response (per BICR)
Median DoR, months (95% CI)
13.9 (8.5, NE)
11.1 (6.7, 12.7)
% with DoR ≥6 months
69%
34%
% with DoR ≥12 months
22%
11%
CI = Confidence interval; CR = Complete response; DoR = Duration of response; N = Number of patients; NE = Not estimable; ORR = Objective
response rate; PR = Partial response.
a.
Stratified by ECOG performance status and geographic region at randomization. Cochran-Mantel-Haenszel test; tested at 1-sided alpha level of
0.001.
14.3 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)
BRAFTOVI in combination with cetuximab was evaluated in a randomized, active-controlled, open-label,
multicenter trial (BEACON CRC; NCT02928224). Eligible patients were required to have BRAF V600E
mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen BRAF V600E
RGQ polymerase chain reaction (PCR) Kit, with disease progression after 1 or 2 prior regimens. Other key
eligibility criteria included absence of prior treatment with a RAF, MEK, or EGFR inhibitor, eligibility to
receive cetuximab per local labeling with respect to tumor RAS status, and ECOG performance status (PS) 0-1.
Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status
(0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EU-
approved).
Patients were randomized 1:1:1 to one of the following treatment arms:
28
Reference ID: 5500726
• BRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm)
• BRAFTOVI 300 mg orally once daily in combination with binimetinib and cetuximab
• Irinotecan with cetuximab or FOLFIRI with cetuximab (control arm)
The dosage of cetuximab in all patients was 400 mg/m2 intravenously for the first dose followed by 250 mg/m2
weekly.
Patients in the control arm received cetuximab with either irinotecan 180 mg/m2 intravenously on Days 1
and 15 of each 28-day cycle or FOLFIRI intravenously (irinotecan 180 mg/m2 on Days 1 and 15; folinic acid
400 mg/m2 on Days 1 and 15; then fluorouracil 400 mg/m2 bolus on Days 1 and 15 followed by fluorouracil
2400 mg/m2/day by continuous infusion over 2 days).
Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved
regimen (BRAFTOVI in combination with cetuximab) are described below.
The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures included
progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR) as assessed by
blinded independent central review (BICR). OS and PFS were assessed in all randomized patients. ORR and
DoR were assessed in the subset of the first 220 patients included in the randomized portion of the
BRAFTOVI/cetuximab and control arm of the study.
A total of 220 patients were randomized to the BRAFTOVI/cetuximab arm and 221 to the control arm. Of these
441 patients, the median age was 61 years; 53% were female; 80% were White, 15% were Asian, and 5% were
other or not reported. Four percent (4%) were Hispanic or Latino, 90% were not Hispanic or Latino, and 6%
were not reported or unknown. Fifty percent (50%) had baseline ECOG performance status of 0; 66% received
1 prior therapy and 34% received 2; 93% received prior oxaliplatin and 52% received prior irinotecan.
BRAFTOVI in combination with cetuximab demonstrated a statistically significant improvement in OS, ORR,
and PFS compared to the active comparator. Efficacy results are summarized in Table 15 and Figure 2.
Table 15: Efficacy Results From BEACON CRC
BRAFTOVI with cetuximab
N=220
Irinotecan with
cetuximab or
FOLFIRI with
cetuximab
N=221
Overall Survival
Number of Events (%)
93 (42)
114 (52)
Median OS, months (95% CI)
8.4 (7.5, 11.0)
5.4 (4.8, 6.6)
HR (95% CI)a,b
0.60 (0.45, 0.79)
P-valuea,c
0.0003
29
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BRAFTOVI with cetuximab
N=220
Irinotecan with
cetuximab or
FOLFIRI with
cetuximab
N=221
Overall Response Rate (per BICR)
ORR (95% CI)d
20% (13%, 29%)
2% (0%, 7%)
CR
5%
0%
PR
15%
2%
P-valuea,e
<0.0001
Median DoR, months (95% CI)
6.1 (4.1, 8.3)
NR (2.6, NR)
Progression Free Survival (per BICR)
Number of events (%)
133 (60)
128 (58)
Progressive disease
110 (50)
101 (46)
Death
23 (10)
27 (12)
Median PFS, months (95% CI)
4.2 (3.7, 5.4)
1.5 (1.4, 1.7)
HR (95% CI)a,b
0.40 (0.31, 0.52)
P-valuea,f
<0.0001
CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NR = Not reached; ORR = Overall response
rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response.
a.
Stratified by ECOG PS, source of cetuximab (US-licensed versus EU-approved) and prior irinotecan use at randomization.
b.
Stratified Cox proportional hazard model.
c.
Stratified log-rank test, tested at alpha level of 0.0084.
d.
BRAFTOVI/cetuximab arm (n=113) and control arm (n=107).
e.
Cochran-Mantel-Haenszel test; tested at alpha level of 0.05.
f.
Stratified log-rank test, tested at alpha level of 0.0234.
30
Reference ID: 5500726
1.0
0.9
0.8
cu
0.7
>
'> ...
::::,
0.6
en -
0
~ 0.5
:.c
0.4
cu
..c
0 ...
a.
0.3
0.2
0.1
0.0
Number of Patients at Risk
BRAFTOVI + cetuximab
Control
0
220
221
2
184
158
4
133
102
6
87
60
8
57
34
10
12
Months
33
18
21
15
14
12
7
BRAFTOVI + cetuximab
Control
16
8
4
18
3
2
20
22
0
0
Figure 2: Kaplan-Meier Curves for Overall Survival in BEACON CRC
14.4 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer
BRAFTOVI in combination with binimetinib was evaluated in an open-label, multicenter, single-arm study in
patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC) (PHAROS;
NCT03915951). Eligible patients had a diagnosis of histologically-confirmed metastatic NSCLC with BRAF
V600E mutation that was treatment-naïve or had been previously treated with 1 prior line of systemic therapy in
the metastatic setting (platinum-based chemotherapy and/or anti-PD-1/PD-L1 therapies), age 18 years or older,
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and measurable disease as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Prior use of BRAF inhibitors or MEK
inhibitors was not allowed.
Patients received BRAFTOVI 450 mg once daily and binimetinib 45 mg orally twice daily until disease
progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR)
per RECIST v1.1 and duration of response (DoR) as assessed by independent review committee (IRC).
In the efficacy population, BRAF V600E mutation status was determined by prospective local testing using
tumor tissue (78%) or blood (22%) specimens. Of the 98 patients with BRAF V600E mutation, 6 patients were
enrolled into the trial based on testing of their tumor tissue specimens with the FoundationOne CDx tissue test.
Of the remaining 92 patients enrolled based on local testing, 68 patients had their tumor tissue specimens
retrospectively confirmed as having BRAF V600E positive status by the FoundationOne CDx tissue test. The
remaining patients had either BRAF V600E negative status (n=5) or had unevaluable results (n=19) by the
FoundationOne CDx tissue test. In addition, plasma samples from 81 out of 98 patients were retrospectively
tested using the FoundationOne Liquid CDx assay. Of the 81 patients, 48 were confirmed positive for BRAF
V600E, while 33 patients were BRAF V600E mutation negative by FoundationOne Liquid CDx assay. The
remaining 17 samples had unevaluable results with FoundationOne Liquid CDx assay.
The efficacy population included 59 treatment-naïve patients and 39 previously-treated patients. Among these
98 patients, the median age was 70 years (range: 47 to 86); 53% female; 88% White, 7% Asian, 3% Black or
African American, and 1% American Indian or Alaska Native; 99% were not Hispanic or Latino; 13% were
31
Reference ID: 5500726
current smokers and 57% were former smokers; 73% had ECOG PS of 1; and 97% had adenocarcinoma. All
patients had metastatic disease, and 8% had brain metastases at baseline.
Efficacy results for patients with BRAF V600E mutation-positive metastatic NSCLC are summarized in
Table 16.
Table 16: Efficacy Results for PHAROS
BRAFTOVI with binimetinib
Efficacy Parameter
Treatment naïve
(N=59)
Previously treated
(N=39)
Objective Response Ratea
ORR (95% CI)
75% (62, 85)
46% (30, 63)
CR
15%
10%
PR
59%
36%
Duration of Responsea
N=44
N=18
Median DoR, months (95% CI)
NE (23.1, NE)
16.7 (7.4, NE)
% with DoR ≥6 months
75%
67%
% with DoR ≥12 months
59%
33%
CI = Confidence interval; CR = Complete response; DoR = Duration of response; N = Number of patients; NE = Not estimable; ORR =
Objective response rate; PR = Partial response.
a.
Assessed by Independent Central Review (ICR).
16 HOW SUPPLIED/STORAGE AND HANDLING
BRAFTOVI (encorafenib) is supplied as 75 mg hard gelatin capsules.
75 mg: stylized “A” on beige cap and “LGX 75mg” on white body, available in cartons (NDC 70255-025-01)
containing two bottles of 90 capsules each (NDC 70255-025-02) and cartons (NDC 70255-025-03) containing
two bottles of 60 capsules each (NDC 70255-025-04).
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP
Controlled Room Temperature]. Do not use if safety seal under cap is broken or missing. Dispense in original
bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the following:
New Primary Malignancies
Advise patients that BRAFTOVI increases the risk of developing new primary cutaneous and noncutaneous
malignancies. Advise patients to contact their healthcare provider immediately for change in or development of
new skin lesions [see Warnings and Precautions (5.1)].
Tumor Promotion in BRAF Wild-Type Tumors
Advise patients of the need to confirm BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see
Warnings and Precautions (5.2)].
Cardiomyopathy
Advise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and
Precautions (5.3)].
Hepatotoxicity
Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment
with BRAFTOVI. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine,
nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding [see Warnings and Precautions (5.4)].
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Hemorrhage
Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage,
such as unusual bleeding [see Warnings and Precautions (5.5)].
Uveitis
Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings
and Precautions (5.6)].
QT Prolongation
Advise patients that BRAFTOVI can cause QTc interval prolongation and to inform their physician if they have
any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.7)].
Embryo-Fetal Toxicity
• Advise females with reproductive potential of the potential risk to a fetus. Advise females to contact their
healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with
BRAFTOVI [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].
• Advise females of reproductive potential to use effective nonhormonal contraception during treatment with
BRAFTOVI and for 2 weeks after the last dose [Use in Specific Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose [see Use
in Specific Populations (8.2)].
Infertility
Advise males of reproductive potential that BRAFTOVI may impair fertility [see Use in Specific Populations
(8.3)].
Drug Interactions
Coadministration of BRAFTOVI with a strong or moderate CYP3A inhibitor may increase encorafenib
concentrations; coadministration of BRAFTOVI with a strong CYP3A inducer may decrease encorafenib
concentrations. Advise patients that they may need to avoid certain medications while taking BRAFTOVI and
to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the
counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit and grapefruit juice while
taking BRAFTOVI [see Drug Interactions (7.1)].
Storage
BRAFTOVI is moisture sensitive. Advise patients to store BRAFTOVI in the original bottle with desiccant and
to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle.
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This product’s labeling may have been updated. For the most recent prescribing information, please visit
www.pfizer.com.
Distributed by:
Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc.
3200 Walnut Street
Boulder, CO 80301
© 2024 Array BioPharma Inc. All rights reserved.
BRAFTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other
countries.
LAB-1428-4.4a
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MEDICATION GUIDE
BRAFTOVI® (braf-TOE-vee)
(encorafenib)
capsules
Important information: BRAFTOVI is used in combination with other medicines, including binimetinib, cetuximab, or
cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin). Read the Medication Guide that comes with
binimetinib if BRAFTOVI is used with binimetinib. Talk to your healthcare provider about cetuximab, or cetuximab and
mFOLFOX 6 if used with BRAFTOVI.
What is the most important information I should know about BRAFTOVI?
BRAFTOVI may cause serious side effects, including:
Risk of new skin cancers. BRAFTOVI when used alone, or with binimetinib or cetuximab, may cause skin cancers
called cutaneous squamous cell carcinoma or basal cell carcinoma.
Talk to your healthcare provider about your risk for these cancers.
Check your skin and tell your healthcare provider right away about any skin changes, including a:
o new wart
o skin sore or reddish bump that bleeds or does not heal
o change in size or color of a mole
Your healthcare provider should check your skin before treatment with BRAFTOVI, every 2 months during treatment,
and for up to 6 months after you stop treatment with BRAFTOVI to look for any new skin cancers.
Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider
about any new symptoms that develop during treatment with BRAFTOVI.
See "What are the possible side effects of BRAFTOVI?" for more information about side effects.
What is BRAFTOVI?
BRAFTOVI is a prescription medicine used:
•
in combination with a medicine called binimetinib to treat people with a type of skin cancer called melanoma:
o
that has spread to other parts of the body or cannot be removed by surgery, and
o
that has a certain type of abnormal "BRAF" gene
•
in combination with a medicine called cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) to treat
people with cancer of the colon or rectum (colorectal cancer):
o
that has spread to other parts of the body, and
o
that has a certain type of abnormal “BRAF” gene
•
in combination with a medicine called cetuximab to treat adults with cancer of the colon or rectum (colorectal
cancer) after past treatment:
o
that has spread to other parts of the body, and
o
that has a certain type of abnormal “BRAF” gene
•
in combination with a medicine called binimetinib to treat adults with a type of lung cancer called non-small cell
lung cancer (NSCLC):
o
that has spread to other parts of the body, and
o
that has a certain type of abnormal “BRAF” gene
BRAFTOVI should not be used to treat people with wild-type BRAF melanoma, wild-type BRAF colorectal cancer, or
wild-type BRAF NSCLC. Your healthcare provider will perform a test to make sure that BRAFTOVI is right for you.
It is not known if BRAFTOVI is safe and effective in children.
Before taking BRAFTOVI, tell your healthcare provider about all of your medical conditions, including if you:
•
have had bleeding problems
•
have eye problems
•
have heart problems, including a condition called long QT syndrome
•
have been told that you have low blood levels of potassium, calcium, or magnesium
•
have liver or kidney problems
•
are pregnant or plan to become pregnant. BRAFTOVI can harm your unborn baby.
o
Females who are able to become pregnant should use effective non-hormonal birth control (contraception)
during treatment with BRAFTOVI and for 2 weeks after the last dose of BRAFTOVI. Birth control methods that
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Reference ID: 5500726
contain hormones (such as birth control pills, injections or transdermal systems) may not work as well during
treatment with BRAFTOVI.
o
Talk to your healthcare provider about birth control methods that may be right for you during this time.
o
Your healthcare provider will do a pregnancy test before you start taking BRAFTOVI. Tell your healthcare
provider right away if you become pregnant or think you might be pregnant during treatment with BRAFTOVI.
•
are breastfeeding or plan to breastfeed. It is not known if BRAFTOVI passes into your breast milk. Do not
breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose of BRAFTOVI. Talk to your
healthcare provider about the best way to feed your baby during this time.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
BRAFTOVI and certain other medicines can affect each other, causing side effects or affecting how BRAFTOVI or the
other medicines work.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a
new medicine.
How should I take BRAFTOVI?
•
Take BRAFTOVI exactly as your healthcare provider tells you. Do not change your dose or stop taking
BRAFTOVI unless your healthcare provider tells you to.
•
Take BRAFTOVI by mouth 1 time each day.
•
BRAFTOVI may be taken with or without food.
•
Avoid grapefruit during treatment with BRAFTOVI. Grapefruit products may increase the amount of BRAFTOVI in
your body.
•
If you miss a dose of BRAFTOVI, take it as soon as you remember. If it is within 12 hours of your next scheduled
dose, take your next dose at your regular time. Do not make up for the missed dose.
•
Do not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time.
•
If you stop treatment with binimetinib or cetuximab, talk to your healthcare provider about your BRAFTOVI
treatment. Your BRAFTOVI dose may need to be changed or stopped.
What are the possible side effects of BRAFTOVI?
BRAFTOVI may cause serious side effects, including:
•
See “What is the most important information I should know about BRAFTOVI?”
•
Heart problems, including heart failure. BRAFTOVI, when taken with binimetinib, can cause heart problems.
Your healthcare provider will check your heart function before and during treatment with BRAFTOVI. Tell your
healthcare provider right away if you get any of the following signs and symptoms of a heart problem:
o
feeling like your heart is pounding or racing
o
shortness of breath
o
swelling in your hands, ankles legs or feet
o
feeling faint or lightheaded
•
Liver problems. BRAFTOVI, when taken with binimetinib, can cause liver problems. Your healthcare provider will
perform blood tests to check your liver function before and during treatment with BRAFTOVI. Tell your healthcare
provider if you get any of the following signs and symptoms of a liver problem:
o
yellowing of your skin or your eyes
o
tiredness
o
dark or brown (tea-colored) urine
o
bruising
o
nausea or vomiting
o
bleeding
o
loss of appetite
•
Bleeding problems. BRAFTOVI, when taken with binimetinib or cetuximab, can cause serious bleeding
problems, including in your stomach or brain, that can lead to death. Tell your healthcare provider and get medical
help right away if you develop any signs of bleeding, including:
o headaches, dizziness, or feeling weak
o cough up blood or blood clots
o vomit blood or your vomit looks like “coffee grounds”
o red or black stools that look like tar
o nose bleeds
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Reference ID: 5500726
•
Eye problems. BRAFTOVI, when taken with binimetinib, can cause eye problems. Your healthcare provider
should perform an eye exam regularly. Tell your healthcare provider right away if you develop any new or
worsening symptoms of eye problems, including:
o
blurred vision, loss of vision, or other vision changes
o
see colored dots
o
see halos (blurred outline around objects)
o
eye pain, swelling, or redness
•
Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular
heartbeats that can be life threatening. Your healthcare provider should do tests before you start taking
BRAFTOVI with binimetinib or cetuximab and during your treatment to check your body salts (electrolytes). Tell
your healthcare provider right away if you feel faint, lightheaded, dizzy or if you feel your heart beating irregularly
or fast during treatment with BRAFTOVI and binimetinib or cetuximab. These symptoms may be related to QT
prolongation.
Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with BRAFTOVI if
you have certain side effects.
The most common side effects of BRAFTOVI when taken in combination with binimetinib for melanoma
include:
•
fatigue
•
nausea
•
vomiting
•
abdominal pain
•
pain or swelling of your joints (arthralgia)
The most common side effects of BRAFTOVI when taken in combination with cetuximab and mFOLFOX6 for
colorectal cancer include:
•
numbness, tingling or burning in your hands or feet
•
decreased appetite
(peripheral neuropathy)
•
vomiting
•
nausea
•
bleeding (hemorrhage)
•
fatigue
•
stomach-area (abdominal) pain
•
rash
•
fever
•
diarrhea
The most common side effects of BRAFTOVI when taken in combination with cetuximab for colorectal cancer
include:
•
fatigue
•
stomach-area (abdominal) pain
•
nausea
•
decreased appetite
•
diarrhea
•
pain or swelling of your joints (arthralgia)
•
acne-like rash (dermatitis acneiform)
•
rash
The most common side effects of BRAFTOVI when taken in combination with binimetinib for NSCLC include:
•
fatigue
•
blurred vision, loss of vision, or other vision changes
•
nausea
•
constipation
•
diarrhea
•
shortness of breath
•
muscle or joint pain
•
rash
•
vomiting
•
cough
•
stomach-area (abdominal) pain
BRAFTOVI may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare
provider if this is a concern for you.
These are not all of the possible side effects of BRAFTOVI.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Pfizer Inc. at 1-800-438-1985.
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Reference ID: 5500726
How should I store BRAFTOVI?
• Store BRAFTOVI at room temperature between 68°F to 77°F (20°C to 25°C).
• Store BRAFTOVI in the original bottle.
• Keep the BRAFTOVI bottle tightly closed and protect it from moisture.
• BRAFTOVI comes with a desiccant packet in the bottle to help protect your medicine from moisture. Do not remove
the desiccant packet from the bottle.
Keep BRAFTOVI and all medicines out of the reach of children.
General information about the safe and effective use of BRAFTOVI.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
BRAFTOVI for a condition for which it was not prescribed. Do not give BRAFTOVI to other people, even if they have
the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for
information about BRAFTOVI that is written for health professionals.
What are the ingredients in BRAFTOVI?
Active ingredient: encorafenib
Inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal
silicon dioxide, and magnesium stearate of vegetable origin
Capsule shell: gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink
(pharmaceutical glaze, ferrosoferric oxide, propylene glycol)
Distributed by: Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc. Boulder, Colorado 80301.
BRAFTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.
LAB-1429-3.4
For more information, go to www.BRAFTOVIMEKTOVI.com or call 1-844-792-7729.
© 2024 Array BioPharma Inc. All rights reserved.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
38
Reference ID: 5500726
| custom-source | 2025-02-12T15:47:58.944175 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/210496s017lbl.pdf', 'application_number': 210496, 'submission_type': 'SUPPL ', 'submission_number': 17} |
80,677 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
CEREZYME® safely and effectively. See full prescribing information for
CEREZYME.
CEREZYME (imiglucerase) for injection, for intravenous use
Initial U.S. Approval: 1994
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING
ANAPHYLAXIS
See full prescribing information for complete boxed warning.
•
Anaphylaxis has occurred during the early course of enzyme
replacement therapy and after extended duration of therapy.
(5.1)
•
Initiate Cerezyme in a healthcare setting with appropriate
medical monitoring and support measures, including access to
cardiopulmonary resuscitation equipment. (5.1)
•
If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs,
discontinue Cerezyme and immediately initiate appropriate
medical treatment, including use of epinephrine. (5.1)
----------------------------RECENT MAJOR CHANGES-------------------------
Boxed Warning
7/2024
Dosage and Administration (2.1)
7/2024
Warnings and Precautions (5.1, 5.2)
7/2024, 12/2024
-----------------------------INDICATIONS AND USAGE--------------------------
Cerezyme is a hydrolytic lysosomal glucocerebrosidase-specific enzyme
indicated for treatment of adults and pediatric patients 2 years of age and older
with Type 1 Gaucher disease that results in one or more of the following
conditions: anemia, thrombocytopenia, bone disease, hepatomegaly or
splenomegaly. (1)
------------------------DOSAGE AND ADMINISTRATION---------------------
• Administration of Cerezyme should be supervised by a healthcare provider
knowledgeable in the management of hypersensitivity reactions including
anaphylaxis. (2.1)
• The recommended dosage ranges from 2.5 units/kg three times a week to
60 units/kg once every two weeks. (2.2)
• Cerezyme is administered by intravenous infusion over 1 to 2 hours. (2.2)
• Titrate the dosage based on clinical manifestations of disease and
therapeutic goals for the patient. (2.2)
• See the full prescribing information for preparation and administration
instructions. (2.3)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
For injection: 400 units of imiglucerase as a lyophilized powder in a single-
dose vial. (3)
-------------------------------CONTRAINDICATIONS-----------------------------
None. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
Infusion-Associated Reactions (IAR): If an IAR occurs, decreasing the
infusion rate, temporarily stopping the infusion, and/or administering
appropriate treatment may ameliorate the symptoms. (5.2)
-------------------------------ADVERSE REACTIONS-----------------------------
• Adverse reactions reported in adults include back pain, chills, dizziness,
fatigue, headache, hypersensitivity reactions, nausea, pyrexia, and
vomiting. (6.1)
• Adverse reactions reported in pediatric patients 2 years of age and older are
similar to adults. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at
1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: HYPERSENSITIVITY REACTIONS
INCLUDING ANAPHYLAXIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommendations Prior to Cerezyme Treatment
2.2
Recommended Dosage
2.3
Preparation and Administration Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions Including Anaphylaxis
5.2
Infusion-Associated Reactions
6
ADVERSE REACTIONS
6.1
Clinical Trials and Postmarketing Experience
6.2
Immunogenicity
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5499246
1
FULL PRESCRIBING INFORMATION
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
Patients treated with enzyme replacement therapies have experienced life-threatening
hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the
early course of enzyme replacement therapy and after extended duration of therapy.
Initiate Cerezyme in a healthcare setting with appropriate medical monitoring and
support measures, including access to cardiopulmonary resuscitation equipment. If a
severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue Cerezyme and
immediately initiate appropriate medical treatment, including use of epinephrine. Inform
patients of the symptoms of life-threatening hypersensitivity reactions, including
anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings
and Precautions (5.1)].
1
INDICATIONS AND USAGE
Cerezyme is indicated for treatment of adults and pediatric patients 2 years of age and older with
Type 1 Gaucher disease that results in one or more of the following conditions:
• anemia
• thrombocytopenia
• bone disease
• hepatomegaly or splenomegaly
2
DOSAGE AND ADMINISTRATION
2.1
Recommendations Prior to Cerezyme Treatment
Administration of Cerezyme should be supervised by a healthcare provider knowledgeable in the
management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions
(5.1)].
Initiate Cerezyme in a healthcare setting with appropriate medical monitoring and support
measures, including access to cardiopulmonary resuscitation equipment [see Warnings and
Precautions (5.1)].
For patients who experience hypersensitivity reactions to Cerezyme, premedicate with
antihistamines and/or corticosteroids. Monitor patients for the occurrence of new
hypersensitivity reactions [see Warnings and Precautions (5.1)].
2.2
Recommended Dosage
Therapy with Cerezyme should be directed by physicians knowledgeable in the management of
patients with Gaucher disease.
The recommended dosage of Cerezyme based upon disease severity ranges from 2.5 units/kg
three times a week to 60 units/kg once every two weeks. For patients weighing 18 kg and
Reference ID: 5499246
2
greater, infuse the diluted Cerezyme solution over 1 to 2 hours. For patients weighing less than
18 kg, infuse the diluted Cerezyme solution over 2 hours [see Dosage and Administration (2.3)].
Titrate the dosage based on clinical manifestations of disease and therapeutic goals for the
patient.
2.3
Preparation and Administration Instructions
Cerezyme does not contain preservatives.
Reconstitution and Dilution Using Aseptic Technique
1. Determine the number of Cerezyme vials to be reconstituted based on the individual
patient's dosage regimen and remove vial(s) from the refrigerator.
2. Reconstitute each 400 unit vial of Cerezyme by slowly injecting 10.2 mL of Sterile Water
for Injection, USP, down the inside wall of each vial.
3. Roll and tilt the vial to allow the powder to dissolve completely. Each vial will yield a
concentration of Cerezyme after reconstitution of 40 units/mL. Visually inspect the
solution after reconstitution for particulate matter and discoloration. Discard if opaque
particles or discoloration are observed.
4. Withdraw up to 10 mL per vial. Discard unused portion.
5. Dilute the Cerezyme solution promptly with 0.9% Sodium Chloride Injection, USP, to a
final volume of 100 to 200 mL. For patients weighing less than 18 kg, dilute Cerezyme to
a final volume of 100 mL. Gently invert infusion bag to mix the solution, avoiding
vigorous shaking and agitation.
Visually inspect the solution prior to administration of the final product for particulate
matter and discoloration. Slight flocculation of protein particles (described as thin
translucent fibers) may occur after dilution and does not affect the quality of the product.
6. For patients weighing 18 kg and greater, infuse the diluted Cerezyme solution over 1 to 2
hours. For patients weighing less than 18 kg, infuse the diluted Cerezyme solution over 2
hours.
7. The diluted solution may be filtered through an in-line low protein-binding 0.2 µm filter
during administration.
Storage and Handling
• If the reconstituted Cerezyme vial is not used immediately, store at room temperature at 68°F
to 77°F (20°C to 25°C) or refrigerated at 36°F to 46°F (2°C to 8°C) for up to 12 hours.
• After dilution, Cerezyme is stable for up to 24 hours when stored refrigerated at 36°F to 46°F
(2°C to 8°C).
3
DOSAGE FORMS AND STRENGTHS
For injection: 400 units of imiglucerase as a white to off-white lyophilized powder in a single-
dose vial for reconstitution.
Reference ID: 5499246
3
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions Including Anaphylaxis
Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients
treated with enzyme replacement therapies, including Cerezyme. In addition, other
hypersensitivity reactions have included pruritus, flushing, urticaria, angioedema, chest
discomfort, dyspnea, cough, cyanosis, tachycardia, and hypotension [see Adverse Reactions
(6.1)]. Patients with antibody to imiglucerase have a higher risk of hypersensitivity reactions.
Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody.
Consider periodic monitoring of patients during the first year of treatment for IgG antibody
formation [see Adverse Reactions (6.2)].
Anaphylaxis has occurred during the early course of enzyme replacement therapy and after
extended duration of therapy. Administration of Cerezyme should be supervised by a healthcare
provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.
Initiate Cerezyme in a healthcare setting with appropriate medical monitoring and support
measures, including access to cardiopulmonary resuscitation equipment.
If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue Cerezyme and
immediately initiate appropriate medical treatment, including use of epinephrine. Consider the
risks and benefits of readministering Cerezyme to individual patients following a severe reaction.
If the decision is made to readminister the product, consider reducing the rate of infusion and
pretreat with antihistamines and/or corticosteroids and monitor patients for the occurrence of
new signs and symptoms of a severe hypersensitivity reaction.
Inform patients of the symptoms of life-threatening hypersensitivity reactions, including
anaphylaxis and to seek immediate medical care should symptoms occur.
5.2
Infusion-Associated Reactions
Infusion-associated reactions (IARs) such as angioedema, pruritus, rash, urticaria, chest
discomfort, chills, fatigue, infusion-site burning, infusion-site discomfort, infusion-site swelling,
pyrexia and hypertension have been observed in patients treated with Cerezyme [see Adverse
Reactions (6.1)].
If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or
administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor
patients who have experienced IARs when re-administering Cerezyme.
6
ADVERSE REACTIONS
6.1
Clinical Trials and Postmarketing Experience
The following adverse reactions associated with the use of imiglucerase were identified in
clinical studies or postmarketing reports. Because some of these reactions were reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Reference ID: 5499246
4
System Organ Class
Adverse Reactions
Nervous system disorders
dizziness, headache
Cardiac disorders
tachycardia
Vascular disorders
cyanosis,* flushing,* hypotension,* hypertension*
Respiratory, thoracic and mediastinal disorders
cough,* dyspnea,* pneumonia, pulmonary hypertension
Gastrointestinal disorders
abdominal pain, diarrhea, nausea, vomiting
Immune system disorders
anaphylaxis,* hypersensitivity
Skin and subcutaneous tissue disorders
angioedema,* pruritus,* rash, urticaria*
Musculoskeletal and connective tissue
disorders
back pain
General disorders and administration site
conditions
chest discomfort,* chills, fatigue, infusion-site burning,
infusion-site discomfort, infusion-site swelling, pyrexia
* Signs and symptoms suggestive of hypersensitivity reactions including anaphylaxis [see Warnings and
Precautions (5.1)] and other infusion-associated reactions [see Warnings and Precautions (5.2)].
Adverse reactions reported in pediatric patients 2 years of age and older were similar to adults.
6.2
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of antibody (including neutralizing antibody) positivity in an assay may be
influenced by several factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons, comparison of
the incidence of antibodies in the studies described below with the incidence of antibodies in
other studies or to other imiglucerase products may be misleading.
Approximately 15% of patients treated and tested to date have developed IgG antibody to
Cerezyme during the first year of therapy. Patients who developed IgG antibody did so largely
within 6 months of treatment and rarely developed antibodies to Cerezyme after 12 months of
therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms
of hypersensitivity. Patients with antibody to Cerezyme have higher risk of hypersensitivity
reaction [see Warnings and Precautions (5.1)]. Patients who developed IgG antibody to
Cerezyme had increased elimination half-life compared to patients without antibody [see
Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
Cerezyme during pregnancy. Pregnant women exposed to Cerezyme and health care providers
are encouraged to contact the Gaucher patient registry at 1-800-745-4447, extension 15500 or
visit www.registrynxt.com.
Risk Summary
Available data on more than 500 pregnancies from the international Gaucher Disease registry,
postmarketing reports, published observational studies and case reports with Cerezyme or non–
US-licensed imiglucerase use in pregnant women have not identified a drug-associated risk of
major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks
Reference ID: 5499246
5
associated with symptomatic Type I Gaucher disease in pregnancy (see Clinical Considerations).
No animal reproduction studies have been conducted with imiglucerase.
The estimated background risk of major birth defects and miscarriage in the indicated population
is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease
manifestations. Untreated symptomatic Type 1 Gaucher may lead to complications during
pregnancy, including hepatosplenomegaly, which can interfere with the normal growth of a
pregnancy and thrombocytopenia, which can lead to excessive bleeding.
8.2
Lactation
Risk Summary
Available published literature suggests a small amount of imiglucerase is present in breast milk
immediately following an infusion of imiglucerase. Published case reports and postmarketing
reports of breastfed infants have not reported adverse effects due to Cerezyme exposure. There
are no data available on the effects on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for Cerezyme and any
potential adverse effects on the breastfed infant from imiglucerase or from the underlying
maternal condition.
Lactating women with Gaucher disease treated with Cerezyme should be encouraged to enroll in
the Gaucher patient registry [see Use in Specific Populations (8.1)].
8.4
Pediatric Use
The safety and effectiveness of Cerezyme for treatment of Type 1 Gaucher disease that results in
one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly
or splenomegaly have been established in pediatric patients 2 years of age and older. Use of
Cerezyme for this indication is supported by evidence from adequate and well-controlled studies
of Cerezyme and alglucerase in adults and pediatric patients 12 years of age and older, with
additional data obtained from the medical literature and from postmarketing experience in
pediatric patients as young as 2 years of age [see Adverse Reactions (6.1), Clinical Studies (14)].
The safety and effectiveness of Cerezyme have not been established in pediatric patients younger
than 2 years of age.
11
DESCRIPTION
Imiglucerase is a hydrolytic lysosomal glucocerebrosidase-specific enzyme. It is an analogue of
the human enzyme b-glucocerebrosidase (b-D-glucosyl-N-acylsphingosine glucohydrolase, E.C.
3.2.1.45), produced by recombinant DNA technology using mammalian cell culture (Chinese
hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids,
containing 4 N-linked glycosylation sites (Mr=60,430). Imiglucerase differs from placental
glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine.
Reference ID: 5499246
6
The oligosaccharide chains at the glycosylation sites have been modified to terminate in
mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different
from those on placental glucocerebrosidase.
Cerezyme (imiglucerase) for injection is intended for intravenous use. It is supplied as a sterile,
nonpyrogenic, white to off-white lyophilized powder for reconstitution with Sterile Water for
Injection, USP. Each single-dose vial contains 424 units imiglucerase, mannitol (340 mg),
polysorbate 80, NF (1.06 mg), and sodium citrates: disodium hydrogen citrate (36 mg) and
trisodium citrate (104 mg).
An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1
micromole of the synthetic substrate para-nitrophenyl-b-D-glucopyranoside (pNP-Glc) per
minute at 37°C. Reconstituted solutions have a pH of approximately 6.1.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, which results
in accumulation of glucocerebroside in various tissues including liver, spleen, and bone marrow.
The mannose sugars on imiglucerase mediate binding to and internalization by cells including
macrophages. Cerezyme catalyzes the hydrolysis of glucocerebroside to glucose and ceramide.
12.2 Pharmacodynamics
No formal pharmacodynamic studies have been conducted with Cerezyme.
12.3 Pharmacokinetics
During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 units/kg) of Cerezyme,
steady-state enzymatic activity was achieved by 30 minutes. Following infusion, the half-life of
plasma enzymatic activity ranged from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to
20.3 mL/min/kg (mean ± SD, 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for
weight ranged from 0.09 to 0.15 L/kg (mean ± SD, 0.12 ± 0.02 L/kg). These variables do not
appear to be influenced by dose or duration of infusion. However, only one or two patients were
studied at each dose level and infusion rate.
Antidrug Antibody Effects on Pharmacokinetics
In patients who developed IgG antibody to Cerezyme, an apparent effect on serum enzyme levels
resulted in diminished volume of distribution and clearance and increased elimination half-life
compared to patients without antibody [see Adverse Reactions (6.2)].
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate carcinogenic potential have not been performed with
imiglucerase.
Reference ID: 5499246
7
Mutagenesis
Imiglucerase was negative in the Ames test.
Impairment of Fertility
An animal fertility study was not performed. No histopathological findings on reproductive
organs were observed in 13-week toxicity studies conducted in rats and monkeys.
14
CLINICAL STUDIES
Study RC 91-0110 was a randomized, double-blind, active-controlled study of 30 patients (17
male and 13 female), aged 12 to 69 years (mean age of 38 years in the Cerezyme group and
mean age of 28 years in the alglucerase group at baseline), with Gaucher disease type 1 and a
hemoglobin of at least 1 g/dL below the lower age limit for age and sex. Patients were
randomized 1:1 to receive either Cerezyme 60 units/kg every other week or alglucerase for 6
months. Primary efficacy parameters were an increase in hemoglobin concentration of at least 1
g/dL, increase in platelet count and decrease in spleen and liver volume at 6 months. Efficacy
results are shown in Table 1.
Table 1: Change from Baseline to Month 6 in Clinical Efficacy Parameters in a
Randomized, Double-Blind Active-Controlled Trial of Cerezyme Compared to Alglucerase
in Patients 12 Years of Age and Older with Gaucher Disease Type 1
Clinical
Parameter
Cerezyme
(N=15)
Alglucerase
(N=15)
Difference
(Cerezyme – Alglucerase)
[95% CI]*
Hemoglobin
concentration
(g/dL)
Baseline
10.7
10.9
–
Absolute Change from Baseline
1.9
1.6
0.3 [-0.6, 1.3]
Platelet count
(× 103/mL3)
Baseline
68.5
74.2
–
Absolute Change from Baseline
22.7
15.8
6.9 [-10.4, 24.1]
Liver volume
(mL)
Baseline
2521
2788
–
Absolute Change from Baseline
-310
-307
-3 [-246, 240]
Percent Change from Baseline
(%)
-11
-10
-1 [-9, 7]
Spleen
volume
(mL)
Baseline
2369
2603
–
Absolute Change from Baseline
-902
-874
-28 [-652, 596]
Percent Change from Baseline
(%)
-35
-30
-5 [-14, 4]
* Confidence intervals were calculated using the t distribution (appropriate for small sample sizes) and the
standard error of the difference in sample means (i.e. the pooled estimate of the common standard deviation,
computed as the weighted average of the standard deviations in the two treatment groups); there was no evidence
that the assumption of equal variances between the groups was violated.
Bone x-rays showed improvements in cortical thickness and lucencies in 7 of 11 Cerezyme
treated patients.
In study RC 92-0501, twenty-nine patients continued treatment for total duration of 24 months.
Patients were unblinded at 9 months and allowed to cross-over to Cerezyme treatment. At 24
months, mean increase in hemoglobin was 2.4 g/dL, mean increase in platelet count was 40
×103/mL3, mean change in liver volume was -20%, and mean change in spleen volume was -57%.
Reference ID: 5499246
8
16
HOW SUPPLIED/STORAGE AND HANDLING
Cerezyme (imiglucerase) for injection, 400 units as a white to off-white lyophilized powder in a
single-dose vial: NDC 58468-4663-1
Store refrigerated at 2°C to 8°C (36°F to 46°F).
For storage of reconstituted and diluted solution [see Dosage and Administration (2.2)].
17
PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions Including Anaphylaxis and Infusion-Associated Reactions
Advise patients and caregivers that life-threatening hypersensitivity reactions, including
anaphylaxis, and infusion reactions may occur with Cerezyme treatment.
Advise patients and caregivers that anaphylaxis has occurred during the early course of enzyme
replacement therapy and after extended duration of therapy.
Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions,
including anaphylaxis, and IARs and to seek immediate medical care should symptoms occur
[see Warnings and Precautions (5.1, 5.2)].
Patient Registry
Inform patients and caregivers that the Gaucher patient registry has been established in order to
better understand the variability and progression of Gaucher disease and to continue to monitor
and evaluate long-term treatment effects of Cerezyme. A pregnancy sub-registry will also
monitor the effects of Cerezyme on pregnant women and their offspring [see Use in Specific
Populations (8.1)]. Encourage patients and caregivers to participate in the Gaucher patient
registry. Advise patients that their participation is voluntary and may involve long-term follow
up. For information regarding the registry program, visit www.registrynxt.com or call 1-800
745-4447, extension 15500.
Manufactured by:
Genzyme Corporation
Cambridge, MA 02141
A SANOFI COMPANY
U.S. License Number: 1596
Cerezyme is a registered trademark of Genzyme Corporation.
Reference ID: 5499246
9
| custom-source | 2025-02-12T15:47:58.960820 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020367s122lbl.pdf', 'application_number': 20367, 'submission_type': 'SUPPL ', 'submission_number': 122} |
80,680 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEFENCATH safely and effectively. See full prescribing
information for DEFENCATH.
DEFENCATH® (taurolidine and heparin) catheter lock solution, for
central venous catheter instillation use
Initial U.S. Approval: 2023
LIMITED POPULATION
-----------------------------RECENT MAJOR CHANGES-------------------------
Dosage and Administration (2)
12/2024
-----------------------------INDICATIONS AND USAGE---------------------------
LIMITED POPULATION: DEFENCATH is a combination of taurolidine,
a thiadiazinane antimicrobial, and heparin, an anti-coagulant, indicated
to reduce the incidence of catheter-related bloodstream infections
(CRBSI) in adult patients with kidney failure receiving chronic
hemodialysis (HD) through a central venous catheter (CVC). This drug
is indicated for use in a limited and specific population of patients. (1)
Limitations of Use
The safety and effectiveness of DEFENCATH have not been
established for use in populations other than adult patients with kidney
failure receiving chronic HD through a CVC. (1)
------------------------DOSAGE AND ADMINISTRATION-----------------------
•
DEFENCATH is for instillation into CVCs only. (2)
•
DEFENCATH is not intended for systemic administration. (2)
•
Do not use DEFENCATH as a catheter lock flush product. (2)
•
Withdraw a sufficient volume of DEFENCATH catheter lock
solution (CLS) from the vial using a sterile needle and syringe to
fill the catheter lumens. (2)
•
Use 3 mL or 5 mL single dose vial (depending on the volume of
the catheter lumens) to instill DEFENCATH into each catheter
lumen at the conclusion of each HD session. (2)
•
DEFENCATH should be aspirated from the catheter and
discarded prior to the initiation of the next HD session. (2)
•
Discard any unused portion of DEFENCATH remaining in the
vial. (2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
•
DEFENCATH is a sterile catheter lock solution available in single-
dose vials in the following strengths:
o
3 mL containing taurolidine 40.5 mg/3 mL (13.5 mg/mL), and
heparin 3,000 USP Units/3 mL (1,000 USP Units/mL) (3)
o
5 mL containing taurolidine 67.5 mg/5 mL (13.5 mg/mL), and
heparin 5,000 USP Units/5 mL (1,000 USP Units/mL) (3)
-------------------------------CONTRAINDICATIONS-------------------------------
•
Known heparin-induced thrombocytopenia. (4)
•
Known hypersensitivity to taurolidine, heparin or the citrate
excipient (components of DEFENCATH), or pork products. (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
•
Heparin-Induced Thrombocytopenia (HIT): HIT was reported in
Trial 1 at an incidence rate of 0.3% in patients using heparin, a
component of DEFENCATH as a CLS. If HIT occurs, discontinue
DEFENCATH and institute appropriate supportive measures.
(5.1)
•
Drug Hypersensitivity Reactions: Drug hypersensitivity reactions
were reported in Trial 1 at an incidence rate of 0.5% in patients
using heparin, a component of DEFENCATH, as a CLS. If a
hypersensitivity reaction occurs, discontinue DEFENCATH and
institute appropriate supportive measures. (5.2)
-------------------------------ADVERSE REACTIONS------------------------------
The most frequently reported adverse reactions occurring in greater
than or equal to 2% of patients in Trial 1 using DEFENCATH as a CLS
were hemodialysis catheter malfunction, hemorrhage/bleeding,
nausea, vomiting, dizziness, musculoskeletal chest pain, and
thrombocytopenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact CorMedix
Inc at 1-844-424-6345 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Heparin-Induced Thrombocytopenia
5.2 Drug Hypersensitivity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
* Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 5499204
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
LIMITED POPULATION: DEFENCATH® is indicated to reduce the incidence of catheter-related
bloodstream infections (CRBSI) in adult patients with kidney failure receiving chronic hemodialysis
(HD) through a central venous catheter (CVC). This drug is indicated for use in a limited and specific
population of patients [see Clinical Studies (14)].
Limitations of Use
The safety and effectiveness of DEFENCATH have not been established for use in populations other
than adult patients with kidney failure receiving chronic HD through a CVC.
2 DOSAGE AND ADMINISTRATION
DEFENCATH is for instillation into CVCs only [see Indications and Usage (1)]. DEFENCATH is not
intended for systemic administration. Do not use DEFENCATH as a catheter lock flush product.
Withdraw a sufficient volume of DEFENCATH catheter lock solution (CLS) from the vial using a sterile
needle and syringe to fill the catheter lumens. Use 3 mL or 5 mL single-dose vial (depending on the
volume of the catheter lumens) to instill DEFENCATH into each catheter lumen at the conclusion of
each HD session for patients with kidney failure requiring chronic HD. Prior to initiation of the next HD
session, DEFENCATH should be aspirated from the catheter and discarded. If DEFENCATH cannot
be aspirated, continue with standard of care CVC preparation and flush with normal saline. If a
catheter malfunction is suspected, appropriate standard of care measures should be instituted.
Each DEFENCATH single-dose vial is designed for use with a single patient as a single instillation in
the CVC. Discard any unused portion of DEFENCATH remaining in the vial.
3 DOSAGE FORMS AND STRENGTHS
DEFENCATH CLS is available as a sterile, preservative-free, clear, aqueous-based solution in the
following strengths:
• 3 mL of catheter lock solution in a single-dose vial containing taurolidine 40.5 mg/3 mL (13.5
mg/mL), and heparin 3,000 USP Units/3 mL (1,000 USP Units/mL)
• 5 mL of catheter lock solution in a single-dose vial containing taurolidine 67.5 mg/5 mL (13.5
mg/mL), and heparin 5,000 USP Units/5 mL (1,000 USP Units/mL)
4 CONTRAINDICATIONS
DEFENCATH is contraindicated in patients with:
• Known heparin-induced thrombocytopenia (HIT) [see Warnings and Precautions (5.1)].
• Known hypersensitivity to taurolidine, heparin or the citrate excipient (components of
DEFENCATH) or pork products [see Warnings and Precautions (5.2)].
5 WARNINGS AND PRECAUTIONS
5.1
Heparin-Induced Thrombocytopenia
Reference ID: 5499204
Heparin-induced thrombocytopenia (HIT) was reported at an incidence rate of 0.3% in Trial 1 in
patients using heparin, a component of DEFENCATH, as a CLS. If HIT occurs, discontinue
DEFENCATH and institute appropriate supportive measures [see Contraindications (4)].
5.2
Drug Hypersensitivity
Drug hypersensitivity reactions were reported at an incidence rate of 0.5% in Trial 1 in patients using
heparin, a component of DEFENCATH, as a CLS. If a hypersensitivity reaction occurs, discontinue
DEFENCATH and institute appropriate supportive measures [see Contraindications (4)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Heparin-Induced Thrombocytopenia [see Warnings and Precautions (5.1)]
• Drug Hypersensitivity [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
Overview of the Safety Evaluation of DEFENCATH
The safety of DEFENCATH was evaluated in a single, active-controlled, double-blind, randomized
Phase 3 trial, LOCK-IT-100 (referred to as Trial 1), in adult patients with kidney failure receiving
chronic HD through a CVC. In Trial 1, the safety population was comprised of 797 patients with 398
patients using DEFENCATH as a CLS and 399 using heparin as a CLS. Patients used DEFENCATH
as a CLS for a mean duration of 173 days, and a range of 4 to 863 days.
The mean age of the patients in Trial 1 was 61 years, 58% of patients identified as male (42%
patients identified as female), 63% of patients identified as white and 30% identified as black or
African-American. Patients with diabetes at baseline accounted for 70% of patients and the mean
body mass index (BMI) of patients in the study was 30. The majority of patients (68%) had been
receiving HD for 12 months or less. The location of the CVC was the jugular vein in 92% of patients.
Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation
In Trial 1, serious adverse reactions occurred in 40% (159/398) of patients receiving DEFENCATH as
a CLS and 42% (167/399) of patients receiving heparin as a CLS. Adverse reactions leading to death
occurred in 5% (18/398) of patients in the DEFENCATH arm and 5% (21/399) of patients in the
heparin arm.
Adverse reactions leading to discontinuation of study drug occurred in 17% (69/398) of patients in the
DEFENCATH arm and 18% (72/399) of patients in the heparin arm.
Common Adverse Reactions
In Trial 1, adverse reactions were reported in 79% (314/398) of patients using DEFENCATH as a
CLS and 79% (315/399) of patients using heparin.
Table 1 lists selected adverse reactions occurring in ≥2% of patients using DEFENCATH or heparin
in Trial 1.
Reference ID: 5499204
Table 1: Selected Adverse Reactions Occurring in Greater Than or Equal to 2% of Patients
Receiving DEFENCATH in Trial 1
Adverse Reactions
DEFENCATH
(N=398)
N (%)
Heparin
(N=399)
N (%)
Product Issues
Hemodialysis catheter malfunctiona
68 (17)
47 (12)
Blood and lymphatic system disorders
Hemorrhage/bleedingb
27 (7)
34 (9)
Thrombocytopenia
7 (2)
4 (1)
Gastrointestinal disorders
Nauseac
28 (7)
44 (11)
Vomitingd
24 (6)
32 (8)
Nervous system disorders
Dizziness
22 (6)
16 (4)
Musculoskeletal and Connective Tissue
Disorders
Musculoskeletal chest paine
11 (3)
7 (2)
a Grouped term includes device malfunction
b Grouped term includes: hematoma/hemorrhage, intracranial hemorrhage, arteriovenous graft or fistula site
hemorrhage, catheter site hematoma/hemorrhage, cerebral/cerebellar hemorrhage, eye/conjunctival hemorrhage,
gastrointestinal hemorrhage, hematuria, hemobilia, hemoptysis, renal hematoma, vaginal/uterine hemorrhage
c Grouped term includes nausea and procedural nausea
d Grouped term includes vomiting and procedural vomiting
e Grouped term Includes non-cardiac chest pain, musculoskeletal chest pain, chest discomfort
Table 2 lists the proportion of patients in Trial 1 that developed loss of catheter patency defined as
requiring use of a thrombolytic agent to resolve catheter thrombosis or removal of the catheter due to
malfunction/dysfunction.
Table 2: Loss of Catheter Patency in Trial 1
DEFENCATH
(N=398)
N (%)
Heparin
(N=399)
N (%)
Loss of Catheter Patency
63 (16)
48 (12)
Use of a Thrombolytic Agenta
46 (12)
33 (8)
Catheter Removalb
28 (7)
26 (7)
Catheter Removal without
Thrombolytic Agent Use
17 (4)
15 (4)
a 11 subjects in each arm had catheter removal following thrombolytic agent use and are included under both categories
of use of a thrombolytic agent and catheter removal.
b Catheter removal refers to catheters removed due to loss of catheter patency. Overall, a total of 236 patients in the
DEFENCATH arm and 225 patients in the heparin arm had a catheter removal for any reason, including loss of catheter
patency.
Other Adverse Reactions
Clinically significant adverse reactions that occurred in fewer than 1% of patients receiving
DEFENCATH in Trial 1 are listed below:
Metabolism and Nutrition Disorders: Hypocalcemia
Nervous System Disorders: Dysgeusia
Reference ID: 5499204
6.2 Postmarketing Experience
The following adverse reaction has been identified during the use of a taurolidine and heparin
containing CLS outside of the United States. Because this reaction is reported from a population of
uncertain size, it is not always possible to reliably estimate its frequency or establish a causal
relationship to drug exposure.
Nervous System Disorders: Paresthesia
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
DEFENCATH is not intended for systemic administration. It is intended for use as a CLS in patients
with kidney failure requiring chronic HD; therefore, maternal use is not expected to result in fetal
exposure to the drug [see Dosage and Administration (2)]. No animal reproduction study was
conducted with DEFENCATH.
8.2 Lactation
Risk Summary
DEFENCATH is not intended for systemic administration. It is intended for use as a CLS in patients
with kidney failure requiring chronic HD; therefore, breastfeeding is not expected to result in exposure
of the infant to DEFENCATH [see Dosage and Administration (2)].
8.4 Pediatric Use
The safety and effectiveness of DEFENCATH have not been established in pediatric patients. There
are no available data on DEFENCATH use in pediatric patients.
8.5 Geriatric Use
There were 327 patients 65 years of age and older in Trial 1 [see Clinical Studies (14)]. Of the total
number of patients using DEFENCATH in this study, 162 (41%) were 65 years of age and older, while
64 (16%) were 75 years of age and older. No overall differences in safety or effectiveness were
observed between patients 65 years of age and older and younger adult patients.
11 DESCRIPTION
DEFENCATH (taurolidine and heparin) CLS contains taurolidine, a thiadiazinane antimicrobial, and
heparin sodium, an anti-coagulant.
Taurolidine
Taurolidine is an antimicrobial agent derived from the naturally occurring amino acid taurine. The
chemical name is 4,4'-methylenebis(1,2,4-thiadiazinane)-1,1,1',1'-tetraoxide. The molecular weight is
284.36, and the molecular formula is C7H16N4O4S2.
The structural formula of taurolidine is:
Reference ID: 5499204
Heparin Sodium
Heparin is an anticoagulant consisting of heterogeneous group of straight-chain anionic
mucopolysaccharides, called glycosaminoglycans. It is composed of polymers of alternating
derivatives of α-D-glucosamido (N-sulfated, O-sulfated, or N-acetylated) and O-sulfated uronic acid
(α-L-iduronic acid or β-D-glucuronic acid). Heparin is derived from porcine intestinal mucosa.
The structure of heparin sodium (representative subunits) is:
DEFENCATH is for central venous catheter instillation use. DEFENCATH CLS is available as a
sterile, non-pyrogenic, preservative-free, clear, aqueous-based solution of taurolidine and heparin
with a pH of 5.5-6.5 in the following strengths:
• 3 mL of catheter lock solution in a single-dose vial containing taurolidine 40.5 mg/3 mL (13.5
mg/mL), and heparin 3,000 USP Units/3 mL (1,000 USP Units/mL)
• 5 mL of catheter lock solution in a single-dose vial containing taurolidine 67.5 mg/5 mL (13.5
mg/mL), and heparin 5,000 USP Units/5 mL (1,000 USP Units/mL)
The heparin potency is determined by a biological assay using a USP reference standard based on
units of heparin activity per milligram. The inactive ingredients are 26.1 mg/mL of citric acid,
anhydrous (which is added to control pH and maintain the solubility of taurolidine),and may include
hydrochloric acid and/or sodium hydroxide for pH adjustment.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Heparin
Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a
conformational change, which markedly enhances the serine protease activity of Antithrombin III,
thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa
Reference ID: 5499204
and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa).
Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin
stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.
Taurolidine
Taurolidine is an antimicrobial drug [see Microbiology (12.4)].
12.2 Pharmacodynamics
The pharmacodynamics of DEFENCATH are unknown.
12.3 Pharmacokinetics
No pharmacokinetic studies were conducted because DEFENCATH is intended to be instilled into the
catheter lumens at the conclusion of each HD session for patients with kidney failure requiring chronic
HD. DEFENCATH is not intended for systemic administration [see Dosage and Administration (2)].
12.4 Microbiology
Mechanism of Action
The mechanism of action of taurolidine and its metabolites is non-specific, causing damage to
microbial cell walls and inhibiting adherence of microorganisms to biological surfaces.
Resistance
Time kill studies showed that taurolidine is bactericidal (>3 log10 CFU reduction) at 1x to 4x minimum
inhibitory concentration (MIC). The frequency of resistant mutants was <10-9 at 2x and 4x MIC for two
strains each of Escherichia coli, Staphylococcus aureus, Enterococcus faecalis, Enterococcus
faecium and Pseudomonas aeruginosa.1
Antimicrobial Activity
The following in vitro data are available but their clinical significance is unknown. Taurolidine has
been shown to be active against most isolates of the following microorganisms:
Gram-positive
Staphylococcus aureus (including methicillin-sensitive Staphylococcus aureus (MSSA) and
methicillin-resistant Staphylococcus aureus (MRSA))
Staphylococcus epidermidis
Enterococcus faecalis
Gram-negative
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Serratia marcescens
Fungi
Candida albicans
Candida glabrata
Reference ID: 5499204
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies in animals have not been conducted with taurolidine or heparin.
Mutagenesis
Taurolidine was positive in vitro in an Ames reverse mutation assay and it increased mutation
frequency in L5178Y mouse lymphoma cells. However, taurolidine was negative in an in vivo
combined micronucleus test and comet assay in rats at the highest dose tested, 600 mg/kg/day
administered intravenously.
No studies have been conducted with heparin to determine its mutagenic potential.
Impairment of Fertility
Fertility studies have not been conducted with DEFENCATH due to its negligible clinical exposure.
14 CLINICAL STUDIES
The efficacy and safety of DEFENCATH for reducing the incidence of CRBSI in patients with kidney
failure receiving chronic HD was evaluated in LOCK-IT-100 (referred to as Trial 1, NCT02651428), a
randomized, double-blind, active-controlled, multicenter trial.
A total of 806 patients were randomized in a 1:1 ratio to receive either DEFENCATH or heparin
(heparin sodium USP 1,000 units/mL, benzyl alcohol 9.45 mg/mL and sodium chloride 9.0 mg/mL) as
a CLS. Enrollment in Trial 1 was not limited to patients with specific types of HD catheters.
DEFENCATH or heparin was instilled into central venous HD catheters at the end of all dialysis
sessions and was withdrawn prior to the initiation of the next dialysis session. The median age of the
study population was 63 years (range 21-94 years); 58% identified as males and 63% identified as
white. The majority of patients (98%) had HD treatment three times per week, and 48% had their
catheter implanted within three months prior to randomization.
A clinical adjudication committee (CAC) assessed the cases of CRBSI. The CAC definition for CRBSI
included one positive blood culture (other than for coagulase-negative staphylococci, which required
a confirmatory culture) from a peripheral site or either the arterial or venous catheter hub or the
arterial or venous dialysis blood line and the patient had to have signs and symptoms of infection and
no other apparent source of bloodstream infection.
Results of analyses of CAC-adjudicated CRBSI among the DEFENCATH and heparin groups in all
randomized patients who received at least one dose of allocated study CLS are presented in Table 3.
Patients in the DEFENCATH group had a lower incidence of CRBSI events compared to patients in
the control group.
Table 3. Results of Analyses of CAC-Adjudicated CRBSI in Patients with Kidney Failure
Receiving HD in Trial 1
DEFENCATH
(N=397)
Heparin
(N=398)
CAC-adjudicated CRBSI
9 (2.3%)
32 (8.0%)
Event rate per 1000 catheter-days (95% CI)
0.13 (0.07, 0.26)
0.46 (0.33, 0.66)
Reference ID: 5499204
Risk reduction (95% CI)*
71% (38%, 86%)
Log-rank test p-value
0.0006
*Based on 1 – Hazard Ratio
In total, 5% [18/397] of subjects in the DEFENCATH arm and 5% [21/398] of subjects in the heparin
arm died during the trial (difference [DEFENCATH – Heparin]: -0.7% with a 95% CI[-3.7%, 2.3%]).
Among the 9 patients in the DEFENCATH arm with a CAC-adjudicated CRBSI, 1 had a gram-
negative organism isolated and 8 had a gram-positive organism isolated; among the 32 patients in
the heparin arm with a CAC-adjudicated CRBSI, 14 had a gram-negative organism isolated and 18
had a gram-positive organism isolated.
15 REFERENCES
1.
Torres-Viera, C, Thauvin-Eliopoulos C., Souli M, DeGirolamin P, Farris MG,
Wennerstein CB, Sofia RD and Eliopoulos GM. 2000. Antimicrobial Agents and
Chemotherapy 44(6):1720 - 1724.
16 HOW SUPPLIED/STORAGE AND HANDLING
DEFENCATH cathether lock solution is available in:
• 3 mL of catheter lock solution in a single-dose vial containing taurolidine 40.5 mg/3 mL (13.5
mg/mL), and heparin 3,000 USP Units/3 mL (1,000 USP Units/mL) (NDC 72990-103-03)
• 5 mL of catheter lock solution in a single-dose vial containing taurolidine 67.5 mg/5 mL (13.5
mg/mL), and heparin 5,000 USP Units/5 mL (1,000 USP Units/mL) (NDC 72990-105-05)
Each vial contains a sterile, preservative-free, clear aqueous-based solution for instillation in central
venous catheters. Each carton contains 10 single-dose vials.
DEFENCATH vials must be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F);
excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Do not freeze. DEFENCATH vials must be stored in the commercial carton, prior to the instillation in
central venous catheters.
Manufactured for:
CorMedix Inc.
300 Connell Drive, Suite 4200
Berkeley Heights, NJ 07922
Reference ID: 5499204
| custom-source | 2025-02-12T15:48:00.318381 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214520s003lbl.pdf', 'application_number': 214520, 'submission_type': 'SUPPL ', 'submission_number': 3} |
80,678 |
SPORANOX®
(itraconazole)
Oral Solution
BOXED WARNING
Congestive Heart Failure, Cardiac Effects and Drug Interactions
Congestive Heart Failure and Cardiac Effects:
• If signs or symptoms of congestive heart failure occur during administration of
SPORANOX® (itraconazole) Oral Solution, continued SPORANOX® use should
be reassessed.
• When itraconazole was administered intravenously to dogs and healthy human
volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS,
WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS:
Postmarketing Experience, and CLINICAL PHARMACOLOGY: Special
Populations for more information.)
Drug Interactions:
• Coadministration of a number of CYP3A4 substrates are contraindicated with
SPORANOX®. Some examples of drugs that are
contraindicated for
coadministration with SPORANOX® Oral Solution are: methadone, disopyramide,
dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as
dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine
(methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam,
felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol,
lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
• Coadministration with colchicine, fesoterodine and solifenacin is contraindicated in
subjects with varying degrees of renal or hepatic impairment.
• Coadministration with eliglustat is contraindicated in subjects that are poor or
intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate
CYP2D6 inhibitors.
• Coadministration with venetoclax is contraindicated in patients with chronic
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose
initiation and ramp-up phase of venetoclax. See PRECAUTIONS: Drug
Interactions Section for specific examples.
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Reference ID: 5499269
• Coadministration with itraconazole can cause elevated plasma concentrations of
these drugs and may increase or prolong both the pharmacologic effects and/or
adverse reactions to these drugs. For example, increased plasma concentrations of
some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias
including occurrences of torsade de pointes, a potentially fatal arrhythmia. See
CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug
Interactions Section for specific examples.
DESCRIPTION
SPORANOX® is the brand name for itraconazole, an azole antifungal agent. Itraconazole is a
1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three
chiral centers. It may be represented by the following structural formula and nomenclature:
(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5-one
mixture
with
(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H
1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4
triazolin-5-one
or
(±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-∆2-1,2,4-triazolin-5-one.
Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is
a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols,
and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values
obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at
pH 8.1.
SPORANOX® (itraconazole) Oral Solution contains 10 mg of itraconazole per mL, solubilized
by hydroxypropyl-β-cyclodextrin (400 mg/mL) as a molecular inclusion complex.
SPORANOX® Oral Solution is clear and yellowish in color with a target pH of 2. Other
2
Reference ID: 5499269
ingredients are hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium
saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism:
Itraconazole
General Pharmacokinetic Characteristics
Peak plasma concentrations are reached within 2.5 hours following administration of the oral
solution. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma
during multiple dosing. Steady-state concentrations are generally reached within about 15 days,
with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state
Cmax values of about 2 μg/mL are reached after oral administration of 200 mg once daily. The
terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and
increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma
concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending
on the dose and duration of treatment. Itraconazole mean total plasma clearance following
intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due
to saturable hepatic metabolism.
Absorption
Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma
concentrations of itraconazole are reached within 2.5 hours following administration of the oral
solution under fasting conditions. The observed absolute bioavailability of itraconazole under
fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting
conditions. Itraconazole exposure is greater with the oral solution than with the capsule
formulation when the same dose of drug is given. (see WARNINGS.)
Distribution
Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main
binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids.
Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a
large apparent volume in the body (>700 L), suggesting extensive distribution into tissues.
Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to
three times higher than corresponding concentrations in plasma, and the uptake into keratinous
tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are
much lower than in plasma.
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Metabolism
Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro
studies have shown that CYP3A4 is the major enzyme involved in the metabolism of
itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity
comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those
of itraconazole.
Excretion
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within
one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite
hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral
radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
Special Populations:
Renal Impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment. A
pharmacokinetic study using a single 200 mg oral dose of itraconazole was conducted in three
groups of patients with renal impairment (uremia: n = 7; hemodialysis: n = 7; and continuous
ambulatory peritoneal dialysis: n = 5). In uremic subjects with a mean creatinine clearance of
13 mL/min.×1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal
population parameters. This study did not demonstrate any significant effect of hemodialysis or
continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax,
and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in
all three groups.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild
(defined in this study as CrCl 50-79 mL/min), moderate (defined in this study as
CrCl 20-49 mL/min), and severe renal impairment (defined in this study as CrCl <20 mL/min)
were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally
impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on
AUC, was decreased in patients with moderate and severe renal impairment by approximately
30% and 40%, respectively, as compared with subjects with normal renal function.
Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis
has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See
PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
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Hepatic Impairment:
Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted
in 6 healthy and 12 cirrhotic subjects who were administered a single 100 mg dose of
itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold
increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted
in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole,
based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in
cirrhotic patients during long-term use of itraconazole. (See CONTRAINDICATIONS,
PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.)
Decreased Cardiac Contractility:
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative
inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous
infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed
using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or
symptoms of congestive heart failure appear during administration of SPORANOX® Oral
Solution, monitor carefully and consider other treatment alternatives which may include
discontinuation of SPORANOX® Oral Solution administration. (See BOXED WARNING,
CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE
REACTIONS: Postmarketing Experience for more information.)
Cystic Fibrosis:
Seventeen cystic fibrosis patients, ages 7 to 28 years old, were administered itraconazole oral
solution 2.5 mg/kg b.i.d. for 14 days in a pharmacokinetic study. Sixteen patients completed the
study. Steady state trough concentrations >250 ng/mL were achieved in 6 out of 11 patients
≥16 years of age but in none of the 5 patients <16 years of age. Large variability was observed
in the pharmacokinetic data (%CV for trough concentrations = 98% and 70% for ≥16 and
<16 years, respectively; %CV for AUC = 75% and 58% for ≥16 and <16 years, respectively). If
a patient with cystic fibrosis does not respond to SPORANOX® Oral Solution, consideration
should be given to switching to alternative therapy.
Hydroxypropyl-ß-Cyclodextrin:
The oral bioavailability of hydroxypropyl-β-cyclodextrin given as a solubilizer of itraconazole
in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-β
cyclodextrin alone. This low oral bioavailability of hydroxypropyl-β-cyclodextrin is not
modified by the presence of food and is similar after single and repeated administrations.
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Reference ID: 5499269
MICROBIOLOGY
Mechanism of Action:
In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent
synthesis of ergosterol, which is a vital component of fungal cell membranes.
Antimicrobial Activity:
Itraconazole has been shown to be active against most strains of the following microorganism,
both in vitro and in clinical infections.
Candida albicans
Susceptibility Testing Methods:
For specific information regarding susceptibility test interpretive criteria and associated test
methods and quality control standards recognized by FDA for this drug, please see:
https://www.fda.gov/STIC.
Drug Resistance:
Isolates from several fungal species with decreased susceptibility to itraconazole have been
isolated in vitro and from patients receiving prolonged therapy.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible
Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp.
and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Cross-Resistance:
In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot
be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before
the start of itraconazole therapy.
Several in vitro studies have reported that some fungal clinical isolates, including Candida
species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to
other azole derivatives. The finding of cross-resistance is dependent on a number of factors,
including the species evaluated, its clinical history, the particular azole compounds compared,
and the type of susceptibility test that is performed.
Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed
by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the
14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol
is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against
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Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical
significance of test results obtained in this study is unknown.
CLINICAL STUDIES
Oropharyngeal Candidiasis:
Two randomized, controlled studies for the treatment of oropharyngeal candidiasis have been
conducted (total n = 344). In one trial, clinical response to either 7 or 14 days of itraconazole oral
solution, 200 mg/day, was similar to fluconazole tablets and averaged 84% across all arms.
Clinical response in this study was defined as cured or improved (only minimal signs and
symptoms with no visible lesions). Approximately 5% of subjects were lost to follow-up before
any evaluations could be performed. Response to 14 days therapy of itraconazole oral solution
was associated with a lower relapse rate than 7 days of itraconazole therapy. In another trial, the
clinical response rate (defined as cured or improved) for itraconazole oral solution was similar
to clotrimazole troches and averaged approximately 71% across both arms, with approximately
3% of subjects lost to follow-up before any evaluations could be performed. Ninety-two percent
of the patients in these studies were HIV seropositive.
In an uncontrolled, open-label study of selected patients clinically unresponsive to fluconazole
tablets (n = 74, all patients HIV seropositive), patients were treated with itraconazole oral
solution 100 mg b.i.d. (Clinically unresponsive to fluconazole in this study was defined as having
received a dose of fluconazole tablets at least 200 mg/day for a minimum of 14 days.) Treatment
duration was 14-28 days based on response. Approximately 55% of patients had complete
resolution of oral lesions. Of patients who responded and then entered a follow-up phase (n = 22),
all relapsed within 1 month (median 14 days) when treatment was discontinued. Although
baseline endoscopies had not been performed, several patients in this study developed symptoms
of esophageal candidiasis while receiving therapy with itraconazole oral solution. Itraconazole
oral solution has not been directly compared to other agents in a controlled trial of similar
patients.
Esophageal Candidiasis:
A double-blind randomized study (n = 119, 111 of whom were HIV seropositive) compared
itraconazole oral solution (100 mg/day) to fluconazole tablets (100 mg/day). The dose of each
was increased to 200 mg/day for patients not responding initially. Treatment continued for
2 weeks following resolution of symptoms, for a total duration of treatment of 3-8 weeks.
Clinical response (a global assessment of cured or improved) was not significantly different
between the two study arms, and averaged approximately 86% with 8% lost to follow-up. Six of
53 (11%) itraconazole-treated patients and 12/57 (21%) fluconazole-treated patients were
escalated to the 200 mg dose in this trial. Of the subgroup of patients who responded and entered
a follow-up phase (n = 88), approximately 23% relapsed across both arms within 4 weeks.
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INDICATIONS AND USAGE
SPORANOX® (itraconazole) Oral Solution is indicated for the treatment of oropharyngeal and
esophageal candidiasis.
(See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and ADVERSE
REACTIONS: Postmarketing Experience for more information.)
CONTRAINDICATIONS
Congestive Heart Failure:
SPORANOX® (itraconazole) Oral Solution should not be administered to patients with evidence
of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for
the treatment of life-threatening or other serious infections. (See BOXED WARNING,
WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, ADVERSE
REACTIONS: Postmarketing Experience, and CLINICAL PHARMACOLOGY: Special
Populations.)
Drug Interactions:
Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®.
Some examples of drugs for which plasma concentrations increase are: methadone,
disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as
dihydroergotamine,
ergometrine
(ergonovine),
ergotamine,
methylergometrine
(methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine,
nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin,
simvastatin, avanafil, ticagrelor, finerenone, voclosporin. In addition, coadministration with
colchicine, fesoterodine, and solifenacin is contraindicated in subjects with varying degrees of
renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects
that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate
CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions Section for specific examples.)
This increase in drug concentrations caused by coadministration with itraconazole may increase
or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example,
increased plasma concentrations of some of these drugs can lead to QT prolongation and
ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal
arrhythmia. Some specific examples are listed in PRECAUTIONS: Drug Interactions.
Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose
initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor
lysis syndrome.
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SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole.
There is limited information regarding cross-hypersensitivity between itraconazole and other
azole antifungal agents. Caution should be used when prescribing SPORANOX® to patients with
hypersensitivity to other azoles.
WARNINGS
Hepatic Effects:
SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver
failure and death. Some of these cases had neither pre-existing liver disease nor a serious
underlying medical condition, and some of these cases developed within the first week of
treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment
should be discontinued and liver function testing performed. Continued SPORANOX® use or
reinstitution of treatment with SPORANOX® is strongly discouraged unless there is a serious or
life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS:
Information for Patients and ADVERSE REACTIONS.)
Cardiac Dysrhythmias:
Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs
such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX® and/or
other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is
contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS:
Drug Interactions.)
Cardiac Disease:
SPORANOX® Oral Solution should not be used in patients with evidence of ventricular
dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for
congestive heart failure, physicians should carefully review the risks and benefits of
SPORANOX® therapy. These risk factors include cardiac disease such as ischemic and valvular
disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal
failure and other edematous disorders. Such patients should be informed of the signs and
symptoms of CHF, should be treated with caution, and should be monitored for signs and
symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration
of SPORANOX® Oral Solution, monitor carefully and consider other treatment alternatives
which may include discontinuation of SPORANOX® Oral Solution administration.
Itraconazole has been shown to have a negative inotropic effect. When itraconazole was
administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was
documented. In a healthy volunteer study of itraconazole intravenous infusion, transient,
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asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT
imaging; these resolved before the next infusion, 12 hours later.
SPORANOX® has been associated with reports of congestive heart failure. In postmarketing
experience, heart failure was more frequently reported in patients receiving a total daily dose of
400 mg although there were also cases reported among those receiving lower total daily doses.
Calcium channel blockers can have negative inotropic effects which may be additive to those of
itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers.
Therefore, caution should be used when co-administering itraconazole and calcium channel
blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and
felodipine or nisoldipine is contraindicated.
Cases of CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing
period among patients being treated for onychomycosis and/or systemic fungal infections. (See
CONTRAINDICATIONS,
CLINICAL
PHARMACOLOGY:
Special
Populations,
PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Postmarketing Experience
for more information.)
Pseudoaldosteronism:
Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and
abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11
deoxycortisol), has been reported with itraconazole use in the postmarketing setting. Monitor
blood pressure and potassium levels and manage as necessary. Management of
pseudoaldosteronism may include discontinuation of SPORANOX®, substitution with an
appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone
receptor antagonists.
Interaction Potential:
SPORANOX® has a potential for clinically important drug interactions. Coadministration of
specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the
coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated,
not recommended or recommended for use with caution in combination with itraconazole are
listed in PRECAUTIONS: Drug Interactions.
Interchangeability:
SPORANOX® (itraconazole) Oral Solution and SPORANOX® Capsules should not be used
interchangeably. This is because drug exposure is greater with the Oral Solution than with the
Capsules when the same dose of drug is given. Only SPORANOX® Oral Solution has been
demonstrated effective for oral and/or esophageal candidiasis.
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Hydroxypropyl-β-cyclodextrin:
SPORANOX® Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin which
produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a
rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity
study. The clinical relevance of these adenocarcinomas is unknown. (See PRECAUTIONS:
Carcinogenesis, Mutagenesis, and Impairment of Fertility.)
Treatment of Severely Neutropenic Patients:
SPORANOX® Oral Solution as treatment for oropharyngeal and/or esophageal candidiasis was
not investigated in severely neutropenic patients. Due to its pharmacokinetic properties,
SPORANOX® Oral Solution is not recommended for initiation of treatment in patients at
immediate risk of systemic candidiasis.
PRECAUTIONS
Hepatotoxicity:
Rare cases of serious hepatotoxicity have been observed with SPORANOX® treatment, including
some cases within the first week. It is recommended that liver function monitoring be considered
in all patients receiving SPORANOX®. Treatment should be stopped immediately and liver
function testing should be conducted in patients who develop signs and symptoms suggestive of
liver dysfunction.
Neuropathy:
If neuropathy occurs that may be attributable to SPORANOX® Oral Solution, the treatment
should be discontinued.
Cystic Fibrosis:
If a patient with cystic fibrosis does not respond to SPORANOX® Oral Solution, consideration
should be given to switching to alternative therapy (see CLINICAL PHARMACOLOGY:
Special Populations).
Hearing Loss:
Transient or permanent hearing loss has been reported in patients receiving treatment with
itraconazole. Several of these reports included concurrent administration of quinidine which is
contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug
Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when
treatment is stopped, but can persist in some patients.
Information for Patients:
• Only SPORANOX® Oral Solution has been demonstrated effective for oral and/or
esophageal candidiasis.
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• SPORANOX® Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin
which produced adenocarcinomas in the large intestine and exocrine pancreatic
adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a
similar mouse carcinogenicity study. The clinical relevance of these adenocarcinomas
is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of
Fertility.)
• Taking SPORANOX® Oral Solution under fasted conditions improves the systemic
availability of itraconazole. Instruct patients to take SPORANOX® Oral Solution
without food, if possible.
• SPORANOX® Oral Solution should not be used interchangeably with SPORANOX®
Capsules.
• Instruct patients about the signs and symptoms of congestive heart failure, and if these
signs or symptoms occur during SPORANOX® administration, they should discontinue
SPORANOX® and contact their healthcare provider immediately.
• Instruct patients to stop SPORANOX® treatment immediately and contact their
healthcare provider if any signs and symptoms suggestive of liver dysfunction develop.
Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or
vomiting, jaundice, dark urine, or pale stools.
• Instruct patients to contact their physician before taking any concomitant medications
with itraconazole to ensure there are no potential drug interactions.
• Instruct patients that hearing loss can occur with the use of itraconazole. The hearing
loss usually resolves when treatment is stopped, but can persist in some patients. Advise
patients to discontinue therapy and inform their physicians if any hearing loss
symptoms occur.
• Instruct patients that dizziness or blurred/double vision can sometimes occur with
itraconazole. Advise patients that if they experience these events, they should not drive
or use machines.
Drug Interactions:
Effect of SPORANOX® on Other Drugs
Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.
Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance
protein (BCRP). Consequently, SPORANOX® has the potential to interact with many
concomitant drugs resulting in either increased or sometimes decreased concentrations of the
concomitant drugs. Increased concentrations may increase the risk of adverse reactions
associated with the concomitant drug which can be severe or life-threatening in some cases (e.g.,
QT prolongation, torsade de pointes, respiratory depression, hepatic adverse reactions,
hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial
fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce
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their efficacy. The table below lists examples of drugs that may have their concentrations affected
by itraconazole, but it is not a comprehensive list.
Refer to the approved product labeling to become familiar with the interaction pathways, risk
potential and specific actions to be taken with regards to each concomitant drug prior to initiating
therapy with SPORANOX®.
Although many of the clinical drug interactions in Table 1 below are based on information with
a similar azole antifungal, ketoconazole, these interactions are expected to occur with
SPORANOX®.
Table 1:
Drug Interactions with SPORANOX® that Affect Concomitant Drug
Concentrations
Examples of Concomitant Drugs Within
Class
Prevention or Management
Drug Interactions with SPORANOX® that Increase Concomitant Drug Concentrations and
May Increase Risk of Adverse Reactions Associated with the Concomitant Drug
Alpha Blockers
Alfuzosin
Silodosin
Tamsulosin
Not recommended during and 2 weeks after
SPORANOX® treatment.
Analgesics
Methadone
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Fentanyl
Not recommended during and 2 weeks after
SPORANOX® treatment.
Alfentanil
Buprenorphine (IV and sublingual)
Oxycodonea
Sufentanil
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antiarrhythmics
Disopyramide
Dofetilide
Dronedarone
Quinidinea
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Digoxina
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antibacterials
Bedaquilineb
Concomitant SPORANOX® not recommended for
more than 2 weeks at any time during bedaquiline
treatment.
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Rifabutin
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 2.
Clarithromycin
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. See also
Table 2.
Trimetrexate
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Anticoagulants and Antiplatelets
Ticagrelor
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Apixaban
Rivaroxaban
Vorapaxar
Not recommended during and 2 weeks after
SPORANOX® treatment.
Cilostazol
Dabigatran
Warfarin
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Anticonvulsants
Carbamazepine
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 2.
Antidiabetic Drugs
Repaglinidea
Saxagliptin
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antihelminthics, Antifungals and Antiprotozoals
Isavuconazonium
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Praziquantel
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Artemether-lumefantrine
Quininea
Monitor for adverse reactions.
Antimigraine Drugs
Ergot alkaloids (e.g., dihydroergotamine,
ergotamine)
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Eletriptan
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antineoplastics
Irinotecan
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Venetoclax
Contraindicated during the dose initiation and
ramp-up phase in patients with CLL/SLL. Refer to
the venetoclax prescribing information for dosing
and safety monitoring instructions.
Mobocertiniba
Avoid use during and 2 weeks after SPORANOX®
treatment.
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Axitinib
Ibrutinib
Bosutinib
Lapatinib
Cabazitaxel
Nilotinib
Cabozantinib
Olapariba
Ceritinib
Pazopanib
Avoid use during and 2 weeks after SPORANOX®
Cobimetiniba
Sunitinib
treatment.
Crizotinib
Trabectedin
Dabrafenib
Trastuzumab-
Dasatinib
emtansine
Docetaxel
Vinca alkaloids
Entrectiniba
Pemigatiniba
Talazopariba
Refer to the entrectinib, pemigatinib and
talazoparib prescribing information for dosing
instructions if concomitant use cannot be avoided.
Glasdegib
Refer to the glasdegib prescribing information for
safety monitoring if concomitant use cannot be
avoided.
Bortezomib
Nintedanib
Brentuximab-
Panobinostat
vedotin
Ponatinib
Busulfan
Ruxolitinib
Erlotinib
Sonidegib
Gefitiniba
Tretinoin (oral)
Idelalisib
Vandetaniba
Imatinib
Ixabepilone
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For idelalisib:
see also Table 2.
Antipsychotics, Anxiolytics and Hypnotics
Alprazolama
Midazolam (IV)a
Aripiprazolea
Quetiapine
Buspironea
Ramelteon
Cariprazine
Risperidonea
Diazepama
Suvorexant
Haloperidola
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Zopiclonea
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Lurasidone
Midazolam (oral)a
Contraindicated during and 2 weeks after
Pimozide
SPORANOX® treatment.
Triazolama
Antivirals
Daclatasvir
Indinavira
Maraviroc
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For indinavir:
see also Table 2.
Cobicistat
Elvitegravir (ritonavir-boosted)
Ombitasvir/Paritaprevir/Ritonavir with or
without Dasabuvir
Monitor for adverse reactions.
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Ritonavir
Saquinavir (unboosted)a
Elbasvir/grazoprevir
Glecaprevir/pibrentasvir
Tenofovir disoproxil fumarate
Not recommended during and 2 weeks after
SPORANOX® treatment.
Monitor for adverse reactions.
Monitor for adverse reactions.
Beta Blockers
Nadolola
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Calcium Channel Blockers
Felodipinea
Nisoldipine
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Diltiazem
Other dihydropyridines
Verapamil
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For diltiazem:
see also Table 2.
Cardiovascular Drugs, Miscellaneous
Ivabradine
Ranolazine
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Aliskirena
Riociguat
Sildenafil (for pulmonary hypertension)
Tadalafil (for pulmonary hypertension)
Not recommended during and 2 weeks after
SPORANOX® treatment. For sildenafil and
tadalafil, see also Urologic Drugs below.
Bosentan
Guanfacine
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Contraceptives*
Dienogest
Ulipristal
Monitor for adverse reactions.
Diuretics
Eplerenone
Finerenone
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Gastrointestinal Drugs
Cisapride
Naloxegol
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Aprepitant
Loperamidea
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Netupitant
Monitor for adverse reactions.
Immunosuppressants
Voclosporin
Contraindicated during and for 2 weeks after
SPORANOX® treatment.
Everolimus
Sirolimus
Temsirolimus (IV)
Not recommended during and 2 weeks after
SPORANOX® treatment.
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Budesonide
(inhalation)a
Budesonide (non-
Fluticasone
inhalation)
(inhalation)a
Ciclesonide
Fluticasone (nasal)
(inhalation)
Methylprednisolonea
Cyclosporine (IV)a
Tacrolimus (IV)a
Cyclosporine (non-
Tacrolimus (oral)
IV)
Dexamethasonea
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Lipid-Lowering Drugs
Lomitapide
Lovastatina
Simvastatina
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Atorvastatina
Monitor for drug adverse reactions. Concomitant
.
drug dose reduction may be necessary.
Respiratory Drugs
Salmeterol
Not recommended during and 2 weeks after
SPORANOX® treatment.
SSRIs, Tricyclics and Related Antidepressants
Venlafaxine
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Urologic Drugs
Avanafil
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Fesoterodine
Patients with moderate to severe renal or hepatic
impairment: Contraindicated during and 2 weeks
after SPORANOX® treatment.
Other patients: Monitor for adverse reactions.
Concomitant drug dose reduction may be
necessary.
Solifenacin
Patients with severe renal or moderate to severe
hepatic impairment: Contraindicated during and
2 weeks after SPORANOX® treatment.
Other patients: Monitor for adverse reactions.
Concomitant drug dose reduction may be
necessary.
Darifenacin
Vardenafil
Not recommended during and 2 weeks after
SPORANOX® treatment.
Dutasteride
Oxybutynina
Sildenafil (for erectile dysfunction)
Tadalafil (for erectile dysfunction and
benign prostatic hyperplasia)
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For sildenafil
and tadalafil, see also Cardiovascular Drugs
above.
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I
I
I
Tolterodine
Miscellaneous Drugs and Other Substances
Colchicine
Patients with renal or hepatic impairment:
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Other patients: Not recommended during and
2 weeks after SPORANOX® treatment.
Eliglustat
CYP2D6 EMsc taking a strong or moderate
CYP2D6 inhibitor, CYP2D6 IMsc, or CYP2D6
PMsc: Contraindicated during and 2 weeks after
SPORANOX® treatment.
CYP2D6 EMsc not taking a strong or moderate
CYP2D6 inhibitor: Monitor for adverse reactions.
Eliglustat dose reduction may be necessary.
Lumacaftor/Ivacaftor
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment.
Alitretinoin (oral)
Cabergoline
Cannabinoids
Cinacalcet
Galantamine
Ivacaftor
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Valbenazine
Concomitant drug dose reduction is necessary.
Refer to the valbenazine prescribing information
for dosing instructions.
Vasopressin Receptor Antagonists
Conivaptan
Tolvaptan
Not recommended during and 2 weeks after
SPORANOX® treatment.
Drug Interactions with SPORANOX® that Decrease Concomitant Drug Concentrations and
May Reduce Efficacy of the Concomitant Drug
Antineoplastics
Regorafenib
Not recommended during and 2 weeks after
SPORANOX® treatment.
Gastrointestinal Drugs
Saccharomyces boulardii
Not recommended during and 2 weeks after
SPORANOX® treatment.
Nonsteroidal Anti-Inflammatory Drugs
Meloxicama
Concomitant drug dose increase may be necessary.
*
CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.
a
Based on clinical drug interaction information with itraconazole.
b
Based on 400 mg bedaquiline once daily for 2 weeks.
c
EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers
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Effect of Other Drugs on SPORANOX®
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this
metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of
itraconazole. Some concomitant drugs have the potential to interact with SPORANOX® resulting
in either increased or sometimes decreased concentrations of SPORANOX®. Increased
concentrations may increase the risk of adverse reactions associated with SPORANOX®.
Decreased concentrations may reduce SPORANOX® efficacy.
The table below lists examples of drugs that may affect itraconazole concentrations, but it is not
a comprehensive list. Refer to the approved product labeling to become familiar with the
interaction pathways, risk potential and specific actions to be taken with regards to each
concomitant drug prior to initiating therapy with SPORANOX®.
Although many of the clinical drug interactions in Table 2 below are based on information with
a similar azole antifungal, ketoconazole, these interactions are expected to occur with
SPORANOX®.
Table 2:
Drug Interactions with Other Drugs that Affect SPORANOX® Concentrations
Examples of Concomitant Drugs Within
Class
Prevention or Management
Drug Interactions with Other Drugs that Increase SPORANOX® Concentrations and May
Increase Risk of Adverse Reactions Associated with SPORANOX®
Antibacterials
Ciprofloxacina
Erythromycina
Clarithromycina
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary.
Antineoplastics
Idelalisib
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary. See also Table 1.
Antivirals
Calcium Channel Blockers
Cobicistat
Darunavir (ritonavir-boosted)
Elvitegravir (ritonavir-boosted)
Monitor for adverse reactions. SPORANOX® dose
Fosamprenavir (ritonavir-boosted)
reduction may be necessary. For Boceprevir,
Indinavira
cobicistat, elvitegravir, indinavir, ombitasvir/
Ombitasvir/ Paritaprevir/ Ritonavir with or
paritaprevir/ ritonavir with or without dasabuvir,
without Dasabuvir
ritonavir and saquinavir, see also Table 1.
Ritonavir
Saquinavir
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Diltiazem
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary. See also the table
above.
Drug Interactions with Other Drugs that Decrease SPORANOX® Concentrations and May
Reduce Efficacy of SPORANOX®
Antibacterials
Isoniazid
Rifampicina
Not recommended 2 weeks before and during
SPORANOX® treatment.
Rifabutina
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 1.
Anticonvulsants
Phenobarbital
Phenytoina
Not recommended 2 weeks before and during
SPORANOX® treatment.
Carbamazepine
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 1.
Antivirals
Efavirenza
Nevirapinea
Not recommended 2 weeks before and during
SPORANOX® treatment.
Miscellaneous Drugs and Other Substances
Lumacaftor/Ivacaftor
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment.
a
Based on clinical drug interaction information with itraconazole.
Pediatric Population
Interaction studies have only been performed in adults.
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Itraconazole
Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for
23 months at dosage levels up to 80 mg/kg/day (approximately 1 time the maximum
recommended human dose [MRHD] of 400 mg/day based on body surface area comparisons).
Male rats treated with 25 mg/kg/day (0.6 times the MRHD based on body surface area
comparisons) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have
been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans,
to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (1.2 times the
MRHD based on body surface area comparisons) had an increased incidence of squamous cell
carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of
squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in
this study was not statistically significant.
20
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Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA
synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and
Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal
mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes,
in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant
lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of
up to 40 mg/kg/day (1 time the MRHD based on body surface area comparisons), even though
parental toxicity was present at this dosage level. More severe signs of parental toxicity,
including death, were present in the next higher dosage level, 160 mg/kg/day (4 times the MRHD
based on body surface area comparisons).
Hydroxypropyl-β-cyclodextrin (HP-β-CD)
Hydroxypropyl-β-cyclodextrin (HP-β-CD) is the solubilizing excipient used in SPORANOX®
Oral Solution.
Hydroxypropyl-β-cyclodextrin (HP-β-CD) was found to produce neoplasms in the large intestine
at 5000 mg/kg/day in rat carcinogenicity study. This dose was about 3 times amount contained
in the recommended clinical dose of SPORANOX® Oral Solution (16 g) based on body surface
area comparisons. The clinical relevance of this finding is unknown. The slightly higher
incidence of adenocarcinomas in the large intestines was linked to the hypertrophic/hyperplastic
and inflammatory changes in the colonic mucosa brought about by HP-β-CD-induced increased
osmotic forces.
In addition, HP-β-CD was found to produce pancreatic exocrine hyperplasia and neoplasia when
administered orally to rats at doses of 500, 2000 or 5000 mg/kg/day for 25 months.
Adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the
untreated group and are not reported in the historical controls. The maximum recommended
clinical dose of SPORANOX® Oral Solution contains approximately 3.3 times the amount of
HP-β-CD as was in the 500 mg/kg/day dose, based on body surface area comparisons. This
finding was not observed in the mouse carcinogenicity study at doses of 500, 2000 or
5000 mg/kg/day for 22-23 months. This finding was also not observed in a 12-month toxicity
study in dogs or in a 2-year toxicity study in female cynomolgus monkeys.
Since the development of the pancreatic tumors may be related to a mitogenic action of
cholecystokinin and since there is no evidence that cholecystokinin has a mitogenic action in
man, the clinical relevance of these findings is unknown.
HP-β-CD has no antifertile effect, and is not mutagenic.
21
Reference ID: 5499269
Pregnancy: Teratogenic Effects:
Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and
teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (1-4 times the MRHD
based on body surface area comparisons), and in mice at dosage levels of approximately
80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has
been shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major
skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.
SPORANOX® Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin (HP-β-CD).
HP-β-CD has no direct embryotoxic and no teratogenic effect.
There are no studies in pregnant women. SPORANOX® should be used in pregnancy only if the
benefit outweighs the potential risk. Highly effective contraception should be continued
throughout SPORANOX® therapy and for 2 months following the end of treatment.
During postmarketing experience, cases of congenital abnormalities have been reported. (See
ADVERSE REACTIONS: Postmarketing Experience.)
Nursing Mothers:
Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX®
therapy for the mother should be weighed against the potential risk from exposure of itraconazole
to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises
HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected
infants.
Pediatric Use:
The efficacy and safety of SPORANOX® have not been established in pediatric patients.
The long-term effects of itraconazole on bone growth in children are unknown. In three
toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as
20 mg/kg/day (0.5 times the MRHD of 400 mg based on body surface area comparisons). The
induced defects included reduced bone plate activity, thinning of the zona compacta of the large
bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (2 times the MRHD based
on body surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on
body surface area comparisons) for 6 months, itraconazole induced small tooth pulp with
hypocellular appearance in some rats.
Geriatric Use:
Clinical studies of SPORANOX® Oral Solution did not include sufficient numbers of subjects
aged 65 years and over to determine whether they respond differently from younger subjects. It
22
Reference ID: 5499269
is advised to use SPORANOX® Oral Solution in these patients only if it is determined that the
potential benefit outweighs the potential risks. In general, it is recommended that the dose
selection for an elderly patient should be taken into consideration, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
drug therapy.
Transient or permanent hearing loss has been reported in elderly patients receiving treatment
with itraconazole. Several of these reports included concurrent administration of quinidine which
is contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS:
Drug Interactions and PRECAUTIONS: Drug Interactions).
Renal Impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment. The
exposure of itraconazole may be lower in some patients with renal impairment. Caution should
be exercised when itraconazole is administered in this patient population and dose adjustment
may be needed. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND
ADMINISTRATION.)
Hepatic Impairment:
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.
Caution should be exercised when this drug is administered in this patient population. It is
recommended that patients with impaired hepatic function be carefully monitored when taking
SPORANOX®. It is recommended that the prolonged elimination half-life of itraconazole
observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be
considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
In patients with elevated or abnormal liver enzymes or active liver disease, or who have
experienced liver toxicity with other drugs, treatment with SPORANOX® is strongly discouraged
unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.
It is recommended that liver function monitoring be done in patients with pre-existing hepatic
function abnormalities or those who have experienced liver toxicity with other medications. (See
CLINICAL
PHARMACOLOGY:
Special
Populations
and
DOSAGE
AND
ADMINISTRATION.)
ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
23
Reference ID: 5499269
SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver
failure and death. Some of these cases had neither pre-existing liver disease nor a serious
underlying medical condition. If clinical signs or symptoms develop that are consistent with liver
disease, treatment should be discontinued and liver function testing performed. The risks and
benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and
PRECAUTIONS: Hepatotoxicity and Information for Patients.)
Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis Trials
U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV
seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. Table 3 below lists
adverse events reported by at least 2% of patients treated with SPORANOX® Oral Solution in U.S.
clinical trials. Data on patients receiving comparator agents in these trials are included for
comparison.
Table 3: Summary of Adverse Events Reported by ≥2% of SPORANOX® Treated Patients in U.S.
Clinical Trials (Total)
Body System/ Adverse
Event
Itraconazole
Total
(n = 350*)
%
All
controlled
studies
(n = 272) %
Fluconazole
(n = 125†) %
Clotrimazole (n = 81‡) %
Gastrointestinal disorders
Nausea
11
10
11
5
Diarrhea
11
10
10
4
Vomiting
7
6
8
1
Abdominal pain
6
4
7
7
Constipation
2
2
1
0
Body as a whole
Fever
7
6
8
5
Chest pain
3
3
2
0
Pain
2
2
4
0
Fatigue
2
1
2
0
Respiratory disorders
Coughing
4
4
10
0
Dyspnea
2
3
5
1
Pneumonia
2
2
0
0
Sinusitis
2
2
4
0
Sputum increased
2
3
3
1
Skin and appendages disorders
Rash
Increased sweating
Skin disorder unspecified
4
3
2
5
4
2
4
6
2
6
1
1
24
Reference ID: 5499269
I
I
I
Central/peripheral nervous system
Headache
Dizziness
4
2
4
2
6
4
6
1
Resistance mechanism disorders
Pneumocystis carinii
infection
2
2
2
0
Psychiatric disorders
Depression
2
1
0
1
* Of the 350 patients, 209 were treated for oropharyngeal candidiasis in controlled studies, 63 were treated for
esophageal candidiasis in controlled studies and 78 were treated for oropharyngeal candidiasis in an open
study.
† Of the 125 patients, 62 were treated for oropharyngeal candidiasis and 63 were treated for esophageal
candidiasis.
‡ All 81 patients were treated for oropharyngeal candidiasis.
Adverse events reported by less than 2% of patients in U.S. clinical trials with SPORANOX®
included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence,
gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection
unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors,
stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal,
and weight decrease. Edema, hypokalemia and menstrual disorders have been reported in clinical
trials with itraconazole capsules.
Adverse Events Reported from Other Clinical Trials
A comparative clinical trial in patients who received intravenous itraconazole followed by
SPORANOX® Oral Solution or received Amphotericin B reported the following adverse events in
the itraconazole intravenous/SPORANOX® Oral Solution treatment arm which are not listed
above in the subsection “Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis
Trials” or listed below as postmarketing reports of adverse drug reactions: serum creatinine
increased,
blood
urea
nitrogen
increased,
renal
function
abnormal,
hypocalcemia,
hypomagnesemia, hypophosphatemia, hypotension, tachycardia and pulmonary infiltration.
In addition, the following adverse drug reactions were reported in patients who participated in
SPORANOX® Oral Solution clinical trials:
Cardiac Disorders: cardiac failure;
General Disorders and Administration Site Conditions: edema;
Hepatobiliary Disorders: hepatic failure, hyperbilirubinemia;
Metabolism and Nutrition Disorders: hypokalemia;
25
Reference ID: 5499269
Reproductive System and Breast Disorders: menstrual disorder
The following is a list of additional adverse drug reactions associated with itraconazole that have
been reported in clinical trials of SPORANOX® Capsules and itraconazole IV excluding the
adverse reaction term “Injection site inflammation” which is specific to the injection route of
administration:
Cardiac Disorders: left ventricular failure;
Gastrointestinal Disorders: gastrointestinal disorder;
General Disorders and Administration Site Conditions: face edema;
Hepatobiliary Disorders: jaundice, hepatic function abnormal;
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood
alkaline
phosphatase
increased,
blood
lactate
dehydrogenase
increased,
gamma
glutamyltransferase increased, urine analysis abnormal;
Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia;
Nervous System Disorders: somnolence;
Psychiatric Disorders: confusional state;
Renal and Urinary Disorders: renal impairment;
Respiratory, Thoracic and Mediastinal Disorders: dysphonia;
Skin and Subcutaneous Tissue Disorders: rash erythematous;
Vascular Disorders: hypertension
In addition, the following adverse drug reaction was reported in children only who participated in
SPORANOX® Oral Solution clinical trials: mucosal inflammation.
Postmarketing Experience
Adverse drug reactions that have been first identified during postmarketing experience with
SPORANOX® (all formulations) are listed in Table 4 below. Because these reactions are reported
voluntarily from a population of uncertain size, reliably estimating their frequency or establishing
a causal relationship to drug exposure is not always possible.
26
Reference ID: 5499269
Table 4:
Postmarketing Reports of Adverse Drug Reactions
Blood and Lymphatic
System Disorders:
Leukopenia, neutropenia, thrombocytopenia
Immune System Disorders:
Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness;
angioneurotic edema
Endocrine Disorders:
Pseudoaldosteronism
Metabolism and Nutrition
Disorders:
Hypertriglyceridemia
Nervous System Disorders:
Peripheral neuropathy, paresthesia, hypoesthesia, tremor
Eye Disorders:
Visual disturbances, including vision blurred and diplopia
Ear and Labyrinth
Disorders:
Transient or permanent hearing loss
Cardiac Disorders:
Congestive heart failure, bradycardia
Respiratory, Thoracic and
Mediastinal Disorders:
Pulmonary edema
Gastrointestinal Disorders:
Pancreatitis
Hepatobiliary Disorders:
Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis,
reversible increases in hepatic enzymes
Skin and Subcutaneous
Tissue Disorders:
Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized
exanthematous pustulosis, erythema multiforme, exfoliative dermatitis,
leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria
Musculoskeletal and
Connective Tissue
Disorders:
Arthralgia
Renal and Urinary
Disorders:
Urinary incontinence, pollakiuria
Reproductive System and
Breast Disorders:
Erectile dysfunction
General Disorders and
Administration Site
Conditions:
Peripheral edema
Investigations:
Blood creatine phosphokinase increased
There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital
abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic
malformations as well as chromosomal and multiple malformations have been reported during
postmarketing experience. A causal relationship with SPORANOX® has not been established. (See
CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS,
and PRECAUTIONS: Drug Interactions for more information.)
OVERDOSAGE
Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures
should be employed. Contact a certified poison control center for the most up to date information
27
Reference ID: 5499269
on the management of SPORANOX® (itraconazole) Oral Solution overdosage (1-800-222-1222
or www.poison.org). In general, adverse events reported with overdose have been consistent with
adverse drug reactions already listed in this package insert for itraconazole. (See ADVERSE
REACTIONS.)
DOSAGE AND ADMINISTRATION
Treatment of Oropharyngeal and Esophageal Candidiasis:
The solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and
swallowed.
The recommended dosage of SPORANOX® (itraconazole) Oral Solution for oropharyngeal
candidiasis is 200 mg (20 mL) daily for 1 to 2 weeks. Clinical signs and symptoms of
oropharyngeal candidiasis generally resolve within several days.
For patients with oropharyngeal candidiasis unresponsive/refractory to treatment with fluconazole
tablets, the recommended dose is 100 mg (10 mL) b.i.d. For patients responding to therapy, clinical
response will be seen in 2 to 4 weeks. Patients may be expected to relapse shortly after
discontinuing therapy. Limited data on the safety of long-term use (>6 months) of SPORANOX®
Oral Solution are available at this time.
The recommended dosage of SPORANOX® Oral Solution for esophageal candidiasis is 100 mg
(10 mL) daily for a minimum treatment of three weeks. Treatment should continue for 2 weeks
following resolution of symptoms. Doses up to 200 mg (20 mL) per day may be used based on
medical judgment of the patient’s response to therapy.
SPORANOX® Oral Solution and SPORANOX® Capsules should not be used interchangeably.
Patients should be instructed to take SPORANOX® Oral Solution without food, if possible. Only
SPORANOX® Oral Solution has been demonstrated effective for oral and/or esophageal
candidiasis.
Use in Patients with Renal Impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution
should be exercised when this drug is administered in this patient population. (See CLINICAL
PHARMACOLOGY: Special Populations and PRECAUTIONS.)
Use in Patients with Hepatic Impairment:
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.
Caution should be exercised when this drug is administered in this patient population. (See
CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.)
28
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HOW SUPPLIED
SPORANOX® (itraconazole) Oral Solution is available in 150 mL amber glass bottles (NDC
50458-295-15) containing 10 mg of itraconazole per mL.
Store at or below 25°C (77°F). Do not freeze.
Revised: 12/2024
For patent information: www.janssenpatents.com
© 2024 Janssen Pharmaceutical Companies
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560, USA
29
Reference ID: 5499269
| custom-source | 2025-02-12T15:48:00.481809 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020657s043lbl.pdf', 'application_number': 20657, 'submission_type': 'SUPPL ', 'submission_number': 43} |
80,681 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AZACITIDINE FOR INJECTION safely and effectively. See full
prescribing information for AZACITIDINE FOR INJECTION.
AZACITIDINE for injection, for subcutaneous or intravenous use
Initial U.S. Approval: 2004
----------------------------INDICATIONS AND USAGE--------------------------
Azacitidine for Injection is a nucleoside metabolic inhibitor indicated for the
treatment of adult patients with the following FAB myelodysplastic syndrome
(MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed
sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or
requiring transfusions), refractory anemia with excess blasts (RAEB),
refractory anemia with excess blasts in transformation (RAEB-T), and chronic
myelomonocytic leukemia (CMMoL) (1).
----------------------DOSAGE AND ADMINISTRATION---------------------
•
Do not substitute Azacitidine for Injection for oral azacitidine. The
indications and dosing regimen for Azacitidine for Injection differ
from that of oral azacitidine (2.1, 5.1).
•
The recommended starting dosage for the first treatment cycle, for all
patients regardless of baseline hematology values, is Azacitidine for
Injection 75 mg/m2 daily for 7 days to be administered by subcutaneous
injection or intravenous infusion. See full prescribing information for
schedule for subsequent cycles. Premedicate for nausea and vomiting
(2.2).
•
Continue treatment as long as the patient continues to benefit (2.3).
•
Monitor all patients for hematologic response and for renal toxicity;
delay or reduce dosage as appropriate (2.4, 2.5, 2.6).
---------------------DOSAGE FORMS AND STRENGTHS--------------------
For Injection: 100 mg as a lyophilized powder in single-dose vial for
reconstitution (3).
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Myelodysplastic Syndromes (MDS)
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Information
2.2 First Treatment Cycle for Adults
2.3 Subsequent Treatment Cycles for Adults
2.4 Dosage Adjustment Based on Hematology Laboratory Values
2.5 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity
2.6 Use in Geriatric Patients
2.7 Preparation of Azacitidine for Injection
2.8 Instructions for Subcutaneous Administration
2.9 Instructions for Intravenous Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risks of Substitution with Other Azacitidine Products
5.2 Anemia, Neutropenia and Thrombocytopenia
5.3 Hepatic Toxicity in Patients with Severe Pre-existing Hepatic
Impairment
5.4 Renal Toxicity
5.5 Tumor Lysis Syndrome
5.6 Embryo-Fetal Toxicity
-------------------------------CONTRAINDICATIONS----------------------------
•
Advanced malignant hepatic tumors (4).
•
Hypersensitivity to azacitidine (4).
-----------------------WARNINGS AND PRECAUTIONS----------------------
•
Risks of Substitution with Other Azacitidine Products: Do not substitute
Azacitidine for Injection for oral azacitidine (2.1, 5.1).
•
Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood
counts (CBC) frequently (5.2).
•
Hepatotoxicity: Patients with severe preexisting hepatic impairment are
at higher risk for toxicity (5.3).
•
Renal Toxicity: Monitor patients with renal impairment for toxicity
since azacitidine and its metabolites are primarily excreted by the
kidneys (5.4).
•
Tumor Lysis Syndrome: Azacitidine for Injection may cause fatal or
serious tumor lysis syndrome, including in patients with MDS. Assess
baseline risk and monitor and treat as appropriate (5.5).
•
Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of
reproductive potential of the potential risk to a fetus and to use effective
contraception (5.6, 8.1, 8.3).
------------------------------ADVERSE REACTIONS-----------------------------
Most common adverse reactions (>30%) in adult patients with MDS by
subcutaneous route are: nausea, anemia, thrombocytopenia, vomiting, pyrexia,
leukopenia, diarrhea, injection site erythema, constipation, neutropenia and
ecchymosis. Most common adverse reactions by intravenous route also
included petechiae, rigors, weakness and hypokalemia (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Actavis at
1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS----------------------
Lactation: Advise not to breastfeed (8.2).
See 17 for PATIENT COUNSELING INFORMATION.
Pediatric use information is approved for Celgene Corporation’s Vidaza®
(azacitidine for injection). However due to Celgene Corporation’s marketing
exclusivity rights, this drug product is not labeled with that information.
Revised: 12/2024
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5499547
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Myelodysplastic Syndromes (MDS)
Azacitidine for Injection is indicated for treatment of adult patients with the following French-American-British
(FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed
sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia
with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic
myelomonocytic leukemia (CMMoL).
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Information
Do not substitute Azacitidine for Injection for oral azacitidine. The indications and dosing regimen for
Azacitidine for Injection differ from that of oral azacitidine [see Warnings and Precautions (5.1)].
2.2 First Treatment Cycle for Adults
The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology
laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days.
Premedicate patients for nausea and vomiting.
Obtain complete blood counts, liver chemistries and serum creatinine prior to the first dose.
2.3 Subsequent Treatment Cycles for Adults
Repeat cycles every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after 2
treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients
be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional
treatment cycles. Treatment may be continued as long as the patient continues to benefit.
Monitor patients for hematologic response and renal toxicities [see Warnings and Precautions (5.4)] and delay
or reduce dosage if necessary as described below.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
2.4 Dosage Adjustment Based on Hematology Laboratory Values
• For adult patients with baseline (start of treatment) WBC greater than or equal to 3 x109/L, ANC greater
than or equal to 1.5 x109/L, and platelets greater than or equal to 75 x109/L, adjust the dose as follows,
based on nadir counts for any given cycle:
Nadir Counts
% Dose in the Next
Course
ANC (x109/L)
Less than 0.5
Platelets (x109/L)
Less than 25
50%
Reference ID: 5499547
0.5 to 1.5
25 to 50
67%
Greater than 1.5
Greater than 50
100%
• For adult patients whose baseline counts are WBC less than 3 x109/L, ANC less than 1.5 x109/L, or
platelets less than 75 x109/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity
at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage
of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next
cycle, in which case continue the current dose.
WBC or Platelet
Nadir
% decrease in
Bone Marrow
Biopsy Cellularity at Time of Nadir
(%)
counts from baseline
30 to 60
15 to 30
Less than 15
% Dose in the Next Course
50 to 75
100
50
33
Greater than 75
75
50
33
If a nadir as defined in the table above has occurred, give the next course 28 days after the start of the preceding
course, provided that both the WBC and the platelet counts are greater than 25% above the nadir and rising. If a
greater than 25% increase above the nadir is not seen by day 28, reassess counts every 7 days. If a 25% increase
is not seen by day 42, reduce the scheduled dose by 50%.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
2.5 Dosage Adjustment Based on Serum Electrolytes and Renal Toxicity
If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, reduce the dosage by 50%
for the next course.
If unexplained elevations of BUN or serum creatinine occur, delay the next cycle until values return to normal
or baseline and reduce the dose by 50% for the next course [see Warnings and Precautions (5.4)].
2.6 Use in Geriatric Patients
Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more
likely to have decreased renal function, select the dose carefully and monitor renal function [see Warnings and
Precautions (5.4) and Use in Specific Populations (8.5)].
2.7 Preparation of Azacitidine for Injection
Azacitidine for Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1
The Azacitidine for Injection vial is single-dose and does not contain any preservatives. Discard unused
portions of each vial properly [see How Supplied/Storage and Handling (16)]. Do not save any unused portions
for later administration.
2.8 Instructions for Subcutaneous Administration
Reference ID: 5499547
Reconstitute Azacitidine for Injection aseptically with 4 mL Sterile Water for Injection to obtain a concentration
of 25 mg/mL. Inject the diluent slowly into the vial. Vigorously shake or roll the vial until a uniform suspension
is achieved. The suspension will be cloudy. Do not filter the suspension after reconstitution. Doing so could
remove the active substance.
Preparation for Immediate Subcutaneous Administration
For doses requiring more than 1 vial, divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2
syringes with 3 mL in each syringe) and inject into two separate sites. Due to retention in the vial and needle, it
may not be feasible to withdraw all of the suspension from the vial. The product may be held at room
temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.
Preparation for Delayed Subcutaneous Administration
The reconstituted product may be kept in the vial or drawn into a syringe. For doses requiring more than 1 vial,
divide the dose equally between the syringes (e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe)
and inject into two separate sites. Due to retention in the vial and needle, it may not be feasible to withdraw all
of the suspension from the vial. The product must be refrigerated immediately.
When Azacitidine for Injection is reconstituted using Sterile Water for Injection that has not been refrigerated,
the reconstituted product may be held under refrigerated conditions (2°C to 8°C, 36°F to 46°F) for up to 12
hours.
When Azacitidine for Injection is reconstituted using refrigerated (2°C to 8°C, 36°F to 46°F) Sterile Water for
Injection, the reconstituted product may be stored under refrigerated conditions (2°C to 8°C, 36°F to 46°F) for
up to 30 hours.
After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature
for up to 30 minutes prior to administration.
Subcutaneous Administration
To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately
prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy
suspension is achieved.
Azacitidine for Injection suspension is administered subcutaneously. Doses greater than 4 mL should be divided
equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or
upper arm). New injections should be given at least one inch from an old site and never into areas where the site
is tender, bruised, red, or hard.
Suspension Stability
Azacitidine for Injection reconstituted with non-refrigerated Sterile Water for Injection for subcutaneous
administration may be stored for up to 2 hours at 25°C (77°F) or for up to 12 hours between 2°C and 8°C (36°F
and 46°F).
When reconstituted with refrigerated (2°C to 8°C, 36°F to 46°F) Sterile Water for Injection, it may be stored for
30 hours between 2°C and 8°C (36°F and 46°F).
2.9 Instructions for Intravenous Administration
Reconstitute the appropriate number of Azacitidine for Injection vials to achieve the desired dose. Reconstitute
each vial with 10 mL Sterile Water for Injection. Vigorously shake or roll the vial until all solids are dissolved.
Reference ID: 5499547
The resulting solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product
should be inspected visually for particulate matter and discoloration prior to administration, whenever solution
and container permit.
Withdraw the required amount of Azacitidine for Injection solution to deliver the desired dose and inject into a
50 to 100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection.
Intravenous Solution Incompatibility
Azacitidine for Injection is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain
bicarbonate. These solutions have the potential to increase the rate of degradation of Azacitidine for Injection
and should therefore be avoided.
Intravenous Administration
Azacitidine for Injection solution is administered intravenously. Administer the total dose over a period of 10 to
40 minutes. The administration must be completed within 1 hour of reconstitution of the Azacitidine for
Injection vial.
Solution Stability
Azacitidine for Injection reconstituted for intravenous administration may be stored at 25°C (77°F), but
administration must be completed within 1 hour of reconstitution.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
3 DOSAGE FORMS AND STRENGTHS
For injection: 100 mg as a lyophilized powder in single-dose vial for reconstitution.
4 CONTRAINDICATIONS
Azacitidine for Injection is contraindicated in patients with
• advanced malignant hepatic tumors [see Warnings and Precautions (5.3)].
• a known hypersensitivity to azacitidine.
5 WARNINGS AND PRECAUTIONS
5.1 Risks of Substitution with Other Azacitidine Products
Due to substantial differences in the pharmacokinetic parameters [see Clinical Pharmacology (12.3)], the
recommended dose and schedule for Azacitidine for Injection are different from those of oral azacitidine
products. Treatment of patients using Azacitidine for Injection at the recommended dosage of oral azacitidine
may result in a fatal adverse reaction. Treatment of patients using oral azacitidine at the doses recommended for
Azacitidine for Injection may not be effective.
Do not substitute Azacitidine for Injection for oral azacitidine [see Dosage and Administration (2.1)].
5.2 Anemia, Neutropenia and Thrombocytopenia
Azacitidine for Injection causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts
frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the
recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and
hematologic response [see Dosage and Administration (2.4)].
Reference ID: 5499547
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
5.3 Hepatic Toxicity in Patients with Severe Pre-existing Hepatic Impairment
Because Azacitidine for Injection is potentially hepatotoxic in patients with severe pre-existing hepatic
impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to
metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine
treatment, especially in such patients with baseline albumin less than 30 g/L.
Azacitidine for Injection is contraindicated in patients with advanced malignant hepatic tumors [see
Contraindications (4)]. Monitor liver chemistries prior to initiation of therapy and with each cycle.
Safety and effectiveness of Azacitidine for Injection in patients with MDS and hepatic impairment have not
been studied as these patients were excluded from the clinical trials.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
5.4 Renal Toxicity
Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients
treated with intravenous azacitidine in combination with other chemotherapeutic agents for non-MDS
conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to less than 20 mEq/L in
association with an alkaline urine and hypokalemia (serum potassium less than 3 mEq/L) developed in 5
patients with CML (an unapproved use) treated with azacitidine and etoposide.
Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained
reductions in serum bicarbonate less than 20 mEq/L or elevations of BUN or serum creatinine occur, reduce or
hold the dose [see Dosage and Administration (2.5)].
Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites
are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity [see Dosage and
Administration (2.5, 2.6)]. Patients with MDS and renal impairment were excluded from the clinical studies.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
5.5 Tumor Lysis Syndrome
Azacitidine for Injection may cause fatal or serious tumor lysis syndrome, including in patients with MDS.
Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and
treat as appropriate.
5.6 Embryo-Fetal Toxicity
Based on the mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when
administered to a pregnant woman. In animal studies, azacitidine caused adverse developmental outcomes when
administered to mice and rats at doses of 3 to 12 mg/m2 and 6 mg/m2 (approximately 4% to 16% and 8%) of the
recommended human daily dose of 75 mg/m2, respectively.
Reference ID: 5499547
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with Azacitidine for Injection and for 6 months following the last dose. Advise
males with female partners of reproductive potential to use effective contraception during treatment with
Azacitidine for Injection and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in labeling:
• Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.2)]
• Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions
(5.3)]
• Renal Toxicity [see Warnings and Precautions (5.4)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The data described below reflect exposure to azacitidine in 443 MDS patients from 4 clinical studies. Study 1
was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies
(one with subcutaneous administration and one with intravenous administration), and Study 4 was an
international randomized trial (subcutaneous administration) [see Clinical Studies (14)].
In Studies 1, 2 and 3, a total of 268 patients were exposed to azacitidine, including 116 exposed for 6 cycles
(approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year).
Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118,
respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years),
68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81
years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between
50 and 100 mg/m2.
In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed
to azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean
age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most
patients received daily azacitidine doses of 75 mg/m2.
Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route) in Adult Patients with
MDS: nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema,
constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included
petechiae, rigors, weakness and hypokalemia.
Adverse Reactions Most Frequently (Greater Than 2%) Resulting in Clinical Intervention (Subcutaneous or
Intravenous Route) in Adult Patients with MDS:
Discontinuation: leukopenia, thrombocytopenia, neutropenia.
Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
Dose Reduced: leukopenia, neutropenia, thrombocytopenia.
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Table 1 presents adverse reactions occurring in at least 5% of patients treated with azacitidine (subcutaneous) in
Studies 1 and 2. It is important to note that duration of exposure was longer for the azacitidine-treated group
than for the observation group; patients received azacitidine for a mean of 11.4 months while mean time in the
observation arm was 6.1 months.
Table 1: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in All
Subcutaneous Azacitidine-Treated Patients; Studies 1 and 2)
Number (%) of Patients
Body System
Adverse Reactiona
All Azacitidineb
(N=220)
Observationc
(N=92)
Blood and lymphatic system disorders
Anemia
153 (70)
59 (64)
Anemia aggravated
12 (6)
5 (5)
Febrile neutropenia
36 (16)
4 (4)
Leukopenia
106 (48)
27 (29)
Neutropenia
71 (32)
10 (11)
Thrombocytopenia
144 (66)
42 (46)
Gastrointestinal disorders
Abdominal tenderness
26 (12)
1 (1)
Constipation
74 (34)
6 (7)
Diarrhea
80 (36)
13 (14)
Gingival bleeding
21 (10)
4 (4)
Loose stools
12 (6)
0
Mouth hemorrhage
11 (5)
1 (1)
Nausea
155 (71)
16 (17)
Stomatitis
17 (8)
0
Vomiting
119 (54)
5 (5)
General disorders and administration site conditions
Chest pain
36 (16)
5 (5)
Injection site bruising
31 (14)
0
Injection site erythema
77 (35)
0
Injection site granuloma
11 (5)
0
Injection site pain
50 (23)
0
Injection site pigmentation changes
11 (5)
0
Injection site pruritus
15 (7)
0
Injection site reaction
30 (14)
0
Injection site swelling
11 (5)
0
Lethargy
17 (8)
2 (2)
Malaise
24 (11)
1 (1)
Pyrexia
114 (52)
28 (30)
Infections and infestations
Nasopharyngitis
32 (15)
3 (3)
Pneumonia
24 (11)
5 (5)
Upper respiratory tract infection
28 (13)
4 (4)
Injury, poisoning, and procedural complications
Post procedural hemorrhage
13 (6)
1 (1)
Metabolism and nutrition disorders
Anorexia
45 (21)
6 (7)
Musculoskeletal and connective tissue disorders
Arthralgia
49 (22)
3 (3)
Chest wall pain
11 (5)
0
Myalgia
35 (16)
2 (2)
Nervous system disorders
Dizziness
41 (19)
5 (5)
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Headache
48 (22)
10 (11)
Psychiatric disorders
Anxiety
29 (13)
3 (3)
Insomnia
24 (11)
4 (4)
Respiratory, thoracic and mediastinal disorders
Dyspnea
64 (29)
11 (12)
Skin and subcutaneous tissue disorders
Dry skin
11 (5)
1 (1)
Ecchymosis
67 (31)
14 (15)
Erythema
37 (17)
4 (4)
Rash
31 (14)
9 (10)
Skin nodule
11 (5)
1 (1)
Urticaria
13 (6)
1 (1)
Vascular disorders
Hematoma
19 (9)
0
Hypotension
15 (7)
2 (2)
Petechiae
52 (24)
8 (9)
a Multiple terms of the same preferred terms for a patient are only counted once within each
treatment group.
b Includes adverse reactions from all patients exposed to azacitidine, including
patients after crossing over from observations.
c Includes adverse reactions from observation period only; excludes any adverse events after
crossover to azacitidine.
Table 2 presents adverse reactions occurring in at least 5% of patients treated with azacitidine in Study 4.
Similar to Studies 1 and 2 described above, duration of exposure to treatment with azacitidine was longer (mean
12.2 months) compared with best supportive care (mean 7.5 months).
Table 2: Most Frequently Observed Adverse Reactions (Greater Than or Equal To 5% in the
Azacitidine-Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4)
Number (%) of Patients
Any Grade
Grade 3/4
Body System
Adverse Reactionsa
Azacitidine
(N=175)
Best
Supportive
Care Only
(N=102)
Azacitidine
(N=175)
Best
Supportive
Care Only
(N=102)
Blood and lymphatic system disorders
Anemia
90 (51)
45 (44)
24 (14)
9 (9)
Febrile neutropenia
24 (14)
10 (10)
22 (13)
7 (7)
Leukopenia
32 (18)
2 (2)
26 (15)
1 (1)
Neutropenia
115 (66)
29 (28)
107 (61)
22 (22)
Thrombocytopenia
122 (70)
35 (34)
102 (58)
29 (28)
Gastrointestinal disorders
Abdominal pain
22 (13)
7 (7)
7 (4)
0
Constipation
88 (50)
8 (8)
2 (1)
0
Dyspepsia
10 (6)
2 (2)
0
0
Nausea
84 (48)
12 (12)
3 (2)
0
Vomiting
47 (27)
7 (7)
0
0
General disorders and administration
site conditions
Fatigue
42 (24)
12 (12)
6 (3)
2 (2)
Injection site bruising
9 (5)
0
0
0
Injection site erythema
75 (43)
0
0
0
Injection site hematoma
11 (6)
0
0
0
Injection site induration
9 (5)
0
0
0
Reference ID: 5499547
Injection site pain
33 (19)
0
0
0
Injection site rash
10 (6)
0
0
0
Injection site reaction
51 (29)
0
1 (1)
0
Pyrexia
53 (30)
18 (18)
8 (5)
1 (1)
Infections and infestations
Rhinitis
10 (6)
1 (1)
0
0
Upper respiratory tract infection
16 (9)
4 (4)
3 (2)
0
Urinary tract infection
15 (9)
3 (3)
3 (2)
0
Investigations
Weight decreased
14 (8)
0
1 (1)
0
Metabolism and nutrition disorders
Hypokalemia
11 (6)
3 (3)
3 (2)
3 (3)
Nervous system disorders
Lethargy
13 (7)
2 (2)
0
1 (1)
Psychiatric disorders
Anxiety
9 (5)
1 (1)
0
0
Insomnia
15 (9)
3 (3)
0
0
Renal and urinary disorders
Hematuria
11 (6)
2 (2)
4 (2)
1 (1)
Respiratory, thoracic and mediastinal
disorders
Dyspnea
26 (15)
5 (5)
6 (3)
2 (2)
Dyspnea exertional
9 (5)
1 (1)
0
0
Pharyngolaryngeal pain
11 (6)
3 (3)
0
0
Skin and subcutaneous tissue disorders
Erythema
13 (7)
3 (3)
0
0
Petechiae
20 (11)
4 (4)
2 (1)
0
Pruritus
21 (12)
2 (2)
0
0
Rash
18 (10)
1 (1)
0
0
Vascular disorders
Hypertension
15 (9)
4 (4)
2 (1)
2 (2)
a Multiple reports of the same preferred term from a patient were only counted once within each treatment.
In Studies 1, 2 and 4 with subcutaneous administration of azacitidine, adverse reactions of neutropenia,
thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended
to increase in incidence with higher doses of azacitidine. Adverse reactions that tended to be more pronounced
during the first 1 to 2 cycles of subcutaneous treatment compared with later cycles included thrombocytopenia,
neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae,
dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased
in frequency over the course of treatment.
Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies.
Adverse reactions that appeared to be specifically associated with the intravenous route of administration
included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or
hemorrhage).
In clinical studies of either subcutaneous or intravenous azacitidine, the following serious adverse reactions
occurring at a rate of less than 5% (and not described in Tables 1 or 2) were reported:
Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly.
Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest,
congestive cardiomyopathy.
Reference ID: 5499547
Eye disorders: eye hemorrhage
Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.
General disorders and administration site conditions: catheter site hemorrhage, general physical health
deterioration, systemic inflammatory response syndrome.
Hepatobiliary disorders: cholecystitis.
Immune system disorders: anaphylactic shock, hypersensitivity.
Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection,
Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock,
Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.
Metabolism and nutrition disorders: dehydration.
Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain.
Neoplasms benign, malignant and unspecified: leukemia cutis.
Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage.
Renal and urinary disorders: loin pain, renal failure.
Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress.
Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration.
Surgical and medical procedures: cholecystectomy.
Vascular disorders: orthostatic hypotension.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of azacitidine. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
• Interstitial lung disease
• Tumor lysis syndrome
• Injection site necrosis
• Sweet’s syndrome (acute febrile neutrophilic dermatosis)
• Necrotizing fasciitis (including fatal cases)
• Differentiation syndrome
Reference ID: 5499547
• Pericardial effusion
• Pericarditis
• Cutaneous vasculitis
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when
administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no data on the use of
azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at
doses lower than the recommended human daily dose (see Data). Advise pregnant women of the potential risk
to the fetus.
The estimated background risk of major birth defects and miscarriage in the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased
resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended
human daily dose on a mg/m2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain
have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3 to 12 mg/m2
(approximately 4% to 16% the recommended human daily dose on a mg/m2 basis).
In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 to 8 (postimplantation) at a dose
of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in
the preimplantation period (on gestation days 1 to 3) had no adverse effect on the embryos. Azacitidine caused
multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended
human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal
death when administered at 3 to 12 mg/m2 on gestation days 9 and 10; average live animals per litter was
reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies
(exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others
(micrognathia, gastroschisis, edema, and rib abnormalities).
8.2 Lactation
Risk Summary
There is no information on the presence of azacitidine or its metabolites in human milk, the effects on a breast
fed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the
potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology (13.1)] and the
potential for serious adverse reactions in a breastfeed child, advise women not to breastfeed during treatment
with Azacitidine for Injection and for 1 week after the last dose.
8.3 Females and Males of Reproductive Potential
Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when
administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Reference ID: 5499547
Verify the pregnancy status of females of reproductive potential prior to initiating Azacitidine for Injection.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for
Injection and for 6 months after the last dose [see Use in Specific Populations (8.1) and Clinical Pharmacology
(12.3)].
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective
contraception during treatment with Azacitidine for Injection and for 3 months after the last dose [see
Nonclinical Toxicology (13.1)].
Infertility
Based on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology
(13.1)].
8.4 Pediatric Use
Safety and effectiveness of Azacitidine for Injection in pediatric patients with MDS have not been established.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
8.5 Geriatric Use
Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and
older. No overall differences in effectiveness were observed between these patients and younger patients. In
addition, there were no relevant differences in the frequency of adverse reactions observed in patients 65 years
and older compared to younger patients.
Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years
and older. Survival data for patients 65 years and older were consistent with overall survival results. The
majority of adverse reactions occurred at similar frequencies in patients less than 65 years of age and patients 65
years of age and older.
Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see
Dosage and Administration (2.6) and Warnings and Precautions (5.4)].
10 OVERDOSAGE
One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea,
nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2, almost 4 times the
recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the
following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and
should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine for
Injection overdosage.
11 DESCRIPTION
Azacitidine is a nucleoside metabolic inhibitor. The molecular formula is C8H12N4O5. The molecular weight is
244. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:
Reference ID: 5499547
HO
OH
OH
Azacitidine is a white to almost white powder. Azacitidine was found to be insoluble in acetone, ethanol, and
methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol;
sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal
saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).
Azacitidine for Injection is supplied in a sterile form for reconstitution as a suspension for subcutaneous
injection or reconstitution as a solution with further dilution for intravenous infusion. Each vial of Azacitidine
for Injection contains 100 mg of azacitidine, 170 mg sucrose, monosodium phosphate monohydrate and
disodium hydrogen phosphate, dihydrate as a sterile lyophilized powder.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic
effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone
marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does
not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are
critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly
dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-
proliferating cells are relatively insensitive to azacitidine.
12.2 Pharmacodynamics
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
12.3 Pharmacokinetics
The area under the curve (AUC) and peak concentration (Cmax) of subcutaneous administration of azacitidine in
patients with cancer were approximately dose proportional within the dose range of 25 mg/m2 (0.33 times the
lowest approved recommended dosage) to 100 mg/m2 (the maximum approved recommended dosage). The
mean and standard deviation (SD) of Cmax was 750 ± 403 ng/mL after a single subcutaneous administration of
75 mg/m2 azacitidine. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
Absorption
Reference ID: 5499547
Azacitidine is rapidly absorbed after subcutaneous administration with a median time to Cmax (Tmax) of 0.5 hour.
The bioavailability of subcutaneous azacitidine relative to intravenous azacitidine is approximately 89%, based
on AUC.
Distribution
Mean volume of distribution following intravenous dosing is 76 ± 26 L.
Elimination
Mean apparent subcutaneous clearance is 167 ± 49 L/hour and mean half-life after subcutaneous administration
is 41 ± 8 minutes.
Excretion
Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its
metabolites. Following intravenous administration of radioactive azacitidine to 5 cancer patients, the cumulative
urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for less than 1% of administered
radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous administration of
14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites)
were similar after intravenous and subcutaneous administrations, about 4 hours.
Specific Populations
The effects of hepatic impairment, gender, or race/ethnicity on the pharmacokinetics of intravenous and
subcutaneous azacitidine have not been studied.
Pediatric Patients
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
Patients with Renal Impairment
In adult patients with cancer, the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr >80
mL/min) and 6 patients with severe renal impairment (CLcr <30 mL/min) were compared following daily
subcutaneous dosing (Days 1 through 5) at 75 mg/m
2/day. Severe renal impairment increased azacitidine exposure by
approximately 70% after single and 41% after multiple subcutaneous administrations.). This increase in exposure
was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with
normal renal function receiving 100 mg/m2 .
Drug Interaction Studies
No formal clinical drug interaction studies with azacitidine have been conducted.
In vitro Studies
Cytochrome P450 (CYP) Enzymes: An in vitro study at azacitidine concentrations up to 100 μM (IV Cmax = 10.6
μM) in human liver microsomes indicated that azacitidine does not cause any inhibition of CYP isoforms CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1 at clinically achievable concentrations.
In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of
1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5.
Reference ID: 5499547
Transporter Systems: An in vitro study with LLC-PK1 cells expressing P-glycoprotein (P-gp) indicated that
azacitidine is not a substrate or inhibitor of P-gp.
Azacitidine does not inhibit, breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and
OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter
(OCT) OCT2 at clinically relevant concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the
hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human
daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks. An increased incidence of
tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine
IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a
week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20%
to 80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular
tumors compared with controls.
The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella
typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P,
WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human
lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster
embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of
azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo
cells.
Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily
dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased
fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3
times per week for 11 or 16 weeks at doses of 15 to 30 mg/m2 (approximately 20% to 40%, the recommended
human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased
sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a
related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated
females when examined on day 2 of gestation.
14 CLINICAL STUDIES
Myelodysplastic Syndromes (MDS)
Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites that compared the safety and
efficacy of subcutaneous azacitidine plus supportive care with supportive care alone (“observation”) in adult
patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA
with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and
chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of
the following criteria: required packed RBC transfusions; had platelet counts less than or equal to 50 x 109/L;
required platelet transfusions; or were neutropenic (ANC less than 1 x 109/L) with infections requiring
treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included.
Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics
and antipyretics. The use of hematopoietic growth factors was prohibited. Baseline patient and disease
characteristics are summarized in Table 3; the 2 groups were similar.
Reference ID: 5499547
Azacitidine was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days every 4 weeks. The dose was
increased to 100 mg/m2 if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or
delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were
allowed by protocol to cross over to azacitidine if they had increases in bone marrow blasts, decreases in
hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a
platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of
assessing efficacy, the primary endpoint was response rate (as defined in Table 4).
Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the
diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate,
although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55%
of the patients randomized to observation crossed over to receive azacitidine treatment.
Table 3. Baseline Demographics and Disease Characteristics
Azacitidine
(N=99)
Observation
(N=92)
Gender (n%)
Male
72 (72.7)
60 (65.2)
Female
27 (27.3)
32 (34.8)
Race (n%)
White
93 (93.9)
85 (92.4)
Black
1 (1.0)
1 (1.1)
Hispanic
3 (3.0)
5 (5.4)
Asian/Oriental
2 (2.0)
1 (1.1)
Age (years)
N
99
91
Mean ± SD
67.3 ± 10.39
68.0 ± 10.23
Range
31 to 92
35 to 88
Adjudicated MDS diagnosis at study
entry (n%)
RA
21 (21.2)
18 (19.6)
RARS
6 (6.1)
5 (5.4)
RAEB
38 (38.4)
39 (42.4)
RAEB-T
16 (16.2)
14 (15.2)
CMMoL
8 (8.1)
7 (7.6)
AML
10 (10.1)
9 (9.8)
Transfusion product used in 3
months before study entry (n%)
Any transfusion product
70 (70.7)
59 (64.1)
Blood cells, packed human
66 (66.7)
55 (59.8)
Platelets, human blood
15 (15.2)
12 (13.0)
Hetastarch
0(0.0)
1(1.1)
Plasma protein fraction
1(1.0)
0(0.0)
Other
2(2.0)
2(2.2)
Table 4. Response Criteria
RA
RARS
RAEB
RAEB-T
CMMoL
Complete
Response
Marrow
<5% blasts
Peripheral
Blood
Normal CBC if abnormal at baseline
Absence of blasts in the peripheral circulation
Reference ID: 5499547
I
(CR), duration
≥4 weeks
Partial
Response
(PR), duration
≥4 weeks
Marrow
No marrow requirements
≥50% decrease in blasts
Improvement of marrow dyspoiesis
Peripheral
Blood
≥50% restoration in the deficit from normal levels of baseline white cells,
hemoglobin and platelets if abnormal at baseline
No blasts in the peripheral circulation
For CMMoL, if WBC is elevated at baseline, a ≥75% reduction in the excess
count over the upper limit of normal
The overall response rate (CR + PR) of 15.7% in azacitidine-treated patients without AML (16.2% for all
azacitidine randomized patients including AML) was statistically significantly higher than the response rate of
0% in the observation group (p<0.0001) (Table 5). The majority of patients who achieved either CR or PR had
either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were
transfusion dependent at baseline. Patients responding to azacitidine had a decrease in bone marrow blasts
percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially
demonstrated these changes by the 5th treatment cycle. All patients who had been transfusion dependent became
transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better
was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at
completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated
baseline diagnosis of AML.
Table 5. Response Rates
Azacitidine
(N=89)
Observation Before
Crossover
(N=83)
Response
n (%)
n (%)
P value
Overall (CR+PR)
14 (15.7)
0 (0.0)
(<0.0001)
Complete (CR)
5 (5.6)
0 (0.0)
(0.06)
Partial (PR)
9 (10.1)
0 (0.0)
-
Patients in the observation group who crossed over to receive azacitidine treatment (47 patients) had a response
rate of 12.8%.
Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML
was also carried out. Treatment with subcutaneous azacitidine resulted in a response rate (CR + PR) of 13.9%,
using criteria similar to those described above. The mean and median duration of clinical response of PR or
better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better
at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients
with RAEB, RAEB-T, or AML, treatment with intravenous azacitidine resulted in a response rate of 18.8%,
again using criteria similar to those described above. The mean and median duration of clinical response of PR
or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or
better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with
adjudicated baseline diagnosis of AML in both of these studies. Azacitidine dosage regimens in these 2 studies
were similar to the regimen used in the controlled study.
Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.”
About 24% of azacitidine-treated patients were considered improved, and about 2/3 of those lost transfusion
Reference ID: 5499547
°'
C
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V1
C
0
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0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
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CL
0.2
0.1
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# at risk
AZA
179
CCR
179
5
152
132
10
15
20
Log- Rank p=0.0001
HR = 0.58 [95% Cl: 0.43- 0.77]
Deaths: Aza = 82, CCR = 113
AZA
25
30
35
40
Time (months) from Randomization
130
85
52
30
10
0
95
69
32
14
5
0
0
dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion
dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195
days.
Study 4 was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T
or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS
classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best
supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105
to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The
primary efficacy endpoint was overall survival.
The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69
years (range was 38 to 88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients
were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS
classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria
for AML.
Azacitidine was administered subcutaneously at a dose of 75 mg/m2 daily for 7 consecutive days every 28 days
(which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after
response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39),
BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5
cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle
(range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).
In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant
difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs.
15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI:
0.43, 0.77).
Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)
Key: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = Hazard Ratio
Reference ID: 5499547
Azacitidine treatment led to a reduced need for red blood cell transfusions (see Table 6). In patients treated with
azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median
duration of RBC transfusion independence was 13.0 months.
Table 6. Effect of Azacitidine on RBC Transfusions in MDS Patients
Efficacy Parameter
Azacitidine plus BSC
(n= 179)
Conventional Care
Regimens
(n= 179)
Number and percent of patients who
were transfusion dependent at
baseline who became transfusion
independent on treatment1
Number and percent of patients who
were transfusion-independent at
baseline who became transfusion-
dependent on treatment
50/111 (45.0%)
(95% CI: 35.6%, 54.8%)
10/68 (14.7%)
(95% CI: 7.3%, 25.4%)
13/114 (11.4%)
(95% CI: 6.2%, 18.7%)
28/65 (43.1%)
(95% CI: 30.9%, 56.0%)
1 A patient was considered RBC transfusion independent during the treatment period if the patient
had no RBC transfusions during any 56 consecutive days or more during the treatment period.
Otherwise, the patient was considered transfusion dependent.
Pediatric use information is approved for Celgene Corporation’s Vidaza® (azacitidine for injection). However
due to Celgene Corporation’s marketing exclusivity rights, this drug product is not labeled with that
information.
15 REFERENCES
1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Azacitidine for Injection is supplied as a 100 mg of lyophilized powder in single-dose vials packaged in cartons
of 1 vial (NDC 0591-2897-49).
Storage
Store unreconstituted vials at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP
Controlled Room Temperature].
Discard unused portion.
Handling and Disposal
Azacitidine for Injection is a hazardous drug. Follow applicable special handling and disposal procedures.1
Sterile, Nonpyrogenic, Preservative-free.
This vial stopper is not made with natural rubber latex.
Reference ID: 5499547
~Actavis
17 PATIENT COUNSELING INFORMATION
Hepatic Toxicity in Patients with Severe Pre-Existing Hepatic Impairment
Instruct patients to inform their healthcare provider about any underlying liver disease [see Warnings and
Precautions (5.3)].
Renal Toxicity
Instruct patients to inform their healthcare provider about any underlying renal disease [see Warnings and
Precautions (5.4)].
Embryo-Fetal Toxicity
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females
of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings
and Precautions (5.6) and Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for
Injection and for 6 months after the last dose [see Use in Specific Populations (8.3)].
Advise male patients with female partners of reproductive potential to use effective contraception during
treatment with Azacitidine for Injection and for 3 months after the last dose [see Use in Specific Populations
(8.3)].
Lactation
Advise women not to breastfeed during treatment with Azacitidine for Injection and for 1 week after the last
dose [see Use in Specific Populations (8.2)].
Infertility
Advise males and females of the potential for reduced fertility from Azacitidine for Injection [see Use in
Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
Manufactured by:
Sindan Pharma SRL
11 Ion Mihalache Blvd.
Bucharest 1, Romania 011171
Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA
Reference ID: 5499547
| custom-source | 2025-02-12T15:48:00.669958 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208216s007lbl.pdf', 'application_number': 208216, 'submission_type': 'SUPPL ', 'submission_number': 7} |
80,679 |
SPORANOX®
(itraconazole)
Capsules
BOXED WARNING
Congestive Heart Failure, Cardiac Effects and Drug Interactions
Congestive Heart Failure and Cardiac Effects:
• SPORANOX® (itraconazole) Capsules should not be administered for the treatment
of onychomycosis in patients with evidence of ventricular dysfunction such as
congestive heart failure (CHF) or a history of CHF. If signs or symptoms of
congestive heart failure occur during administration of SPORANOX® Capsules,
discontinue administration.
• When itraconazole was administered intravenously to dogs and healthy human
volunteers, negative inotropic effects were seen. (See CONTRAINDICATIONS,
WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS:
Postmarketing Experience, and CLINICAL PHARMACOLOGY: Special
Populations for more information.)
Drug Interactions:
• Coadministration of a number of CYP3A4 substrates are contraindicated with
SPORANOX®. Some examples of drugs that are
contraindicated for
coadministration with SPORANOX® Capsules are: methadone, disopyramide,
dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as
dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine
(methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam,
felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol,
lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
• Coadministration with colchicine, fesoterodine and solifenacin is contraindicated in
subjects with varying degrees of renal or hepatic impairment.
• Coadministration with eliglustat is contraindicated in subjects that are poor or
intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate
CYP2D6 inhibitors.
• Coadministration with venetoclax is contraindicated in patients with chronic
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose
1
Reference ID: 5499269
initiation and ramp-up phase of venetoclax. See PRECAUTIONS: Drug
Interactions Section for specific examples.
• Coadministration with itraconazole can cause elevated plasma concentrations of
these drugs and may increase or prolong both the pharmacologic effects and/or
adverse reactions to these drugs. For example, increased plasma concentrations of
some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias
including occurrences of torsade de pointes, a potentially fatal arrhythmia. See
CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug
Interactions Section for specific examples.
DESCRIPTION
SPORANOX® is the brand name for itraconazole, an azole antifungal agent. Itraconazole is a
1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three
chiral centers. It may be represented by the following structural formula and nomenclature:
(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one
mixture
with
(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H
1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4
triazolin-5-one
or
(±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one
Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is
a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols,
and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values
obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at
pH 8.1.
2
Reference ID: 5499269
SPORANOX® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of
sucrose, maize starch, and purified water). Inactive ingredients are hard gelatin capsule,
hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No. 1, FD&C
Blue No. 2, D&C Red No. 22 and D&C Red No. 28.
Meets USP Dissolution Test 2.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism:
General Pharmacokinetic Characteristics
Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral
administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in
plasma during multiple dosing. Steady-state concentrations are generally reached within about
15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of
100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of
itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours
with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to
an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of
treatment. Itraconazole mean total plasma clearance following intravenous administration is
278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
Absorption
Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of
itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute
oral bioavailability of itraconazole is about 55%.
The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole) Capsules
are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects
with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion
suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria
caused by certain diseases. (See PRECAUTIONS: Drug Interactions.) Absorption of itraconazole
under fasted conditions in these subjects is increased when SPORANOX® Capsules are
administered with an acidic beverage (such as a non-diet cola). When SPORANOX® Capsules
were administered as a single 200-mg dose under fasted conditions with non-diet cola after
ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that
observed when SPORANOX® Capsules were administered alone. (See PRECAUTIONS: Drug
Interactions.)
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Itraconazole exposure is lower with the Capsule formulation than with the Oral Solution when the
same dose of drug is given. (See WARNINGS.)
Distribution
Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main
binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids.
Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a
large apparent volume in the body (>700 L), suggesting extensive distribution into tissues.
Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to
three times higher than corresponding concentrations in plasma, and the uptake into keratinous
tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are
much lower than in plasma.
Metabolism
Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro
studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole.
The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to
itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.
Excretion
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within
one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite
hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral
radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of
itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the
concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in
nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for
at least six months after the end of a 3-month treatment period.
Special Populations:
Renal Impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment. A
pharmacokinetic study using a single 200 mg oral dose of itraconazole was conducted in three
groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous
ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of
13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal
population parameters. This study did not demonstrate any significant effect of hemodialysis or
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continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and
AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all
three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in
patients with mild (defined in this study as CrCl 50-79 mL/min), moderate (defined in this study
as CrCl 20-49 mL/min), and severe renal impairment (defined in this study as CrCl <20 mL/min)
were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired
patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was
decreased in patients with moderate and severe renal impairment by approximately 30% and 40%,
respectively, as compared with subjects with normal renal function. Data are not available in
renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-
life or clearance of itraconazole or hydroxy-itraconazole. (See PRECAUTIONS and DOSAGE
AND ADMINISTRATION.)
Hepatic Impairment:
Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted
in 6 healthy and 12 cirrhotic subjects who were administered a single 100 mg dose of itraconazole
as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the
elimination half-life (37±17 hours vs. 16±5 hours) of itraconazole were noted in cirrhotic subjects
compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was
similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients
during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug
Interactions and DOSAGE AND ADMINISTRATION.)
Decreased Cardiac Contractility:
When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative
inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion,
transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated
SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of
congestive heart failure appear during administration of SPORANOX® Capsules, SPORANOX®
should be discontinued. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS,
PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Postmarketing Experience for
more information.)
MICROBIOLOGY
Mechanism of Action:
In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent
synthesis of ergosterol, which is a vital component of fungal cell membranes.
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Antimicrobial Activity:
Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum,
Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species (See
INDICATIONS AND USAGE: Description of Clinical Studies).
Susceptibility Testing Methods:
For specific information regarding susceptibility test interpretive criteria and associated test
methods and quality control standards recognized by FDA for this drug, please see:
https://www.fda.gov/STIC.
Resistance:
Isolates from several fungal species with decreased susceptibility to itraconazole have been
isolated in vitro and from patients receiving prolonged therapy.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp.
and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Cross-Resistance:
Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility
to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding
of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical
history, the particular azole compounds compared, and the type of susceptibility test that is
performed.
Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed
by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation
step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for
amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus
fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of
test results obtained in this study is unknown.
INDICATIONS AND USAGE
SPORANOX® (itraconazole) Capsules are indicated for the treatment of the following fungal
infections in immunocompromised and non-immunocompromised patients:
1.
Blastomycosis, pulmonary and extrapulmonary
2.
Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-
meningeal histoplasmosis, and
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3.
Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are
refractory to amphotericin B therapy.
Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology,
serology) should be obtained before therapy to isolate and identify causative organisms. Therapy
may be instituted before the results of the cultures and other laboratory studies are known;
however, once these results become available, antiinfective therapy should be adjusted
accordingly.
SPORANOX® Capsules are also indicated for the treatment of the following fungal infections in
non-immunocompromised patients:
1.
Onychomycosis of the toenail, with or without fingernail involvement, due to
dermatophytes (tinea unguium), and
2.
Onychomycosis of the fingernail due to dermatophytes (tinea unguium).
Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation,
fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
(See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS,
WARNINGS, and ADVERSE REACTIONS: Postmarketing Experience for more information.)
Description of Clinical Studies:
Blastomycosis:
Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73
combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day.
A response for most signs and symptoms was observed within the first 2 weeks, and all signs and
symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial
evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the
natural history of untreated cases.
Histoplasmosis:
Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34
combined) in patients with normal or abnormal immune status (not including HIV-infected
patients). The median dose was 200 mg/day. A response for most signs and symptoms was
observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.
Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole
for the treatment of histoplasmosis, compared with the natural history of untreated cases.
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Histoplasmosis in HIV-infected patients:
Data from a small number of HIV-infected patients suggested that the response rate of
histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical
course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance
therapy to prevent relapse.
Aspergillosis:
Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to
make itraconazole available in the U.S. for patients who either failed or were intolerant of
amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label
studies (N=31 combined) in the same patient population. Most adult patients were treated with a
daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies
demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the
treatment of aspergillosis compared with the natural history of the disease in patients who either
failed or were intolerant of amphotericin B therapy.
Onychomycosis of the toenail:
Analyses were conducted on data from three double-blind, placebo-controlled studies
(N=214 total; 110 given SPORANOX® Capsules) in which patients with onychomycosis of the
toenails received 200 mg of SPORANOX® Capsules once daily for 12 consecutive weeks. Results
of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative
KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were
considered an overall success (mycologic cure plus clear or minimal nail involvement with
significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure
(clearance of all signs, with or without residual nail deformity). The mean time to overall success
was approximately 10 months. Twenty-one percent (21%) of the overall success group had a
relapse (worsening of the global score or conversion of KOH or culture from negative to positive).
Onychomycosis of the fingernail:
Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37
given SPORANOX® Capsules) in which patients with onychomycosis of the fingernails received
a 1-week course (pulse) of 200 mg of SPORANOX® Capsules b.i.d., followed by a 3-week period
without SPORANOX®, which was followed by a second 1-week pulse of 200 mg of
SPORANOX® Capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six
percent (56%) of patients were considered an overall success and 47% of patients demonstrated
mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months.
None of the patients who achieved overall success relapsed.
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CONTRAINDICATIONS
Congestive Heart Failure:
SPORANOX® (itraconazole) Capsules should not be administered for the treatment of
onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart
failure (CHF) or a history of CHF. (See BOXED WARNING, WARNINGS, PRECAUTIONS:
Drug Interactions-Calcium Channel Blockers, ADVERSE REACTIONS: Postmarketing
Experience, and CLINICAL PHARMACOLOGY: Special Populations.)
Drug Interactions:
Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®.
Some examples of drugs for which plasma concentrations increase are: methadone, disopyramide,
dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine,
ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan,
lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine,
eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor,
finerenone, voclosporin. In addition, coadministration with colchicine, fesoterodine and
solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and
coadministration with eliglustat is contraindicated in subjects that are poor or intermediate
metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See
PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug
concentrations caused by coadministration with itraconazole may increase or prolong both the
pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma
concentrations of some of these drugs can lead to QT prolongation and ventricular
tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Some
specific examples are listed in PRECAUTIONS: Drug Interactions.
Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose
initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis
syndrome.
SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients
or to women contemplating pregnancy.
SPORANOX® is contraindicated for patients who have shown hypersensitivity to itraconazole.
There is limited information regarding cross-hypersensitivity between itraconazole and other azole
antifungal agents. Caution should be used when prescribing SPORANOX® to patients with
hypersensitivity to other azoles.
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WARNINGS
Hepatic Effects:
SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver
failure and death. Some of these cases had neither pre-existing liver disease nor a serious
underlying medical condition, and some of these cases developed within the first week of
treatment. If clinical signs or symptoms develop that are consistent with liver disease,
treatment should be discontinued and liver function testing performed. Continued
SPORANOX® use or reinstitution of treatment with SPORANOX® is strongly discouraged
unless there is a serious or life-threatening situation where the expected benefit exceeds the
risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)
Cardiac Dysrhythmias:
Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs
such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX® and/or
other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX® is
contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS:
Drug Interactions.)
Cardiac Disease:
SPORANOX® Capsules should not be administered for the treatment of onychomycosis in
patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or
a history of CHF. SPORANOX® Capsules should not be used for other indications in patients
with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.
For patients with risk factors for congestive heart failure, physicians should carefully review the
risks and benefits of SPORANOX® therapy. These risk factors include cardiac disease such as
ischemic and valvular disease; significant pulmonary disease such as chronic obstructive
pulmonary disease; and renal failure and other edematous disorders. Such patients should be
informed of the signs and symptoms of CHF, should be treated with caution, and should be
monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear
during administration of SPORANOX® Capsules, discontinue administration.
Itraconazole has been shown to have a negative inotropic effect. When itraconazole was
administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was
documented. In a healthy volunteer study of itraconazole intravenous infusion, transient,
asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT
imaging; these resolved before the next infusion, 12 hours later.
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SPORANOX® has been associated with reports of congestive heart failure. In postmarketing
experience, heart failure was more frequently reported in patients receiving a total daily dose of
400 mg although there were also cases reported among those receiving lower total daily doses.
Calcium channel blockers can have negative inotropic effects which may be additive to those of
itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers.
Therefore, caution should be used when co-administering itraconazole and calcium channel
blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® and
felodipine or nisoldipine is contraindicated.
Cases of CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing
period among patients being treated for onychomycosis and/or systemic fungal infections. (See
CLINICAL
PHARMACOLOGY:
Special
Populations,
CONTRAINDICATIONS,
PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Postmarketing Experience
for more information.)
Pseudoaldosteronism:
Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and
abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11
deoxycortisol), has been reported with itraconazole use in the postmarketing setting. Monitor
blood pressure and potassium levels and manage as necessary. Management of
pseudoaldosteronism may include discontinuation of SPORANOX®, substitution with an
appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone
receptor antagonists.
Interaction Potential:
SPORANOX® has a potential for clinically important drug interactions. Coadministration of
specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the
coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated,
not recommended or recommended for use with caution in combination with itraconazole are listed
in PRECAUTIONS: Drug Interactions.
Interchangeability:
SPORANOX® (itraconazole) Capsules and SPORANOX® Oral Solution should not be used
interchangeably. This is because drug exposure is greater with the Oral Solution than with the
Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure
may be different between the two formulations. Only the Oral Solution has been demonstrated
effective for oral and/or esophageal candidiasis.
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PRECAUTIONS
General:
SPORANOX® (itraconazole) Capsules should be administered after a full meal. (See CLINICAL
PHARMACOLOGY: Pharmacokinetics and Metabolism).
Under fasted conditions, itraconazole absorption was decreased in the presence of decreased
gastric acidity. The absorption of itraconazole may be decreased with the concomitant
administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted
conditions demonstrated that administration with 8 ounces of a non-diet cola beverage resulted in
increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This
increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY:
Pharmacokinetics and Metabolism).
Hepatotoxicity:
Rare cases of serious hepatotoxicity have been observed with SPORANOX® treatment, including
some cases within the first week. It is recommended that liver function monitoring be considered
in all patients receiving SPORANOX®. Treatment should be stopped immediately and liver
function testing should be conducted in patients who develop signs and symptoms suggestive of
liver dysfunction.
Neuropathy:
If neuropathy occurs that may be attributable to SPORANOX® Capsules, the treatment should be
discontinued.
Immunocompromised Patients:
In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the
oral bioavailability of SPORANOX® capsules may be decreased. Therefore, the dose should be
adjusted based on the clinical response in these patients.
Cystic Fibrosis:
If a cystic fibrosis patient does not respond to SPORANOX® Capsules, consideration should be
given to switching to alternative therapy. For more information concerning the use of itraconazole
in cystic fibrosis patients see the prescribing information for SPORANOX® Oral Solution.
Hearing Loss:
Transient or permanent hearing loss has been reported in patients receiving treatment with
itraconazole. Several of these reports included concurrent administration of quinidine which is
contraindicated (See BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug
Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when
treatment is stopped, but can persist in some patients.
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Information for Patients:
•
The topical effects of mucosal exposure may be different between the SPORANOX®
Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for
oral and/or esophageal candidiasis. SPORANOX® Capsules should not be used
interchangeably with SPORANOX® Oral Solution.
•
Instruct patients to take SPORANOX® Capsules with a full meal. SPORANOX® Capsules
must be swallowed whole.
•
Instruct patients about the signs and symptoms of congestive heart failure, and if these
signs or symptoms occur during SPORANOX® administration, they should discontinue
SPORANOX® and contact their healthcare provider immediately.
•
Instruct patients to stop SPORANOX® treatment immediately and contact their healthcare
provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs
and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice,
dark urine, or pale stools.
•
Instruct patients to contact their physician before taking any concomitant medications with
itraconazole to ensure there are no potential drug interactions.
•
Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss
usually resolves when treatment is stopped, but can persist in some patients. Advise
patients to discontinue therapy and inform their physicians if any hearing loss symptoms
occur.
•
Instruct patients that dizziness or blurred/double vision can sometimes occur with
itraconazole. Advise patients that if they experience these events, they should not drive or
use machines.
Drug Interactions:
Effect of SPORANOX® on Other Drugs
Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.
Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance
protein (BCRP). Consequently, SPORANOX® has the potential to interact with many concomitant
drugs resulting in either increased or sometimes decreased concentrations of the concomitant
drugs. Increased concentrations may increase the risk of adverse reactions associated with the
concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation,
torsade de pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions,
myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism).
Reduced concentrations of concomitant drugs may reduce their efficacy. Table 1 lists examples of
drugs that may have their concentrations affected by itraconazole, but it is not a comprehensive
list.
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Refer to the approved product labeling to become familiar with the interaction pathways, risk
potential, and specific actions to be taken with regards to each concomitant drug prior to initiating
therapy with SPORANOX®.
Although many of the clinical drug interactions in Table 1 are based on information with a similar
azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX®.
Table 1:
Drug Interactions with SPORANOX® that Affect Concomitant Drug
Concentrations
Examples of Concomitant Drugs Within
Class
Prevention or Management
Drug Interactions with SPORANOX® that Increase Concomitant Drug Concentrations and
May Increase Risk of Adverse Reactions Associated with the Concomitant Drug
Alpha Blockers
Alfuzosin
Silodosin
Tamsulosin
Not recommended during and 2 weeks after
SPORANOX® treatment.
Analgesics
Methadone
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Fentanyl
Not recommended during and 2 weeks after
SPORANOX® treatment.
Alfentanil
Buprenorphine (IV and sublingual)
Oxycodonea
Sufentanil
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antiarrhythmics
Disopyramide
Dofetilide
Dronedarone
Quinidinea
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Digoxina
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antibacterials
Bedaquilineb
Concomitant SPORANOX® not recommended for
more than 2 weeks at any time during bedaquiline
treatment.
Rifabutin
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 2.
Clarithromycin
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. See also
Table 2.
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Trimetrexate
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Anticoagulants and Antiplatelets
Ticagrelor
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Apixaban
Rivaroxaban
Vorapaxar
Not recommended during and 2 weeks after
SPORANOX® treatment.
Cilostazol
Dabigatran
Warfarin
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Anticonvulsants
Carbamazepine
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 2.
Antidiabetic Drugs
Repaglinidea
Saxagliptin
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antihelminthics, Antifungals and Antiprotozoals
Isavuconazonium
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Praziquantel
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Artemether-lumefantrine
Quininea
Monitor for adverse reactions.
Antimigraine Drugs
Ergot alkaloids (e.g., dihydroergotamine,
ergotamine)
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Eletriptan
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Antineoplastics
Irinotecan
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Venetoclax
Contraindicated during the dose initiation and
ramp-up phase in patients with CLL/SLL. Refer to
the venetoclax prescribing information for dosing
and safety monitoring instructions.
Mobocertiniba
Avoid use during and 2 weeks after SPORANOX®
treatment.
Axitinib
Ibrutinib
Bosutinib
Lapatinib
Cabazitaxel
Nilotinib
Cabozantinib
Olapariba
Ceritinib
Pazopanib
Cobimetiniba
Sunitinib
Crizotinib
Trabectedin
Avoid use during and 2 weeks after SPORANOX®
treatment.
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Dabrafenib
Trastuzumab-
Dasatinib
emtansine
Docetaxel
Vinca alkaloids
Entrectiniba
Pemigatiniba
Talazopariba
Refer to the entrectinib, pemigatinib and
talazoparib prescribing information for dosing
instructions if concomitant use cannot be avoided.
Glasdegib
Refer to the glasdegib prescribing information for
safety monitoring if concomitant use cannot be
avoided.
Bortezomib
Brentuximab-
Nintedanib
vedotin
Panobinostat
Busulfana
Ponatinib
Erlotinib
Ruxolitinib
Gefitiniba
Sonidegib
Idelalisib
Tretinoin (oral)
Imatinib
Vandetaniba
Ixabepilone
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For idelalisib,
see also Table 2.
Antipsychotics, Anxiolytics and Hypnotics
Alprazolama
Midazolam (IV)a
Aripiprazolea
Quetiapine
Buspironea
Ramelteon
Cariprazine
Risperidonea
Diazepama
Suvorexant
Haloperidola
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Zopiclonea
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Lurasidone
Midazolam (oral)a
Contraindicated during and 2 weeks after
Pimozide
SPORANOX® treatment.
Triazolama
Antivirals
Daclatasvir
Indinavira
Maraviroc
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For indinavir,
see also Table 2.
Cobicistat
Elvitegravir (ritonavir-boosted)
Ombitasvir/Paritaprevir/Ritonavir with or
without Dasabuvir
Ritonavir
Saquinavir (unboosted)a
Monitor for adverse reactions. See also Table 2.
Elbasvir/grazoprevir
Glecaprevir/pibrentasvir
Not recommended during and 2 weeks after
SPORANOX® treatment.
Monitor for adverse reactions.
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Tenofovir disoproxil fumarate
Monitor for adverse reactions.
Beta Blockers
Nadolola
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Calcium Channel Blockers
Felodipinea
Nisoldipine
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Diltiazem
Other dihydropyridines
Verapamil
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For diltiazem,
see also Table 2.
Cardiovascular Drugs, Miscellaneous
Ivabradine
Ranolazine
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Aliskirena
Riociguat
Sildenafil (for pulmonary hypertension)
Tadalafil (for pulmonary hypertension)
Not recommended during and 2 weeks after
SPORANOX® treatment. For sildenafil and
tadalafil, see also Urologic Drugs below.
Bosentan
Guanfacine
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Contraceptives*
Dienogest
Ulipristal
Monitor for adverse reactions.
Diuretics
Eplerenone
Finerenone
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Gastrointestinal Drugs
Cisapride
Naloxegol
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Aprepitant
Loperamidea
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Netupitant
Monitor for adverse reactions.
Immunosuppressants
Voclosporin
Contraindicated during and for 2 weeks after
SPORANOX® treatment.
Everolimus
Sirolimus
Temsirolimus (IV)
Not recommended during and 2 weeks after
SPORANOX® treatment.
Budesonide
Fluticasone
(inhalation)a
(inhalation)a
Budesonide (non-
Fluticasone (nasal)
inhalation)
Methylprednisolonea
Ciclesonide
Tacrolimus (IV)a
(inhalation)
Tacrolimus (oral)
Cyclosporine (IV)a
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
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Cyclosporine (non-
IV)
Dexamethasonea
Lipid-Lowering Drugs
Lomitapide
Lovastatina
Simvastatina
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Atorvastatina
Monitor for drug adverse reactions. Concomitant
drug dose reduction may be necessary.
Respiratory Drugs
Salmeterol
Not recommended during and 2 weeks after
SPORANOX® treatment.
SSRIs, Tricyclics and Related Antidepressants
Venlafaxine
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Urologic Drugs
Avanafil
Contraindicated during and 2 weeks after
SPORANOX® treatment.
Fesoterodine
Patients with moderate to severe renal or hepatic
impairment: Contraindicated during and 2 weeks
after SPORANOX® treatment.
Other patients: Monitor for adverse reactions.
Concomitant drug dose reduction may be
necessary.
Solifenacin
Patients with severe renal or moderate to severe
hepatic impairment: Contraindicated during and
2 weeks after SPORANOX® treatment.
Other patients: Monitor for adverse reactions.
Concomitant drug dose reduction may be
necessary.
Darifenacin
Vardenafil
Not recommended during and 2 weeks after
SPORANOX® treatment.
Dutasteride
Oxybutynina
Sildenafil (for erectile dysfunction)
Tadalafil (for erectile dysfunction and
benign prostatic hyperplasia)
Tolterodine
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary. For sildenafil
and tadalafil, see also Cardiovascular Drugs
above.
Miscellaneous Drugs and Other Substances
Colchicine
Patients with renal or hepatic impairment:
Contraindicated during and 2 weeks after
SPORANOX® treatment.
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I
I
I
Other patients: Not recommended during and
2 weeks after SPORANOX® treatment.
Eliglustat
CYP2D6 EMsc taking a strong or moderate
CYP2D6 inhibitor, CYP2D6 IMsc, or CYP2D6
PMsc: Contraindicated during and 2 weeks after
SPORANOX® treatment.
CYP2D6 EMsc not taking a strong or moderate
CYP2D6 inhibitor: Monitor for adverse reactions.
Eliglustat dose reduction may be necessary.
Lumacaftor/Ivacaftor
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment.
Alitretinoin (oral)
Cabergoline
Cannabinoids
Cinacalcet
Galantamine
Ivacaftor
Monitor for adverse reactions. Concomitant drug
dose reduction may be necessary.
Valbenazine
Concomitant drug dose reduction is necessary.
Refer to the valbenazine prescribing information
for dosing instructions.
Vasopressin Receptor Antagonists
Conivaptan
Tolvaptan
Not recommended during and 2 weeks after
SPORANOX® treatment.
Drug Interactions with SPORANOX® that Decrease Concomitant Drug Concentrations and
May Reduce Efficacy of the Concomitant Drug
Antineoplastics
Regorafenib
Not recommended during and 2 weeks after
SPORANOX® treatment.
Gastrointestinal Drugs
Saccharomyces boulardii
Not recommended during and 2 weeks after
SPORANOX® treatment.
Nonsteroidal Anti-Inflammatory Drugs
Meloxicama
Concomitant drug dose increase may be necessary.
*
CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.
a
Based on clinical drug interaction information with itraconazole.
b
Based on 400 mg bedaquiline once daily for 2 weeks.
c
EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers
Effect of Other Drugs on SPORANOX®
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this
metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of
itraconazole. Some concomitant drugs have the potential to interact with SPORANOX® resulting
in either increased or sometimes decreased concentrations of SPORANOX®. Increased
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concentrations may increase the risk of adverse reactions associated with SPORANOX®.
Decreased concentrations may reduce SPORANOX® efficacy.
Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a
comprehensive list. Refer to the approved product labeling to become familiar with the interaction
pathways, risk potential and specific actions to be taken with regards to each concomitant drug
prior to initiating therapy with SPORANOX®.
Although many of the clinical drug interactions in Table 2 are based on information with a similar
azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX®.
Table 2:
Drug Interactions with Other Drugs that Affect SPORANOX® Concentrations
Examples of Concomitant Drugs Within
Prevention or Management
Class
Drug Interactions with Other Drugs that Increase SPORANOX® Concentrations and May
Increase Risk of Adverse Reactions Associated with SPORANOX®
Antibacterials
Ciprofloxacina
Erythromycina
Clarithromycina
Antineoplastics
Idelalisib
Antivirals
Cobicistat
Darunavir (ritonavir-boosted)
Elvitegravir (ritonavir-boosted)
Fosamprenavir (ritonavir-boosted)
Indinavira
Ombitasvir/ Paritaprevir/ Ritonavir with or
without Dasabuvir
Ritonavir
Saquinavir
Isoniazid
Rifampicina
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary.
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary. See also Table 1.
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary. For, cobicistat,
elvitegravir, indinavir, ombitasvir/ paritaprevir/
ritonavir with or without dasabuvir, ritonavir, and
saquinavir, see also Table 1.
Not recommended 2 weeks before and during
SPORANOX® treatment.
20
Calcium Channel Blockers
Diltiazem
Monitor for adverse reactions. SPORANOX® dose
reduction may be necessary. See also Table 1.
Drug Interactions with Other Drugs that Decrease SPORANOX® Concentrations and May
Reduce Efficacy of SPORANOX®
Antibacterials
Reference ID: 5499269
Rifabutina
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 1.
Anticonvulsants
Phenobarbital
Phenytoina
Not recommended 2 weeks before and during
SPORANOX® treatment.
Carbamazepine
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment. See also
Table 1.
Antivirals
Efavirenza
Nevirapinea
Not recommended 2 weeks before and during
SPORANOX® treatment.
Gastrointestinal Drugs
Drugs that reduce gastric acidity e.g. acid
neutralizing medicines such as aluminum
hydroxide, or acid secretion suppressors
such as H2- receptor antagonists and proton
pump inhibitors.
Use with caution. Administer acid neutralizing
medicines at least 2 hours before or 2 hours after the
intake of SPORANOX® capsules.
Miscellaneous Drugs and Other Substances
Lumacaftor/Ivacaftor
Not recommended 2 weeks before, during, and
2 weeks after SPORANOX® treatment.
a
Based on clinical drug interaction information with itraconazole.
Pediatric Population
Interaction studies have only been performed in adults.
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months
at dosage levels up to 80 mg/kg/day (approximately 1 time the maximum recommended human
dose [MRHD] of 400 mg/day based on body surface area comparisons). Male rats treated with
25 mg/kg/day (0.6 times the MRHD based on body surface area comparisons) had a slightly
increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of
hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole
administration. Female rats treated with 50 mg/kg/day (1.2 times the MRHD based on body
surface area comparisons) had an increased incidence of squamous cell carcinoma of the lung
(2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma
in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically
significant.
Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA
synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and
Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal
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mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes,
in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant
lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of
up to 40 mg/kg/day (1 time the MRHD based on body surface area comparisons), even though
parental toxicity was present at this dosage level. More severe signs of parental toxicity, including
death, were present in the next higher dosage level, 160 mg/kg/day (4 times the MRHD based on
body surface area comparisons).
Pregnancy: Teratogenic Effects:
Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and
teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (1-4 times the MRHD
based on body surface area comparisons), and in mice at dosage levels of approximately
80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has been
shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major skeletal
defects; in mice, it consisted of encephaloceles and/or macroglossia.
There are no studies in pregnant women. SPORANOX® should be used for the treatment of
systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.
SPORANOX® should not be administered for the treatment of onychomycosis to pregnant patients
or to women contemplating pregnancy. SPORANOX® should not be administered to women of
childbearing potential for the treatment of onychomycosis unless they are using effective measures
to prevent pregnancy and they begin therapy on the second or third day following the onset of
menses. Highly effective contraception should be continued throughout SPORANOX® therapy
and for 2 months following the end of treatment.
During postmarketing experience, cases of congenital abnormalities have been reported. (See
ADVERSE REACTIONS: Postmarketing Experience.)
Nursing Mothers:
Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX® therapy
for the mother should be weighed against the potential risk from exposure of itraconazole to the
infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-
infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.
Pediatric Use:
The efficacy and safety of SPORANOX® have not been established in pediatric patients.
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The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology
studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day
(0.5 times the MRHD of 400 mg based on body surface area comparisons). The induced defects
included reduced bone plate activity, thinning of the zona compacta of the large bones, and
increased bone fragility. At a dosage level of 80 mg/kg/day (2 times the MRHD based on body
surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on body
surface area comparisons) for 6 months, itraconazole induced small tooth pulp with hypocellular
appearance in some rats.
Geriatric Use:
Clinical studies of SPORANOX® Capsules did not include sufficient numbers of subjects aged
65 years and over to determine whether they respond differently from younger subjects. It is
advised to use SPORANOX® Capsules in these patients only if it is determined that the potential
benefit outweighs the potential risks. In general, it is recommended that the dose selection for an
elderly patient should be taken into consideration, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Transient or permanent hearing loss has been reported in elderly patients receiving treatment with
itraconazole. Several of these reports included concurrent administration of quinidine which is
contraindicated (See BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug
Interactions and PRECAUTIONS: Drug Interactions).
HIV-Infected Patients:
Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of
itraconazole in these patients may be decreased.
Renal Impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment. The
exposure of itraconazole may be lower in some patients with renal impairment. Caution should be
exercised when itraconazole is administered in this patient population and dose adjustment may
be needed. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND
ADMINISTRATION.)
Hepatic Impairment:
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.
Caution should be exercised when this drug is administered in this patient population. It is
recommended that patients with impaired hepatic function be carefully monitored when taking
SPORANOX®. It is recommended that the prolonged elimination half-life of itraconazole
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observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be
considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
In patients with elevated or abnormal liver enzymes or active liver disease, or who have
experienced liver toxicity with other drugs, treatment with SPORANOX® is strongly discouraged
unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.
It is recommended that liver function monitoring be done in patients with pre-existing hepatic
function abnormalities or those who have experienced liver toxicity with other medications. (See
CLINICAL
PHARMACOLOGY:
Special
Populations
and
DOSAGE
AND
ADMINISTRATION.)
ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in clinical practice.
SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure
and death. Some of these cases had neither pre-existing liver disease nor a serious underlying
medical condition. If clinical signs or symptoms develop that are consistent with liver disease,
treatment should be discontinued and liver function testing performed. The risks and benefits of
SPORANOX®
use should be reassessed. (See WARNINGS: Hepatic Effects and
PRECAUTIONS: Hepatotoxicity and Information for Patients.)
Adverse Events in the Treatment of Systemic Fungal Infections
Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S.
clinical trials who were immunocompromised or receiving multiple concomitant medications.
Treatment was discontinued in 10.5% of patients due to adverse events. The median duration
before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events
reported by at least 1% of patients.
Table 3:
Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of
Greater than or Equal to 1%
Body System/Adverse Event
Incidence (%) (N=602)
Gastrointestinal
Nausea
Vomiting
Diarrhea
Abdominal Pain
Anorexia
11
5
3
2
1
Body as a Whole
Edema
Fatigue
4
3
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Fever
Malaise
3
1
Skin and Appendages
Rash*
Pruritus
9
3
Central/Peripheral Nervous System
Headache
Dizziness
4
2
Psychiatric
Libido Decreased
Somnolence
1
1
Cardiovascular
Hypertension
3
Metabolic/Nutritional
Hypokalemia
2
Urinary System
Albuminuria
1
Liver and Biliary System
Hepatic Function Abnormal
3
Reproductive System, Male
Impotence
1
* Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.
Adverse events infrequently reported in all studies included constipation, gastritis, depression,
insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.
Adverse Events Reported in Toenail Onychomycosis Clinical Trials
Patients in these trials were on a continuous dosing regimen of 200 mg once daily for
12 consecutive weeks.
The following adverse events led to temporary or permanent discontinuation of therapy.
Table 4:
Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or
Permanent Discontinuation of Therapy
Adverse Event
Incidence (%)
Itraconazole (N=112)
Elevated Liver Enzymes (greater than twice the upper limit of normal)
4
Gastrointestinal Disorders
4
Rash
3
Hypertension
2
Orthostatic Hypotension
1
Headache
1
Malaise
1
Myalgia
1
Vasculitis
1
Vertigo
1
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The following adverse events occurred with an incidence of greater than or equal to 1% (N=112):
headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea,
dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver
function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis,
gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%.
Adverse Events Reported in Fingernail Onychomycosis Clinical Trials
Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of
200 mg twice daily, separated by a 3-week period without drug.
The following adverse events led to temporary or permanent discontinuation of therapy.
Table 5:
Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or
Permanent Discontinuation of Therapy
Adverse Event
Incidence (%)
Itraconazole (N=37)
Rash/Pruritus
3
Hypertriglyceridemia
3
The following adverse events occurred with an incidence of greater than or equal to 1% (N=37):
headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation,
abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis,
fatigue, malaise, pain, injury: 3%.
Adverse Events Reported from Other Clinical Trials
In addition, the following adverse drug reaction was reported in patients who participated in
SPORANOX® Capsules clinical trials: Hepatobiliary Disorders: hyperbilirubinemia.
The following is a list of additional adverse drug reactions associated with itraconazole that have
been reported in clinical trials of SPORANOX® Oral Solution and itraconazole IV excluding the
adverse reaction term “Injection site inflammation” which is specific to the injection route of
administration:
Cardiac Disorders: cardiac failure, left ventricular failure, tachycardia;
General Disorders and Administration Site Conditions: face edema, chest pain, chills;
Hepatobiliary Disorders: hepatic failure, jaundice;
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Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood
alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased,
gamma-glutamyltransferase increased, urine analysis abnormal;
Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia, hypomagnesemia;
Psychiatric Disorders: confusional state;
Renal and Urinary Disorders: renal impairment;
Respiratory, Thoracic and Mediastinal Disorders: dysphonia, cough;
Skin and Subcutaneous Tissue Disorders: rash erythematous, hyperhidrosis;
Vascular Disorders: hypotension
Postmarketing Experience
Adverse drug reactions that have been first identified during postmarketing experience with
SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported
voluntarily from a population of uncertain size, reliably estimating their frequency or establishing
a causal relationship to drug exposure is not always possible.
Table 6:
Postmarketing Reports of Adverse Drug Reactions
Blood and Lymphatic System Disorders:
Leukopenia, neutropenia, thrombocytopenia
Immune System Disorders:
Anaphylaxis; anaphylactic, anaphylactoid and allergic
reactions; serum sickness; angioneurotic edema
Endocrine Disorders:
Pseudoaldosteronism
Nervous System Disorders:
Peripheral neuropathy, paresthesia, hypoesthesia,
tremor
Eye Disorders:
Visual disturbances, including vision blurred and
diplopia
Ear and Labyrinth Disorders:
Transient or permanent hearing loss
Cardiac Disorders:
Congestive heart failure, bradycardia
Respiratory, Thoracic and Mediastinal Disorders:
Pulmonary edema, dyspnea
Gastrointestinal Disorders:
Pancreatitis, dysgeusia
Hepatobiliary Disorders:
Serious hepatotoxicity (including some cases of fatal
acute liver failure), hepatitis
Skin and Subcutaneous Tissue Disorders:
Toxic epidermal necrolysis, Stevens-Johnson
syndrome, acute generalized exanthematous pustulosis,
erythema multiforme, exfoliative dermatitis,
leukocytoclastic vasculitis, alopecia, photosensitivity,
urticaria
Musculoskeletal and Connective Tissue Disorders:
Arthralgia
Renal and Urinary Disorders:
Urinary incontinence, pollakiuria
Reproductive System and Breast Disorders:
Erectile dysfunction
General Disorders and Administration Site
Conditions:
Peripheral edema
Investigations:
Blood creatine phosphokinase increased
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There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital
abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic
malformations as well as chromosomal and multiple malformations have been reported during
postmarketing experience. A causal relationship with SPORANOX® has not been established. (See
CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS,
and PRECAUTIONS: Drug Interactions for more information.)
OVERDOSAGE
Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures
should be employed. Contact a certified poison control center for the most up to date information
on the management of SPORANOX® Capsules overdosage (1-800-222-1222 or www.poison.org).
In general, adverse events reported with overdose have been consistent with adverse drug reactions
already listed in this package insert for itraconazole. (See ADVERSE REACTIONS.)
DOSAGE AND ADMINISTRATION
SPORANOX® (itraconazole) Capsules should be taken with a full meal to ensure maximal
absorption. SPORANOX® (itraconazole) Capsules must be swallowed whole.
SPORANOX® Capsules is a different preparation than SPORANOX® Oral Solution and should
not be used interchangeably.
Treatment of Blastomycosis and Histoplasmosis:
The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or
there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments
to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses.
Treatment of Aspergillosis:
A daily dose of 200 to 400 mg is recommended.
Treatment in Life-Threatening Situations:
In life-threatening situations, a loading dose should be used.
Although clinical studies did not provide for a loading dose, it is recommended, based on
pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day)
be given for the first 3 days of treatment.
Treatment should be continued for a minimum of three months and until clinical parameters and
laboratory tests indicate that the active fungal infection has subsided. An inadequate period of
treatment may lead to recurrence of active infection.
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SPORANOX® Capsules and SPORANOX® Oral Solution should not be used interchangeably.
Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.
Treatment of Onychomycosis:
Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules)
once daily for 12 consecutive weeks.
Treatment of Onychomycosis:
Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of
200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period
without SPORANOX®.
Use in Patients with Renal Impairment:
Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution
should be exercised when this drug is administered in this patient population. (See CLINICAL
PHARMACOLOGY: Special Populations and PRECAUTIONS.)
Use in Patients with Hepatic Impairment:
Limited data are available on the use of oral itraconazole in patients with hepatic impairment.
Caution should be exercised when this drug is administered in this patient population. (See
CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.)
HOW SUPPLIED
SPORANOX® (itraconazole) Capsules are available containing 100 mg of itraconazole, with a
blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.”
The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290-01) and
bottles of 30 capsules (NDC 50458-290-04).
Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture.
For patent information: www.janssenpatents.com
© 2024 Janssen Pharmaceutical Companies
Revised: 12/2024
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560, USA
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Reference ID: 5499269
PATIENT INFORMATION
SPORANOX® (SPOR-ah-nox)
(itraconazole)
Capsules
Read this Patient Information that comes with SPORANOX before you start taking it and each time you get a refill.
There may be new information. This information does not take the place of talking with your healthcare provider
about your medical condition or your treatment.
What is the most important information I should know about SPORANOX?
SPORANOX can cause serious side effects, including:
1. Heart failure. Do not take SPORANOX if you have had heart failure, including congestive heart failure.
Stop taking SPORANOX and call your healthcare provider right away if you have any of these symptoms
of congestive heart failure:
• shortness of breath
• coughing up white or pink mucus (phlegm)
• swelling of your feet, ankles or legs
• fast heartbeat
• sudden weight gain
• waking up at night more than normal for you
• increased tiredness
2. Heart problems and other serious medical problems. Serious medical problems that affect the heart and
other parts of your body can happen if you take SPORANOX with certain other medicines. Do not take
SPORANOX if you also take the following medicines:
• methadone
• irinotecan
• naloxegol
• disopyramide
• lurasidone
• lomitapide
• dofetilide
• oral midazolam
• lovastatin
• dronedarone
• pimozide
• simvastatin
• quinidine
• triazolam
• avanafil
• isavuconazole
• felodipine
• ticagrelor
• ergot alkaloids (such as
• nisoldipine
• venetoclax (see below)
dihydroergotamine,
• ivabradine
• finerenone
ergometrine ergonovine)
• ranolazine
• voclosporin
• ergotamine
• eplerenone
• methylergometrine
• cisapride
(methylergonovine)
Do not take SPORANOX with venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma when
you first start treatment with venetoclax or with increasing doses of venetoclax.
This is not a complete list of medicines that can interact with SPORANOX. SPORANOX may affect the way other
medicines work, and other medicines may affect how SPORANOX works. You can ask your pharmacist for a list
of medicines that interact with SPORANOX.
Before you start taking SPORANOX, tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins, and herbal supplements.
Before you start any new medicine, ask your healthcare provider or pharmacist if it is safe to take it with
SPORANOX.
3. Liver problems. SPORANOX can cause serious liver problems which may be severe and lead to death. Stop
taking SPORANOX and call your healthcare provider right away if you have any of these symptoms of
liver problems:
• tiredness
• your skin or the white part of your eyes turn yellow
• loss of appetite for several days or longer
(jaundice)
• nausea or vomiting
• light-colored stools (bowel movement)
• dark or “tea-colored” urine
For more information about side effects, see “What are the possible side effects of SPORANOX?”
What is SPORANOX?
•
SPORANOX is a prescription medicine used to treat the following fungal infections of the toenails, fingernails
and other parts of the body: blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
•
It is not known if SPORANOX is safe and effective in children.
Do not take SPORANOX if you:
•
have or have had heart failure, including congestive heart failure.
•
take certain medicines. See “What is the most important information I should know about SPORANOX?”
•
are pregnant or plan to become pregnant. SPORANOX can harm your unborn baby. Tell your healthcare
provider right away if you become pregnant while taking SPORANOX. Females who are able to become
pregnant must use effective forms of birth control during treatment and for 2 months after stopping treatment with
SPORANOX.
1
Reference ID: 5499269
•
are allergic to itraconazole or any of the ingredients in SPORANOX. See the end of this Patient Information
leaflet for a complete list of ingredients in SPORANOX.
Before taking SPORANOX, tell your healthcare provider about all of your medical conditions, including if
you:
•
have heart problems.
•
have liver problems.
•
have kidney problems.
•
have a weakened immune system (immunocompromised).
•
have lung problems including cystic fibrosis.
•
are breastfeeding or plan to breastfeed. SPORANOX can pass into your breast milk. You and your healthcare
provider should decide if you will take SPORANOX or breastfeed.
Taking SPORANOX with certain medicines may affect each other. Taking SPORANOX with other medicines can
cause serious side effects.
How should I take SPORANOX?
•
Take SPORANOX exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how
much SPORANOX to take and when to take it.
•
You will receive SPORANOX capsules in a blister pack or bottle. Your healthcare provider will decide the type of
SPORANOX that is right for you.
•
Take SPORANOX with a full meal.
•
Swallow SPORANOX capsules whole.
•
You should not take SPORANOX oral solution instead of SPORANOX capsules, because they will not work the
same way.
•
If you take too much SPORANOX, call your healthcare provider or go to the nearest hospital emergency room
right away.
What should I avoid while taking SPORANOX?
SPORANOX can cause dizziness and vision problems. Do not drive or operate machinery until you know how
SPORANOX affects you.
What are the possible side effects of SPORANOX?
SPORANOX may cause serious side effects, including:
•
See “What is the most important information I should know about SPORANOX?”
•
New or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism).
Your healthcare provider should check your blood pressure and potassium levels.
•
Nerve problems (neuropathy). Call your healthcare provider right away if you have tingling or numbness in
your hands or feet. Your healthcare provider may stop your treatment with SPORANOX if you have nerve
problems.
•
Hearing loss. Hearing loss can happen for a short time or permanently in some people who take SPORANOX.
Stop taking SPORANOX and call your healthcare provider right away if you have any changes in your hearing.
The most common side effects of SPORANOX include: headache, rash, digestive system problems (such as
nausea and vomiting), and edema.
Additional possible side effects include upset stomach, constipation, fever, inflammation of the pancreas, increase in
blood pressure, menstrual disorder, erectile dysfunction, dizziness, muscle pain, painful joints, unpleasant taste, or
hair loss.
These are not all the possible side effects of SPORANOX.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store SPORANOX?
•
Store SPORANOX at room temperature between 59°F to 77°F (15°C to 25°C).
•
Keep SPORANOX dry and away from light.
Keep SPORANOX and all medicines out of the reach of children.
General information about the safe and effective use of SPORANOX.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
SPORANOX for a condition for which it was not prescribed. Do not give SPORANOX to other people, even if they
have the same symptoms that you have. It may harm them.
You can ask your doctor or pharmacist for information about SPORANOX that is written for health professionals.
What are the ingredients in SPORANOX?
Active ingredients: itraconazole
Inactive ingredients: hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C
Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28.
Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA
For patent information: www.janssenpatents.com
© 2024 Janssen Pharmaceutical Companies
For more information or call 1-800-526-7736.
2
Reference ID: 5499269
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 10/2024
3
Reference ID: 5499269
| custom-source | 2025-02-12T15:48:00.782786 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020083s070lbl.pdf', 'application_number': 20083, 'submission_type': 'SUPPL ', 'submission_number': 70} |
80,682 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
XOFLUZA safely and effectively. See full prescribing information for
XOFLUZA.
XOFLUZA® (baloxavir marboxil) tablets, for oral use
XOFLUZA® (baloxavir marboxil) for oral suspension
Initial U.S. Approval: 2018
-----------------------------RECENT MAJOR CHANGES---------------------
Indications and Usage
Treatment of Influenza (1.1)
03/2024
-----------------------------INDICATIONS AND USAGE----------------------
XOFLUZA is an influenza virus polymerase acidic (PA) endonuclease
inhibitor indicated for:
• Treatment of acute uncomplicated influenza in patients 5 years of age and
older who have been symptomatic for no more than 48 hours and who are
otherwise healthy or at high risk of developing influenza-related
complications. (1.1)
• Post-exposure prophylaxis of influenza in patients 5 years of age and older
following contact with an individual who has influenza. (1.2)
Limitations of Use
Influenza viruses change over time, and factors such as the virus type or
subtype, emergence of resistance, or changes in viral virulence could diminish
the clinical benefit of antiviral drugs. Consider available information on drug
susceptibility patterns for circulating influenza virus strains when deciding
whether to use XOFLUZA. (1.3)
------------------------DOSAGE AND ADMINISTRATION------------------
Treatment and Post-Exposure Prophylaxis of Influenza
XOFLUZA should be taken as a single dose as soon as possible and within 48
hours of influenza symptom onset for treatment of acute uncomplicated
influenza or following contact with an individual who has influenza.
XOFLUZA may be taken with or without food. (2.1, 2.2)
Patient Body
Weight (kg)
Recommended Single Oral Dose in Patients 5 Years
of Age and Older (Tablets)
20 kg to
less than 80 kg
One 40 mg tablet
(blister card contains one 40 mg tablet)
At least 80 kg
One 80 mg tablet
(blister card contains one 80 mg tablet)
Patient Body
Weight (kg)
Recommended Single Oral Dose in Patients 5 Years
of Age and Older (For Oral Suspension)
Less than 20 kg
2 mg/kg taken as a single dose
20 kg to less
than 80 kg
40 mg (20 mL) taken as a single dose
At least 80 kg
80 mg (40 mL) taken as a single dose
Refer to the Full Prescribing Information for additional information on the
recommended dosage and preparation of XOFLUZA for oral suspension for
oral or enteral use in patients 5 years of age and older. (2.2, 2.3)
---------------------DOSAGE FORMS AND STRENGTHS------------------
• Tablets: 40 mg and 80 mg. (3)
• For oral suspension: 40 mg/20 mL when constituted for final concentration
of 2 mg/mL. (3)
-------------------------------CONTRAINDICATIONS-------------------------
XOFLUZA is contraindicated in patients with a history of hypersensitivity to
baloxavir marboxil or any of its ingredients. (4)
--------------------------WARNINGS AND PRECAUTIONS-----------------
• Hypersensitivity such as anaphylaxis, angioedema, urticaria, and erythema
multiforme: Initiate appropriate treatment if an allergic-like reaction occurs
or is suspected. (5.1)
• Increased incidence of Treatment-Emergent Resistance in Patients Less
Than 5 Years of Age: XOFLUZA is not indicated in patients less than 5
years of age due to increased incidence of treatment-emergent resistance in
this age group. In clinical trials, incidence of virus with treatment-emergent
substitutions associated with reduced susceptibility to baloxavir (resistance)
was higher in pediatric subjects younger than 5 years of age than older
subjects. (5.2)
• Risk of bacterial infection: Serious bacterial infections may begin with
influenza-like symptoms or may coexist with, or occur as, a complication
of influenza. XOFLUZA has not been shown to prevent such
complications. Prescribers should be alert to potential secondary bacterial
infections and treat them as appropriate. (5.3)
-------------------------------ADVERSE REACTIONS-----------------------------
Adverse events reported in at least 1% of adult and adolescent influenza
subjects treated with XOFLUZA included diarrhea (3%), bronchitis (3%),
nausea (2%), sinusitis (2%), and headache (1%). (6.1)
Adverse events reported in at least 5% of pediatric subjects (5 to < 12 years)
treated with XOFLUZA included vomiting (5%) and diarrhea (5%).
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
• Avoid coadministration of XOFLUZA with dairy products, calcium-
fortified beverages, polyvalent cation-containing laxatives, antacids, or oral
supplements (e.g., calcium, iron, magnesium, selenium, or zinc). (2.1,7.1)
• Live attenuated influenza vaccines may be affected by antivirals. (7.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved- patient labeling.
Revised: 12/2024
Reference ID: 5498100
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Influenza
1.2 Post-Exposure Prophylaxis of Influenza
1.3 Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1 Dosage and Administration Overview
2.2 Recommended Dosage
2.3 Preparation of XOFLUZA for Oral Suspension by Healthcare
Provider
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity
5.2 Increased Incidence of Treatment-Emergent Resistance in Patients
Less Than 5 Years of Age
5.3 Risk of Bacterial Infections
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Effect of Other Drugs on XOFLUZA
7.2 Vaccines
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4
Microbiology
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Treatment of Acute Uncomplicated Influenza—Otherwise
Healthy Subjects (12 Years of Age and Older)
14.2
Treatment of Acute Uncomplicated Influenza—High Risk
Subjects (12 Years of Age and Older)
14.3
Treatment of Acute Uncomplicated Influenza—Otherwise
Healthy and High Risk Pediatric Subjects (5 to < 12 Years of
Age)
14.4
Post-Exposure Prophylaxis of Influenza (5 Years of Age and
Older)
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 5498100
1
2
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1.1
Treatment of Influenza
XOFLUZA is indicated for treatment of acute uncomplicated influenza in patients 5 years of age and older
who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of
developing influenza-related complications1 [see Clinical Studies (14)].
1.2
Post-Exposure Prophylaxis of Influenza
XOFLUZA is indicated for post-exposure prophylaxis of influenza in persons 5 years of age and older
following contact with an individual who has influenza [see Clinical Studies (14.4)].
1.3
Limitations of Use
Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance,
or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available
information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to
use XOFLUZA [see Warnings and Precautions (5.2), Microbiology (12.4) and Clinical Studies (14)].
DOSAGE AND ADMINISTRATION
2.1
Dosage and Administration Overview
XOFLUZA is available in two dosage forms:
• XOFLUZA tablets (40 mg and 80 mg).
• XOFLUZA for oral suspension (2 mg/mL). This granule formulation is intended for patients who are
unable to or have difficulty swallowing tablets, or those who require enteral administration [see
Dosage and Administration (2.3)].
XOFLUZA should be taken as soon as possible after influenza symptom onset or exposure to influenza and
may be taken with or without food. However, coadministration of XOFLUZA with dairy products, calcium-
fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron,
magnesium, selenium, or zinc) should be avoided [see Drug Interactions (7.1) and Clinical Pharmacology
(12.3)].
Reference ID: 5498100
2.2
Recommended Dosage
Treatment of Acute Uncomplicated Influenza or Post-Exposure Prophylaxis in Adults, and Pediatric Patients
(5 Years of Age and Older)
XOFLUZA should be taken as a single dose as soon as possible and within 48 hours of influenza symptom
onset for treatment of acute uncomplicated influenza or following contact with an individual who has
influenza. The recommended dosage of XOFLUZA in patients 5 years of age or older is a single weight-
based dose displayed in Tables 1 and 2.
Table 1
Recommended XOFLUZA Tablet Dosage in Adults and Pediatric Patients 5 Years of
Age and Older
Patient Body Weight
(kg)
Recommended Single Oral Dose (Tablets)
20 kg to less than 80 kg
One 40 mg tablet
(blister card contains one 40 mg tablet)
At least 80 kg
One 80 mg tablet
(blister card contains one 80 mg tablet)
Table 2
Recommended XOFLUZA for Oral Suspension Dosage in Adults and Pediatric Patients
5 Years of Age and Older
Patient Body Weight
(kg)
Recommended Single Oral Dosea, b (For Oral Suspension)
Less than 20 kg
2 mg/kg taken as a single dose
20 kg to less than 80 kg
40 mg (20 mL) taken as a single dose
At least 80 kg
80 mg (40 mLc) taken as a single dose
a Recommended XOFLUZA dosage is based on the patient’s weight.
b Use a measuring device (oral syringe) to measure the prescribed dose for use.
c Dosage requires two bottles of XOFLUZA for oral suspension.
2.3
Preparation of XOFLUZA for Oral Suspension by Healthcare Provider
Prior to dispensing to the patient, constitute XOFLUZA for oral suspension with 20 mL of drinking water or
sterile water. After constitution, each bottle of XOFLUZA for oral suspension contains 40 mg of baloxavir
marboxil per 20 mL of volume for a final concentration of 2 mg/mL. This dosage form can be used for oral
or enteral use. The contents of the full bottle(s) of XOFLUZA for oral suspension should not be taken
without use of measuring device (oral syringe). Ensure the caregiver or patient uses an oral syringe to
measure the prescribed dose of XOFLUZA for oral suspension. Patients may need to draw up XOFLUZA
for oral suspension multiple times using the oral syringe to receive the full dose.
Constituting XOFLUZA for Oral Suspension
Prepare the suspension at the time of dispensing. Administration must occur within 10 hours after
constitution because the product does not contain a preservative.
1. Gently tap the bottom of the bottle to loosen the granules.
2. Constitute XOFLUZA for oral suspension with 20 mL of drinking water or sterile water.
3. Gently swirl the suspension to ensure that the granules are evenly suspended. Do not shake.
4. Write the expiration time and date on the bottle label in the space provided (10 hours from
constitution time).
Reference ID: 5498100
Important Information for the Healthcare Provider
• Provide caregiver or patient with a measuring device (oral syringe) to deliver the prescribed dose of
the suspension for oral use. For enteral administration (i.e., feeding tube), draw up suspension with
an enteral syringe. Flush with 1 mL of water before and after enteral administration.
• Instruct the caregiver or patient that the total prescribed dose of XOFLUZA for oral suspension may
require:
o less than one bottle (e.g., for pediatric patients 5 years of age and older who weigh less than
20 kg)
o one bottle (e.g., for adults and adolescents weighing 20 kg to less than 80 kg), or
o two bottles (e.g., for adults and adolescents weighing at least 80 kg).
3
DOSAGE FORMS AND STRENGTHS
XOFLUZA Tablets:
XOFLUZA 40 mg tablets are white to light yellow, oblong-shaped, film-coated tablets debossed with
“BXM40” on one side.
XOFLUZA 80 mg tablets are white to light yellow, oblong shaped, film-coated tablets debossed with
“BXM80” on one side.
XOFLUZA for Oral Suspension:
XOFLUZA for oral suspension contains 40 mg/20 mL or 2 mg/mL baloxavir marboxil after constitution
with 20 mL of drinking water or sterile water. The granules are white to light yellow. The constituted
product is a greyish white, white to light yellow opaque suspension with strawberry flavor.
4
CONTRAINDICATIONS
XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of
its ingredients. Serious allergic reactions have included anaphylaxis, angioedema, urticaria, and erythema
multiforme [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity
Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported in postmarketing
experience with XOFLUZA. Appropriate treatment should be instituted if an allergic-like reaction occurs or
is suspected. The use of XOFLUZA is contraindicated in patients with known hypersensitivity to
XOFLUZA [see Contraindications (4) and Adverse Reactions (6.2)].
5.2
Increased Incidence of Treatment-Emergent Resistance in Patients Less Than 5 Years of Age
XOFLUZA is not indicated in patients less than 5 years of age due to increased incidence of treatment-
emergent resistance in this age group. In clinical trials, the incidence of virus with treatment-emergent
substitutions associated with reduced susceptibility to baloxavir (resistance) was higher in pediatric subjects
younger than 5 years of age (40%, 38/96) than in pediatric subjects ≥ 5 years to < 12 years of age (16%,
19/117) or subjects ≥ 12 years of age (7%, 60/842). The potential for transmission of resistant strains in the
community has not been determined [see Indications and Usage (1), Use in Specific Populations (8.4), and
Microbiology (12.4)].
5.3
Risk of Bacterial Infections
There is no evidence of efficacy of XOFLUZA in any illness caused by pathogens other than influenza
viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with, or occur
as, a complication of influenza. XOFLUZA has not been shown to prevent such complications. Prescribers
should be alert to potential secondary bacterial infections and treat them as appropriate.
Reference ID: 5498100
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The overall safety profile of XOFLUZA is based on data from 2,079 subjects, 5 years of age and older in 5
controlled clinical trials who received XOFLUZA. Of these subjects, 1,943 were adults and adolescents (≥
12 years of age) and 136 were in the pediatric age group (5 to < 12 years of age) [see Clinical Studies (14)].
Treatment of Acute Uncomplicated Influenza
Adult and Adolescent Subjects (≥ 12 Years of Age):
The safety of XOFLUZA in adult and adolescent subjects is based on data from 3 placebo-controlled trials
in which a total of 1,640 subjects received XOFLUZA: 1,334 (81%) subjects were 18 to 64 years of age, 209
(13%) subjects were adults 65 years of age or older, and 97 (6%) subjects were adolescents 12 to 17 years of
age. These trials included otherwise healthy adults and adolescents (N=910) and subjects at high risk of
developing complications associated with influenza (N=730). Of these, 1,440 subjects received XOFLUZA
at the recommended dose [see Clinical Studies (14.1, 14.2)]. Trial T0821 was a phase 2 dose-finding
placebo-controlled trial where otherwise healthy adult subjects 20 to 64 years of age received single oral
dose of XOFLUZA or placebo. Trial T0831 was a placebo- and active-controlled trial in otherwise healthy
adults and adolescents 12 to 64 years of age; subjects received weight-based XOFLUZA or placebo as a
single oral dose on Day 1 or oseltamivir twice a day for 5 days. Trial T0832 was a randomized, double-
blind, placebo- and active-controlled trial where adults and adolescents at high risk of influenza
complications 12 years of age and older received either XOFLUZA, placebo or oseltamivir.
Table 3 displays the most common adverse events (regardless of causality assessment) reported in at least
1% of adult and adolescent subjects who received XOFLUZA at the recommended dose in Trials T0821,
T0831, and T0832.
Table 3
Incidence of Adverse Events Occurring in at Least 1% of Adult and Adolescent
Subjects Receiving XOFLUZA in the Acute Uncomplicated Influenza Trials T0821,
T0831, and T0832
Adverse Event
XOFLUZA
(N=1,440)
Placebo
(N=1,136)
Diarrhea
3%
4%
Bronchitis
3%
4%
Nausea
2%
3%
Sinusitis
2%
3%
Headache
1%
1%
Pediatric Subjects (5 to < 12 Years of Age):
In an active-controlled, double-blind trial Trial CP40563 in pediatric subjects, a total of 79 subjects 5 to less
than 12 years of age, received the recommended weight-based dosage of XOFLUZA, and 39 subjects
received oseltamivir. Of the 118 subjects 5 to less than 12 years of age in Trial CP40563, 15 subjects in the
XOFLUZA arm and 4 subjects in the oseltamivir arm were at high risk of developing influenza
complications. The most frequently reported AEs (≥ 5%) in all subjects in the XOFLUZA treatment arm
were vomiting (5%) and diarrhea (5%). Vomiting was reported in 18% of subjects in the oseltamivir arm
[see Clinical Studies (14.1)]. There are limited safety data in patients 5 to <12 years at high risk of
developing influenza complications.
Reference ID: 5498100
Post-Exposure Prophylaxis of Influenza
In a placebo-controlled clinical trial, Trial T0834, conducted in adults, and pediatric subjects ≥ 5 years of
age, a total of 360 subjects received XOFLUZA, of which 291 (81%) were adults ≥ 18 years; 12 (3%)
subjects were adolescents ≥ 12 to 17 years and 57 (16%) were pediatric subjects 5 to < 12 years of age. The
safety profile was similar in pediatric patients aged 5 to < 12 years old as that reported in adults and
adolescents 12 years of age and older [see Clinical Studies (14.3)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of XOFLUZA. Because
these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably
estimate their frequency or establish a causal relationship to XOFLUZA exposure.
Immune System Disorders: Anaphylactic reactions, anaphylactic shock, anaphylactoid reactions,
hypersensitivity reactions, angioedema (swelling of face, eyelids, tongue and lips)
Skin and Subcutaneous Tissue Disorders: Rash, urticaria, erythema multiforme
Gastrointestinal Disorders: Vomiting, hematochezia, melena, colitis
Psychiatric Disorders: Delirium, abnormal behavior, hallucinations
7
DRUG INTERACTIONS
7.1
Effect of Other Drugs on XOFLUZA
Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium.
Coadministration with polyvalent cation-containing products may decrease plasma concentrations of
baloxavir [see Clinical Pharmacology (12.3)], which may reduce XOFLUZA efficacy. Avoid
coadministration of XOFLUZA with dairy products, calcium-fortified beverages, polyvalent cation-
containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc).
7.2
Vaccines
The concurrent use of XOFLUZA with intranasal live attenuated influenza vaccine (LAIV) has not been
evaluated. Concurrent administration of antiviral drugs may inhibit viral replication of LAIV and thereby
decrease the effectiveness of LAIV vaccination. Interactions between inactivated influenza vaccines and
XOFLUZA have not been evaluated.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no adequate and well-controlled studies with XOFLUZA in pregnant women to inform a drug-
associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with
influenza virus infection in pregnancy (see Clinical Considerations). In animal reproduction studies, no
adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir
marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic baloxavir exposure at the
maximum recommended human dose (MRHD) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the
U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2%–4% and 15%–20%, respectively.
Reference ID: 5498100
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse
pregnancy and/or fetal outcomes, including maternal death, stillbirth, birth defects, preterm delivery, low
birth weight, and small for gestational age.
Data
Animal Data
Baloxavir marboxil was administered orally to pregnant rats (20, 200, or 1,000 mg/kg/day from gestation
day 6 to 17) and rabbits (30, 100, or 1,000 mg/kg/day from gestation day 7 to 19). No adverse embryo-fetal
effects were observed in rats up to the highest dose of baloxavir marboxil (1,000 mg/kg/day), resulting in
systemic baloxavir exposure (AUC) of approximately 5 times the exposure at the MRHD. In rabbits, fetal
skeletal variations occurred at a maternally toxic dose (1,000 mg/kg/day) resulting in 2 abortions out of
19 pregnancies. No adverse maternal or embryo-fetal effects were observed in rabbits at the middle dose
(100 mg/kg/day) resulting in systemic baloxavir exposure (AUC) approximately 7 times the exposure at the
MRHD.
In the prenatal and postnatal development study in rats, baloxavir marboxil was administered orally at 20,
200, or 1,000 mg/kg/day from gestation day 6 to postpartum/lactation day 20. No significant effects were
observed in the offspring at maternal systemic baloxavir exposure (AUC) approximately 5 times the
exposure at the MRHD.
8.2
Lactation
Risk Summary
There are no data on the presence of baloxavir marboxil in human milk, the effects on the breastfed infant,
or the effects on milk production. Baloxavir and its related metabolites were present in the milk of lactating
rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for XOFLUZA and any potential adverse effects on the breastfed child from the drug
or from the underlying maternal condition.
Data
In a lactation study, baloxavir and its related metabolites were excreted in the milk of lactating rats
administered baloxavir marboxil (1 mg/kg) on postpartum/lactation day 11, with peak milk concentration
approximately 5 times that of maternal plasma concentrations occurring 2 hours post-dose. No effects of
baloxavir marboxil on growth and postnatal development were observed in nursing pups at the highest oral
dose tested in rats. Maternal systemic exposure was approximately 5 times the baloxavir exposure in humans
at the MRHD.
8.4
Pediatric Use
Treatment of Acute Uncomplicated Influenza in Adolescent Subjects (≥ 12 Years of Age)
The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in adolescent
subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind,
controlled trial in otherwise healthy subjects Trial T0831 and one trial in subjects at high risk of developing
influenza-related complications Trial T0832 [see Clinical Studies (14.1)]. A total of 117 otherwise healthy
adolescents 12 to17 years of age were randomized and received either XOFLUZA (N=76) or placebo
(N=41) in Trial T0831; 38 adolescents 12 to 17 years of age at high risk for influenza complications were
randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial T0832. The median time to
alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial T0831 was
comparable to that observed in adults. In Trial T0832, the median time to improvement of symptoms in the
limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA
Reference ID: 5498100
and placebo arms [see Clinical Studies (14.1)]. Adverse events reported in adolescents in both trials were
similar to those reported in adults [see Adverse Reactions (6.1)].
Treatment of Acute Uncomplicated Influenza in Pediatric Subjects (5 to < 12 Years of Age)
The safety and effectiveness of XOFLUZA in pediatric subjects 5 to less than 12 years of age is supported
by one randomized, double-blind, controlled trial Trial CP40563 with a primary endpoint of safety. In this
trial, 118 pediatric subjects were randomized and treated in a 2:1 ratio and received either XOFLUZA
(N=79) or oseltamivir (N=39). Efficacy was extrapolated from adults and adolescents based on comparable
PK exposures in adults, adolescents and pediatric subjects 5 to less than 12 years of age. The median time to
alleviation of signs and symptoms in influenza-infected subjects was comparable in the XOFLUZA and
oseltamivir arms. Adverse events reported with XOFLUZA in pediatric subjects were similar to those
observed in adults and adolescents except for vomiting and diarrhea, which were both more commonly
reported in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical
Studies (14.1)].
Post-Exposure Prophylaxis of Influenza in Pediatric and Adolescent Subjects (5 to < 18 Years of Age)
The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in pediatric and adolescent
subjects 5 to less than 18 years of age is supported by one randomized, double-blind, controlled trial
conducted in Japan Trial T0834 [see Clinical Studies (14.3)]. Subjects in this trial were randomized in a 1:1
ratio to receive XOFLUZA or placebo. A total of 69 subjects from 5 to <18 years of age in Trial T0834
received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza in pediatric subjects 5 to
<18 years of age was similar to that observed in adult subjects [see Clinical Pharmacology (12.3), and
Clinical Studies (14.3)]. Efficacy was extrapolated from adults based on comparable PK exposures in adults,
adolescents and pediatric subjects 5 to <18 years of age.
Adverse events reported in pediatric and adolescent subjects were similar to those reported in adults in the
same trial [see Adverse Reactions (6.1)].
Pediatric Subjects (< 5 Years of Age)
The safety and effectiveness of XOFLUZA for treatment and post-exposure prophylaxis of influenza in
pediatric subjects less than 5 years of age, including neonates, have not been established [see Warnings and
Precautions (5.2) and Microbiology (12.4)].
8.5
Geriatric Use
The safety and effectiveness of XOFLUZA in subjects 65 years of age and older has been established and is
supported by one randomized, double-blind, controlled trial [see Clinical Studies (14.2)]. In Trial T0832, of
730 XOFLUZA-treated subjects at high risk of influenza-related complications, 209 (29%) subjects were 65
years of age and older. The median time to improvement of influenza symptoms in subjects 65 years of age
and older was 70 hours in subjects who received XOFLUZA (N=112) and 88 hours in those who received
placebo (N=102). The safety profile observed for this population was similar to that reported in the overall
trial population except for nausea, which was reported in 6% of elderly subjects compared to 1% of subjects
from 18 to 64 years of age.
10
OVERDOSAGE
Treatment of an overdose of XOFLUZA should consist of general supportive measures, including
monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for
overdose with XOFLUZA.
Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding [see Clinical
Pharmacology (12.3)].
11
DESCRIPTION
XOFLUZA (baloxavir marboxil) is an influenza virus PA endonuclease inhibitor.
Reference ID: 5498100
F
F
The active component of XOFLUZA is baloxavir marboxil. The chemical name of baloxavir marboxil is
({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a
hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate. The
empirical formula of baloxavir marboxil is C27H23F2N3O7S, and the chemical structure is shown below.
Baloxavir marboxil has a molecular mass of 571.55 grams per mole and a partition coefficient (log P) of
2.26. It is freely soluble in dimethylsulfoxide, soluble in acetonitrile, slightly soluble in methanol and
ethanol, and practically insoluble in water.
XOFLUZA is supplied as tablets and as granules for oral suspension:
XOFLUZA tablets are white to light yellow, film-coated tablets for oral administration. The 40 mg film-
coated tablet contains 40 mg of baloxavir marboxil and the 80 mg film-coated tablet contains 80 mg of
baloxavir marboxil. The inactive ingredients of XOFLUZA tablets are: croscarmellose sodium,
hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and
titanium dioxide.
XOFLUZA for oral suspension is supplied as white to light yellow granules in an amber glass bottle. Each
bottle contains 40 mg (nominal) of baloxavir marboxil. The granules must be constituted with 20 mL of
drinking water or sterile water to yield a 2 mg/mL greyish white, white to light yellow opaque suspension
with strawberry flavor. The inactive ingredients are: colloidal silicon dioxide, hypromellose, maltitol,
mannitol, povidone K25, sodium chloride, strawberry flavor, sucralose and talc.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].
12.2
Pharmacodynamics
Cardiac Electrophysiology
At twice the expected exposure from recommended dosing, XOFLUZA did not prolong the QTc interval.
Exposure-Response Relationships
In patients 5 years of age and older, when XOFLUZA is dosed by weight as recommended, a flat baloxavir
exposure-response (time to alleviation of influenza symptoms) relationship has been observed.
12.3
Pharmacokinetics
Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir,
following oral administration.
Baloxavir pharmacokinetic parameters are presented for healthy adults and adolescents as the mean
[% coefficient of variation (%CV)], unless otherwise specified, in Table 4. Absorption, distribution,
metabolism, and elimination data for XOFLUZA is presented in Table 5.
Reference ID: 5498100
Table 4
Pharmacokinetic Parameters of Plasma Baloxavir in Adults and Adolescents (≥ 12
Years of Age)
Pharmacokinetic Parameters of Plasma Baloxavir in Adults
and Adolescentsa
XOFLUZA dose
40 mg
XOFLUZA dose
80 mg
AUC (ng·hr/mL)
5520 (46.3%)
6930 (48.6%)
Cmax (ng/mL)
68.9 (44.9%)
82.5 (43.0%)
C24 (ng/mL)
50.9 (45.8%)
62.6 (45.9%)
C72 (ng/mL)
24.2 (45.5%)
30.8 (47.0%)
a Trial T0831 summary data, mean (%CV)
Table 5
Baloxavir Absorption, Distribution, Metabolism, Elimination Data
Absorption
Tmax (hr)a
4
Effect of food (relative to fasting)b
Cmax: ↓48%, AUC0-inf: ↓36%
Distribution
% bound to human serum proteinsc
92.9–93.9
Ratio of blood cell to blood
48.5%–54.4%
Volume of distribution (V/F, L)d
1180 (20.8%)
Elimination
Clearance (CL/F, L/hr)
10.3 (22.5%)
Apparent terminal elimination half-life (hr)
79.1 (22.4%)
Metabolism
Metabolic pathways
Primary: UGT1A3
Secondary: CYP3A4
Excretion
% of dose excretede
Urine: 14.7 (total radioactivity); 3.3 (baloxavir)
Feces: 80.1 (total radioactivity)
a Median
b Meal: approximately 400 to 500 kcal including 150 kcal from fat
c in vitro
dGeometric mean (geometric CV%)
e Ratio of radioactivity to radio-labeled baloxavir marboxil dose in mass balance study
No clinically significant differences in the pharmacokinetics of baloxavir were observed based on age, sex,
presence of risk factors for complicated influenza, creatinine clearance (CrCl: 50 mL/min and above), or
moderate hepatic impairment (Child-Pugh class B). The effect of severe renal or hepatic impairment on
baloxavir pharmacokinetics has not been evaluated.
Pediatrics (5 to < 12 Years of Age)
Mean (CV%) baloxavir pharmacokinetics in pediatric subjects 5 to < 12 years of age are described in Table
6. Following the approved recommended dosage, baloxavir exposures are similar in pediatric subjects (5 to
< 12 years of age) compared to adult and adolescent subjects.
Table 6
Pharmacokinetic Parameters of Plasma Baloxavir in Pediatrics (5 to < 12 Years of Age)
Pharmacokinetic Parameters of Plasma
Baloxavir in Pediatricsa
XOFLUZA Dose for Subjects Weighing
< 20 kg
(n=8)
2 mg/kg
XOFLUZA Dose for Subjects Weighing
≥ 20 kg
(n=55)
40 mg
AUCinf (ng.h/mL)
5830 (48.5)
4360 (48.9)
Cmax (ng/mL)
148 (48.7)
81.1 (44.0)
Tmax (h)b
3.5 (2-5.5)
4.5 (2-23.5)
C24 (ng/mL)
77.9 (49.2)
52.4 (43.2)
C72 (ng/mL)
19.3 (49.7)
18.0 (50.9)
a Trial CP40563 summary data, mean (%CV); patients not receiving the recommended dose (n=3) were excluded
b Median (range)
Reference ID: 5498100
Body Weight
Baloxavir exposure decreases as body weight increases. No clinically significant difference in exposure was
observed between body weight groups in adult and pediatric subjects following the approved recommended
dosage.
Race/Ethnicity
Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-
Asians as compared to Asians; this difference is not considered clinically significant when the recommended
dose was administered.
Drug Interaction Studies
Clinical Studies
No clinically significant changes in the pharmacokinetics of baloxavir marboxil and its active metabolite,
baloxavir, were observed when coadministered with itraconazole (combined strong CYP3A and P-gp
inhibitor), probenecid (UGT inhibitor), or oseltamivir.
No clinically significant changes in the pharmacokinetics of the following drugs were observed when
coadministered with baloxavir marboxil: midazolam (CYP3A4 substrate), digoxin (P-gp substrate),
rosuvastatin (BCRP substrate), or oseltamivir.
Animal Studies
Polyvalent Cations: In monkeys, a 48% to 63% decrease in baloxavir exposure was observed when
XOFLUZA was coadministered with calcium, aluminum, magnesium, or iron. No study has been conducted
in humans.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Both baloxavir marboxil and baloxavir do not inhibit CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and do not induce CYP1A2, CYP2B6, or CYP3A4.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Both baloxavir marboxil and
baloxavir do not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.
Transporter Systems: Both baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp).
Baloxavir does not inhibit organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, organic cation
transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion
(MATE) 1, or MATE2K.
12.4
Microbiology
Mechanism of Action
Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-
influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein,
an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene
transcription, resulting in inhibition of influenza virus replication. The 50% inhibitory concentration (IC50)
values of baloxavir ranged from 1.4 to 3.1 nM (n=4) for influenza A viruses and 4.5 to 8.9 nM (n=3) for
influenza B viruses in a PA endonuclease assay. Viruses with reduced susceptibility to baloxavir have amino
acid substitutions in the PA protein.
Antiviral Activity
The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B
viruses was determined in an MDCK cell-based plaque reduction assay. The median 50% effective
concentration (EC50) values of baloxavir were 0.73 nM (n=31; range: 0.20–1.85 nM) for subtype A/H1N1
strains, 0.83 nM (n=33; range: 0.35–2.63 nM) for subtype A/H3N2 strains, and 5.97 nM (n=30; range: 2.67–
14.23 nM) for type B strains. In an MDCK cell-based virus titer reduction assay, the 90% effective
concentration (EC90) values of baloxavir against avian subtypes A/H5N1 and A/H7N9 were in the range of
Reference ID: 5498100
0.80 to 3.16 nM. The relationship between antiviral activity in cell culture and clinical response to treatment
in humans has not been established.
Resistance
Cell Culture
Influenza A virus isolates with reduced susceptibility to baloxavir were selected by serial passage of virus in
cell culture in the presence of increasing concentrations of baloxavir. Reduced susceptibility of influenza A
virus to baloxavir was conferred by amino acid substitutions I38T (A/H1N1 and A/H3N2), E198K
(A/H1N1) and E199G (A/H3N2) in the PA protein of the viral RNA polymerase complex. An E18G
(A/H1N1) substitution in the PA protein, selected by a baloxavir analog, also conferred reduced
susceptibility to baloxavir.
Clinical Studies
Treatment-emergent substitutions were identified in influenza A and B viruses in clinical studies.
Substitutions associated with a >3-fold reduction in susceptibility to baloxavir are shown in Table 7.
Table 7
Treatment-Emergent Amino Acid Substitutions in PA Associated with Reduced
Susceptibility to Baloxavir Identified in Clinical Specimens
Influenza Type/Subtype
A/H1N1
A/H3N2
B
Amino Acid Substitution
E23G/K/R, A37T,
I38F/N/S/T
E23G/K, A37T,
I38M/T, E199G
T20K, I38T
Clinical studies in adult and adolescent subjects ≥ 12 years of age:
In adult and adolescent subjects who had a confirmed influenza virus infection, the overall frequencies of
treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir were 5%
(6/134), 11% (53/485), and 1% (2/224) in influenza A/H1N1, A/H3N2, and B virus infections, respectively,
in pooled data from Trials T0821, T0831, and T0832 [see Clinical Studies (14)]. In Trial T0834, of 303
subjects ≥ 12 years of age who received XOFLUZA post-exposure prophylaxis, 32 were viral RNA-positive
post-baseline, including 17 subjects who were evaluated for resistance. Of these 17 subjects, influenza virus
with substitutions associated with reduced susceptibility to baloxavir was identified in 4/4 subjects who
developed clinical influenza (as described for the primary endpoint) and 6/13 other subjects evaluated who
did not meet the primary endpoint definition for clinical influenza [see Clinical Studies (14)].
Clinical studies in pediatric subjects 5 to < 12 years of age:
Selection of influenza viruses with treatment-emergent amino acid substitutions associated with reduced
susceptibility to baloxavir has occurred at higher frequencies in pediatric subjects 5 to <12 years of age
compared to subjects ≥ 12 years of age. Such viruses were detected with overall frequencies of 17% (2/12),
18% (17/93), and 0% (0/13) in influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled
data from 4 pediatric treatment trials in subjects 5 to < 12 years of age.
In Trial T0834, of a subgroup of 57 subjects 5 to < 12 years of age who received XOFLUZA post-exposure
prophylaxis, 12 were viral-RNA positive post-baseline, including 10 subjects who were evaluated for
resistance. Of these 10 subjects, influenza virus with substitutions associated with reduced susceptibility to
baloxavir was identified in 2/2 subjects who developed clinical influenza (as described for the primary
endpoint) and 1/8 other subjects who did not meet the primary endpoint definition for clinical influenza [see
Clinical Studies (14)].
Clinical studies in pediatrics subjects < 5 years of age:
The highest frequencies of treatment-emergent resistance have been observed in pediatric subjects < 5 years
of age. In treatment trials in subjects < 5 years of age, treatment-emergent amino acid substitutions
associated with reduced susceptibility to baloxavir occurred in 23% (5/22), 58% (32/55), and 5% (1/19) of
influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled data from 5 pediatric treatment
trials.
Reference ID: 5498100
Surveillance Studies
Amino acid substitutions associated with reduced susceptibility to baloxavir have also been identified in
surveillance studies or in cell culture studies evaluating the impact of resistance substitutions identified in
one influenza virus type/subtype on baloxavir susceptibility when introduced into other influenza virus
types/subtypes (Table 8).
Table 8
Amino Acid Substitutions in PA Associated with Reduced Susceptibility to
Baloxavir Identified in Surveillance and in Cell Culture Resistance Studies
Influenza Type/Subtype
A/H1N1
A/H3N2
B
Amino Acid Substitution
A36V†, I38L†/M‡
E23R‡, A36V‡,
I38F‡/N‡/S‡
I38F‡/M‡/N‡/S‡
† Identified in human surveillance isolates, antiviral treatment unknown
‡ Known substitution associated with reduced susceptibility to baloxavir identified in clinical specimens or surveillance isolates but evaluated in
the indicated alternative type/subtype by reverse genetics
None of the treatment-emergent substitutions associated with reduced susceptibility to baloxavir were
identified in virus from pretreatment respiratory specimens in the clinical studies.
Treatment-emergent resistance has been associated with influenza virus rebound and prolonged virus
shedding; however, the impact of prolonged shedding on clinical outcomes and virus transmission potential
is currently unknown.
The frequency of baloxavir resistance and the prevalence of such resistant virus may vary seasonally and
geographically. Prescribers should consider available information from the U.S. CDC and/or a local health
department on current influenza virus drug susceptibility patterns and treatment effects when deciding
whether to use XOFLUZA.
Cross-Resistance
Cross-resistance between baloxavir and neuraminidase (NA) inhibitors, or between baloxavir and M2 proton
pump inhibitors (adamantanes), is not expected because these drugs target different viral proteins. The NA
inhibitor oseltamivir is active against viruses with reduced susceptibility to baloxavir, including A/H1N1
virus with PA substitutions E23K or I38F/T; A/H3N2 virus with PA substitutions E23G/K, A37T, I38M/T,
or E199G; and type B virus with the PA substitution I38T. Influenza virus may carry amino acid
substitutions in PA that reduce susceptibility to baloxavir and at the same time carry resistance-associated
substitutions for NA inhibitors and M2 proton pump inhibitors.
Baloxavir is active against NA inhibitor-resistant strains, including A/H1N1 and A/H5N1 viruses with the
NA substitution H275Y (A/H1N1 numbering), A/H3N2 virus with the NA substitutions E119V or R292K,
A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA
substitutions R152K or D198E (A/H3N2 numbering). The clinical relevance of phenotypic cross-resistance
evaluations has not been established.
Immune Response
Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not been performed with baloxavir marboxil.
Reference ID: 5498100
Mutagenesis
Baloxavir marboxil and the active metabolite, baloxavir, were not mutagenic in in vitro and in in vivo
genotoxicity assays, which included bacterial mutation assays in S. typhimurium and E. coli, micronucleus
tests with cultured mammalian cells, and in the rodent micronucleus assay.
Impairment of Fertility
In a fertility and early embryonic development study in rats, doses of baloxavir marboxil at 20, 200, or
1,000 mg/kg/day were administered to females for 2 weeks before mating, during mating, and until day 7 of
pregnancy. Males were dosed for 4 weeks before mating and throughout mating. There were no effects on
fertility, mating performance, or early embryonic development at any dose level, resulting in systemic drug
exposure (AUC) approximately 5 times the MRHD.
14
CLINICAL STUDIES
14.1
Treatment of Acute Uncomplicated Influenza—Otherwise Healthy Subjects (12 Years of Age
and Older)
Two randomized, controlled, double-blinded clinical trials conducted in two different influenza seasons
evaluated efficacy and safety of XOFLUZA in otherwise healthy subjects with acute uncomplicated
influenza.
In Trial T0821, a placebo-controlled phase 2 dose-finding trial, a single oral dose of XOFLUZA was
compared with placebo in 400 adult subjects 20 to 64 years of age in Japan. All subjects in Trial T0821 were
Asian, the majority of subjects were male (62%), and the mean age was 38 years. In this trial, among
subjects who received XOFLUZA and had influenza virus typed, influenza A/H1N1 was the predominant
strain (63%), followed by influenza B (25%), and influenza A/H3N2 (12%).
In Trial T0831 (NCT02954354), a phase 3, randomized, double-blind, active- and placebo-controlled trial,
XOFLUZA was studied in 1,436 otherwise healthy adults and adolescents with signs and symptoms of
influenza in the U.S. and Japan. Subjects were 12 to 64 years of age and weighed at least 40 kg. Adults aged
20 to 64 years received weight-based XOFLUZA (subjects who weighed 40 to less than 80 kg received 40
mg and subjects who weighed 80 kg and above received 80 mg) (N=612) or placebo as a single oral dose on
day 1 (N=310) or oseltamivir twice a day for 5 days (N=514). Subjects in the XOFLUZA and placebo arms
received a placebo for the duration of oseltamivir dosing after XOFLUZA or placebo dosing in that arm.
Adolescent subjects 12 to less than 20 years of age received weight-based XOFLUZA or placebo as a single
oral dose.
Seventy-eight percent of subjects in Trial T0831 were Asian, 17% were White, and 4% were Black or
African American. The mean age was 34 years, and 11% of subjects were less than 20 years of age; 54% of
subjects were male and 46% female. In Trial T0831, 1,062 of 1,436 enrolled subjects had influenza
confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=455, placebo N=230, or
oseltamivir N=377). Among subjects who received XOFLUZA and had influenza virus typed, influenza
A/H3N2 was the predominant strain (90%), followed by influenza B (9%), and influenza A/H1N1 (2%).
In both Trials T0821 and T0831, eligible subjects had an axillary temperature of at least 38˚C, at least one
moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate
or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were
treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their
influenza symptoms as “none,” “mild,” “moderate,” or “severe” twice daily. The primary efficacy
population was defined as those with a positive rapid influenza diagnostic test (Trial T0821) or positive
influenza reverse transcription polymerase chain reaction (RT-PCR) (Trial T0831) at trial entry.
The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven
symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been
assessed by the subject as none or mild for a duration of at least 21.5 hours.
Reference ID: 5498100
In both trials, XOFLUZA treatment at the recommended dose resulted in a statistically significant shorter
time to alleviation of symptoms compared with placebo in the primary efficacy population (Tables 9 and
10).
Table 9
Time to Alleviation of Symptoms After Single Dose in Otherwise Healthy Adults
with Acute Uncomplicated Influenza in Trial T0821 (Median Hours)
XOFLUZA 40 mg
(95% CIa)
N=100
Placebo
(95% CIa)
N=100
Adults (20 to 64 Years of Age)
50 hoursb
(45, 64)
78 hours
(68, 89)
aCI: Confidence interval
bXOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Gehan
Breslow’s generalized Wilcoxon test (p-value: 0.014, adjusted for multiplicity using the Bonferroni method). The primary analysis using the Cox
Proportional Hazards Model did not reach statistical significance (p-value: 0.165).
Table 10
Time to Alleviation of Symptoms After Single Dose in Otherwise Healthy Subjects
12 Years of Age and Older with Acute Uncomplicated Influenza in Trial T0831
(Median Hours)
XOFLUZA 40 mg or 80 mg
(95% CIa)
N=455
Placebo
(95% CIa)
N=230
Subjects (≥ 12 Years of Age)
54 hoursb
(50, 59)
80 hours
(73, 87)
aCI: Confidence interval
bXOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Peto
Prentice’s generalized Wilcoxon test (p-value: < 0.001).
In Trial T0831, there was no difference in the time to alleviation of symptoms between subjects (age ≥ 20
years) who received XOFLUZA (54 hours) and those who received oseltamivir (54 hours). For adolescent
subjects (12 to 17 years of age) in Trial T0831, the median time to alleviation of symptoms for subjects
infected with influenza and who received XOFLUZA (N=63) was 54 hours (95% CI of 43, 81) compared to
93 hours (95% CI of 64, 118) in the placebo arm (N=27).
The number of subjects who received XOFLUZA at the recommended dose and who were infected with
influenza type B virus was limited, including 24 subjects in Trial T0821 and 38 subjects in Trial T0831. In
the influenza B subset in Trial T0821, the median time to alleviation of symptoms in subjects who received
40 mg XOFLUZA was 63 hours (95% CI of 43, 70) compared to 83 hours (95% CI of 58, 93) in subjects
who received placebo. In the influenza B subset in Trial T0831, the median time to alleviation of symptoms
in subjects who received 40 mg or 80 mg XOFLUZA was 93 hours (95% CI of 53, 135) compared to 77
hours (95% CI of 47, 189) in subjects who received placebo.
14.2
Treatment of Acute Uncomplicated Influenza—High Risk Subjects (12 Years of Age and
Older)
Trial T0832 (NCT02949011) was a randomized, double-blind, placebo- and active-controlled trial to
evaluate the efficacy and safety of a single oral dose of XOFLUZA compared with placebo or oseltamivir in
adult and adolescent subjects 12 years of age or older with influenza who were at high risk of developing
influenza-related complications.
A total of 2,182 subjects with signs and symptoms of influenza were randomized to receive a single oral
dose of 40 mg or 80 mg of XOFLUZA according to body weight (subjects who weighed 40 to less than 80
kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=729), oseltamivir 75 mg
twice daily for 5 days (N=725), or placebo (N=728). Twenty-eight percent of subjects were Asian, 59% were
White, and 10% were Black or African American. The mean age was 52 years, and 3% of subjects were less
Reference ID: 5498100
than 18 years of age; 43% of subjects were male and 57% female.
High risk factors were based on the Centers for Disease Control and Prevention definition1 of health factors
known to increase the risk of developing serious complications from influenza. The majority of subjects had
underlying asthma or chronic lung disease, diabetes, heart disease, morbid obesity, or were 65 years of age
or older.
In Trial T0832, 1,158 of the 2,182 enrolled subjects had influenza confirmed by RT-PCR and were included
in the efficacy analysis (XOFLUZA N=385, placebo N=385, or oseltamivir N=388). Among subjects in
whom only one type/subtype of influenza virus was identified, 50% were infected with subtype A/H3N2,
43% were infected with type B, and 7% were infected with subtype A/H1N1.
Eligible subjects had an axillary temperature of at least 38˚C, at least one moderate or severe respiratory
symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom
(headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of
symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as
“none,” “mild,” “moderate,” or “severe” twice daily. A total of 215 subjects (19%) had preexisting
symptoms (cough, muscle or joint pain, or fatigue) associated with their underlying high risk condition that
were worsened due to influenza infection. The primary efficacy endpoint was time to improvement of
influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint
pain, and fatigue). This endpoint included alleviation of new symptoms and improvement of any preexisting
symptoms that had worsened due to influenza. A statistically significant improvement in the primary
endpoint was observed for XOFLUZA when compared with placebo (see Table 11).
Table 11
Time to Improvement of Symptoms After Single Dose in High Risk Subjects 12 Years
of Age and Older with Acute Uncomplicated Influenza in Trial T0832 (Median Hours)
XOFLUZA 40 mg or 80 mga
(95% CIb)
N=385
Placebo
(95% CIb)
N=385
73 hoursc
(67, 85)
102 hoursc
(93, 113)
aThe dosage of XOFLUZA was based on subject’s weight.
bCI: Confidence interval
cXOFLUZA treatment resulted in a significant reduction in Time to Improvement of Influenza Symptoms compared to placebo using Peto
Prentice’s generalized Wilcoxon test (p-value: < 0.001).
There was no statistically significant difference in the median time to improvement of influenza symptoms
in the subjects who received XOFLUZA (73 hours) and those who received oseltamivir (81 hours). The
median time to improvement of influenza symptoms in the limited number of adolescent subjects aged 12 to
17 years infected with influenza virus was similar for subjects who received XOFLUZA (188 hours) or
placebo (191 hours) (N=13 and N=12, respectively).
For subjects infected with type B virus, the median time to improvement of influenza symptoms was 75
hours in the XOFLUZA group (95% CI of 67, 90) compared to 101 hours in the placebo group (95% CI of
83, 116).
14.3
Treatment of Acute Uncomplicated Influenza—Otherwise Healthy and High-Risk Pediatric
Subjects (5 to < 12 Years of Age)
Trial CP40563 (NCT03629184) was a randomized, double-blind, multicenter, active-controlled trial,
designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of XOFLUZA
compared with oseltamivir in otherwise healthy pediatric subjects (including subjects aged 5 to < 12 years of
age) with influenza-like symptoms. Eligible subjects had a tympanic temperature of at least 38°C and at
least one respiratory symptom of either cough or nasal congestion.
A total of 118 subjects 5 to less than 12 years of age were randomized and received a single one-time oral
dose of XOFLUZA (N=79) based on body weight (2 mg/kg for subjects weighing < 20 kg or 40 mg for
subjects weighing ≥ 20 kg) or oseltamivir (N=39) for 5 days (dose based on body weight). Subjects at high
Reference ID: 5498100
risk of developing complications associated with influenza were included in the trial [16% (19/118)]. The
primary objective was to compare the safety of a single one-time dose of XOFLUZA with 5 days of
oseltamivir administered twice daily. The secondary efficacy endpoint included time to alleviation of
influenza signs and symptoms, which was defined as the time when all of the following were met for at least
21.5 hours: cough and nasal symptoms were assessed by the caregiver as no problem or minor problem,
subject was able to return to normal daily activity, and subject was afebrile (temperature ≤ 37.2°C).
However, the trial was not powered to detect statistically significant differences in this secondary endpoint.
Of the 118 randomized subjects 5 to less than 12 years of age in Trial CP40563, 94 subjects had influenza
confirmed by RT-PCR at baseline or during the trial; 89% percent of subjects were White, 3% Black or
African American and 8% Other/unknown/multiple races. The mean age was 8 years [SD=1.97]; 56% of
subjects were female and 44% male. The predominant influenza virus strain in this trial was the A/H3N2
subtype (67%), followed by A/H1N1 (20%) and type B (9%).
The median time to alleviation of influenza signs and symptoms was 138 hours in the XOFLUZA arm (95%
CI of 117, 163) and 126 hours in the oseltamivir arm (95% CI of 96, 166).
14.4
Post-Exposure Prophylaxis of Influenza (5 Years of Age and Older)
Trial T0834 was a phase 3, randomized, double-blind, multicenter, placebo-controlled trial designed to
evaluate the efficacy of a single oral dose of XOFLUZA compared with placebo in the prevention of
influenza in subjects who were household contacts of influenza-infected patients in Japan. Influenza-
infected index patients were required to have onset of symptoms for ≤ 48 hours, and subjects (household
contacts) were required to have lived with the influenza-infected index patient for ≥ 48 hours.
A total of 715 subjects (XOFLUZA N=360, placebo N=355) 5 years of age and older were randomized and
received a single oral dose of XOFLUZA according to body weight and age, or placebo, on Day 1. Subjects
received a single dose of XOFLUZA according to body weight. The primary efficacy endpoint was the
proportion of household subjects who were infected with influenza virus and presented with fever and at
least one respiratory symptom from day 1 to day 10. Influenza infection was confirmed by RT-PCR, fever
was defined as a body temperature (axillary) ≥ 37.5°C, and respiratory symptoms were defined as having a
symptom of “cough” or “nasal discharge/nasal congestion” with a severity of moderate or severe as assessed
by the subject.
The mean age of subjects that were ≥ 5 years of age in Trial T0834 was 35 years; 108 (15%) were 5 to < 12
years, 33 (5%) were ≥ 12 to < 18 years of age, 551 (77%) were ≥ 18 to < 65 years of age, and 23 (3%) were
≥ 65 years of age. All subjects were Asian, 80% were female, and 20% were male.
In subjects that were 5 years of age and older, there was a statistically significant reduction in the proportion
of household contacts (subjects) with laboratory-confirmed clinical influenza from 13% in the placebo group
to 2% in the XOFLUZA group (see Table 12).
Table 12
Proportion of Household Contacts (Subjects 5 Years of Age and Older) Infected with
Influenza Virus with Fever and at Least One Respiratory Symptom (Trial T0834)
XOFLUZA
Placebo
(95% CIa)
(95% CIa)
N=360
N=355
6 (2%)
47 (13%)
(1%, 4%)
(10%, 17%)
aCI: Confidence interval (%)
XOFLUZA treatment resulted in a significant reduction in the risk ratio of patients who were infected with influenza virus and presented with
fever compared to placebo using modified Poisson regression for a binary response (p-value: < 0.0001).
In the 108 pediatric subjects 5 to less than 12 years of age enrolled in Trial T0834, 57 subjects received
XOFLUZA and 51 received placebo. In this age group, the proportion of subjects with laboratory-confirmed
clinical influenza was 4% in the XOFLUZA group and 14% in the placebo group.
Reference ID: 5498100
15
REFERENCES
1. “People at High Risk For Flu Complications.” Refer to U.S. Centers for Disease Control and
Prevention “Influenza (Flu)” website.
16
HOW SUPPLIED/STORAGE AND HANDLING
XOFLUZA is available as tablets (40 mg and 80 mg) and as oral suspension [40 mg/20 mL (2 mg/mL)]. The
single oral dose to be administered depends on body weight [see Dosage and Administration (2)].
XOFLUZA Tablets
How Supplied
• 40 mg white to light yellow, oblong-shaped, film-coated tablets debossed with “BXM40” on one side
available as:
o 1 x 40 mg tablet per blister card in secondary packaging: NDC 50242-860-01
• 80 mg white to light yellow, oblong shaped, film-coated tablets debossed with “BXM80” on one side
available as:
o 1 x 80 mg tablet per blister card in secondary packaging: NDC 50242-877-01
Storage
Store XOFLUZA Tablets in their blister package at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to
15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].
XOFLUZA for Oral Suspension
How Supplied
XOFLUZA for oral suspension 40 mg/20 mL (2 mg/mL) are white to light yellow granules and is supplied
in an amber glass bottle with a child-resistant cap. When constituted with drinking water or sterile water, the
usable volume of suspension is 20 mL, equivalent to 40 mg of baloxavir marboxil. XOFLUZA for oral
suspension is available as:
• 40 mg/20 mL (2 mg/mL) for oral suspension: NDC 50242-583-01
Handling
The product contains no preservative and must be administered within 10 hours after constitution.
Storage
Store granules at room temperature 20°C to 25°C (68°F to 77°F) and keep in the original bottle; excursions
are permitted between 15°C and 30°C (59°F and 86°F).
Store constituted suspension no longer than 10 hours at room temperature 20°C to 25°C (68°F to 77°F)
when constituted with drinking water or sterile water. The suspension must be discarded if not used within
10 hours of preparation or if suspension has been stored above 25°C (77°F).
Reference ID: 5498100
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Important Dosing Information
Instruct patients to begin treatment with XOFLUZA as soon as possible at the first appearance of influenza
symptoms, within 48 hours of onset of symptoms. Instruct patients to start taking XOFLUZA for prevention
as soon as possible after exposure [see Dosage and Administration (2)].
XOFLUZA can be taken with or without food, but advise patients not to take with dairy products, calcium-
fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron,
magnesium, selenium, or zinc) [see Dosage and Administration (2) and Drug Interactions (7.1)].
Advise patients to follow the healthcare provider’s dosing recommendation for a single, one-time dose of
XOFLUZA. XOFLUZA is dosed based on weight and is available in tablet form or as for oral suspension
for oral or enteral use.
Tablets: Provided as a blister card containing either one tablet of 40 mg, or one tablet of 80 mg as a single
dose [see Dosage and Administration (2.2)].
For oral suspension: Provided in a bottle containing 40 mg/20 mL (2 mg/mL) after constitution by the
healthcare provider [see How Supplied/Storage and Handling (16)]. Advise the patients and/or caregiver to
use a measuring device (oral syringe) to measure their prescribed dose. Counsel patients and/or caregivers
how to use the measuring device (oral syringe) provided and inform patients that they may need to draw up
XOFLUZA for oral suspension multiple times using the oral syringe to receive the full dosage. The
suspension should be taken as soon as possible but no later than 10 hours after constitution by the healthcare
provider because the product does not contain a preservative [see Dosage and Administration (2.2, 2.3)].
Hypersensitivity
Advise patients and/or caregivers of the risk of severe allergic reactions such as anaphylaxis, angioedema,
urticaria, and erythema multiforme. Instruct patients and/or caregivers to seek immediate medical attention
if an allergic-like reaction occurs or is suspected [see Contraindications (4) and Warnings and Precautions
(5.1)].
Influenza Vaccines
Because of the potential for antivirals to decrease the effectiveness of live attenuated influenza vaccines,
advise patients to consult their healthcare provider prior to receiving a live attenuated influenza vaccine after
taking XOFLUZA [see Drug Interactions (7.2)].
Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
XOFLUZA® is a registered trademark of Genentech, Inc.
© 2024 Genentech USA, Inc.
Reference ID: 5498100
PATIENT INFORMATION
XOFLUZA® (zoh-FLEW-zuh)
XOFLUZA® (zoh-FLEW-zuh)
(baloxavir marboxil)
(baloxavir marboxil)
Tablets
for oral suspension
What is XOFLUZA?
XOFLUZA is a prescription medicine used to:
• treat the flu (influenza) in people 5 years of age and older who have flu symptoms for no more than 48 hours and
who are:
o
otherwise healthy or
o
at high risk of developing problems from the flu.
• prevent the flu in people 5 years of age and older following contact with a person who has the flu (post-exposure
prophylaxis).
XOFLUZA does not treat or prevent illness that is caused by infections other than the influenza virus.
XOFLUZA does not prevent bacterial infections that may happen with the flu.
It is not known if XOFLUZA is safe and effective for the treatment and prevention of the flu in children less than 5
years of age. XOFLUZA is not for use in children less than 5 years of age.
Do not take XOFLUZA if you are allergic to baloxavir marboxil or any of the ingredients in XOFLUZA. See the end
of this leaflet for a complete list of ingredients in XOFLUZA.
Before you take XOFLUZA, tell your healthcare provider about all of your medical conditions, including if
you:
• are pregnant or plan to become pregnant. It is not known if XOFLUZA can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if XOFLUZA passes into your breast milk.
Talk to your healthcare provider before you receive a live flu vaccine after taking XOFLUZA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a
new medicine.
How should I take XOFLUZA?
• Take XOFLUZA exactly as directed by your healthcare provider or pharmacist.
• Your healthcare provider will either prescribe:
o
XOFLUZA tablet as a single, one-time dose, or
o
XOFLUZA oral suspension provided with an oral syringe to be given as a single, one-time dose.
• XOFLUZA may be given through a feeding tube. Follow your healthcare provider’s instructions for giving
XOFLUZA through a feeding tube.
• Take XOFLUZA with or without food.
• Do not take XOFLUZA with dairy products, calcium-fortified beverages, laxatives, antacids or oral supplements
containing iron, zinc, selenium, calcium or magnesium.
• If you take too much XOFLUZA, go to the nearest emergency room right away.
If you are taking XOFLUZA for oral suspension:
•
The pharmacist will mix XOFLUZA for oral suspension before it is given to you. If XOFLUZA is not given to you
as a liquid or an oral syringe was not provided, contact your pharmacist.
•
Take XOFLUZA before the expiration time and date written by the pharmacist on the bottle label. Do not
take XOFLUZA if the expiration time and date have passed. Throw away (discard) the bottle and contact your
healthcare provider.
•
Your healthcare provider will prescribe XOFLUZA based on your or your child’s weight. The total prescribed
dose of XOFLUZA for oral suspension may require less than one bottle, one bottle, or two bottles of XOFLUZA.
•
The total prescribed dose of XOFLUZA for oral suspension may require more than one withdrawal from the
bottle with the oral syringe.
•
Contact your healthcare provider or pharmacist if you have any questions on how to take or give the
prescribed dose of XOFLUZA for oral suspension.
Taking or giving a dose of XOFLUZA for oral suspension:
Step 1. Swirl the XOFLUZA for oral suspension bottle well before each use. Do not shake.
Step 2. Open the bottle by pushing downward on the child resistant bottle cap and twisting it in the direction of the
arrow.
Reference ID: 5498100
Step 3. Measure the oral suspension with the oral syringe provided by the pharmacist to be sure you give the
prescribed dose. If the prescribed dose requires more than one withdrawal from the bottle, repeat Steps 3 and 4 for
each withdrawal until you take or give the prescribed dose.
Step 4. Take or give the full contents of the oral syringe.
Step 5. Close the bottle. Throw away any remaining oral suspension and the oral syringe.
What are the possible side effects of XOFLUZA?
XOFLUZA may cause serious side effects, including:
• Allergic reactions. Get emergency medical help right away if you develop any of these signs or symptoms of
an allergic reaction:
o
trouble breathing
o
swelling of your face, throat or mouth
o
skin rash, hives or blisters
o
dizziness or lightheadedness
The most common side effects of XOFLUZA for treatment of the flu in adults and adolescents (12 years of
age and older) include:
• diarrhea
• sinusitis
• bronchitis
• headache
• nausea
The most common side effects of XOFLUZA for treatment of the flu in children (5 years of age to less than
12 years of age) include:
• vomiting
• diarrhea
XOFLUZA is not effective in treating or preventing infections other than influenza. Other kinds of infections can
appear like flu or occur along with flu and may need different kinds of treatment.
Tell your healthcare provider if you feel worse or develop new symptoms during or after treatment with XOFLUZA or
if your flu symptoms do not start to get better.
These are not all the possible side effects of XOFLUZA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store XOFLUZA?
XOFLUZA tablets:
• Store XOFLUZA tablet at room temperature between 68°F to 77°F (20°C to 25°C).
• Store XOFLUZA tablet in the blister package that it comes in.
XOFLUZA for oral suspension:
• Store XOFLUZA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep XOFLUZA for oral suspension in the original container.
• Use XOFLUZA for oral suspension by the expiration time and date written on bottle label. Throw away any
XOFLUZA for oral suspension not used by the time and date on the bottle label, or if it has been stored at a
temperature above 77°F (25°C).
Keep XOFLUZA and all medicines out of the reach of children.
General information about the safe and effective use of XOFLUZA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
XOFLUZA for a condition for which it was not prescribed. Do not give XOFLUZA to other people, even if they have
the same symptoms that you have. It may harm them. You can ask for information about XOFLUZA that is written
for health professionals.
What are the ingredients in XOFLUZA?
Active ingredient: baloxavir marboxil
XOFLUZA tablets inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate,
microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and titanium dioxide.
XOFLUZA for oral suspension inactive ingredients: colloidal silicon dioxide, hypromellose, maltitol, mannitol,
povidone K25, sodium chloride, strawberry flavor, sucralose and talc.
Distributed by: Genentech USA, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990
XOFLUZA® is a registered trademark of Genentech, Inc. © 2024 Genentech USA, Inc.
For more information, go to www.XOFLUZA.com or call 1-855-XOFLUZA (1-855-963-5892).
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 03/2024
Reference ID: 5498100
| custom-source | 2025-02-12T15:48:01.208379 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/210854s021,214410s007lbl.pdf', 'application_number': 210854, 'submission_type': 'SUPPL ', 'submission_number': 21} |
80,683 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
XOFLUZA safely and effectively. See full prescribing information for
XOFLUZA.
XOFLUZA® (baloxavir marboxil) tablets, for oral use
XOFLUZA® (baloxavir marboxil) for oral suspension
Initial U.S. Approval: 2018
-----------------------------RECENT MAJOR CHANGES---------------------
Indications and Usage
Treatment of Influenza (1.1)
03/2024
-----------------------------INDICATIONS AND USAGE----------------------
XOFLUZA is an influenza virus polymerase acidic (PA) endonuclease
inhibitor indicated for:
• Treatment of acute uncomplicated influenza in patients 5 years of age and
older who have been symptomatic for no more than 48 hours and who are
otherwise healthy or at high risk of developing influenza-related
complications. (1.1)
• Post-exposure prophylaxis of influenza in patients 5 years of age and older
following contact with an individual who has influenza. (1.2)
Limitations of Use
Influenza viruses change over time, and factors such as the virus type or
subtype, emergence of resistance, or changes in viral virulence could diminish
the clinical benefit of antiviral drugs. Consider available information on drug
susceptibility patterns for circulating influenza virus strains when deciding
whether to use XOFLUZA. (1.3)
------------------------DOSAGE AND ADMINISTRATION------------------
Treatment and Post-Exposure Prophylaxis of Influenza
XOFLUZA should be taken as a single dose as soon as possible and within 48
hours of influenza symptom onset for treatment of acute uncomplicated
influenza or following contact with an individual who has influenza.
XOFLUZA may be taken with or without food. (2.1, 2.2)
Patient Body
Weight (kg)
Recommended Single Oral Dose in Patients 5 Years
of Age and Older (Tablets)
20 kg to
less than 80 kg
One 40 mg tablet
(blister card contains one 40 mg tablet)
At least 80 kg
One 80 mg tablet
(blister card contains one 80 mg tablet)
Patient Body
Weight (kg)
Recommended Single Oral Dose in Patients 5 Years
of Age and Older (For Oral Suspension)
Less than 20 kg
2 mg/kg taken as a single dose
20 kg to less
than 80 kg
40 mg (20 mL) taken as a single dose
At least 80 kg
80 mg (40 mL) taken as a single dose
Refer to the Full Prescribing Information for additional information on the
recommended dosage and preparation of XOFLUZA for oral suspension for
oral or enteral use in patients 5 years of age and older. (2.2, 2.3)
---------------------DOSAGE FORMS AND STRENGTHS------------------
• Tablets: 40 mg and 80 mg. (3)
• For oral suspension: 40 mg/20 mL when constituted for final concentration
of 2 mg/mL. (3)
-------------------------------CONTRAINDICATIONS-------------------------
XOFLUZA is contraindicated in patients with a history of hypersensitivity to
baloxavir marboxil or any of its ingredients. (4)
--------------------------WARNINGS AND PRECAUTIONS-----------------
• Hypersensitivity such as anaphylaxis, angioedema, urticaria, and erythema
multiforme: Initiate appropriate treatment if an allergic-like reaction occurs
or is suspected. (5.1)
• Increased incidence of Treatment-Emergent Resistance in Patients Less
Than 5 Years of Age: XOFLUZA is not indicated in patients less than 5
years of age due to increased incidence of treatment-emergent resistance in
this age group. In clinical trials, incidence of virus with treatment-emergent
substitutions associated with reduced susceptibility to baloxavir (resistance)
was higher in pediatric subjects younger than 5 years of age than older
subjects. (5.2)
• Risk of bacterial infection: Serious bacterial infections may begin with
influenza-like symptoms or may coexist with, or occur as, a complication
of influenza. XOFLUZA has not been shown to prevent such
complications. Prescribers should be alert to potential secondary bacterial
infections and treat them as appropriate. (5.3)
-------------------------------ADVERSE REACTIONS-----------------------------
Adverse events reported in at least 1% of adult and adolescent influenza
subjects treated with XOFLUZA included diarrhea (3%), bronchitis (3%),
nausea (2%), sinusitis (2%), and headache (1%). (6.1)
Adverse events reported in at least 5% of pediatric subjects (5 to < 12 years)
treated with XOFLUZA included vomiting (5%) and diarrhea (5%).
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
• Avoid coadministration of XOFLUZA with dairy products, calcium-
fortified beverages, polyvalent cation-containing laxatives, antacids, or oral
supplements (e.g., calcium, iron, magnesium, selenium, or zinc). (2.1,7.1)
• Live attenuated influenza vaccines may be affected by antivirals. (7.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved- patient labeling.
Revised: 12/2024
Reference ID: 5498100
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Influenza
1.2 Post-Exposure Prophylaxis of Influenza
1.3 Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1 Dosage and Administration Overview
2.2 Recommended Dosage
2.3 Preparation of XOFLUZA for Oral Suspension by Healthcare
Provider
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity
5.2 Increased Incidence of Treatment-Emergent Resistance in Patients
Less Than 5 Years of Age
5.3 Risk of Bacterial Infections
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Effect of Other Drugs on XOFLUZA
7.2 Vaccines
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4
Microbiology
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Treatment of Acute Uncomplicated Influenza—Otherwise
Healthy Subjects (12 Years of Age and Older)
14.2
Treatment of Acute Uncomplicated Influenza—High Risk
Subjects (12 Years of Age and Older)
14.3
Treatment of Acute Uncomplicated Influenza—Otherwise
Healthy and High Risk Pediatric Subjects (5 to < 12 Years of
Age)
14.4
Post-Exposure Prophylaxis of Influenza (5 Years of Age and
Older)
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 5498100
1
2
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
1.1
Treatment of Influenza
XOFLUZA is indicated for treatment of acute uncomplicated influenza in patients 5 years of age and older
who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of
developing influenza-related complications1 [see Clinical Studies (14)].
1.2
Post-Exposure Prophylaxis of Influenza
XOFLUZA is indicated for post-exposure prophylaxis of influenza in persons 5 years of age and older
following contact with an individual who has influenza [see Clinical Studies (14.4)].
1.3
Limitations of Use
Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance,
or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available
information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to
use XOFLUZA [see Warnings and Precautions (5.2), Microbiology (12.4) and Clinical Studies (14)].
DOSAGE AND ADMINISTRATION
2.1
Dosage and Administration Overview
XOFLUZA is available in two dosage forms:
• XOFLUZA tablets (40 mg and 80 mg).
• XOFLUZA for oral suspension (2 mg/mL). This granule formulation is intended for patients who are
unable to or have difficulty swallowing tablets, or those who require enteral administration [see
Dosage and Administration (2.3)].
XOFLUZA should be taken as soon as possible after influenza symptom onset or exposure to influenza and
may be taken with or without food. However, coadministration of XOFLUZA with dairy products, calcium-
fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron,
magnesium, selenium, or zinc) should be avoided [see Drug Interactions (7.1) and Clinical Pharmacology
(12.3)].
Reference ID: 5498100
2.2
Recommended Dosage
Treatment of Acute Uncomplicated Influenza or Post-Exposure Prophylaxis in Adults, and Pediatric Patients
(5 Years of Age and Older)
XOFLUZA should be taken as a single dose as soon as possible and within 48 hours of influenza symptom
onset for treatment of acute uncomplicated influenza or following contact with an individual who has
influenza. The recommended dosage of XOFLUZA in patients 5 years of age or older is a single weight-
based dose displayed in Tables 1 and 2.
Table 1
Recommended XOFLUZA Tablet Dosage in Adults and Pediatric Patients 5 Years of
Age and Older
Patient Body Weight
(kg)
Recommended Single Oral Dose (Tablets)
20 kg to less than 80 kg
One 40 mg tablet
(blister card contains one 40 mg tablet)
At least 80 kg
One 80 mg tablet
(blister card contains one 80 mg tablet)
Table 2
Recommended XOFLUZA for Oral Suspension Dosage in Adults and Pediatric Patients
5 Years of Age and Older
Patient Body Weight
(kg)
Recommended Single Oral Dosea, b (For Oral Suspension)
Less than 20 kg
2 mg/kg taken as a single dose
20 kg to less than 80 kg
40 mg (20 mL) taken as a single dose
At least 80 kg
80 mg (40 mLc) taken as a single dose
a Recommended XOFLUZA dosage is based on the patient’s weight.
b Use a measuring device (oral syringe) to measure the prescribed dose for use.
c Dosage requires two bottles of XOFLUZA for oral suspension.
2.3
Preparation of XOFLUZA for Oral Suspension by Healthcare Provider
Prior to dispensing to the patient, constitute XOFLUZA for oral suspension with 20 mL of drinking water or
sterile water. After constitution, each bottle of XOFLUZA for oral suspension contains 40 mg of baloxavir
marboxil per 20 mL of volume for a final concentration of 2 mg/mL. This dosage form can be used for oral
or enteral use. The contents of the full bottle(s) of XOFLUZA for oral suspension should not be taken
without use of measuring device (oral syringe). Ensure the caregiver or patient uses an oral syringe to
measure the prescribed dose of XOFLUZA for oral suspension. Patients may need to draw up XOFLUZA
for oral suspension multiple times using the oral syringe to receive the full dose.
Constituting XOFLUZA for Oral Suspension
Prepare the suspension at the time of dispensing. Administration must occur within 10 hours after
constitution because the product does not contain a preservative.
1. Gently tap the bottom of the bottle to loosen the granules.
2. Constitute XOFLUZA for oral suspension with 20 mL of drinking water or sterile water.
3. Gently swirl the suspension to ensure that the granules are evenly suspended. Do not shake.
4. Write the expiration time and date on the bottle label in the space provided (10 hours from
constitution time).
Reference ID: 5498100
Important Information for the Healthcare Provider
• Provide caregiver or patient with a measuring device (oral syringe) to deliver the prescribed dose of
the suspension for oral use. For enteral administration (i.e., feeding tube), draw up suspension with
an enteral syringe. Flush with 1 mL of water before and after enteral administration.
• Instruct the caregiver or patient that the total prescribed dose of XOFLUZA for oral suspension may
require:
o less than one bottle (e.g., for pediatric patients 5 years of age and older who weigh less than
20 kg)
o one bottle (e.g., for adults and adolescents weighing 20 kg to less than 80 kg), or
o two bottles (e.g., for adults and adolescents weighing at least 80 kg).
3
DOSAGE FORMS AND STRENGTHS
XOFLUZA Tablets:
XOFLUZA 40 mg tablets are white to light yellow, oblong-shaped, film-coated tablets debossed with
“BXM40” on one side.
XOFLUZA 80 mg tablets are white to light yellow, oblong shaped, film-coated tablets debossed with
“BXM80” on one side.
XOFLUZA for Oral Suspension:
XOFLUZA for oral suspension contains 40 mg/20 mL or 2 mg/mL baloxavir marboxil after constitution
with 20 mL of drinking water or sterile water. The granules are white to light yellow. The constituted
product is a greyish white, white to light yellow opaque suspension with strawberry flavor.
4
CONTRAINDICATIONS
XOFLUZA is contraindicated in patients with a history of hypersensitivity to baloxavir marboxil or any of
its ingredients. Serious allergic reactions have included anaphylaxis, angioedema, urticaria, and erythema
multiforme [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity
Cases of anaphylaxis, urticaria, angioedema, and erythema multiforme have been reported in postmarketing
experience with XOFLUZA. Appropriate treatment should be instituted if an allergic-like reaction occurs or
is suspected. The use of XOFLUZA is contraindicated in patients with known hypersensitivity to
XOFLUZA [see Contraindications (4) and Adverse Reactions (6.2)].
5.2
Increased Incidence of Treatment-Emergent Resistance in Patients Less Than 5 Years of Age
XOFLUZA is not indicated in patients less than 5 years of age due to increased incidence of treatment-
emergent resistance in this age group. In clinical trials, the incidence of virus with treatment-emergent
substitutions associated with reduced susceptibility to baloxavir (resistance) was higher in pediatric subjects
younger than 5 years of age (40%, 38/96) than in pediatric subjects ≥ 5 years to < 12 years of age (16%,
19/117) or subjects ≥ 12 years of age (7%, 60/842). The potential for transmission of resistant strains in the
community has not been determined [see Indications and Usage (1), Use in Specific Populations (8.4), and
Microbiology (12.4)].
5.3
Risk of Bacterial Infections
There is no evidence of efficacy of XOFLUZA in any illness caused by pathogens other than influenza
viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with, or occur
as, a complication of influenza. XOFLUZA has not been shown to prevent such complications. Prescribers
should be alert to potential secondary bacterial infections and treat them as appropriate.
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6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The overall safety profile of XOFLUZA is based on data from 2,079 subjects, 5 years of age and older in 5
controlled clinical trials who received XOFLUZA. Of these subjects, 1,943 were adults and adolescents (≥
12 years of age) and 136 were in the pediatric age group (5 to < 12 years of age) [see Clinical Studies (14)].
Treatment of Acute Uncomplicated Influenza
Adult and Adolescent Subjects (≥ 12 Years of Age):
The safety of XOFLUZA in adult and adolescent subjects is based on data from 3 placebo-controlled trials
in which a total of 1,640 subjects received XOFLUZA: 1,334 (81%) subjects were 18 to 64 years of age, 209
(13%) subjects were adults 65 years of age or older, and 97 (6%) subjects were adolescents 12 to 17 years of
age. These trials included otherwise healthy adults and adolescents (N=910) and subjects at high risk of
developing complications associated with influenza (N=730). Of these, 1,440 subjects received XOFLUZA
at the recommended dose [see Clinical Studies (14.1, 14.2)]. Trial T0821 was a phase 2 dose-finding
placebo-controlled trial where otherwise healthy adult subjects 20 to 64 years of age received single oral
dose of XOFLUZA or placebo. Trial T0831 was a placebo- and active-controlled trial in otherwise healthy
adults and adolescents 12 to 64 years of age; subjects received weight-based XOFLUZA or placebo as a
single oral dose on Day 1 or oseltamivir twice a day for 5 days. Trial T0832 was a randomized, double-
blind, placebo- and active-controlled trial where adults and adolescents at high risk of influenza
complications 12 years of age and older received either XOFLUZA, placebo or oseltamivir.
Table 3 displays the most common adverse events (regardless of causality assessment) reported in at least
1% of adult and adolescent subjects who received XOFLUZA at the recommended dose in Trials T0821,
T0831, and T0832.
Table 3
Incidence of Adverse Events Occurring in at Least 1% of Adult and Adolescent
Subjects Receiving XOFLUZA in the Acute Uncomplicated Influenza Trials T0821,
T0831, and T0832
Adverse Event
XOFLUZA
(N=1,440)
Placebo
(N=1,136)
Diarrhea
3%
4%
Bronchitis
3%
4%
Nausea
2%
3%
Sinusitis
2%
3%
Headache
1%
1%
Pediatric Subjects (5 to < 12 Years of Age):
In an active-controlled, double-blind trial Trial CP40563 in pediatric subjects, a total of 79 subjects 5 to less
than 12 years of age, received the recommended weight-based dosage of XOFLUZA, and 39 subjects
received oseltamivir. Of the 118 subjects 5 to less than 12 years of age in Trial CP40563, 15 subjects in the
XOFLUZA arm and 4 subjects in the oseltamivir arm were at high risk of developing influenza
complications. The most frequently reported AEs (≥ 5%) in all subjects in the XOFLUZA treatment arm
were vomiting (5%) and diarrhea (5%). Vomiting was reported in 18% of subjects in the oseltamivir arm
[see Clinical Studies (14.1)]. There are limited safety data in patients 5 to <12 years at high risk of
developing influenza complications.
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Post-Exposure Prophylaxis of Influenza
In a placebo-controlled clinical trial, Trial T0834, conducted in adults, and pediatric subjects ≥ 5 years of
age, a total of 360 subjects received XOFLUZA, of which 291 (81%) were adults ≥ 18 years; 12 (3%)
subjects were adolescents ≥ 12 to 17 years and 57 (16%) were pediatric subjects 5 to < 12 years of age. The
safety profile was similar in pediatric patients aged 5 to < 12 years old as that reported in adults and
adolescents 12 years of age and older [see Clinical Studies (14.3)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of XOFLUZA. Because
these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably
estimate their frequency or establish a causal relationship to XOFLUZA exposure.
Immune System Disorders: Anaphylactic reactions, anaphylactic shock, anaphylactoid reactions,
hypersensitivity reactions, angioedema (swelling of face, eyelids, tongue and lips)
Skin and Subcutaneous Tissue Disorders: Rash, urticaria, erythema multiforme
Gastrointestinal Disorders: Vomiting, hematochezia, melena, colitis
Psychiatric Disorders: Delirium, abnormal behavior, hallucinations
7
DRUG INTERACTIONS
7.1
Effect of Other Drugs on XOFLUZA
Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium.
Coadministration with polyvalent cation-containing products may decrease plasma concentrations of
baloxavir [see Clinical Pharmacology (12.3)], which may reduce XOFLUZA efficacy. Avoid
coadministration of XOFLUZA with dairy products, calcium-fortified beverages, polyvalent cation-
containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc).
7.2
Vaccines
The concurrent use of XOFLUZA with intranasal live attenuated influenza vaccine (LAIV) has not been
evaluated. Concurrent administration of antiviral drugs may inhibit viral replication of LAIV and thereby
decrease the effectiveness of LAIV vaccination. Interactions between inactivated influenza vaccines and
XOFLUZA have not been evaluated.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no adequate and well-controlled studies with XOFLUZA in pregnant women to inform a drug-
associated risk of adverse developmental outcomes. There are risks to the mother and fetus associated with
influenza virus infection in pregnancy (see Clinical Considerations). In animal reproduction studies, no
adverse developmental effects were observed in rats or rabbits with oral administration of baloxavir
marboxil at exposures approximately 5 (rats) and 7 (rabbits) times the systemic baloxavir exposure at the
maximum recommended human dose (MRHD) (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the
U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2%–4% and 15%–20%, respectively.
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Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse
pregnancy and/or fetal outcomes, including maternal death, stillbirth, birth defects, preterm delivery, low
birth weight, and small for gestational age.
Data
Animal Data
Baloxavir marboxil was administered orally to pregnant rats (20, 200, or 1,000 mg/kg/day from gestation
day 6 to 17) and rabbits (30, 100, or 1,000 mg/kg/day from gestation day 7 to 19). No adverse embryo-fetal
effects were observed in rats up to the highest dose of baloxavir marboxil (1,000 mg/kg/day), resulting in
systemic baloxavir exposure (AUC) of approximately 5 times the exposure at the MRHD. In rabbits, fetal
skeletal variations occurred at a maternally toxic dose (1,000 mg/kg/day) resulting in 2 abortions out of
19 pregnancies. No adverse maternal or embryo-fetal effects were observed in rabbits at the middle dose
(100 mg/kg/day) resulting in systemic baloxavir exposure (AUC) approximately 7 times the exposure at the
MRHD.
In the prenatal and postnatal development study in rats, baloxavir marboxil was administered orally at 20,
200, or 1,000 mg/kg/day from gestation day 6 to postpartum/lactation day 20. No significant effects were
observed in the offspring at maternal systemic baloxavir exposure (AUC) approximately 5 times the
exposure at the MRHD.
8.2
Lactation
Risk Summary
There are no data on the presence of baloxavir marboxil in human milk, the effects on the breastfed infant,
or the effects on milk production. Baloxavir and its related metabolites were present in the milk of lactating
rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for XOFLUZA and any potential adverse effects on the breastfed child from the drug
or from the underlying maternal condition.
Data
In a lactation study, baloxavir and its related metabolites were excreted in the milk of lactating rats
administered baloxavir marboxil (1 mg/kg) on postpartum/lactation day 11, with peak milk concentration
approximately 5 times that of maternal plasma concentrations occurring 2 hours post-dose. No effects of
baloxavir marboxil on growth and postnatal development were observed in nursing pups at the highest oral
dose tested in rats. Maternal systemic exposure was approximately 5 times the baloxavir exposure in humans
at the MRHD.
8.4
Pediatric Use
Treatment of Acute Uncomplicated Influenza in Adolescent Subjects (≥ 12 Years of Age)
The safety and effectiveness of XOFLUZA for the treatment of acute uncomplicated influenza in adolescent
subjects 12 years of age and older weighing at least 40 kg is supported by one randomized, double-blind,
controlled trial in otherwise healthy subjects Trial T0831 and one trial in subjects at high risk of developing
influenza-related complications Trial T0832 [see Clinical Studies (14.1)]. A total of 117 otherwise healthy
adolescents 12 to17 years of age were randomized and received either XOFLUZA (N=76) or placebo
(N=41) in Trial T0831; 38 adolescents 12 to 17 years of age at high risk for influenza complications were
randomized and received either XOFLUZA (N=21) or placebo (N=17) in Trial T0832. The median time to
alleviation of symptoms in influenza-infected adolescent subjects aged 12 to 17 years in Trial T0831 was
comparable to that observed in adults. In Trial T0832, the median time to improvement of symptoms in the
limited number of influenza-infected adolescent subjects aged 12 to 17 years was similar in the XOFLUZA
Reference ID: 5498100
and placebo arms [see Clinical Studies (14.1)]. Adverse events reported in adolescents in both trials were
similar to those reported in adults [see Adverse Reactions (6.1)].
Treatment of Acute Uncomplicated Influenza in Pediatric Subjects (5 to < 12 Years of Age)
The safety and effectiveness of XOFLUZA in pediatric subjects 5 to less than 12 years of age is supported
by one randomized, double-blind, controlled trial Trial CP40563 with a primary endpoint of safety. In this
trial, 118 pediatric subjects were randomized and treated in a 2:1 ratio and received either XOFLUZA
(N=79) or oseltamivir (N=39). Efficacy was extrapolated from adults and adolescents based on comparable
PK exposures in adults, adolescents and pediatric subjects 5 to less than 12 years of age. The median time to
alleviation of signs and symptoms in influenza-infected subjects was comparable in the XOFLUZA and
oseltamivir arms. Adverse events reported with XOFLUZA in pediatric subjects were similar to those
observed in adults and adolescents except for vomiting and diarrhea, which were both more commonly
reported in pediatric subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical
Studies (14.1)].
Post-Exposure Prophylaxis of Influenza in Pediatric and Adolescent Subjects (5 to < 18 Years of Age)
The safety and effectiveness of XOFLUZA for post-exposure prophylaxis in pediatric and adolescent
subjects 5 to less than 18 years of age is supported by one randomized, double-blind, controlled trial
conducted in Japan Trial T0834 [see Clinical Studies (14.3)]. Subjects in this trial were randomized in a 1:1
ratio to receive XOFLUZA or placebo. A total of 69 subjects from 5 to <18 years of age in Trial T0834
received XOFLUZA. The incidence of RT-PCR-confirmed symptomatic influenza in pediatric subjects 5 to
<18 years of age was similar to that observed in adult subjects [see Clinical Pharmacology (12.3), and
Clinical Studies (14.3)]. Efficacy was extrapolated from adults based on comparable PK exposures in adults,
adolescents and pediatric subjects 5 to <18 years of age.
Adverse events reported in pediatric and adolescent subjects were similar to those reported in adults in the
same trial [see Adverse Reactions (6.1)].
Pediatric Subjects (< 5 Years of Age)
The safety and effectiveness of XOFLUZA for treatment and post-exposure prophylaxis of influenza in
pediatric subjects less than 5 years of age, including neonates, have not been established [see Warnings and
Precautions (5.2) and Microbiology (12.4)].
8.5
Geriatric Use
The safety and effectiveness of XOFLUZA in subjects 65 years of age and older has been established and is
supported by one randomized, double-blind, controlled trial [see Clinical Studies (14.2)]. In Trial T0832, of
730 XOFLUZA-treated subjects at high risk of influenza-related complications, 209 (29%) subjects were 65
years of age and older. The median time to improvement of influenza symptoms in subjects 65 years of age
and older was 70 hours in subjects who received XOFLUZA (N=112) and 88 hours in those who received
placebo (N=102). The safety profile observed for this population was similar to that reported in the overall
trial population except for nausea, which was reported in 6% of elderly subjects compared to 1% of subjects
from 18 to 64 years of age.
10
OVERDOSAGE
Treatment of an overdose of XOFLUZA should consist of general supportive measures, including
monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for
overdose with XOFLUZA.
Baloxavir is unlikely to be significantly removed by dialysis due to high serum protein binding [see Clinical
Pharmacology (12.3)].
11
DESCRIPTION
XOFLUZA (baloxavir marboxil) is an influenza virus PA endonuclease inhibitor.
Reference ID: 5498100
F
F
The active component of XOFLUZA is baloxavir marboxil. The chemical name of baloxavir marboxil is
({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a
hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate. The
empirical formula of baloxavir marboxil is C27H23F2N3O7S, and the chemical structure is shown below.
Baloxavir marboxil has a molecular mass of 571.55 grams per mole and a partition coefficient (log P) of
2.26. It is freely soluble in dimethylsulfoxide, soluble in acetonitrile, slightly soluble in methanol and
ethanol, and practically insoluble in water.
XOFLUZA is supplied as tablets and as granules for oral suspension:
XOFLUZA tablets are white to light yellow, film-coated tablets for oral administration. The 40 mg film-
coated tablet contains 40 mg of baloxavir marboxil and the 80 mg film-coated tablet contains 80 mg of
baloxavir marboxil. The inactive ingredients of XOFLUZA tablets are: croscarmellose sodium,
hypromellose, lactose monohydrate, microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and
titanium dioxide.
XOFLUZA for oral suspension is supplied as white to light yellow granules in an amber glass bottle. Each
bottle contains 40 mg (nominal) of baloxavir marboxil. The granules must be constituted with 20 mL of
drinking water or sterile water to yield a 2 mg/mL greyish white, white to light yellow opaque suspension
with strawberry flavor. The inactive ingredients are: colloidal silicon dioxide, hypromellose, maltitol,
mannitol, povidone K25, sodium chloride, strawberry flavor, sucralose and talc.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].
12.2
Pharmacodynamics
Cardiac Electrophysiology
At twice the expected exposure from recommended dosing, XOFLUZA did not prolong the QTc interval.
Exposure-Response Relationships
In patients 5 years of age and older, when XOFLUZA is dosed by weight as recommended, a flat baloxavir
exposure-response (time to alleviation of influenza symptoms) relationship has been observed.
12.3
Pharmacokinetics
Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir,
following oral administration.
Baloxavir pharmacokinetic parameters are presented for healthy adults and adolescents as the mean
[% coefficient of variation (%CV)], unless otherwise specified, in Table 4. Absorption, distribution,
metabolism, and elimination data for XOFLUZA is presented in Table 5.
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Table 4
Pharmacokinetic Parameters of Plasma Baloxavir in Adults and Adolescents (≥ 12
Years of Age)
Pharmacokinetic Parameters of Plasma Baloxavir in Adults
and Adolescentsa
XOFLUZA dose
40 mg
XOFLUZA dose
80 mg
AUC (ng·hr/mL)
5520 (46.3%)
6930 (48.6%)
Cmax (ng/mL)
68.9 (44.9%)
82.5 (43.0%)
C24 (ng/mL)
50.9 (45.8%)
62.6 (45.9%)
C72 (ng/mL)
24.2 (45.5%)
30.8 (47.0%)
a Trial T0831 summary data, mean (%CV)
Table 5
Baloxavir Absorption, Distribution, Metabolism, Elimination Data
Absorption
Tmax (hr)a
4
Effect of food (relative to fasting)b
Cmax: ↓48%, AUC0-inf: ↓36%
Distribution
% bound to human serum proteinsc
92.9–93.9
Ratio of blood cell to blood
48.5%–54.4%
Volume of distribution (V/F, L)d
1180 (20.8%)
Elimination
Clearance (CL/F, L/hr)
10.3 (22.5%)
Apparent terminal elimination half-life (hr)
79.1 (22.4%)
Metabolism
Metabolic pathways
Primary: UGT1A3
Secondary: CYP3A4
Excretion
% of dose excretede
Urine: 14.7 (total radioactivity); 3.3 (baloxavir)
Feces: 80.1 (total radioactivity)
a Median
b Meal: approximately 400 to 500 kcal including 150 kcal from fat
c in vitro
dGeometric mean (geometric CV%)
e Ratio of radioactivity to radio-labeled baloxavir marboxil dose in mass balance study
No clinically significant differences in the pharmacokinetics of baloxavir were observed based on age, sex,
presence of risk factors for complicated influenza, creatinine clearance (CrCl: 50 mL/min and above), or
moderate hepatic impairment (Child-Pugh class B). The effect of severe renal or hepatic impairment on
baloxavir pharmacokinetics has not been evaluated.
Pediatrics (5 to < 12 Years of Age)
Mean (CV%) baloxavir pharmacokinetics in pediatric subjects 5 to < 12 years of age are described in Table
6. Following the approved recommended dosage, baloxavir exposures are similar in pediatric subjects (5 to
< 12 years of age) compared to adult and adolescent subjects.
Table 6
Pharmacokinetic Parameters of Plasma Baloxavir in Pediatrics (5 to < 12 Years of Age)
Pharmacokinetic Parameters of Plasma
Baloxavir in Pediatricsa
XOFLUZA Dose for Subjects Weighing
< 20 kg
(n=8)
2 mg/kg
XOFLUZA Dose for Subjects Weighing
≥ 20 kg
(n=55)
40 mg
AUCinf (ng.h/mL)
5830 (48.5)
4360 (48.9)
Cmax (ng/mL)
148 (48.7)
81.1 (44.0)
Tmax (h)b
3.5 (2-5.5)
4.5 (2-23.5)
C24 (ng/mL)
77.9 (49.2)
52.4 (43.2)
C72 (ng/mL)
19.3 (49.7)
18.0 (50.9)
a Trial CP40563 summary data, mean (%CV); patients not receiving the recommended dose (n=3) were excluded
b Median (range)
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Body Weight
Baloxavir exposure decreases as body weight increases. No clinically significant difference in exposure was
observed between body weight groups in adult and pediatric subjects following the approved recommended
dosage.
Race/Ethnicity
Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-
Asians as compared to Asians; this difference is not considered clinically significant when the recommended
dose was administered.
Drug Interaction Studies
Clinical Studies
No clinically significant changes in the pharmacokinetics of baloxavir marboxil and its active metabolite,
baloxavir, were observed when coadministered with itraconazole (combined strong CYP3A and P-gp
inhibitor), probenecid (UGT inhibitor), or oseltamivir.
No clinically significant changes in the pharmacokinetics of the following drugs were observed when
coadministered with baloxavir marboxil: midazolam (CYP3A4 substrate), digoxin (P-gp substrate),
rosuvastatin (BCRP substrate), or oseltamivir.
Animal Studies
Polyvalent Cations: In monkeys, a 48% to 63% decrease in baloxavir exposure was observed when
XOFLUZA was coadministered with calcium, aluminum, magnesium, or iron. No study has been conducted
in humans.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Both baloxavir marboxil and baloxavir do not inhibit CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 and do not induce CYP1A2, CYP2B6, or CYP3A4.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Both baloxavir marboxil and
baloxavir do not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.
Transporter Systems: Both baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp).
Baloxavir does not inhibit organic anion-transporting polypeptides (OATP) 1B1, OATP1B3, organic cation
transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion
(MATE) 1, or MATE2K.
12.4
Microbiology
Mechanism of Action
Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-
influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein,
an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene
transcription, resulting in inhibition of influenza virus replication. The 50% inhibitory concentration (IC50)
values of baloxavir ranged from 1.4 to 3.1 nM (n=4) for influenza A viruses and 4.5 to 8.9 nM (n=3) for
influenza B viruses in a PA endonuclease assay. Viruses with reduced susceptibility to baloxavir have amino
acid substitutions in the PA protein.
Antiviral Activity
The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B
viruses was determined in an MDCK cell-based plaque reduction assay. The median 50% effective
concentration (EC50) values of baloxavir were 0.73 nM (n=31; range: 0.20–1.85 nM) for subtype A/H1N1
strains, 0.83 nM (n=33; range: 0.35–2.63 nM) for subtype A/H3N2 strains, and 5.97 nM (n=30; range: 2.67–
14.23 nM) for type B strains. In an MDCK cell-based virus titer reduction assay, the 90% effective
concentration (EC90) values of baloxavir against avian subtypes A/H5N1 and A/H7N9 were in the range of
Reference ID: 5498100
0.80 to 3.16 nM. The relationship between antiviral activity in cell culture and clinical response to treatment
in humans has not been established.
Resistance
Cell Culture
Influenza A virus isolates with reduced susceptibility to baloxavir were selected by serial passage of virus in
cell culture in the presence of increasing concentrations of baloxavir. Reduced susceptibility of influenza A
virus to baloxavir was conferred by amino acid substitutions I38T (A/H1N1 and A/H3N2), E198K
(A/H1N1) and E199G (A/H3N2) in the PA protein of the viral RNA polymerase complex. An E18G
(A/H1N1) substitution in the PA protein, selected by a baloxavir analog, also conferred reduced
susceptibility to baloxavir.
Clinical Studies
Treatment-emergent substitutions were identified in influenza A and B viruses in clinical studies.
Substitutions associated with a >3-fold reduction in susceptibility to baloxavir are shown in Table 7.
Table 7
Treatment-Emergent Amino Acid Substitutions in PA Associated with Reduced
Susceptibility to Baloxavir Identified in Clinical Specimens
Influenza Type/Subtype
A/H1N1
A/H3N2
B
Amino Acid Substitution
E23G/K/R, A37T,
I38F/N/S/T
E23G/K, A37T,
I38M/T, E199G
T20K, I38T
Clinical studies in adult and adolescent subjects ≥ 12 years of age:
In adult and adolescent subjects who had a confirmed influenza virus infection, the overall frequencies of
treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir were 5%
(6/134), 11% (53/485), and 1% (2/224) in influenza A/H1N1, A/H3N2, and B virus infections, respectively,
in pooled data from Trials T0821, T0831, and T0832 [see Clinical Studies (14)]. In Trial T0834, of 303
subjects ≥ 12 years of age who received XOFLUZA post-exposure prophylaxis, 32 were viral RNA-positive
post-baseline, including 17 subjects who were evaluated for resistance. Of these 17 subjects, influenza virus
with substitutions associated with reduced susceptibility to baloxavir was identified in 4/4 subjects who
developed clinical influenza (as described for the primary endpoint) and 6/13 other subjects evaluated who
did not meet the primary endpoint definition for clinical influenza [see Clinical Studies (14)].
Clinical studies in pediatric subjects 5 to < 12 years of age:
Selection of influenza viruses with treatment-emergent amino acid substitutions associated with reduced
susceptibility to baloxavir has occurred at higher frequencies in pediatric subjects 5 to <12 years of age
compared to subjects ≥ 12 years of age. Such viruses were detected with overall frequencies of 17% (2/12),
18% (17/93), and 0% (0/13) in influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled
data from 4 pediatric treatment trials in subjects 5 to < 12 years of age.
In Trial T0834, of a subgroup of 57 subjects 5 to < 12 years of age who received XOFLUZA post-exposure
prophylaxis, 12 were viral-RNA positive post-baseline, including 10 subjects who were evaluated for
resistance. Of these 10 subjects, influenza virus with substitutions associated with reduced susceptibility to
baloxavir was identified in 2/2 subjects who developed clinical influenza (as described for the primary
endpoint) and 1/8 other subjects who did not meet the primary endpoint definition for clinical influenza [see
Clinical Studies (14)].
Clinical studies in pediatrics subjects < 5 years of age:
The highest frequencies of treatment-emergent resistance have been observed in pediatric subjects < 5 years
of age. In treatment trials in subjects < 5 years of age, treatment-emergent amino acid substitutions
associated with reduced susceptibility to baloxavir occurred in 23% (5/22), 58% (32/55), and 5% (1/19) of
influenza A/H1N1, A/H3N2, and B virus infections, respectively, in pooled data from 5 pediatric treatment
trials.
Reference ID: 5498100
Surveillance Studies
Amino acid substitutions associated with reduced susceptibility to baloxavir have also been identified in
surveillance studies or in cell culture studies evaluating the impact of resistance substitutions identified in
one influenza virus type/subtype on baloxavir susceptibility when introduced into other influenza virus
types/subtypes (Table 8).
Table 8
Amino Acid Substitutions in PA Associated with Reduced Susceptibility to
Baloxavir Identified in Surveillance and in Cell Culture Resistance Studies
Influenza Type/Subtype
A/H1N1
A/H3N2
B
Amino Acid Substitution
A36V†, I38L†/M‡
E23R‡, A36V‡,
I38F‡/N‡/S‡
I38F‡/M‡/N‡/S‡
† Identified in human surveillance isolates, antiviral treatment unknown
‡ Known substitution associated with reduced susceptibility to baloxavir identified in clinical specimens or surveillance isolates but evaluated in
the indicated alternative type/subtype by reverse genetics
None of the treatment-emergent substitutions associated with reduced susceptibility to baloxavir were
identified in virus from pretreatment respiratory specimens in the clinical studies.
Treatment-emergent resistance has been associated with influenza virus rebound and prolonged virus
shedding; however, the impact of prolonged shedding on clinical outcomes and virus transmission potential
is currently unknown.
The frequency of baloxavir resistance and the prevalence of such resistant virus may vary seasonally and
geographically. Prescribers should consider available information from the U.S. CDC and/or a local health
department on current influenza virus drug susceptibility patterns and treatment effects when deciding
whether to use XOFLUZA.
Cross-Resistance
Cross-resistance between baloxavir and neuraminidase (NA) inhibitors, or between baloxavir and M2 proton
pump inhibitors (adamantanes), is not expected because these drugs target different viral proteins. The NA
inhibitor oseltamivir is active against viruses with reduced susceptibility to baloxavir, including A/H1N1
virus with PA substitutions E23K or I38F/T; A/H3N2 virus with PA substitutions E23G/K, A37T, I38M/T,
or E199G; and type B virus with the PA substitution I38T. Influenza virus may carry amino acid
substitutions in PA that reduce susceptibility to baloxavir and at the same time carry resistance-associated
substitutions for NA inhibitors and M2 proton pump inhibitors.
Baloxavir is active against NA inhibitor-resistant strains, including A/H1N1 and A/H5N1 viruses with the
NA substitution H275Y (A/H1N1 numbering), A/H3N2 virus with the NA substitutions E119V or R292K,
A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA
substitutions R152K or D198E (A/H3N2 numbering). The clinical relevance of phenotypic cross-resistance
evaluations has not been established.
Immune Response
Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not been performed with baloxavir marboxil.
Reference ID: 5498100
Mutagenesis
Baloxavir marboxil and the active metabolite, baloxavir, were not mutagenic in in vitro and in in vivo
genotoxicity assays, which included bacterial mutation assays in S. typhimurium and E. coli, micronucleus
tests with cultured mammalian cells, and in the rodent micronucleus assay.
Impairment of Fertility
In a fertility and early embryonic development study in rats, doses of baloxavir marboxil at 20, 200, or
1,000 mg/kg/day were administered to females for 2 weeks before mating, during mating, and until day 7 of
pregnancy. Males were dosed for 4 weeks before mating and throughout mating. There were no effects on
fertility, mating performance, or early embryonic development at any dose level, resulting in systemic drug
exposure (AUC) approximately 5 times the MRHD.
14
CLINICAL STUDIES
14.1
Treatment of Acute Uncomplicated Influenza—Otherwise Healthy Subjects (12 Years of Age
and Older)
Two randomized, controlled, double-blinded clinical trials conducted in two different influenza seasons
evaluated efficacy and safety of XOFLUZA in otherwise healthy subjects with acute uncomplicated
influenza.
In Trial T0821, a placebo-controlled phase 2 dose-finding trial, a single oral dose of XOFLUZA was
compared with placebo in 400 adult subjects 20 to 64 years of age in Japan. All subjects in Trial T0821 were
Asian, the majority of subjects were male (62%), and the mean age was 38 years. In this trial, among
subjects who received XOFLUZA and had influenza virus typed, influenza A/H1N1 was the predominant
strain (63%), followed by influenza B (25%), and influenza A/H3N2 (12%).
In Trial T0831 (NCT02954354), a phase 3, randomized, double-blind, active- and placebo-controlled trial,
XOFLUZA was studied in 1,436 otherwise healthy adults and adolescents with signs and symptoms of
influenza in the U.S. and Japan. Subjects were 12 to 64 years of age and weighed at least 40 kg. Adults aged
20 to 64 years received weight-based XOFLUZA (subjects who weighed 40 to less than 80 kg received 40
mg and subjects who weighed 80 kg and above received 80 mg) (N=612) or placebo as a single oral dose on
day 1 (N=310) or oseltamivir twice a day for 5 days (N=514). Subjects in the XOFLUZA and placebo arms
received a placebo for the duration of oseltamivir dosing after XOFLUZA or placebo dosing in that arm.
Adolescent subjects 12 to less than 20 years of age received weight-based XOFLUZA or placebo as a single
oral dose.
Seventy-eight percent of subjects in Trial T0831 were Asian, 17% were White, and 4% were Black or
African American. The mean age was 34 years, and 11% of subjects were less than 20 years of age; 54% of
subjects were male and 46% female. In Trial T0831, 1,062 of 1,436 enrolled subjects had influenza
confirmed by RT-PCR and were included in the efficacy analysis (XOFLUZA N=455, placebo N=230, or
oseltamivir N=377). Among subjects who received XOFLUZA and had influenza virus typed, influenza
A/H3N2 was the predominant strain (90%), followed by influenza B (9%), and influenza A/H1N1 (2%).
In both Trials T0821 and T0831, eligible subjects had an axillary temperature of at least 38˚C, at least one
moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate
or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue), and all were
treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their
influenza symptoms as “none,” “mild,” “moderate,” or “severe” twice daily. The primary efficacy
population was defined as those with a positive rapid influenza diagnostic test (Trial T0821) or positive
influenza reverse transcription polymerase chain reaction (RT-PCR) (Trial T0831) at trial entry.
The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven
symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been
assessed by the subject as none or mild for a duration of at least 21.5 hours.
Reference ID: 5498100
In both trials, XOFLUZA treatment at the recommended dose resulted in a statistically significant shorter
time to alleviation of symptoms compared with placebo in the primary efficacy population (Tables 9 and
10).
Table 9
Time to Alleviation of Symptoms After Single Dose in Otherwise Healthy Adults
with Acute Uncomplicated Influenza in Trial T0821 (Median Hours)
XOFLUZA 40 mg
(95% CIa)
N=100
Placebo
(95% CIa)
N=100
Adults (20 to 64 Years of Age)
50 hoursb
(45, 64)
78 hours
(68, 89)
aCI: Confidence interval
bXOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Gehan
Breslow’s generalized Wilcoxon test (p-value: 0.014, adjusted for multiplicity using the Bonferroni method). The primary analysis using the Cox
Proportional Hazards Model did not reach statistical significance (p-value: 0.165).
Table 10
Time to Alleviation of Symptoms After Single Dose in Otherwise Healthy Subjects
12 Years of Age and Older with Acute Uncomplicated Influenza in Trial T0831
(Median Hours)
XOFLUZA 40 mg or 80 mg
(95% CIa)
N=455
Placebo
(95% CIa)
N=230
Subjects (≥ 12 Years of Age)
54 hoursb
(50, 59)
80 hours
(73, 87)
aCI: Confidence interval
bXOFLUZA treatment resulted in a statistically significant shorter time to alleviation of symptoms compared to placebo using the Peto
Prentice’s generalized Wilcoxon test (p-value: < 0.001).
In Trial T0831, there was no difference in the time to alleviation of symptoms between subjects (age ≥ 20
years) who received XOFLUZA (54 hours) and those who received oseltamivir (54 hours). For adolescent
subjects (12 to 17 years of age) in Trial T0831, the median time to alleviation of symptoms for subjects
infected with influenza and who received XOFLUZA (N=63) was 54 hours (95% CI of 43, 81) compared to
93 hours (95% CI of 64, 118) in the placebo arm (N=27).
The number of subjects who received XOFLUZA at the recommended dose and who were infected with
influenza type B virus was limited, including 24 subjects in Trial T0821 and 38 subjects in Trial T0831. In
the influenza B subset in Trial T0821, the median time to alleviation of symptoms in subjects who received
40 mg XOFLUZA was 63 hours (95% CI of 43, 70) compared to 83 hours (95% CI of 58, 93) in subjects
who received placebo. In the influenza B subset in Trial T0831, the median time to alleviation of symptoms
in subjects who received 40 mg or 80 mg XOFLUZA was 93 hours (95% CI of 53, 135) compared to 77
hours (95% CI of 47, 189) in subjects who received placebo.
14.2
Treatment of Acute Uncomplicated Influenza—High Risk Subjects (12 Years of Age and
Older)
Trial T0832 (NCT02949011) was a randomized, double-blind, placebo- and active-controlled trial to
evaluate the efficacy and safety of a single oral dose of XOFLUZA compared with placebo or oseltamivir in
adult and adolescent subjects 12 years of age or older with influenza who were at high risk of developing
influenza-related complications.
A total of 2,182 subjects with signs and symptoms of influenza were randomized to receive a single oral
dose of 40 mg or 80 mg of XOFLUZA according to body weight (subjects who weighed 40 to less than 80
kg received 40 mg and subjects who weighed 80 kg and above received 80 mg) (N=729), oseltamivir 75 mg
twice daily for 5 days (N=725), or placebo (N=728). Twenty-eight percent of subjects were Asian, 59% were
White, and 10% were Black or African American. The mean age was 52 years, and 3% of subjects were less
Reference ID: 5498100
than 18 years of age; 43% of subjects were male and 57% female.
High risk factors were based on the Centers for Disease Control and Prevention definition1 of health factors
known to increase the risk of developing serious complications from influenza. The majority of subjects had
underlying asthma or chronic lung disease, diabetes, heart disease, morbid obesity, or were 65 years of age
or older.
In Trial T0832, 1,158 of the 2,182 enrolled subjects had influenza confirmed by RT-PCR and were included
in the efficacy analysis (XOFLUZA N=385, placebo N=385, or oseltamivir N=388). Among subjects in
whom only one type/subtype of influenza virus was identified, 50% were infected with subtype A/H3N2,
43% were infected with type B, and 7% were infected with subtype A/H1N1.
Eligible subjects had an axillary temperature of at least 38˚C, at least one moderate or severe respiratory
symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom
(headache, feverishness or chills, muscle or joint pain, or fatigue), and all were treated within 48 hours of
symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as
“none,” “mild,” “moderate,” or “severe” twice daily. A total of 215 subjects (19%) had preexisting
symptoms (cough, muscle or joint pain, or fatigue) associated with their underlying high risk condition that
were worsened due to influenza infection. The primary efficacy endpoint was time to improvement of
influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint
pain, and fatigue). This endpoint included alleviation of new symptoms and improvement of any preexisting
symptoms that had worsened due to influenza. A statistically significant improvement in the primary
endpoint was observed for XOFLUZA when compared with placebo (see Table 11).
Table 11
Time to Improvement of Symptoms After Single Dose in High Risk Subjects 12 Years
of Age and Older with Acute Uncomplicated Influenza in Trial T0832 (Median Hours)
XOFLUZA 40 mg or 80 mga
(95% CIb)
N=385
Placebo
(95% CIb)
N=385
73 hoursc
(67, 85)
102 hoursc
(93, 113)
aThe dosage of XOFLUZA was based on subject’s weight.
bCI: Confidence interval
cXOFLUZA treatment resulted in a significant reduction in Time to Improvement of Influenza Symptoms compared to placebo using Peto
Prentice’s generalized Wilcoxon test (p-value: < 0.001).
There was no statistically significant difference in the median time to improvement of influenza symptoms
in the subjects who received XOFLUZA (73 hours) and those who received oseltamivir (81 hours). The
median time to improvement of influenza symptoms in the limited number of adolescent subjects aged 12 to
17 years infected with influenza virus was similar for subjects who received XOFLUZA (188 hours) or
placebo (191 hours) (N=13 and N=12, respectively).
For subjects infected with type B virus, the median time to improvement of influenza symptoms was 75
hours in the XOFLUZA group (95% CI of 67, 90) compared to 101 hours in the placebo group (95% CI of
83, 116).
14.3
Treatment of Acute Uncomplicated Influenza—Otherwise Healthy and High-Risk Pediatric
Subjects (5 to < 12 Years of Age)
Trial CP40563 (NCT03629184) was a randomized, double-blind, multicenter, active-controlled trial,
designed to evaluate the safety, efficacy, and pharmacokinetics of a single oral dose of XOFLUZA
compared with oseltamivir in otherwise healthy pediatric subjects (including subjects aged 5 to < 12 years of
age) with influenza-like symptoms. Eligible subjects had a tympanic temperature of at least 38°C and at
least one respiratory symptom of either cough or nasal congestion.
A total of 118 subjects 5 to less than 12 years of age were randomized and received a single one-time oral
dose of XOFLUZA (N=79) based on body weight (2 mg/kg for subjects weighing < 20 kg or 40 mg for
subjects weighing ≥ 20 kg) or oseltamivir (N=39) for 5 days (dose based on body weight). Subjects at high
Reference ID: 5498100
risk of developing complications associated with influenza were included in the trial [16% (19/118)]. The
primary objective was to compare the safety of a single one-time dose of XOFLUZA with 5 days of
oseltamivir administered twice daily. The secondary efficacy endpoint included time to alleviation of
influenza signs and symptoms, which was defined as the time when all of the following were met for at least
21.5 hours: cough and nasal symptoms were assessed by the caregiver as no problem or minor problem,
subject was able to return to normal daily activity, and subject was afebrile (temperature ≤ 37.2°C).
However, the trial was not powered to detect statistically significant differences in this secondary endpoint.
Of the 118 randomized subjects 5 to less than 12 years of age in Trial CP40563, 94 subjects had influenza
confirmed by RT-PCR at baseline or during the trial; 89% percent of subjects were White, 3% Black or
African American and 8% Other/unknown/multiple races. The mean age was 8 years [SD=1.97]; 56% of
subjects were female and 44% male. The predominant influenza virus strain in this trial was the A/H3N2
subtype (67%), followed by A/H1N1 (20%) and type B (9%).
The median time to alleviation of influenza signs and symptoms was 138 hours in the XOFLUZA arm (95%
CI of 117, 163) and 126 hours in the oseltamivir arm (95% CI of 96, 166).
14.4
Post-Exposure Prophylaxis of Influenza (5 Years of Age and Older)
Trial T0834 was a phase 3, randomized, double-blind, multicenter, placebo-controlled trial designed to
evaluate the efficacy of a single oral dose of XOFLUZA compared with placebo in the prevention of
influenza in subjects who were household contacts of influenza-infected patients in Japan. Influenza-
infected index patients were required to have onset of symptoms for ≤ 48 hours, and subjects (household
contacts) were required to have lived with the influenza-infected index patient for ≥ 48 hours.
A total of 715 subjects (XOFLUZA N=360, placebo N=355) 5 years of age and older were randomized and
received a single oral dose of XOFLUZA according to body weight and age, or placebo, on Day 1. Subjects
received a single dose of XOFLUZA according to body weight. The primary efficacy endpoint was the
proportion of household subjects who were infected with influenza virus and presented with fever and at
least one respiratory symptom from day 1 to day 10. Influenza infection was confirmed by RT-PCR, fever
was defined as a body temperature (axillary) ≥ 37.5°C, and respiratory symptoms were defined as having a
symptom of “cough” or “nasal discharge/nasal congestion” with a severity of moderate or severe as assessed
by the subject.
The mean age of subjects that were ≥ 5 years of age in Trial T0834 was 35 years; 108 (15%) were 5 to < 12
years, 33 (5%) were ≥ 12 to < 18 years of age, 551 (77%) were ≥ 18 to < 65 years of age, and 23 (3%) were
≥ 65 years of age. All subjects were Asian, 80% were female, and 20% were male.
In subjects that were 5 years of age and older, there was a statistically significant reduction in the proportion
of household contacts (subjects) with laboratory-confirmed clinical influenza from 13% in the placebo group
to 2% in the XOFLUZA group (see Table 12).
Table 12
Proportion of Household Contacts (Subjects 5 Years of Age and Older) Infected with
Influenza Virus with Fever and at Least One Respiratory Symptom (Trial T0834)
XOFLUZA
Placebo
(95% CIa)
(95% CIa)
N=360
N=355
6 (2%)
47 (13%)
(1%, 4%)
(10%, 17%)
aCI: Confidence interval (%)
XOFLUZA treatment resulted in a significant reduction in the risk ratio of patients who were infected with influenza virus and presented with
fever compared to placebo using modified Poisson regression for a binary response (p-value: < 0.0001).
In the 108 pediatric subjects 5 to less than 12 years of age enrolled in Trial T0834, 57 subjects received
XOFLUZA and 51 received placebo. In this age group, the proportion of subjects with laboratory-confirmed
clinical influenza was 4% in the XOFLUZA group and 14% in the placebo group.
Reference ID: 5498100
15
REFERENCES
1. “People at High Risk For Flu Complications.” Refer to U.S. Centers for Disease Control and
Prevention “Influenza (Flu)” website.
16
HOW SUPPLIED/STORAGE AND HANDLING
XOFLUZA is available as tablets (40 mg and 80 mg) and as oral suspension [40 mg/20 mL (2 mg/mL)]. The
single oral dose to be administered depends on body weight [see Dosage and Administration (2)].
XOFLUZA Tablets
How Supplied
• 40 mg white to light yellow, oblong-shaped, film-coated tablets debossed with “BXM40” on one side
available as:
o 1 x 40 mg tablet per blister card in secondary packaging: NDC 50242-860-01
• 80 mg white to light yellow, oblong shaped, film-coated tablets debossed with “BXM80” on one side
available as:
o 1 x 80 mg tablet per blister card in secondary packaging: NDC 50242-877-01
Storage
Store XOFLUZA Tablets in their blister package at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to
15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature].
XOFLUZA for Oral Suspension
How Supplied
XOFLUZA for oral suspension 40 mg/20 mL (2 mg/mL) are white to light yellow granules and is supplied
in an amber glass bottle with a child-resistant cap. When constituted with drinking water or sterile water, the
usable volume of suspension is 20 mL, equivalent to 40 mg of baloxavir marboxil. XOFLUZA for oral
suspension is available as:
• 40 mg/20 mL (2 mg/mL) for oral suspension: NDC 50242-583-01
Handling
The product contains no preservative and must be administered within 10 hours after constitution.
Storage
Store granules at room temperature 20°C to 25°C (68°F to 77°F) and keep in the original bottle; excursions
are permitted between 15°C and 30°C (59°F and 86°F).
Store constituted suspension no longer than 10 hours at room temperature 20°C to 25°C (68°F to 77°F)
when constituted with drinking water or sterile water. The suspension must be discarded if not used within
10 hours of preparation or if suspension has been stored above 25°C (77°F).
Reference ID: 5498100
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Important Dosing Information
Instruct patients to begin treatment with XOFLUZA as soon as possible at the first appearance of influenza
symptoms, within 48 hours of onset of symptoms. Instruct patients to start taking XOFLUZA for prevention
as soon as possible after exposure [see Dosage and Administration (2)].
XOFLUZA can be taken with or without food, but advise patients not to take with dairy products, calcium-
fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron,
magnesium, selenium, or zinc) [see Dosage and Administration (2) and Drug Interactions (7.1)].
Advise patients to follow the healthcare provider’s dosing recommendation for a single, one-time dose of
XOFLUZA. XOFLUZA is dosed based on weight and is available in tablet form or as for oral suspension
for oral or enteral use.
Tablets: Provided as a blister card containing either one tablet of 40 mg, or one tablet of 80 mg as a single
dose [see Dosage and Administration (2.2)].
For oral suspension: Provided in a bottle containing 40 mg/20 mL (2 mg/mL) after constitution by the
healthcare provider [see How Supplied/Storage and Handling (16)]. Advise the patients and/or caregiver to
use a measuring device (oral syringe) to measure their prescribed dose. Counsel patients and/or caregivers
how to use the measuring device (oral syringe) provided and inform patients that they may need to draw up
XOFLUZA for oral suspension multiple times using the oral syringe to receive the full dosage. The
suspension should be taken as soon as possible but no later than 10 hours after constitution by the healthcare
provider because the product does not contain a preservative [see Dosage and Administration (2.2, 2.3)].
Hypersensitivity
Advise patients and/or caregivers of the risk of severe allergic reactions such as anaphylaxis, angioedema,
urticaria, and erythema multiforme. Instruct patients and/or caregivers to seek immediate medical attention
if an allergic-like reaction occurs or is suspected [see Contraindications (4) and Warnings and Precautions
(5.1)].
Influenza Vaccines
Because of the potential for antivirals to decrease the effectiveness of live attenuated influenza vaccines,
advise patients to consult their healthcare provider prior to receiving a live attenuated influenza vaccine after
taking XOFLUZA [see Drug Interactions (7.2)].
Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
XOFLUZA® is a registered trademark of Genentech, Inc.
© 2024 Genentech USA, Inc.
Reference ID: 5498100
PATIENT INFORMATION
XOFLUZA® (zoh-FLEW-zuh)
XOFLUZA® (zoh-FLEW-zuh)
(baloxavir marboxil)
(baloxavir marboxil)
Tablets
for oral suspension
What is XOFLUZA?
XOFLUZA is a prescription medicine used to:
• treat the flu (influenza) in people 5 years of age and older who have flu symptoms for no more than 48 hours and
who are:
o
otherwise healthy or
o
at high risk of developing problems from the flu.
• prevent the flu in people 5 years of age and older following contact with a person who has the flu (post-exposure
prophylaxis).
XOFLUZA does not treat or prevent illness that is caused by infections other than the influenza virus.
XOFLUZA does not prevent bacterial infections that may happen with the flu.
It is not known if XOFLUZA is safe and effective for the treatment and prevention of the flu in children less than 5
years of age. XOFLUZA is not for use in children less than 5 years of age.
Do not take XOFLUZA if you are allergic to baloxavir marboxil or any of the ingredients in XOFLUZA. See the end
of this leaflet for a complete list of ingredients in XOFLUZA.
Before you take XOFLUZA, tell your healthcare provider about all of your medical conditions, including if
you:
• are pregnant or plan to become pregnant. It is not known if XOFLUZA can harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if XOFLUZA passes into your breast milk.
Talk to your healthcare provider before you receive a live flu vaccine after taking XOFLUZA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a
new medicine.
How should I take XOFLUZA?
• Take XOFLUZA exactly as directed by your healthcare provider or pharmacist.
• Your healthcare provider will either prescribe:
o
XOFLUZA tablet as a single, one-time dose, or
o
XOFLUZA oral suspension provided with an oral syringe to be given as a single, one-time dose.
• XOFLUZA may be given through a feeding tube. Follow your healthcare provider’s instructions for giving
XOFLUZA through a feeding tube.
• Take XOFLUZA with or without food.
• Do not take XOFLUZA with dairy products, calcium-fortified beverages, laxatives, antacids or oral supplements
containing iron, zinc, selenium, calcium or magnesium.
• If you take too much XOFLUZA, go to the nearest emergency room right away.
If you are taking XOFLUZA for oral suspension:
•
The pharmacist will mix XOFLUZA for oral suspension before it is given to you. If XOFLUZA is not given to you
as a liquid or an oral syringe was not provided, contact your pharmacist.
•
Take XOFLUZA before the expiration time and date written by the pharmacist on the bottle label. Do not
take XOFLUZA if the expiration time and date have passed. Throw away (discard) the bottle and contact your
healthcare provider.
•
Your healthcare provider will prescribe XOFLUZA based on your or your child’s weight. The total prescribed
dose of XOFLUZA for oral suspension may require less than one bottle, one bottle, or two bottles of XOFLUZA.
•
The total prescribed dose of XOFLUZA for oral suspension may require more than one withdrawal from the
bottle with the oral syringe.
•
Contact your healthcare provider or pharmacist if you have any questions on how to take or give the
prescribed dose of XOFLUZA for oral suspension.
Taking or giving a dose of XOFLUZA for oral suspension:
Step 1. Swirl the XOFLUZA for oral suspension bottle well before each use. Do not shake.
Step 2. Open the bottle by pushing downward on the child resistant bottle cap and twisting it in the direction of the
arrow.
Reference ID: 5498100
Step 3. Measure the oral suspension with the oral syringe provided by the pharmacist to be sure you give the
prescribed dose. If the prescribed dose requires more than one withdrawal from the bottle, repeat Steps 3 and 4 for
each withdrawal until you take or give the prescribed dose.
Step 4. Take or give the full contents of the oral syringe.
Step 5. Close the bottle. Throw away any remaining oral suspension and the oral syringe.
What are the possible side effects of XOFLUZA?
XOFLUZA may cause serious side effects, including:
• Allergic reactions. Get emergency medical help right away if you develop any of these signs or symptoms of
an allergic reaction:
o
trouble breathing
o
swelling of your face, throat or mouth
o
skin rash, hives or blisters
o
dizziness or lightheadedness
The most common side effects of XOFLUZA for treatment of the flu in adults and adolescents (12 years of
age and older) include:
• diarrhea
• sinusitis
• bronchitis
• headache
• nausea
The most common side effects of XOFLUZA for treatment of the flu in children (5 years of age to less than
12 years of age) include:
• vomiting
• diarrhea
XOFLUZA is not effective in treating or preventing infections other than influenza. Other kinds of infections can
appear like flu or occur along with flu and may need different kinds of treatment.
Tell your healthcare provider if you feel worse or develop new symptoms during or after treatment with XOFLUZA or
if your flu symptoms do not start to get better.
These are not all the possible side effects of XOFLUZA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store XOFLUZA?
XOFLUZA tablets:
• Store XOFLUZA tablet at room temperature between 68°F to 77°F (20°C to 25°C).
• Store XOFLUZA tablet in the blister package that it comes in.
XOFLUZA for oral suspension:
• Store XOFLUZA for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep XOFLUZA for oral suspension in the original container.
• Use XOFLUZA for oral suspension by the expiration time and date written on bottle label. Throw away any
XOFLUZA for oral suspension not used by the time and date on the bottle label, or if it has been stored at a
temperature above 77°F (25°C).
Keep XOFLUZA and all medicines out of the reach of children.
General information about the safe and effective use of XOFLUZA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
XOFLUZA for a condition for which it was not prescribed. Do not give XOFLUZA to other people, even if they have
the same symptoms that you have. It may harm them. You can ask for information about XOFLUZA that is written
for health professionals.
What are the ingredients in XOFLUZA?
Active ingredient: baloxavir marboxil
XOFLUZA tablets inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate,
microcrystalline cellulose, povidone, sodium stearyl fumarate, talc, and titanium dioxide.
XOFLUZA for oral suspension inactive ingredients: colloidal silicon dioxide, hypromellose, maltitol, mannitol,
povidone K25, sodium chloride, strawberry flavor, sucralose and talc.
Distributed by: Genentech USA, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990
XOFLUZA® is a registered trademark of Genentech, Inc. © 2024 Genentech USA, Inc.
For more information, go to www.XOFLUZA.com or call 1-855-XOFLUZA (1-855-963-5892).
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 03/2024
Reference ID: 5498100
| custom-source | 2025-02-12T15:48:01.550670 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/210854s021,214410s007lbl.pdf', 'application_number': 214410, 'submission_type': 'SUPPL ', 'submission_number': 7} |
80,684 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
VEKLURY safely and effectively. See full prescribing information
for VEKLURY.
VEKLURY® (remdesivir) for injection, for intravenous use
VEKLURY® (remdesivir) injection, for intravenous use
Initial U.S. Approval: 2020
---------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
02/2024
Dosage and Administration
Dosage and Administration Overview (2.1)
02/2024
Recommended Dosage in Adults and Pediatric Patients
(Birth to Less than 18 Years of Age Weighing at Least
1.5 kg) (2.3)
02/2024
Dosage Preparation and Administration in Pediatric
Patients (Birth to Less than 18 Years of Age) Weighing
1.5 kg to Less than 40 kg (2.6)
02/2024
---------------------------INDICATIONS AND USAGE----------------------------
VEKLURY is a severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) nucleotide analog RNA polymerase inhibitor indicated
for the treatment of coronavirus disease 2019 (COVID-19) in adults
and pediatric patients (birth to less than 18 years of age weighing at
least 1.5 kg) who are:
• Hospitalized, or
• Not hospitalized and have mild-to-moderate COVID-19, and are at
high risk for progression to severe COVID-19, including
hospitalization or death. (1)
------------------------DOSAGE AND ADMINISTRATION----------------------
• The only approved dosage form of VEKLURY for pediatric patients
weighing 1.5 kg to less than 40 kg is VEKLURY for injection
(supplied as 100 mg lyophilized powder in vial). (2.1)
• Testing: In all patients, before starting VEKLURY and during
treatment as clinically appropriate, perform hepatic laboratory
testing. Assess prothrombin time before starting VEKLURY and
monitor as clinically appropriate. (2.2)
• Recommended dosage:
o Adults and pediatric patients weighing at least 40 kg: a single
loading dose of VEKLURY 200 mg on Day 1 followed by once-
daily maintenance doses of VEKLURY 100 mg from Day 2 via
intravenous infusion. (2.3)
o Pediatric patients (birth to less than 18 years of age) weighing
1.5 kg to less than 40 kg: Recommended dosage is based on
weight. Refer to Table 1 of the full prescribing information for
specific dosing guidelines based on body weight. (2.3)
• Hospitalized patients: The treatment course of VEKLURY should be
initiated as soon as possible after diagnosis of symptomatic COVID
19 has been made. (2.3)
o For hospitalized patients requiring invasive mechanical
ventilation and/or ECMO, the recommended total treatment
duration is 10 days. (2.3)
o For hospitalized patients not requiring invasive mechanical
ventilation and/or ECMO, the recommended treatment duration
is 5 days. If a patient does not demonstrate clinical improvement,
treatment may be extended for up to 5 additional days for a total
treatment duration of up to 10 days. (2.3)
• Non-hospitalized patients: The treatment course of VEKLURY
should be initiated as soon as possible after diagnosis of
symptomatic COVID-19 has been made and within 7 days of
symptom onset. (2.3)
o For non-hospitalized patients diagnosed with mild-to-moderate
COVID-19 who are at high risk for progression to severe COVID
19, including hospitalization or death, the recommended total
treatment duration is 3 days (2.3).
• Renal impairment: No dosage adjustment of VEKLURY is
recommended in patients with any degree of renal impairment,
including those on dialysis. (2.4)
• Administer VEKLURY via intravenous (IV) infusion over 30 to 120
minutes. (2.5, 2.6)
• Dose preparation and administration: Refer to the full prescribing
information for further details for both formulations. (2.5, 2.6)
• Storage of prepared dosages: VEKLURY contains no preservative.
(2.7)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
• For injection: 100 mg of remdesivir as a lyophilized powder, in a
single-dose vial. (3)
• Injection: 100 mg/20 mL (5 mg/mL) remdesivir, in a single-dose vial.
(3)
-------------------------------CONTRAINDICATIONS------------------------------
VEKLURY is contraindicated in patients with a history of clinically
significant hypersensitivity reactions to VEKLURY or any components
of the product. (4)
--------------------------WARNINGS AND PRECAUTIONS--------------------
• Hypersensitivity including infusion-related and anaphylactic
reactions: Hypersensitivity reactions have been observed during and
following administration of VEKLURY. Slower infusion rates, with a
maximum infusion time of up to 120 minutes, can be considered to
potentially prevent signs and symptoms of hypersensitivity. Monitor
patients during infusion and observe patients for at least one
hour after infusion is complete for signs and symptoms of
hypersensitivity as clinically appropriate. If signs and symptoms of a
clinically significant hypersensitivity reaction occur, immediately
discontinue administration of VEKLURY and initiate appropriate
treatment. (5.1)
• Increased risk of transaminase elevations: Transaminase elevations
have been observed in healthy volunteers and have also been
reported in patients with COVID-19 who received VEKLURY.
Perform hepatic laboratory testing in all patients before starting
VEKLURY and while receiving VEKLURY as clinically appropriate.
Consider discontinuing VEKLURY if ALT levels increase to greater
than 10 times the upper limit of normal. Discontinue VEKLURY if
ALT elevation is accompanied by signs or symptoms of liver
inflammation. (5.2)
• Risk of reduced antiviral activity when coadministered with
chloroquine phosphate or hydroxychloroquine sulfate:
Coadministration of VEKLURY and chloroquine phosphate or
hydroxychloroquine sulfate is not recommended based on data from
cell culture experiments demonstrating a potential antagonistic
effect of chloroquine on the intracellular metabolic activation and
antiviral activity of VEKLURY. (5.3)
------------------------------ ADVERSE REACTIONS -----------------------------
The most common adverse reactions (incidence greater than or equal
to 5%, all grades) observed with treatment with VEKLURY are nausea,
ALT increased, and AST increased. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
1
Reference ID: 5499606
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Dosage and Administration Overview
2.2
Testing Before Starting and During Treatment with
VEKLURY
2.3
Recommended Dosage in Adults and Pediatric Patients
(Birth to Less than 18 Years of Age Weighing at Least
1.5 kg)
2.4
Renal Impairment
2.5
Dosage Preparation and Administration in Adults and
Pediatric Patients Weighing at Least 40 kg
2.6
Dosage Preparation and Administration in Pediatric Patients
(Birth to Less than 18 Years of Age) Weighing 1.5 kg to Less
than 40 kg
2.7
Storage of Prepared Dosages
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Including Infusion-related and Anaphylactic
Reactions
5.2
Increased Risk of Transaminase Elevations
5.3
Risk of Reduced Antiviral Activity When Coadministered with
Chloroquine Phosphate or Hydroxychloroquine Sulfate
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
7 DRUG INTERACTIONS
7.1
Effects of Other Drugs on VEKLURY
7.2
Effects of VEKLURY on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
14.2 NIAID ACTT-1 Study in Hospitalized Subjects with
Mild/Moderate and Severe COVID-19
14.3 Study GS-US-540-5773 in Hospitalized Subjects with Severe
COVID-19
14.4 Study GS-US-540-5774 in Hospitalized Subjects with
Moderate COVID-19
14.5 Study GS-US-540-9012 in Non-Hospitalized Subjects with
Mild-to-Moderate COVID-19 and at High Risk for
Progression to Severe Disease
14.6 Study GS-US-540-5823 in Hospitalized Pediatric Subjects
with COVID-19
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
2
Reference ID: 5499606
1
2
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
VEKLURY is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and
pediatric patients (birth to less than 18 years of age weighing at least 1.5 kg) who are [see Clinical
Studies (14)]:
• Hospitalized, or
• Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to
severe COVID-19, including hospitalization or death.
DOSAGE AND ADMINISTRATION
2.1 Dosage and Administration Overview
• VEKLURY may only be administered in settings in which healthcare providers have immediate
access to medications to treat a severe infusion or hypersensitivity reaction, such as anaphylaxis,
and the ability to activate the emergency medical system (EMS), as necessary [see Dosage and
Administration (2.5, 2.6), Warnings and Precautions (5.1)].
• Administer VEKLURY for the treatment of COVID-19 in adults and pediatric patients (birth to less
than 18 years of age weighing at least 1.5 kg) by intravenous infusion only. Do not administer by
any other route.
• There are TWO different formulations of VEKLURY:
o VEKLURY for injection (supplied as 100 mg lyophilized powder in vial) must be reconstituted
with Sterile Water for Injection prior to diluting with 0.9% sodium chloride injection.
•
The only approved dosage form of VEKLURY for pediatric patients weighing 1.5 kg
to less than 40 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder
in vial).
o VEKLURY injection (supplied as 100 mg/20 mL [5 mg/mL] solution in vial) must be further
diluted in 250 mL of 0.9% sodium chloride injection infusion bag.
• There are differences in the way the two formulations are prepared. Carefully follow the product-
specific preparation instructions below [see Dosage and Administration (2.5, 2.6)].
2.2 Testing Before Starting and During Treatment with VEKLURY
Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving
VEKLURY as clinically appropriate [see Warnings and Precautions (5.2) and Use in Specific
Populations (8.7)].
Determine prothrombin time in all patients before starting VEKLURY and monitor while receiving
VEKLURY as clinically appropriate [see Adverse Reactions (6.1)].
3
Reference ID: 5499606
2.3 Recommended Dosage in Adults and Pediatric Patients (Birth to Less than 18 Years of
Age Weighing at Least 1.5 kg)
• The recommended dosage for adults and pediatric patients weighing at least 40 kg is a single
loading dose of VEKLURY 200 mg on Day 1 via intravenous infusion followed by once-daily
maintenance doses of VEKLURY 100 mg from Day 2 via intravenous infusion.
• The recommended dosage for pediatric patients weighing 1.5 kg to less than 40 kg is presented in
Table 1.
Table 1
Recommended Dosage in Pediatric Patients Including Terma Neonates and
Infants Weighing 1.5 kg to Less than 40 kg
Pediatric Patient Population
Loading Dose
Via Intravenous Infusion
Maintenance Dose
Via Intravenous Infusion
Less than 28 days old
and at least 1.5 kg
VEKLURY 2.5 mg/kg on Day 1
VEKLURY 1.25 mg/kg
once daily from Day 2
At least 28 days old
and 1.5 kg to less than 3 kg
At least 28 days old
and 3 kg to less than 40 kg
VEKLURY 5 mg/kg on Day 1
VEKLURY 2.5 mg/kg once
daily from Day 2
a.
Gestational age greater than 37 weeks.
The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of
symptomatic COVID-19 has been made.
• The recommended total treatment duration for hospitalized patients requiring invasive mechanical
ventilation and/or extracorporeal membrane oxygenation (ECMO) is 10 days.
• The recommended treatment duration for hospitalized patients not requiring invasive mechanical
ventilation and/or ECMO is 5 days. If a patient does not demonstrate clinical improvement,
treatment may be extended for up to 5 additional days for a total treatment duration of up to 10
days.
Non-hospitalized patients:
The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of
symptomatic COVID-19 has been made and within 7 days of symptom onset.
• The recommended total treatment duration for non-hospitalized patients diagnosed with mild-to
moderate COVID-19 who are at high risk for progression to severe COVID-19, including
hospitalization or death, is 3 days.
VEKLURY must be diluted prior to intravenous infusion. Refer to Dosage and Administration (2.5, 2.6)
for detailed preparation and administration instructions.
4
Reference ID: 5499606
2.4 Renal Impairment
No dosage adjustment of VEKLURY is recommended in patients with any degree of renal
impairment, including patients on dialysis. VEKLURY may be administered without regard to the
timing of dialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.4, 8.6)].
2.5 Dosage Preparation and Administration in Adults and Pediatric Patients Weighing at
Least 40 kg
There are differences in the way the two formulations are prepared. Carefully follow the
product-specific preparation instructions below.
VEKLURY for Injection (Supplied as 100 mg Lyophilized Powder in Vial)
Reconstitution Instructions
Remove the required number of single-dose vial(s) from storage. For each vial:
• Aseptically reconstitute VEKLURY lyophilized powder by adding 19 mL of Sterile Water for
Injection using a suitably sized syringe and needle per vial, and insert the needle in the center of
the vial stopper.
• Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder.
• Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial.
• Immediately shake the vial for 30 seconds.
• Allow the contents of the vial to settle for 2 to 3 minutes. A clear, colorless to yellow solution, free
of visible particles, should result.
• If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and
allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the
contents of the vial are completely dissolved. Discard the vial if the contents are not completely
dissolved.
• Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution.
• Use reconstituted product immediately to prepare the diluted drug product [see Dosage and
Administration (2.7)].
Dilution Instructions
Care should be taken during admixture to prevent inadvertent microbial contamination. As
there is no preservative or bacteriostatic agent present in this product, aseptic technique must be
used in preparation of the final parenteral solution. It is always recommended to administer
intravenous medication immediately after preparation when possible.
• Reconstituted VEKLURY for injection, containing 100 mg/20 mL remdesivir solution, must be
further diluted in either a 100 mL or 250 mL 0.9% sodium chloride injection infusion bag. Refer to
Table 2 for instructions.
5
Reference ID: 5499606
Table 2
Recommended Dilution Instructions—Reconstituted VEKLURY for Injection
Lyophilized Powder in Adults and Pediatric Patients Weighing at Least 40 kg
VEKLURY dose
0.9% sodium
chloride
injection
infusion bag
volume to be
used
Volume to be withdrawn
and discarded from
0.9% sodium chloride
injection infusion bag
Required volume of
reconstituted VEKLURY
for injection
Loading dose
200 mg
(2 vials)
250 mL
40 mL
40 mL (2 × 20 mL)
100 mL
40 mL
40 mL (2 × 20 mL)
Maintenance dose
100 mg
(1 vial)
250 mL
20 mL
20 mL
100 mL
20 mL
20 mL
• Withdraw and discard the required volume of 0.9% sodium chloride injection from the bag
following instructions in Table 2, using an appropriately sized syringe and needle.
• Withdraw the required volume of reconstituted VEKLURY for injection from the VEKLURY vial
following instructions in Table 2, using an appropriately sized syringe. Discard any unused portion
remaining in the reconstituted vial.
• Transfer the required volume of reconstituted VEKLURY for injection to the selected infusion bag.
• Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
• The prepared infusion solution can be stored for 24 hours at room temperature (20°C to 25°C
[68°F to 77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) prior to
administration.
Administration Instructions
Do not administer the prepared diluted solution simultaneously with any other medication. The
compatibility of VEKLURY injection with intravenous solutions and medications other than 0.9%
sodium chloride injection, USP is not known. Administer VEKLURY via intravenous infusion over 30
to 120 minutes.
Administration should be under conditions where management of severe hypersensitivity reactions,
such as anaphylaxis, is possible. Monitor patients during infusion and observe patients for at least
one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically
appropriate [see Warnings and Precautions (5.1)].
Administer the diluted solution with the infusion rate described in Table 3.
6
Reference ID: 5499606
Table 3
Recommended Rate of Infusion—Diluted VEKLURY for Injection Lyophilized
Powder in Adults and Pediatric Patients Weighing at Least 40 kg
Infusion bag volume
Infusion time
Rate of infusion
30 min
8.33 mL/min
250 mL
60 min
4.17 mL/min
120 min
2.08 mL/min
30 min
3.33 mL/min
100 mL
60 min
1.67 mL/min
120 min
0.83 mL/min
VEKLURY Injection (Supplied as 100 mg/20 mL [5 mg/mL] Solution in Vial)
Dilution Instructions
Care should be taken during admixture to prevent inadvertent microbial contamination. As
there is no preservative or bacteriostatic agent present in this product, aseptic technique must be
used in preparation of the final parenteral solution. It is always recommended to administer
intravenous medication immediately after preparation when possible.
• Remove the required number of single-dose vial(s) from storage. Each vial contains 100 mg/20
mL of remdesivir. For each vial:
• Equilibrate to room temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to
12 hours at room temperature prior to dilution.
• Inspect the vial to ensure the container closure is free from defects and the solution is free of
particulate matter.
• VEKLURY injection must be diluted in an infusion bag containing 250 mL of 0.9% sodium chloride
injection only. Refer to Table 4 for instructions.
7
Reference ID: 5499606
Table 4
Recommended Dilution Instructions—VEKLURY Injection (Supplied as Solution
in Vial) in Adults and Pediatric Patients Weighing at Least 40 kg
0.9% sodium
Volume to be
chloride
withdrawn and
VEKLURY dose
injection
infusion bag
volume to be
used
discarded from
0.9% sodium
chloride injection
infusion bag
Required volume of
VEKLURY injection
Loading dose
200 mg
(2 vials)
250 mL
40 mL
40 mL (2 × 20 mL)
Maintenance dose
100 mg
(1 vial)
20 mL
20 mL
• Withdraw and discard the required volume of 0.9% sodium chloride injection from the bag
following instructions in Table 4, using an appropriately sized syringe and needle.
• Withdraw the required volume of VEKLURY injection from the VEKLURY vial following instructions
in Table 4, using an appropriately sized syringe.
• Pull the syringe plunger rod back to fill the syringe with approximately 10 mL of air.
• Inject the air into the VEKLURY injection vial above the level of the solution.
• Invert the vial and withdraw the required volume of VEKLURY injection solution into the syringe.
The last 5 mL of solution requires more force to withdraw.
• Transfer the required volume of VEKLURY injection to the infusion bag.
• Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
• The prepared infusion solution is stable for 24 hours at room temperature (20°C to 25°C [68°F to
77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
Administration Instructions
Do not administer the prepared diluted solution simultaneously with any other medication. The
compatibility of VEKLURY injection with intravenous solutions and medications other than 0.9%
sodium chloride injection, USP is not known. Administer VEKLURY via intravenous infusion over 30
to 120 minutes.
Administration should be under conditions where management of severe hypersensitivity reactions,
such as anaphylaxis, is possible. Monitor patients during infusion and observe patients for at least
one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically
appropriate [see Warnings and Precautions (5.1)].
Administer the diluted solution with the infusion rate described in Table 5.
8
Reference ID: 5499606
Table 5
Recommended Rate of Infusion—Diluted VEKLURY Injection Solution in Adults
and Pediatric Patients Weighing at Least 40 kg
Infusion bag volume
Infusion time
Rate of infusion
30 min
8.33 mL/min
250 mL
60 min
4.17 mL/min
120 min
2.08 mL/min
2.6 Dosage Preparation and Administration in Pediatric Patients (Birth to Less than 18 Years
of Age) Weighing 1.5 kg to Less than 40 kg
The only approved dosage form of VEKLURY for pediatric patients weighing 1.5 kg to less
than 40 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder in vial). Carefully
follow the product-specific preparation instructions below.
Use VEKLURY for Injection (Supplied as 100 mg Lyophilized Powder in Vial) only.
Reconstitution Instructions
Remove the required number of single-dose vial(s) from storage. For each vial:
• Aseptically reconstitute VEKLURY lyophilized powder by adding 19 mL of Sterile Water for
Injection using a suitably sized syringe and needle per vial, and insert the needle in the center of
the vial stopper.
• Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder.
• Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial.
• Immediately shake the vial for 30 seconds.
• Allow the contents of the vial to settle for 2 to 3 minutes. A clear, colorless to yellow solution, free
of visible particles, should result.
• If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and
allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the
contents of the vial are completely dissolved. Discard the vial if the contents are not completely
dissolved.
• Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution.
• Use reconstituted product immediately to prepare the diluted drug product [see Dosage and
Administration (2.7)].
Dilution Instructions
• For pediatric patients (birth to less than 18 years of age) weighing 1.5 kg to less than 40 kg, the
100 mg/20 mL (5 mg/mL) remdesivir reconstituted solution should be further diluted to a fixed
concentration of 1.25 mg/mL using 0.9% sodium chloride injection.
• The final required infusion volume concentration of 1.25 mg/mL remdesivir diluted solution for
infusion is based on the pediatric weight-based dosing regimens.
• Small 0.9% sodium chloride injection infusion bags (e.g., 25, 50, or 100 mL) or an appropriately
sized syringe should be used for pediatric dosing. The recommended dose is administered via
9
Reference ID: 5499606
intravenous infusion in a total volume dependent on the dose to yield the target remdesivir
concentration of 1.25 mg/mL.
• A syringe and syringe pump may be used for infusion volumes less than 50 mL.
Infusion with IV Bag
• Determine the total infusion volume needed to achieve a final infusion volume concentration of
1.25 mg/mL of remdesivir diluted solution based on the patient’s calculated dose.
• Select an appropriately sized infusion bag (either prefilled with 0.9% sodium chloride injection or
empty) to prepare VEKLURY diluted solution.
• If using a prefilled 0.9% sodium chloride injection infusion bag, withdraw and discard the amount
of diluent equal to the volume of reconstituted VEKLURY solution needed per patient’s dose plus
a quantity sufficient to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted
solution.
• Withdraw the required volume of reconstituted VEKLURY solution into an appropriately sized
syringe.
• Transfer the required volume of reconstituted VEKLURY solution to the 0.9% sodium chloride
injection infusion bag.
• Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
• If using an empty infusion bag, transfer the required volume of reconstituted VEKLURY solution to
the bag, followed by a volume of 0.9% sodium chloride injection sufficient to achieve a 1.25
mg/mL final volume concentration of remdesivir diluted solution.
• The prepared infusion solution is stable for 24 hours at room temperature (20°C to 25°C [68°F to
77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
Infusion with Syringe
• Determine the total infusion volume needed to achieve a final infusion volume concentration of
1.25 mg/mL of remdesivir diluted solution based on patient’s calculated dose.
• Select an appropriately sized syringe equal to or larger than the calculated total infusion volume of
1.25 mg/mL remdesivir solution needed.
• Withdraw the required volume of reconstituted VEKLURY solution from the vial into the syringe
based on patient’s calculated dose, followed by the required volume of 0.9% sodium chloride
injection needed to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted
solution.
• Gently invert the syringe 20 times to mix the solution in the syringe. Do not shake.
• The prepared diluted solution should be used immediately.
Administration Instructions
The prepared diluted solution should not be administered simultaneously with any other medication.
The compatibility of VEKLURY with IV solutions and medications other than 0.9% sodium chloride
injection, USP is not known. Administer VEKLURY via intravenous infusion over 30 to 120 minutes.
The rate of infusion (mL/min) should be calculated based on the total infusion volume and total
infusion time.
Administration should be under conditions where management of severe hypersensitivity reactions,
such as anaphylaxis, is possible. Monitor patients during infusion and observe patients for at least
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one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically
appropriate [see Warnings and Precautions (5.1)].
2.7 Storage of Prepared Dosages
VEKLURY for Injection (Supplied as Lyophilized Powder in Vial)
After reconstitution, use vials immediately to prepare diluted solution. The diluted VEKLURY solution
in the infusion bags can be stored up to 24 hours at room temperature (20°C to 25°C [68°F to 77°F])
prior to administration or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
VEKLURY Injection (Supplied as Solution in Vial)
Store VEKLURY injection after dilution in the infusion bags up to 24 hours at room temperature (20°C
to 25°C [68°F to 77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
IMPORTANT:
This product contains no preservative. Any unused portion of a single-dose VEKLURY vial should be
discarded after a diluted solution is prepared.
3
DOSAGE FORMS AND STRENGTHS
• VEKLURY for injection, 100 mg, available as a sterile, preservative-free white to off-white to
yellow lyophilized powder in single-dose vial for reconstitution.
• VEKLURY injection, 100 mg/20 mL (5 mg/mL), available as a clear, colorless to yellow solution,
free of visible particles in single-dose vial.
4
CONTRAINDICATIONS
VEKLURY is contraindicated in patients with a history of clinically significant hypersensitivity reactions
to VEKLURY or any components of the product [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Including Infusion-related and Anaphylactic Reactions
Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observed
during and following administration of VEKLURY; most occurred within one hour. Signs and
symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea,
wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slower infusion rates, with a
maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs
and symptoms. Monitor patients during infusion and observe patients for at least one hour after
infusion is complete for signs and symptoms of hypersensitivity as clinically appropriate. If signs and
symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue
administration of VEKLURY and initiate appropriate treatment. The use of VEKLURY is
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6
contraindicated in patients with known hypersensitivity to VEKLURY or any components of the
product [see Contraindications (4)].
5.2 Increased Risk of Transaminase Elevations
Transaminase elevations have been observed in healthy volunteers who received 200 mg of
VEKLURY followed by 100 mg doses for up to 10 days; the transaminase elevations were mild
(Grade 1) to moderate (Grade 2) in severity and resolved upon discontinuation of
VEKLURY. Transaminase elevations have also been reported in patients with COVID-19 who
received VEKLURY [see Adverse Reactions (6.1)]. Because transaminase elevations have been
reported as a clinical feature of COVID-19, and the incidence was similar in patients receiving
placebo versus VEKLURY in clinical trials of VEKLURY, discerning the contribution of VEKLURY to
transaminase elevations in patients with COVID-19 can be challenging.
Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving
VEKLURY as clinically appropriate [see Dosage and Administration (2.1) and Use in Specific
Populations (8.7)].
• Consider discontinuing VEKLURY if ALT levels increase to greater than 10 times the upper limit of
normal.
• Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver
inflammation.
5.3 Risk of Reduced Antiviral Activity When Coadministered with Chloroquine Phosphate or
Hydroxychloroquine Sulfate
Coadministration of VEKLURY and chloroquine phosphate or hydroxychloroquine sulfate is not
recommended based on data from cell culture experiments demonstrating a potential antagonistic
effect of chloroquine on the intracellular metabolic activation and antiviral activity of VEKLURY [see
Drug Interactions (7) and Microbiology (12.4)].
ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
• Hypersensitivity Including Infusion-related and Anaphylactic Reactions [see Warnings and
Precautions (5.1)]
• Increased Risk of Transaminase Elevations [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
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Clinical Trials in Adult Subjects
The safety of VEKLURY is based on data from four Phase 3 studies in 1,476 hospitalized adult
subjects with COVID-19, one Phase 3 study in 279 non-hospitalized adult and pediatric subjects (12
years of age and older weighing at least 40 kg) with mild-to-moderate COVID-19, four Phase 1
studies in 131 healthy adults, and from patients with COVID-19 who received VEKLURY under the
Emergency Use Authorization or in a compassionate use program.
Clinical Trials Experience in Adults with COVID-19
NIAID ACTT-1 was a randomized, double-blind, placebo-controlled clinical trial in hospitalized
subjects with mild, moderate, and severe COVID-19 treated with VEKLURY (n=532) or placebo
(n=516) for up to 10 days. Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg
once daily on subsequent days [see Clinical Studies (14.1)]. The collection of adverse event data in
this trial was limited to severe (Grade 3) or potentially life-threatening (Grade 4) adverse events,
serious adverse events, adverse events leading to study drug discontinuation, and moderate (Grade
2) severity or higher hypersensitivity reactions. Rates of adverse reactions (≥ Grade 3), serious
adverse reactions, and adverse reactions leading to treatment discontinuation are presented in
Table 6.
Table 6
Summary of Adverse Reaction Rates in Hospitalized Subjects with Mild,
Moderate, or Severe COVID-19 in NIAID ACTT-1
Types of Adverse Reactions
VEKLURY
N=532
n (%)
Placebo
N=516
n (%)
Adverse reactions, Grades ≥3
41 (8%)
46 (9%)
Serious adverse reactions
2 (0.4%)a
3 (0.6%)
Adverse reactions leading to treatment
discontinuation
11 (2%)b
15 (3%)
a. Seizure (n=1), infusion-related reaction (n=1).
b. Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST increased
(n=1), GFR decreased (n=2), acute kidney injury (n=3).
Study GS-US-540-5773 was a randomized, open-label clinical trial in hospitalized subjects with
severe COVID-19 treated with VEKLURY 200 mg on Day 1 and 100 mg once daily for 5 (n=200) or
10 days (n=197). Adverse reactions were reported in 33 (17%) subjects in the 5-day group and 40
(20%) subjects in the 10-day group [see Clinical Studies (14.2)]. The most common adverse reactions
occurring in at least 5% of subjects in either the VEKLURY 5-day or 10-day group, respectively, were
nausea (5% vs 3%), AST increased (3% vs 6%), and ALT increased (2% vs 7%). Rates of any
adverse reactions, serious adverse reactions, and adverse reactions leading to treatment
discontinuation are presented in Table 7.
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Table 7
Summary of Adverse Reaction Rates in Hospitalized Subjects with Severe COVID
19 in Study 5773
Types of Adverse Reactions
VEKLURY
5 Days
N=200
n (%)
VEKLURY
10 Days
N=197
n (%)
Any adverse reaction, all Grades
33 (17%)
40 (20%)
Serious adverse reactions
3 (2%)a
4 (2%)a
Adverse reactions leading to treatment discontinuation
5 (3%)b
9 (5%)b
a. Transaminases increased (n=5), hepatic enzyme increased (n=1), hypertransaminasaemia (n=1).
b. Transaminases increased (n=4), hepatic enzyme increased (n=2), LFT increased (n=2), hypertransaminasaemia
(n=1), ALT increased (n=1), ALT increased and AST increased (n=2), injection site erythema (n=1), rash (n=1).
Study GS-US-540-5774 was a randomized, open-label clinical trial in hospitalized subjects with
moderate COVID-19 treated with VEKLURY 200 mg on Day 1 and 100 mg daily for 5 (n=191) or 10
days (n=193), or standard of care (SOC) only (n=200) [see Clinical Studies (14.3)]. Adverse reactions
were reported in 36 (19%) subjects in the 5-day group and 25 (13%) subjects in the 10-day group.
The most common adverse reaction occurring in at least 5% of subjects in the VEKLURY groups was
nausea (7% in the 5-day group, 4% in the 10-day group). Rates of any adverse reactions, serious
adverse reactions, and adverse reactions leading to treatment discontinuation are presented in
Table 8.
Table 8
Summary of Adverse Reactiona Rates in Hospitalized Subjects with Moderate
COVID-19 in Study 5774
Types of Adverse Reactions
VEKLURY
5 Days
N=191
n (%)
VEKLURY
10 Days
N=193
n (%)
Any adverse reaction, all Grades
36 (19%)
25 (13%)
Serious adverse reactions
1 (<1%)b
0
Adverse reactions leading to treatment discontinuation
4 (2%)c
4 (2%)c
a. Attribution of events to study drug was not performed for the SOC group.
b. Heart rate decreased.
c. ALT increased (n=2), ALT increased and AST increased (n=1), hypertransaminasaemia (n=1), blood alkaline
phosphatase increased (n=1), rash (n=2), heart rate decreased (n=1).
Study GS-US-540-9012 was a randomized, double-blind, placebo-controlled clinical trial in subjects
who were non-hospitalized, were symptomatic for COVID-19 for ≤7 days, had confirmed SARS-CoV
2 infection, and had at least one risk factor for progression to hospitalization treated with VEKLURY
(n=279; 276 adults and 3 pediatric subjects 12 years of age and older weighing at least 40 kg) or
placebo (n=283; 278 adults and 5 pediatric subjects 12 years of age and older weighing at least
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40 kg) for 3 days. Of the 279 subjects treated with VEKLURY, 227 subjects received at least one
dose of VEKLURY at an outpatient facility, 44 subjects received at least one dose of VEKLURY in a
home healthcare setting, and 8 subjects received at least one dose of VEKLURY at a skilled nursing
facility. Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg once daily on
subsequent days [see Clinical Studies (14.4)]. Adverse reactions (all grades) were reported in 34
(12%) subjects in the VEKLURY group and 25 (9%) subjects in the placebo group. The most common
adverse reaction occurring in at least 5% of subjects in the VEKLURY group was nausea (6%). There
were no serious adverse reactions or adverse reactions leading to treatment discontinuation in either
treatment group. Safety in subjects who received VEKLURY in a home healthcare setting was
comparable to that observed in the overall GS-US-540-9012 study population, but these findings are
based on limited data.
Less Common Adverse Reactions in Adults from Clinical Trials
Clinically significant adverse reactions that were reported in <2% of subjects exposed to VEKLURY in
clinical trials are listed below:
• Hypersensitivity reactions [see Warnings and Precautions (5.1)].
• Generalized seizure
• Rash
Laboratory Abnormalities
Study GS-US-399-5505 was a Phase 1, randomized, blinded, placebo-controlled clinical trial in
healthy volunteers administered VEKLURY 200 mg on Day 1 and 100 mg for either 4 days or 9 days.
Mild (Grade 1, n=8) to moderate (Grade 2, n=1) elevations in ALT were observed in 9 of 20 subjects
receiving 10 days of VEKLURY; the elevations in ALT resolved upon discontinuation of VEKLURY.
No subjects (0 of 9) who received 5 days of VEKLURY had graded increases in ALT.
The frequencies of laboratory abnormalities (Grades 3-4) occurring in at least 3% of subjects with
COVID-19 receiving VEKLURY in Trials NIAID ACTT-1, 5773, and 5774 are presented in Table 9,
Table 10, and Table 11, respectively.
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Table 9
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
with Mild, Moderate, or Severe COVID-19 in NIAID ACTT-1
Laboratory Parameter Abnormalitya
VEKLURY 10 Days
N=532
Placebo
N=516
ALT increased
3%
6%
AST increased
6%
8%
Bilirubin increased
2%
5%
Creatinine clearance decreasedb
18%
20%
Creatinine increased
15%
16%
eGFR decreased
18%
24%
Glucose increased
12%
13%
Hemoglobin decreased
15%
22%
Lymphocytes decreased
11%
18%
Prothrombin time increased
9%
4%
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
Table 10
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
with Severe COVID-19 in Trial 5773
Laboratory Parameter Abnormalitya
VEKLURY
5 Days
N=200
VEKLURY
10 Days
N=197
ALT increased
6%
8%
AST increased
7%
6%
Creatinine clearance decreasedb
10%
19%
Creatinine increased
5%
15%
Glucose increased
11%
8%
Hemoglobin decreased
6%
8%
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
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Table 11
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
with Moderate COVID-19 in Trial 5774
Laboratory Parameter Abnormalitya
VEKLURY
5 Days
N=191
VEKLURY 10
Days
N=193
SOC
N=200
ALT increased
2%
3%
8%
Creatinine clearance decreasedb
2%
5%
8%
Glucose increased
4%
3%
2%
Hemoglobin decreased
3%
1%
6%
SOC=Standard of care.
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
The frequencies of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects with
COVID-19 receiving VEKLURY in Trial GS-US-540-9012 are presented in Table 12.
Table 12
Laboratory Abnormalities (Grades 3-4) Reported in ≥2% of Non-Hospitalized
Subjects in Trial 9012
Laboratory Parameter Abnormalitya
VEKLURY 3 Days
N=279
Placebo
N=283
Creatinine clearance decreasedb
6%
2%
Creatinine increased
3%
1%
Glucose increased
6%
6%
Lymphocytes decreased
2%
1%
Prothrombin time increased
1%
2%
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
Clinical Trials Experience in Adults with COVID-19 and Renal Impairment
Study GS-US-540-5912 was a randomized, double-blind, placebo-controlled clinical trial in which 163
hospitalized subjects with confirmed COVID-19 and acute kidney injury (AKI; N=60), chronic kidney
disease (CKD; eGFR <30 mL/minute/1.73m2; N=44), or end-stage renal disease (ESRD; eGFR <15
mL/minute/1.73m2; N=59) on hemodialysis received VEKLURY for up to 5 days [see Use in Specific
Populations (8.6)]. The adverse reactions observed were consistent with those observed in clinical
trials of VEKLURY in adults. Adverse reactions (all grades) were reported in 13 (8%) subjects in the
VEKLURY group and 3 (4%) subjects in the placebo group. The most common adverse reactions
were nausea (1%), abdominal pain (1%), and diarrhea (1%). No subjects experienced serious
adverse reactions. One subject permanently discontinued treatment due to an adverse reaction:
lipase increased.
The frequencies of laboratory abnormalities (Grades 3-4) occurring in at least 3% of subjects with
COVID-19 receiving VEKLURY in Trial GS-US-540-5912 are presented in Table 13.
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Table 13
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
in Trial 5912
Laboratory Parameter Abnormalitya
VEKLURY 5 Days
N=163
Placebo
N=80
Lymphocytes decreased
27%
27%
Hemoglobin decreased
25%
25%
Glucose increased
15%
19%
Uric acid increased
11%
4%
Creatinine increased
12%
14%
Albumin decreased
12%
10%
Lipase increased
12%
7%
Prothrombin time increased
11%
4%
Prothrombin INR increased
7%
4%
AST increased
6%
4%
Thromboplastin time increased
5%
4%
ALT increased
5%
6%
Sodium increased
3%
3%
Calcium increased
3%
0
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
Clinical Trials in Pediatric Subjects
Study GS-US-540-5823 was a Phase 2/3, single-arm, open-label clinical trial in hospitalized subjects
from birth to <18 years of age and weighing at least 1.5 kg with mild, moderate, and severe COVID
19 treated with weight-based VEKLURY (n=58) for up to 10 days [see Clinical Studies (14.6)]:
• Cohorts 1, 8: Subjects ≥12 years and weighing ≥40 kg (n=12) and subjects <12 years and
weighing ≥40 kg (n=5): Received 200 mg on Day 1 and 100 mg once daily on subsequent days.
• Cohorts 2-4: Subjects ≥28 days and weighing ≥20 to <40 kg (n=12); subjects ≥28 days and
weighing ≥12 to <20 kg (n=12); and subjects ≥28 days and weighing ≥3 to <12 kg (n=12):
Received 5 mg/kg on Day 1 and 2.5 mg/kg once daily on subsequent days.
• Cohort 5: Subjects 14 to <28 days old, gestational age (GA) >37 weeks, and weighing ≥2.5 kg
(n=3): Received 5 mg/kg on Day 1 and 2.5 mg/kg once daily on subsequent days.
• Cohorts 6-7: Subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and
subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1): Received 2.5 mg/kg on
Day 1 and 1.25 mg/kg once daily on subsequent days.
The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in
adults.
Infants, children, and adolescents; Cohorts 1-4, 8: Adverse reactions (all grades) were reported in 8
(15%) subjects. The most common adverse reaction occurring in at least 5% of subjects was ALT
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7
increased (6%). No subjects experienced serious adverse reactions. Two (4%) subjects permanently
discontinued treatment due to adverse reactions (ALT increased [n=1], ALT increased and AST
increased and hyperbilirubinemia [n=1]). Laboratory abnormalities (Grades 3-4) occurring in at least
3% of subjects with COVID-19 receiving VEKLURY in Trial 5823 and who had at least one post-
baseline value for the specified test were hemoglobin decreased (18%, 9/51), eGFR decreased (18%,
7/40), creatinine increased (10%, 5/52), direct bilirubin increased (9%, 2/23), prothrombin time
increased (7%, 3/46), APTT increased (7%, 3/45), lymphocytes decreased (6% 2/33), proteinuria
(6%, 2/36), WBC decreased (4%, 2/51), ALT increased (4%, 2/51), glucose increased (4%, 2/52),
glycosuria (4%, 2/46), potassium decreased (4%, 2/52).
Neonates and infants; Cohorts 5-7: Laboratory abnormalities (Grades 3-4) were reported in 3/5
subjects: APTT increased (2/5); direct bilirubin increased (1/5); creatinine increased (1/5);
prothrombin time increased (1/5); prothrombin/INR increased (1/5); and potassium increased (1/5).
Emergency Use Authorization Experience in Subjects with COVID-19
The following adverse reactions have been identified during use of VEKLURY under Emergency Use
Authorization:
• General disorders and administration site conditions: Administration site extravasation
• Skin and subcutaneous tissue disorders: Rash
• Immune system disorders: Anaphylaxis, angioedema, infusion-related reactions, hypersensitivity
• Investigations: Transaminase elevations
DRUG INTERACTIONS
7.1 Effects of Other Drugs on VEKLURY
Due to potential antagonism based on data from cell culture experiments, concomitant use of
VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended [see
Warnings and Precautions (5.3) and Microbiology (12.4)]. Based on drug interaction studies
conducted with VEKLURY, no clinically significant drug interactions are expected with inducers of
cytochrome P450 (CYP) 3A4 or inhibitors of Organic Anion Transporting Polypeptides (OATP)
1B1/1B3 and, P-glycoprotein (P-gp) [see Clinical Pharmacology (12.3)].
7.2 Effects of VEKLURY on Other Drugs
Based on drug interaction studies conducted with VEKLURY, it is a weak inhibitor of CYP3A and
does not inhibit OATP1B1/1B3 [see Clinical Pharmacology (12.3)].
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8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data from a clinical trial (IMPAACT 2032), published reports, the COVID-PR pregnancy
exposure registry, and compassionate use of remdesivir in pregnant individuals have not identified a
drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
following exposure in the second and third trimester. However, there are insufficient pregnancy data
available to evaluate the risk of remdesivir exposure during the first trimester. A study evaluating the
pharmacokinetics of remdesivir during pregnancy demonstrated no clinically relevant differences
between pregnant and non-pregnant individuals. No dose adjustments are recommended in patients
who receive VEKLURY during pregnancy (see Data) and [see Clinical Pharmacology (12.3)]. In
nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryo-fetal
development when administered to pregnant animals at systemic exposures (AUC) of the
predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the
exposure in humans at the recommended human dose (RHD) (see Data). There are maternal and
fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations).
The background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo-fetal risk
COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including
preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic
disease, and fetal death.
Data
Human Data
A non-randomized, open-label clinical study (IMPAACT 2032) evaluated pharmacokinetics and safety
of up to 10 days of treatment with VEKLURY in 25 hospitalized pregnant and 28 hospitalized non-
pregnant individuals of childbearing potential. Subjects received VEKLURY 200 mg once daily for 1
day followed by VEKLURY 100 mg once daily on subsequent days via intravenous infusion. Subjects
were enrolled prior to their fourth VEKLURY infusion. Assessments occurred at the following
intervals: Screening; Pre-infusion (defined as 48 hours prior to start of first infusion); each infusion
day; 48 hours after the last infusion; 7 days after the last infusion; 4 weeks after the last infusion.
Assessments also occurred 24 hours post-delivery in subjects who delivered. Treatment with
VEKLURY was stopped in subjects who were discharged from the hospital prior to the completion of
10 days of treatment.
Of the 25 pregnant subjects, median age was 33 years (Q1, Q3: 27 years, 37 years); 40% were
White, 24% were Black, and 48% were Hispanic or Latino. A total of 9 subjects (36%) were on high-
flow oxygen; 12 subjects (48%) were on low-flow oxygen; and 1 subject (4%) was on room air, at
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baseline. Three subjects (12%) did not have data available on baseline oxygen status. The overall
median (Q1, Q3) duration of symptoms prior to hospitalization was 7 (6, 9) days. The overall median
(Q1, Q3) duration of symptoms prior to first dose of VEKLURY was 8 (6, 9) days.
Of the 25 pregnant subjects, median gestational age was 28 weeks at baseline (range 22 to 33
weeks) and about half of subjects were in each of the second and third trimester of pregnancy. No
clinically relevant differences in the pharmacokinetics of remdesivir or its metabolites (GS-704277
and GS-441524) were observed between pregnant (n=21) and non-pregnant (n=22) individuals [see
Clinical Pharmacology (12.3)]. No difference in pharmacokinetics of remdesivir or its metabolites is
expected between the first and second/third trimesters. The adverse reactions observed were
consistent with those observed in clinical trials of VEKLURY in adults [see Adverse Reactions (6.1)].
There were no adverse reactions in infants born during the study (n=16).
Animal Data
Remdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20
mg/kg/day) on Gestation Days 6 through 17, and 7 through 20, respectively, and also to rats from
Gestation Day 6 to Lactation/Post-partum Day 20. No adverse effects on embryo-fetal (rats and
rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in
pregnant animals. During organogenesis, exposures to the predominant circulating metabolite (GS
441524) were 4 times higher (rats and rabbits) than the exposure in humans at the RHD. In a
pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir
(GS-441524) were similar to the human exposures at the RHD.
8.2 Lactation
Risk Summary
A published case report describes the presence of remdesivir and active metabolite GS-441524 in
human milk. Available data (n=11) from pharmacovigilance reports do not indicate adverse effects on
breastfed infants from exposure to remdesivir and its metabolite through breastmilk. There are no
available data on the effects of remdesivir on milk production. In animal studies, remdesivir and
metabolites have been detected in the nursing pups of mothers given remdesivir, likely due to the
presence of remdesivir in milk (see Data). The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for VEKLURY and any potential adverse
effects on the breastfed child from VEKLURY or from the underlying maternal condition.
Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to
avoid exposing the infant to COVID-19.
Data
Remdesivir and its metabolites were detected in the plasma of nursing rat pups, likely due to the
presence of remdesivir and/or its metabolites in milk, following daily intravenous administration of
remdesivir to pregnant rats from Gestation Day 6 to Lactation Day 20. Exposures in nursing pups
were approximately 1% that of maternal exposure on Lactation Day 10. The concentration of
remdesivir in animal milk does not necessarily predict the concentration of drug in human milk.
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8.4 Pediatric Use
The safety and effectiveness of VEKLURY for the treatment of COVID-19 have been established in
pediatric patients from birth to less than 18 years of age and weighing at least 1.5 kg, who are:
• Hospitalized, or
• Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to
severe COVID-19, including hospitalization or death.
Use in this age group is supported by the following:
• Trials in adults [see Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5)]
• An open-label trial (Study 5823) in 58 hospitalized pediatric subjects [see Adverse Reactions
(6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)].
Use of VEKLURY in pediatric patients from birth to less than 18 years of age and weighing at least
1.5 kg is supported by Study 5823 where 58 hospitalized pediatric subjects were treated with weight-
based VEKLURY for up to 10 days in the following cohorts:
• Cohorts 1-4, 8; infants, children, and adolescents: Subjects ≥12 years and weighing ≥40 kg
(n=12); subjects <12 years and weighing ≥40 kg (n=5); subjects ≥28 days and weighing ≥20 to
<40 kg (n=12); subjects ≥28 days and weighing ≥12 to <20 kg (n=12); and subjects ≥28 days
and weighing ≥3 to <12 kg (n=12);
• Cohorts 5-7; neonates and infants: Subjects 14 to <28 days old, GA >37 weeks, and weighing
≥2.5 kg (n=3); subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and
subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1).
The safety and pharmacokinetic results in pediatric subjects were similar to those in adults [see
Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)].
Use of VEKLURY in pediatric patients weighing at least 40 kg is further supported by a clinical trial of
VEKLURY in non-hospitalized subjects that included 3 pediatric subjects 12 years and older, and by
clinical trials in hospitalized subjects that included 30 adult subjects weighing 40 to 50 kg. The safety
in this weight group was comparable to adult subjects weighing greater than 50 kg. Thirty-nine
pediatric patients 12 years and older and weighing at least 40 kg received VEKLURY in a
compassionate use program in hospitalized subjects; the available clinical data from these patients
are limited [see Adverse Reactions (6.1) and Clinical Studies (14)].
Use of VEKLURY in pediatric patients with renal impairment is supported by safety data in adults [see
Adverse Reactions (6.1), Use in Specific Populations (8.6)]. Limited data are available regarding the
safety of VEKLURY in pediatric patients with mild or moderate renal impairment. No data are
available regarding the safety of VEKLURY in pediatric patients with severe renal impairment. In
adults with severe renal impairment, including those requiring dialysis, exposures of GS-441524 and
GS-704277, the metabolites of remdesivir, and betadex sulfobutyl ether sodium (SBECD) are
increased [see Clinical Pharmacology (12.3)]. VEKLURY contains SBECD which, when administered
intravenously, is eliminated through glomerular filtration and therefore when administered to pediatric
patients with renal immaturity or renal impairment, may result in higher exposure to SBECD.
The safety and effectiveness of VEKLURY have not been established in pediatric patients weighing
less than 1.5 kg.
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8.5 Geriatric Use
Of the 1,062 hospitalized subjects with SARS-CoV-2 infection randomized in ACTT-1, 36% were 65
years or older. Of the 397 hospitalized subjects with SARS-CoV-2 infection randomized in Study GS
US-540-5773, 42% were 65 years or older. Of the 584 hospitalized subjects with SARS-CoV-2
infection randomized in Study GS-US-540-5774, 27% were 65 years or older. Of the 562 non-
hospitalized subjects with SARS-CoV-2 infection randomized in Study GS-US-540-9012, 17% were
65 years or older. Reported clinical experience has not identified differences in responses between
the elderly and younger patients [see Clinical Studies (14)]. No dosage adjustment is required in
patients over the age of 65 years. In general, appropriate caution should be exercised in the
administration of VEKLURY and monitoring of elderly patients, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
Use of VEKLURY in patients with COVID-19 and renal impairment, including those on dialysis, is
supported by safety and pharmacokinetic data from the following:
• a randomized, double-blind, placebo-controlled trial (Study 5912) in adults [see Adverse
Reactions (6.1) and Clinical Pharmacology (12.3)].
• an open-label, parallel-group, single-dose trial in subjects with normal renal function and renal
impairment (Study 9015) [see Clinical Pharmacology (12.3)].
The pharmacokinetics and safety of VEKLURY in patients with COVID-19 and renal impairment,
including those on dialysis, were evaluated in 163 subjects in a randomized, double-blind, placebo-
controlled trial, Study GS-US-540-5912 [see Adverse Reactions (6.1) and Clinical Pharmacology
(12.3)].
Study GS-US-540-5912 evaluated VEKLURY 200 mg once daily for 1 day followed by VEKLURY 100
mg once daily for 4 days (for a total of up to 5 days of intravenously administered therapy) in 243
hospitalized adult subjects with confirmed COVID-19 and renal impairment. The trial included 90
subjects (37%) with AKI (defined as a 50% increase in serum creatinine within a 48-hour period that
was sustained for ≥6 hours despite supportive care), 64 subjects (26%) with CKD (eGFR <30
mL/minute/1.73m2), and 89 subjects (37%) with ESRD (eGFR <15 mL/minute/1.73m2) requiring
hemodialysis. Subjects were randomized in a 2:1 manner, stratified by ESRD, high-flow oxygen
requirement, and region (US vs ex-US) to receive VEKLURY (n=163) or placebo (n=80), plus
standard of care.
At baseline, mean age was 69 years (with 62% of subjects aged 65 or older); 57% of subjects were
male, 67% were White, 26% were Black, and 3% were Asian. The most common baseline risk factors
were hypertension (89%), diabetes mellitus (79%), and cardiovascular or cerebrovascular disease
(51%); the distribution of risk factors was similar between the two treatment groups. A total of 45
subjects (19%) were on high-flow oxygen, 144 (59%) were on low-flow oxygen, and 54 (22%) were
on room air at baseline; no subjects were on invasive mechanical ventilation (IMV). A total of 182
subjects (75%) were not on renal replacement therapy, and 31 subjects (13%) had received a
COVID-19 vaccine.
The safety results in subjects with COVID-19 and renal impairment, including those on dialysis, were
consistent with those observed in clinical trials of VEKLURY in adults [see Adverse Reactions (6.1)].
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Study GS-US-540-5912 closed prematurely due to feasibility issues and was underpowered to
assess for efficacy because of lower than expected enrollment.
The pharmacokinetics and safety of VEKLURY in subjects with normal renal function and renal
impairment, including those on dialysis, were evaluated in 75 subjects (43 subjects with renal
impairment plus 32 matched control subjects with normal renal function) in an open-label, parallel-
group, single-dose trial, Study GS-US-540-9015 [see Clinical Pharmacology (12.3)].
In studies GS-US-540-5912 and GS-US-540-9015, exposures of GS-441524 and GS-704277, the
metabolites of remdesivir, and SBECD are increased in subjects with mild to severe renal impairment,
including those requiring dialysis, relative to subjects with normal renal function [see Clinical
Pharmacology (12.3)].
No dosage adjustment of VEKLURY is recommended for patients with any degree of renal
impairment, including those on dialysis [see Dosage and Administration (2.2, 2.4), Use in Specific
Populations (8.4)].
8.7 Hepatic Impairment
No dosage adjustment of VEKLURY is recommended for patients with mild, moderate, or severe
hepatic impairment (Child-Pugh Class A, B, or C) [see Clinical Pharmacology (12.3)].
Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving
VEKLURY as clinically appropriate [see Dosage and Administration (2.2) and Warnings and
Precautions (5.2)].
10 OVERDOSAGE
There is no human experience of acute overdosage with VEKLURY. Treatment of overdose with
VEKLURY should consist of general supportive measures including monitoring of vital signs and
observation of the clinical status of the patient. There is no specific antidote for overdose with
VEKLURY.
11 DESCRIPTION
VEKLURY contains remdesivir, a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. The
chemical name for remdesivir is 2-ethylbutyl N-{(S)-[2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5
anhydro-d-altrononitril-6-O-yl]phenoxyphosphoryl}-L-alaninate. It has a molecular formula of
C27H35N6O8P and a molecular weight of 602.6 g/mol. Remdesivir has the following structural formula:
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VEKLURY for injection contains 100 mg of remdesivir as a sterile, preservative-free lyophilized white
to off-white to yellow powder in a single-dose clear glass vial. It requires reconstitution and then
further dilution prior to administration by intravenous infusion [see Dosage and Administration (2.5,
2.6)]. The inactive ingredients are 3 g betadex sulfobutyl ether sodium and may include hydrochloric
acid and/or sodium hydroxide for pH adjustment.
VEKLURY injection contains 100 mg/20 mL (5 mg/mL) of remdesivir as a sterile, preservative-free,
clear, colorless to yellow solution in a single-dose clear glass vial. It requires dilution prior to
administration by intravenous infusion [see Dosage and Administration (2.5, 2.6)]. The inactive
ingredients are 6 g betadex sulfobutyl ether sodium, Water for Injection, USP, and may include
hydrochloric acid and/or sodium hydroxide for pH adjustment.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Remdesivir is an antiviral drug with activity against severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) [see Microbiology (12.4)].
12.2 Pharmacodynamics
Remdesivir and metabolites exposure-response relationships and the time course of
pharmacodynamics response are unknown.
12.3 Pharmacokinetics
The pharmacokinetic (PK) properties of remdesivir and metabolites are provided in Table 14. The
multiple dose PK parameters of remdesivir and metabolites in adults with COVID-19 are provided in
Table 15.
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Table 14
Pharmacokinetic Properties of Remdesivir and Metabolites (GS-441524 and GS
704277)
Remdesivir
GS-441524
GS-704277
Absorption
Tmax (h)a
0.67-0.68
1.51-2.00
0.75-0.75
Distribution
% bound to human plasma
proteins
88-93.6b
2
1
Blood-to-plasma ratio
0.68-1.0
1.19
0.56
Elimination
t1/2 (h)c
1
27
1.3
Metabolism
Metabolic pathway(s)
CES1 (80%)
Cathepsin A (10%)
CYP3A (10%)
Not significantly
metabolized
HINT1
Excretion
Major route of elimination
Metabolism
Glomerular filtration
and active tubular
secretion
Metabolism
% of dose excreted in
urined
10
49
2.9
% of dose excreted in
fecesd
ND
0.5
ND
ND=not detected
a. Remdesivir administered as a 30-minute IV infusion (Study GS-US-399-5505); range of median observed on Day 1
and Day 5 or 10.
b. Range of protein binding for remdesivir from 2 independent experiments show no evidence of concentration-
dependent protein binding for remdesivir.
c. Median (Study GS-US-399-4231).
d. Mean (Study GS-US-399-4231).
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Table 15
Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS
704277) Following IV Administration of VEKLURY 100 mg to Adults with COVID-19
Parameter
Meanb (95% CI)
Remdesivir
GS-441524
GS-704277
Cmax
(nanogram per mL)
2700 (2440,
2990)
143 (135, 152)
198 (180, 218)
AUCtau
(nanogram•h per mL)
1710 (1480,
1980)
2410 (2250, 2580)
392 (348, 442)
Ctrough
(nanogram per mL)
ND
61.5 (56.5, 66.8)
ND
CI=Confidence Interval; ND=Not detectable (at 24 hours post-dose)
a. Population PK estimates for 30-minute IV infusion of remdesivir for 3 days (Study GS-US-540-9012, n=147).
b. Geometric mean estimates.
Specific Populations
Pharmacokinetic differences based on sex, race, age, and renal function on the exposures of
remdesivir were evaluated using population pharmacokinetic analysis. Sex and race did not affect the
pharmacokinetics of remdesivir and its metabolites (GS-441524 and GS-704277).
Pregnant Individuals
The pharmacokinetics of remdesivir and its circulating metabolites (GS-441524 and GS-704277)
were evaluated in pregnant individuals with COVID-19. Exposures (AUCtau, Cmax, and Ctau) of
remdesivir and its circulating metabolites during pregnancy were similar to those in non-pregnant
individuals (see Table 16).
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Table 16
Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS
704277) Following Intravenous Administration of VEKLURY to Pregnant and Non-
Pregnant Individuals with COVID-19
Parameter
Meanb (90% CI)
Pregnant Individuals
(N=21)
Non-Pregnant Individuals
(N=22)
Remdesivir
Cmax (nanogram per mL)
1360 (978, 1890)
1240 (891, 1720)
AUCtau (nanogram•h per mL)
1250 (916, 1700)c
1300 (1070, 1590)d
GS-441524
Cmax (nanogram per mL)
113 (102, 126)
121 (108, 136)
AUCtau (nanogram•h per mL)
1840 (1630, 2070)e
2050 (1780, 2350)f
Ctau (nanogram per mL)
51.6 (44.7, 59.6)e
57.1 (48.7, 66.9)f
GS-704277
Cmax (nanogram per mL)
217 (187, 252)
213 (188, 240)
AUCtau (nanogram•h per mL)
454 (406, 508)e
437 (384, 497)
CI=Confidence Interval
a. Study CO-US-590-5961 (IMPAACT).
b. Geometric mean estimates.
c. N=18
d. N=17
e. N=20
f.
N=21
Patients with Renal Impairment
The pharmacokinetics of remdesivir and its metabolites (GS-441524 and GS-704277) and excipient
SBECD were evaluated in healthy subjects, those with mild (eGFR 60-89 mL/minute/1.73m2),
moderate (eGFR 30-59 mL/minute/1.73m2), severe (eGFR 15-29 mL/minute/1.73m2) renal
impairment, or kidney failure (eGFR <15 mL/minute/1.73m2) on dialysis or not on dialysis following a
single dose of up to 100 mg of VEKLURY (see Table 16); and in COVID-19 patients with severely
reduced kidney function (AKI [defined as a 50% increase in serum creatinine within a 48-hour period
that was sustained for ≥6 hours despite supportive care]; CKD [eGFR <30 mL/minute/1.73m2]; or
ESRD [eGFR <15 mL/minute/1.73m2] requiring hemodialysis) receiving VEKLURY 200 mg loading
dose on Day 1 followed by 100 mg from Day 2 to Day 5 (see Table 17). Pharmacokinetic exposures
of remdesivir were not affected by renal function or timing of VEKLURY administration around
dialysis.
Exposures of GS-441524, GS-704277, and SBECD were up to 7.9-fold, 2.8-fold, and 21-fold higher,
respectively, in those with renal impairment compared to those with normal renal function (see Table
17 and Table 18). These changes are not considered to be clinically significant [see Adverse
Reactions (6.1) and Use in Specific Populations (8.6)].
Remdesivir was not efficiently removed through hemodialysis. Average hemodialysis clearance of
GS-441524 and GS-704277 was 149 mL/minute and 92.6 mL/minute, respectively.
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Table 17
Comparison of PK Parametersa of Remdesivir and Metabolites (GS-441524 and
GS-704277) Following IV Administration of Single Dose VEKLURY to Adults with
Renal Impairmentb as Compared to Adults with Normal Renal Function
Mean Ratio
(90% CI)c
60-89 mL
per
minuteb
N=10
30-59 mL
per
minuteb
N=10
15-29 mL
per minuteb
N=10
<15 mL per minuteb
Pre
hemodialysis
N=6
Post
hemodialysis
N=6
No
dialysis
N=3
Remdesivir
Cmax
0.96
(0.71, 1.31)
1.20
(1.01, 1.42)
0.97
(0.83, 1.13)
0.89
(0.67, 1.18)
1.13
(0.79, 1.60)
0.94
(0.65, 1.35)
AUCinf
1.00
(0.75, 1.32)
1.22
(0.98, 1.52)
0.94
(0.83, 1.07)
0.80
(0.59, 1.08)
1.08
(0.72, 1.63)
0.89
(0.55, 1.43)
GS-441524
Cmax
1.07
(0.90, 1.26)
1.44
(1.13, 1.85)
1.68
(1.28, 2.20)
2.27
(1.72, 2.99)
3.07
(2.21, 4.26)
3.00
(2.63, 3.42)
AUCinf
1.19
(0.97, 1.47)
2.02
(1.57, 2.62)
3.26
(2.39, 4.46)
4.97
(3.65, 6.77)
6.22
(4.44, 8.71)
7.87
(6.49, 9.53)
GS-704277
Cmax
2.25
(1.20, 4.20)
1.83
(1.34, 2.49)
1.27
(0.96, 1.68)
1.43
(1.00, 2.05)
1.23
(0.84, 1.80)
1.76
(1.19, 2.61)
AUCinf
1.39
(1.13, 1.71)
2.01
(1.48, 2.73)
1.78
(1.27, 2.49)
2.18
(1.61, 2.95)
2.06
(1.42, 2.97)
2.81
(1.79, 4.43)
CI=Confidence Interval
a. Exposures were estimated using noncompartmental analysis from a dedicated Phase 1 renal impairment Study GS
US-540-9015; single doses up to 100 mg were administered; each subject with renal impairment had a matched
control participant enrolled with normal renal function (eGFR ≥90 mL/minute/1.73m2), same sex, and similar BMI (±
20%) and age (± 10 years).
b. eGFR was calculated using Modification of Diet in Renal Disease equation and values represent mL/minute/1.73m2.
c. No effect=1.0 (0.5-2.0)
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Table 18
Comparison of PK Parameters of Remdesivir and Metabolites (GS-441524 and
GS-704277) Following IV Administration of VEKLURY (200 mg on Day 1 Followed
by 100 mg Daily on Days 2-5) in Adults with COVID-19 witha or withoutb Severely
Reduced Kidney Functionc
Mean Ratio (90% CI)d
Remdesivir
GS-441524
GS-704277
Cmax
1.39 (1.25, 1.54)
4.98 (4.61, 5.38)
1.84 (1.63, 2.08)
AUCtau
1.79 (1.59, 2.01)
6.59 (6.05, 7.18)
3.94 (3.50, 4.43)
Ctau
ND
5.82 (5.25, 6.45)
ND
CI=Confidence Interval; ND=Not detectable (at 24 hours post-dose)
a. Population PK estimates for 30-minute IV infusion of remdesivir for 5 days (Study GS-US-540-5912, n=90).
b. Population PK estimates for 30-minute IV infusion of remdesivir for 3 days (Study GS-US-540-9012, n=148).
c. AKI (defined as a 50% increase in serum creatinine within a 48-hour period that was sustained for ≥6 hours despite
supportive care); CKD (eGFR <30 mL/minute/1.73m2); or ESRD (eGFR <15 mL/minute/1.73m2) requiring
hemodialysis.
d. No effect=1.0 (0.5-2.0)
Patients with Hepatic Impairment
The pharmacokinetics of remdesivir and GS-441524 were evaluated in healthy subjects and those
with moderate or severe hepatic impairment (Child-Pugh Class B or C) following a single dose of 100
mg of VEKLURY (see Table 19). Relative to subjects with normal hepatic function, mean exposures
(AUCinf, Cmax) of remdesivir and GS-441524 were similar in subjects with moderate hepatic
impairment and higher in subjects with severe hepatic impairment. The exposure differences in
subjects with severe hepatic impairment are not considered to be clinically significant [see Use in
Specific Populations (8.7)].
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Table 19
Comparison of PK Parameters of Remdesivir and GS-441524 Following IV
Administration of Single Dose VEKLURY to Adults with Hepatic Impairment as
Compared to Adults with Normal Hepatic Function
Mean Ratio (90% CI)a
Moderate Hepatic Impairment
N=10
Severe Hepatic Impairment
N=6
Remdesivir
AUCinf
1.21 (0.87, 1.67)
1.56 (1.20, 2.03)
Cmax
1.10 (0.75, 1.60)
1.03 (0.70, 1.51)
Unbound AUCinf
1.15 (0.86, 1.54)
2.44 (1.93, 3.08)
Unbound Cmax
1.04 (0.73, 1.48)
1.57 (1.08, 2.29)
GS-441524
AUCinf
0.90 (0.69, 1.17)
1.31 (0.93, 1.84)
Cmax
1.09 (0.86, 1.38)
1.48 (1.17, 1.86)
C24
0.93 (0.69, 1.24)
1.16 (0.76, 1.77)
CI=Confidence Interval
a. No effect=1.0 (0.5-2.0)
Pediatric Patients
Population pharmacokinetic models for remdesivir and its circulating metabolites (GS-441524 and
GS-704277), developed using pooled data from studies in healthy subjects and in adult and pediatric
patients with COVID-19, were used to estimate pharmacokinetic exposures in pediatric patients aged
from birth to <18 years and weighing ≥1.5 kg (Study 5823). Geometric mean estimated exposures
(AUCtau, Cmax, and Ctau) for patients ≥28 days to <18 years old and weighing ≥3 kg (Cohorts 1-4 and
8, n=50) at the doses administered were 33% to 130% higher for remdesivir, 3% lower to 60% higher
for GS-441524, and 32% to 124% higher for GS-704277 as compared to those in adult patients with
COVID-19; however, the increases were not considered clinically significant. Individual estimated
exposures (AUCtau, Cmax, and Ctau) for patients 14 to <28 days old, GA >37 weeks, and weighing ≥2.5
kg (Cohort 5, n=3); patients <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (Cohort 6,
n=1); and patients <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (Cohort 7, n=1) at the
doses administered were higher for remdesivir, GS-441524, and GS-704277 as compared to median
exposures in adult patients with COVID-19; however, the increases were not considered clinically
significant. As limited PK data were available in Cohorts 5-7, additional analyses were conducted
using a simulated population.
Using age and weight distributions from pediatric growth charts, simulated population datasets were
created for Cohorts 5-6. Modeling and simulation incorporating maturation functions that account for
renal function and drug metabolizing enzyme ontogeny with age were used to predict exposures for
subjects <28 days old, GA >37 weeks, and weighing ≥1.5 kg and subjects ≥28 days old and weighing
≥1.5 to <3 kg. Predicted geometric mean exposures (AUCtau, Cmax, and Ctau) at the recommended
doses were 10% to 96% higher for remdesivir, 15% lower to 3% higher for GS-441524, and 14%
lower to 132% higher for GS-704277 as compared to those in adult patients with COVID-19; however,
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changes in exposure were not considered clinically significant. Results of simulated population led to
the recommended dosing regimen as they more closely align with adult exposures compared to the
doses studied.
Plasma exposures of excipient SBECD were generally similar for all pediatric patients at the doses
administered in Study GS-US-540-5823 and were similar compared to adults with normal renal
function, although data are very limited [see Use in Specific Populations (8.4)].
The multiple dose PK parameters of remdesivir and metabolites in pediatric patients with COVID-19
in Cohorts 1-4 and 8 are provided in Table 20.
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Table 20
Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS
704277) Following Intravenous Administration of VEKLURY 100 mg (Cohorts 1
and 8) or 2.5 mg/kg (Cohorts 2-4) to Pediatric Patients with COVID-19
Parameter
Meanb (95% CI)
Cohort 1
Cohort 8
Cohort 2
Cohort 3
Cohort 4
12 to
<18 Years
and
Weighing
≥40 kg
(N=12)
<12 Years
and
Weighing
≥40 kg
(N=5)
28 Days to
<18 Years
and
Weighing
20 to <40 kg
(N=12)
28 Days to
<18 Years
and
Weighing
12 to <20 kg
(N=11)
28 Days to
<18 Years
and
Weighing
3 to <12 kg
(N=10)
Remdesivir
Cmax (nanogram
per mL)
3890 (3110,
4870)
3920 (2260,
6820)
5730 (4660,
7050)
5570 (4250,
7300)
4870 (3750,
6340)
AUCtau
(nanogram•h per
mL)
2470 (1920,
3160)
2270 (1200,
4310)
3510 (2560,
4820)
3930 (2140,
7210)
2910 (1880,
4510)
GS-441524
Cmax (nanogram
per mL)
196 (122,
315)
163 (57.6,
461)
183 (129,
260)
171 (130,
223)
205 (174,
241)
AUCtau
(nanogram•h per
mL)
3430 (1980,
5920)
2640 (767,
9100)
2370 (1500,
3740)
2410 (1740,
3340)
2850 (2290,
3540)
Ctau (nanogram
per mL)
98.5 (59.1,
164)
76.2 (23.9,
243)
59.9 (34.2,
105)
68.9 (47.4,
100)
79.7 (59.5,
107)
GS-704277
Cmax (nanogram
per mL)
308 (211,
450)
266 (137,
514)
419 (306,
575)
444 (335,
587)
385 (294,
504)
AUCtau
(nanogram•h per
mL)
819 (474,
1420)
518 (192,
1400)
753 (542,
1050)
733 (504,
1060)
687 (484,
973)
CI=Confidence Interval
a. Population PK estimates for 30-minutes IV infusion of remdesivir for up to 10 days (Study GS-US-540-5823).
b. Geometric mean estimates.
Drug Interaction Studies
In vitro, remdesivir is a substrate for enzymes CYP3A, carboxylesterase 1 (CES1), and cathepsin A
(CatA) and OATP1B1 and P-gp transporters; GS-704277 is a substrate for OATP1B1 and OATP1B3.
In vitro, remdesivir is an inhibitor of CYP3A, UGT1A1, OATP1B1, OATP1B3, and MATE1; however,
no clinically significant effects on substrates of UGT1A1 or MATE1 are expected. No inhibitory
interactions were identified for GS-704277 or GS-441524 in vitro.
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Reference ID: 5499606
Remdesivir is not a substrate for CYP1A1, 1A2, 2B6, 2C9, 2C19, or OATP1B3. GS-704277 and GS
441524 are not substrates for CYP1A1, 1A2, 2B6, 2C8, 2C9, 2D6, or 3A5. GS-441524 is also not a
substrate for CYP2C19 or 3A4. GS-704277 and GS-441524 are not substrates for OAT1, OAT3,
OCT1, OCT2, MATE1, or MATE2k. GS-441524 is also not a substrate for OATP1B1 or OATP1B3.
Drug-drug interaction studies were conducted with VEKLURY. Table 21 summarizes the
pharmacokinetic effects of other drugs on remdesivir and metabolites GS-704277 and GS-441524.
Table 22 summarizes the effects of remdesivir on the pharmacokinetics of other drugs.
Table 21
Effect of Other Drugs on Remdesivir and Metabolites GS-704277 and GS-441524
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Remdesivir
Dose
(mg)
N
Mean Ratio (90% CI) of Remdesivir, GS
704277, and GS-441524 PK With/Without
Coadministered Drug
No Effect = 1.00 (0.70-1.43)
Cmax
AUCinf
C24
Cyclosporin Aa
400 single dose
100 single
dose
9
remdesivir
1.49
(1.38
1.60)
1.89
(1.77
2.02)
-
GS-704277
2.51
(2.26
2.78)
2.97
(2.75
3.20)
-
GS-441524
1.17
(1.12
1.22)
1.03
(0.99
1.08)
1.02
(0.95
1.10)
Carbamazepinea
300 twice daily
100 single
dose
8
remdesivir
0.87
(0.78
0.97)
0.92
(0.83
1.02)
-
GS-704277
0.96
(0.84
1.10)
0.98
(0.92
1.05)
-
GS-441524
0.97
(0.88
1.07)
0.83
(0.78
0.89)
0.71
(0.64
0.78)
CI=confidence interval
a. Interaction study conducted in healthy volunteers.
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Table 22
Effect of Remdesivir on the Pharmacokinetics of Other Drugs
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Remdesivir
Dose
(mg)
N
Mean Ratio (90% CI) of Coadministered
Drug PK With/Without Remdesivir
No Effect = 1.00 (0.80-1.25)
Cmax
AUCinf
Midazolama
2.5 single dose
200 single
dose
19
1.29 (1.19-1.41)
1.20 (1.14-1.26)
Midazolama
2.5 single dose
200 single
dose
followed by
100 once
daily (10
doses)b
14
1.45 (1.23- 1.70)
1.30 (1.16- 1.45)
Pitavastatina
2 single dose
200 single
dose
20
1.05 (0.92-1.20)
1.17 (1.09-1.24)
CI=confidence interval
a. Interaction study conducted in healthy volunteers.
b. Midazolam administered with last dose of remdesivir.
12.4 Microbiology
Mechanism of Action
Remdesivir is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is
essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that distributes into cells
where it is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or
cathepsin A, depending upon the cell type. The nucleoside monophosphate is subsequently
phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate
metabolite (GS-443902). Remdesivir triphosphate (RDV-TP) acts as an analog of adenosine
triphosphate (ATP) and competes with high selectivity (3.65-fold) over the natural ATP substrate for
incorporation into nascent RNA chains by the SARS-CoV-2 RdRp, which results in delayed chain
termination (position i+3) during replication of the viral RNA. In a biochemical assay assessing RDV
TP incorporation by the MERS-CoV RdRp complex, RDV-TP inhibited RNA synthesis with an IC50
value of 0.032 µM. RDV-TP can also inhibit viral RNA synthesis following its incorporation into the
template viral RNA as a result of read-through by the viral polymerase that may occur at higher
nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the
efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting
viral RNA synthesis. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA
polymerases, including human mitochondrial RNA polymerase.
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Antiviral Activity
In Cell Culture
Remdesivir exhibited cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary
human airway epithelial (HAE) cells with a 50% effective concentration (EC50) of 9.9 nM after 48
hours of treatment. Remdesivir inhibited the replication of SARS-CoV-2 in the continuous human lung
epithelial cell lines Calu-3 and A549-hACE2 with EC50 values of 280 nM after 72 hours of treatment
and 115 nM after 48 hours of treatment, respectively.
Remdesivir EC50 values for SARS-CoV-2 in A549-hACE2 cells were not different when combined with
chloroquine phosphate or hydroxychloroquine sulfate at concentrations up to 2.5 μM. In a separate
study, the antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-
dependent manner when the two drugs were co-incubated at clinically relevant concentrations in
HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were
observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of
chloroquine phosphate or hydroxychloroquine sulfate reduced formation of remdesivir triphosphate in
A549-hACE2, HEp-2, and normal human bronchial epithelial cells.
Based on cell culture susceptibility testing by virus yield reduction assay and/or N protein ELISA
assay, remdesivir retained similar antiviral activity against clinical isolates of SARS-CoV-2 variants
compared to an earlier lineage SARS-CoV-2 (lineage A) isolate, including Alpha (B.1.1.7), Beta
(B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.429), Zeta (P.2), Iota (B.1.526), Kappa
(B.1.617.1), Lambda (C.37), and Omicron variants (including B.1.1.529/BA.1, BA.2, BA.2.12.1,
BA.2.75, BA.4, BA.4.6, BA.5, BF.5, BF.7, BQ.1, BQ.1.1, CH.1.1, EG.1.2, EG.5.1, FL.22, XBB,
XBB.1.5, XBB.1.16, XBB.2.3.2, and XBF). For these variants, the EC50 fold change values ranged
between 0.2 and 2.3 compared to an earlier lineage SARS-CoV-2 (lineage A) isolate. Using the
SARS-CoV-2 replicon system, remdesivir retained similar antiviral activity against Omicron
subvariants BA.2.86 and XBB.1.9.2 compared to the wildtype reference replicon (lineage B).
In Clinical Trials
SARS-CoV-2 RNA shedding results from GS-US-540-5776 (ACTT-1) indicate that remdesivir does
not significantly reduce the amount of detectable SARS-CoV-2 RNA in oropharyngeal or
nasopharyngeal swabs or plasma samples in hospitalized patients compared to placebo, and SARS
CoV-2 RNA shedding results from GS-US-540-9012 indicate that remdesivir does not significantly
reduce the amount of detectable SARS-CoV-2 RNA in nasopharyngeal swabs in non-hospitalized
patients compared to placebo.
Resistance
In Cell Culture
SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. In a
selection with GS-441524, the parent nucleoside of remdesivir, virus pools emerged expressing
amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in the viral RdRp
(nsp12). When these substitutions were individually introduced into a wild-type recombinant virus by
site-directed mutagenesis, 1.7- to 3.5-fold reductions in susceptibility to remdesivir were observed. In
a cell culture resistance selection experiment with remdesivir, nsp12 amino acid substitution E802D
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Reference ID: 5499606
emerged, resulting in a 1.4- to 2.5-fold reduction in susceptibility to remdesivir. In another selection
with remdesivir using a SARS-CoV-2 isolate containing the P323L substitution in the viral
polymerase, a single amino acid substitution at V166L emerged. Recombinant SARS-CoV-2 with
substitutions at P323L alone or P323L+V166L in combination exhibited 1.3- and 1.5-fold reductions in
remdesivir susceptibility, respectively.
Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified
two substitutions (F476L and V553L) in the viral RdRp (nsp12) at residues conserved across CoVs.
Introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold
reduction in susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a
mouse model. When individually introduced into a SARS-CoV-2 recombinant virus, the corresponding
substitutions at F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir.
In Clinical Studies
In a literature publication, the SARS-CoV-2 nsp12 E802D substitution previously identified in a
resistance selection experiment emerged in one individual treated with remdesivir. The E802D
substitution resulted in a 1.4- to 2.5-fold increase in the remdesivir EC50 value.
In Study CO-US-540-5776 (ACTT-1), among 61 subjects with baseline and post-baseline sequencing
data available, the rate of emerging substitutions in the viral RdRp (nsp12) was similar in subjects
treated with VEKLURY compared to placebo. Two subjects treated with VEKLURY had an emergent
substitution previously identified in resistance selection experiments (nsp12 V792I in one and C799F
in the other). These substitutions are associated with 2.2- and 2.5-fold decreases in remdesivir
susceptibility, respectively, based on assessments of clinical isolates. In one subject treated with
VEKLURY, nsp12 V792F emerged at low frequency and was associated with a 1.8-fold decrease in
remdesivir susceptibility.
In Study GS-US-540-5773, among 19 subjects treated with VEKLURY with baseline and post-
baseline sequencing data available, the V792F substitution in viral RdRp (nsp12) emerged at low
frequency in one subject.
In Study GS-US-540-9012, among 244 subjects with baseline and post-baseline sequencing data
available, the rate of emerging substitutions in the viral RdRp (nsp12) was similar in subjects treated
with VEKLURY compared to placebo. In one subject treated with VEKLURY, one substitution in the
RdRp (nsp12 A376V) emerged and was associated with a 12.6-fold decrease in remdesivir
susceptibility in a subgenomic replicon assay. This subject was not hospitalized and showed
alleviation of all baseline symptoms, except loss of taste and smell, prior to or on Day 14.
In Study GS-US-540-5912, among 60 subjects with baseline and post-baseline sequencing data
available, substitutions in the viral RdRp (nsp12) emerged in 8 subjects treated with VEKLURY. In 4
subjects treated with VEKLURY, three substitutions in the RdRp (nsp12 E136V, M794I, or C799F)
emerged and were associated with 2.9-, 2.9-, and 3.4-fold reduced susceptibility to remdesivir in a
subgenomic replicon assay.
In Study GS-US-540-5823, among pediatric subjects with baseline and post-baseline sequencing
data available, treatment-emergent substitutions in the viral RdRp (nsp12) were observed in 3 of 27
subjects treated with VEKLURY and were evaluated for susceptibility to remdesivir. In one subject,
two substitutions (nsp12 substitutions V166L and V792I) emerged and were associated with
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Reference ID: 5499606
1.85- and 3.6-fold decreases in remdesivir susceptibility relative to reference, respectively. This
subject was hospitalized at baseline, recovered from COVID-19, and was released from the hospital
on Day 13. None of the substitutions observed in any of the other genes (nsp9-10, nsp13-14)
encoding for proteins of the viral replication-transcription complex have been associated with reduced
susceptibility to remdesivir.
The relationship between the level of reduced susceptibility to remdesivir observed in subgenomic
replicon assays and the inhibition of SARS-CoV-2 replication by remdesivir in humans has not been
fully established.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Given the short-term administration of VEKLURY for the treatment of COVID-19, long-term animal
studies to evaluate the carcinogenic potential of remdesivir were not conducted.
Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome
aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.
Impairment of Fertility
Nonclinical toxicity studies in rats demonstrated no adverse effect on male fertility at exposures of the
predominant circulating metabolite (GS-441524) approximately 2 times the exposure in humans at
the RHD.
Reproductive toxicity, including decreases in corpora lutea, numbers of implantation sites, and viable
embryos, was seen when remdesivir was administered by daily intravenous administration at a
systemically toxic dose (10 mg/kg) in female rats 14 days prior to mating and during conception;
exposures of the predominant circulating metabolite (GS-441524) were 1.3 times the exposure in
humans at the RHD.
13.2 Animal Toxicology and/or Pharmacology
Intravenous administration (slow bolus) of remdesivir to male rhesus monkeys at dosage levels of 5,
10, and 20 mg/kg/day for 7 days resulted, at all dose levels, in increased mean urea nitrogen and
increased mean creatinine, renal tubular atrophy, and basophilia and casts.
Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of ≥3 mg/kg/day for up
to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction.
Kidney-related effects in rats and monkeys were observed at exposures of the predominant
circulating metabolite (GS-441524) that are lower than the exposure in humans at the RHD.
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14 CLINICAL STUDIES
14.1 Description of Clinical Trials
The efficacy and safety of VEKLURY were evaluated in the trials summarized in Table 23.
Table 23
Trials Conducted with VEKLURY in Subjects with COVID-19
Trial
Population
Trial Arms (N)
Timepoint
NIAID ACTT-1a
(NCT04280705)
Hospitalized with
mild/moderate and severe
COVID-19
VEKLURY 10 Days (532)
Placebo (516)
29 Days after
Randomization
GS-US-540-5773b
(NCT04292899)
Hospitalized with severe
COVID-19
VEKLURY 5 Days (200)
VEKLURY 10 Days (197)
Day 14
GS-US-540-5774b
(NCT04292730)
Hospitalized with moderate
COVID-19
VEKLURY 5 Days (191)
VEKLURY 10 Days (193)
Standard of care (200)
Day 11
GS-US-540-9012a
(NCT04501952)
Non-hospitalized with mild
to-moderate COVID-19 and
at high risk for progression
to severe disease
VEKLURY 3 Days (279)
Placebo (283)
Day 28
GS-US-540-5823
(Cohorts 1-8)c
(NCT04431453)
Hospitalized pediatric
subjects from birth to <18
years of age and weighing
at least 1.5 kg with COVID
19
VEKLURY up to 10 Days
(58)
Day 10
COVID-19: coronavirus disease 2019
a. Randomized, double-blind, placebo-controlled trial.
b. Randomized, open-label trial.
c. Open-label trial, descriptive outcome analyses.
14.2 NIAID ACTT-1 Study in Hospitalized Subjects with Mild/Moderate and Severe COVID-19
A randomized, double-blind, placebo-controlled clinical trial (ACTT-1) of hospitalized adult subjects
with confirmed SARS-CoV-2 infection and mild, moderate, or severe COVID-19 compared treatment
with VEKLURY for 10 days (n=541) with placebo (n=521). Mild/moderate disease was defined as
SpO2 >94% and respiratory rate <24 breaths/minute without supplemental oxygen; severe disease
was defined as an SpO2 ≤94% on room air, a respiratory rate ≥24 breaths/minute, an oxygen
requirement, or a requirement for mechanical ventilation. Subjects had to have at least one of the
following to be enrolled in the trial: radiographic infiltrates by imaging, SpO2 ≤94% on room air, a
requirement for supplemental oxygen, or a requirement for mechanical ventilation. Subjects treated
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with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days, for 10 days of
treatment via intravenous infusion. Treatment with VEKLURY was stopped in subjects who were
discharged from the hospital prior to the completion of 10 days of treatment.
At baseline, mean age was 59 years (with 36% of subjects aged 65 or older); 64% of subjects were
male, 53% were White, 21% were Black, and 13% were Asian; 24% were Hispanic or Latino; 105
subjects had mild/moderate disease (10% in both treatment groups); 957 subjects had severe
disease (90% in both treatment groups). Subjects in this trial were unvaccinated. A total of 285
subjects (27%) (n=131 received VEKLURY) were on invasive mechanical ventilation or ECMO. The
most common comorbidities were hypertension (51%), obesity (45%), and type 2 diabetes mellitus
(31%); the distribution of comorbidities was similar between the two treatment groups.
The primary clinical endpoint was time to recovery within 29 days after randomization. Recovery was
defined as discharged from the hospital without limitations on activities, discharged from the hospital
with limitations on activities and/or requiring home oxygen, or hospitalized but not requiring
supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery
was 10 days in the VEKLURY group compared to 15 days in the placebo group (recovery rate ratio
1.29 [95% CI 1.12 to 1.49], p<0.001). Among subjects with mild/moderate disease at enrollment
(n=105), the median time to recovery was 5 days in both the VEKLURY and placebo groups
(recovery rate ratio 1.22 [95% CI 0.82 to 1.81]). Among subjects with severe disease at enrollment
(n=957), the median time to recovery was 11 days in the VEKLURY group compared to 18 days in
the placebo group (recovery rate ratio 1.31 [95% CI 1.12 to 1.52]).
A key secondary endpoint was clinical status on Day 15 assessed on an 8-point ordinal scale
consisting of the following categories:
1. not hospitalized, no limitations on activities;
2. not hospitalized, limitation on activities and/or requiring home oxygen;
3. hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care;
4. hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19
related or otherwise);
5. hospitalized, requiring supplemental oxygen;
6. hospitalized, on noninvasive ventilation or high-flow oxygen devices;
7. hospitalized, on invasive mechanical ventilation or ECMO; and
8. death.
Overall, the odds of improvement in the ordinal scale were higher in the VEKLURY group at Day 15
when compared to the placebo group (odds ratio 1.54 [95% CI 1.25 to 1.91]).
Overall, 29-day mortality was 11% for the VEKLURY group vs 15% for the placebo group (hazard
ratio 0.73 [95% CI 0.52 to 1.03]).
14.3 Study GS-US-540-5773 in Hospitalized Subjects with Severe COVID-19
A randomized, open-label multi-center clinical trial (Study 5773) in adult subjects with confirmed
SARS-CoV-2 infection, an SpO2 of ≤94% on room air, and radiological evidence of pneumonia
compared 200 subjects who received VEKLURY for 5 days with 197 subjects who received
VEKLURY for 10 days. Treatment with VEKLURY was stopped in subjects who were discharged from
the hospital prior to completion of their protocol-defined duration of treatment. Subjects on
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mechanical ventilation at screening were excluded. All subjects received 200 mg of VEKLURY on
Day 1 and 100 mg once daily on subsequent days via intravenous infusion, plus standard of care.
At baseline, the median age of subjects was 61 years (range, 20 to 98 years); 64% were male, 75%
were White, 12% were Black, and 12% were Asian; 22% were Hispanic or Latino. More subjects in
the 10-day group than the 5-day group required invasive mechanical ventilation or ECMO (5% vs
2%), or high-flow oxygen support (30% vs 25%), at baseline. Subjects in this trial were unvaccinated.
Median duration of symptoms and hospitalization prior to first dose of VEKLURY were similar across
treatment groups.
The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale consisting of
the following categories:
1. death;
2. hospitalized, receiving invasive mechanical ventilation or ECMO;
3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices;
4. hospitalized, requiring low-flow supplemental oxygen;
5. hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or
not related to COVID-19);
6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that
specified in the protocol for remdesivir administration); and
7. not hospitalized.
Overall, after adjusting for between-group differences at baseline, subjects receiving a 5-day course
of VEKLURY had similar clinical status at Day 14 as those receiving a 10-day course (odds ratio for
improvement 0.75 [95% CI 0.51 to 1.12]). There were no statistically significant differences in
recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between-group
differences at baseline. All-cause mortality at Day 28 was 12% vs 14% in the 5- and 10-day treatment
groups, respectively.
14.4 Study GS-US-540-5774 in Hospitalized Subjects with Moderate COVID-19
A randomized, open-label multi-center clinical trial (Study 5774) of hospitalized adult subjects with
confirmed SARS-CoV-2 infection, SpO2 >94% and radiological evidence of pneumonia compared
treatment with VEKLURY for 5 days (n=191) and treatment with VEKLURY for 10 days (n=193) with
standard of care (n=200). Treatment with VEKLURY was stopped in subjects who were discharged
from the hospital prior to completion of their protocol-defined duration of treatment. Subjects treated
with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days via
intravenous infusion.
At baseline, the median age of subjects was 57 years (range, 12 to 95 years); 61% were male, 61%
were White, 19% were Black, and 19% were Asian; 18% were Hispanic or Latino. Subjects in this trial
were unvaccinated. Baseline clinical status, oxygen support status, and median duration of symptoms
and hospitalization prior to first dose of VEKLURY were similar across treatment groups.
The primary endpoint was clinical status on Day 11 assessed on a 7-point ordinal scale consisting of
the following categories:
1. death;
2. hospitalized, receiving invasive mechanical ventilation or ECMO;
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3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices;
4. hospitalized, requiring low-flow supplemental oxygen;
5. hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or
not related to COVID-19);
6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that
specified in the protocol for remdesivir administration); and
7. not hospitalized.
Overall, the odds of improvement in the ordinal scale were higher in the 5-day VEKLURY group at
Day 11 when compared to those receiving only standard of care (odds ratio 1.65 [95% CI 1.09 to
2.48], p=0.017). The odds of improvement in clinical status with the 10-day treatment group when
compared to those receiving only standard of care were not statistically significant (odds ratio 1.31
[95% CI 0.88 to 1.95]). All-cause mortality at Day 28 was ≤2% in all treatment groups.
14.5 Study GS-US-540-9012 in Non-Hospitalized Subjects with Mild-to-Moderate COVID-19 and
at High Risk for Progression to Severe Disease
A randomized, double-blind, placebo-controlled, clinical trial (Study 9012) evaluated VEKLURY 200
mg once daily for 1 day followed by VEKLURY 100 mg once daily for 2 days (for a total of 3 days of
intravenously administered therapy) in 554 adult and 8 pediatric subjects (12 years of age and older
and weighing at least 40 kg) who were non-hospitalized, had mild-to-moderate COVID-19, were
symptomatic for COVID-19 for ≤7 days, had confirmed SARS-CoV-2 infection, and had at least one
risk factor for progression to hospitalization. Risk factors for progression to hospitalization included
age ≥60 years, obesity (BMI ≥30), chronic lung disease, hypertension, cardiovascular or
cerebrovascular disease, diabetes mellitus, immunocompromised state, chronic mild or moderate
kidney disease, chronic liver disease, current cancer, and sickle cell disease. Subjects who received,
required, or were expected to require supplemental oxygen were excluded from the trial. Subjects
were randomized in a 1:1 manner, stratified by residence in a skilled nursing facility (yes/no), age
(<60 vs ≥60 years), and region (US vs ex-US) to receive VEKLURY (n=279) or placebo (n=283), plus
standard of care.
At baseline, mean age was 50 years (with 30% of subjects aged 60 or older); 52% were male, 80%
were White, 8% were Black, and 2% were Asian; 44% were Hispanic or Latino; median body mass
index was 30.7 kg/m2. Subjects in this trial were unvaccinated. VEKLURY or placebo was first
administered to subjects in outpatient facilities (84%), home healthcare settings (13%), or skilled
nursing facilities (3%). The most common comorbidities were diabetes mellitus (62%), obesity (56%),
and hypertension (48%). Median (Q1, Q3) duration of symptoms prior to treatment was 5 (3, 6) days;
median viral load was 6.3 log10 copies/mL at baseline. The baseline demographics and disease
characteristics were well balanced across the VEKLURY and placebo treatment groups.
The primary endpoint was the proportion of subjects with COVID-19 related hospitalization (defined
as at least 24 hours of acute care) or all-cause mortality through Day 28. Events occurred in 2 (0.7%)
subjects treated with VEKLURY compared to 15 (5.3%) subjects concurrently randomized to placebo
(hazard ratio 0.134 [95% CI 0.031 to 0.586]; p=0.0076). No deaths were observed through Day 28.
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14.6 Study GS-US-540-5823 in Hospitalized Pediatric Subjects with COVID-19
The primary objectives of this Phase 2/3 single-arm, open-label clinical trial (Study GS-US-540-5823)
were to evaluate pharmacokinetics and safety of up to 10 days of treatment with VEKLURY in
pediatric subjects. A total of 58 pediatric subjects from birth (including preterm to term infants) to
<18 years of age and weighing at least 1.5 kg with confirmed SARS-CoV-2 infection and mild,
moderate, or severe COVID-19 was evaluated in eight cohorts:
• Cohorts 1-4, 8; infants, children, and adolescents: Subjects ≥12 years and weighing ≥40 kg
(n=12); subjects <12 years and weighing ≥40 kg (n=5); subjects ≥28 days and weighing ≥20 to
<40 kg (n=12); subjects ≥28 days and weighing ≥12 to <20 kg (n=12); and subjects ≥28 days
and weighing ≥3 to <12 kg (n=12). Subjects weighing ≥40 kg received 200 mg of VEKLURY on
Day 1 followed by VEKLURY 100 mg once daily on subsequent days; subjects weighing ≥3 kg
to <40 kg received VEKLURY 5 mg/kg on Day 1 followed by VEKLURY 2.5 mg/kg once daily
on subsequent days;
• Cohorts 5-7; neonates and infants: Subjects 14 to <28 days old, GA >37 weeks, and weighing
≥2.5 kg (n=3); subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and
subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1). Subjects 14 to <28
days old, GA >37 weeks, and weighing ≥2.5 kg received VEKLURY 5 mg/kg on Day 1 followed
by VEKLURY 2.5 mg/kg once daily on subsequent days. Subjects <14 days old, GA >37
weeks, and weighing at least 2.5 kg at birth, and subjects <56 days old, GA ≤37 weeks, and
weighing ≥1.5 kg at birth, received VEKLURY 2.5 mg/kg on Day 1 followed by VEKLURY 1.25
mg/kg once daily on subsequent days.
Assessments occurred at the following intervals: Screening; Day 1 (Baseline); Days 2-10, or until
discharge, whichever came earlier; Follow-Up on Day 30 (±5). Treatment with VEKLURY was
stopped in subjects who were discharged from the hospital prior to the completion of 10 days of
treatment.
Infants, children, and adolescents: At baseline, median age was 7 years (Q1, Q3: 2 years, 12 years);
57% were female, 70% were White, 30% were Black, and 44% were Hispanic or Latino; median
weight was 25 kg (range: 4 to 192 kg). Subjects in this trial were unvaccinated. A total of 12 subjects
(23%) were on invasive mechanical ventilation, 18 (34%) were on non-invasive ventilation or high-
flow oxygen; 10 (19%) were on low-flow oxygen; and 13 (25%) were on room air, at baseline. The
overall median (Q1, Q3) duration of symptoms and hospitalization prior to first dose of VEKLURY was
5 (3, 7) days and 1 (1, 3) day, respectively.
The descriptive outcome analyses showed treatment with VEKLURY for up to 10 days resulted in an
overall median (Q1, Q3) change from baseline in clinical status (assessed on a 7-point ordinal scale
ranging from death [score of 1] to ventilatory support and decreasing levels of oxygen to hospital
discharge [score of 7]) of +2.0 (1.0, 4.0) points on Day 10.
Recovery (defined as an improvement from a baseline clinical status score of 2 through 5 to a score
of 6 or 7, or an improvement from a baseline score of 6 to a score of 7) was reported for 62% of
subjects on Day 10; median (Q1, Q3) time to recovery was 7 (5, 16) days.
43
Reference ID: 5499606
Overall, 60% of subjects were discharged by Day 10, and 83% of subjects were discharged by Day
30. Three subjects (6%) from Cohorts 1-4 and Cohort 8 died during the study.
Neonates and infants: At baseline, subjects ranged in age from 12 to 30 days; 3/5 were female, 4/5
were White, 1/5 was Black; weight ranged from 2.2 to 3.5 kg. Three subjects were on invasive
mechanical ventilation and 2 were on high-flow oxygen. The duration of symptoms and hospitalization
prior to first dose of VEKLURY ranged from 2 to 9 days and 1 to 9 days, respectively.
The descriptive outcome analyses showed treatment with VEKLURY for up to 10 days resulted in
recovery (defined as an improvement from a baseline clinical status score of 2 through 5 to a score of
6 or 7, or an improvement from a baseline score of 6 to a score of 7) for 3 subjects, including for one
subject by Day 10. Time to recovery ranged from 9 to 19 days.
Overall, a total of 3 subjects were discharged by Day 30, of which one subject was discharged by Day
10. No subjects from Cohorts 5-7 died during the study.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
VEKLURY for injection: 100 mg (NDC 61958-2901-2), is supplied as a single-dose vial containing a
sterile, preservative-free white to off-white to yellow lyophilized powder. It requires reconstitution and
further dilution prior to administration by intravenous infusion [see Dosage and Administration (2.4)].
Discard unused portion. The container closure is not made with natural rubber latex.
VEKLURY injection: 100 mg/20 mL (5 mg/mL) (NDC 61958-2902-2), is supplied as a single-dose vial
containing a sterile, preservative-free, clear, colorless to yellow aqueous-based solution. It requires
dilution prior to administration by intravenous infusion [see Dosage and Administration (2.4)]. Discard
unused portion. The container closure is not made with natural rubber latex.
Storage and Handling
Do not reuse or save reconstituted or diluted VEKLURY for future use. These products contain no
preservative; therefore, partially used vials should be discarded [see Dosage and Administration
(2.5)].
VEKLURY for Injection
Store VEKLURY for injection, 100 mg vials below 30°C (below 86°F) until required for use.
After reconstitution, use vials immediately to prepare diluted solution. Dilute the reconstituted solution
in 0.9% sodium chloride injection, USP within the same day as administration. The diluted VEKLURY
solution in the infusion bags can be stored up to 24 hours at room temperature (20°C to 25°C [68°F to
77°F]) prior to administration or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
44
Reference ID: 5499606
VEKLURY Injection
Store VEKLURY injection vials at refrigerated temperature (2°C to 8°C [36°F to 46°F]) until required
for use.
Dilute within the same day as administration. Prior to dilution, equilibrate VEKLURY injection to room
temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to 12 hours at room
temperature prior to dilution. Store VEKLURY injection after dilution in the infusion bags for no more
than 24 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 48 hours at refrigerated
temperature (2°C to 8°C [36°F to 46°F]).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions have been seen in patients receiving VEKLURY during
and after infusion. Advise patients to inform their healthcare provider if they experience any of the
following: changes in heart rate; fever; shortness of breath, wheezing; swelling of the lips, face, or
throat; rash; nausea; sweating; or shivering [see Warnings and Precautions (5.1)].
Increased Risk of Transaminase Elevations
Inform patients that VEKLURY may increase the risk of hepatic laboratory abnormalities. Advise
patients to alert their healthcare provider immediately if they experience any symptoms of liver
inflammation [see Warnings and Precaution (5.2)].
Drug Interactions
Inform patients that VEKLURY may interact with other drugs. Advise patients to report to their
healthcare provider the use of any other prescription or nonprescription medication or herbal
products, including chloroquine phosphate or hydroxychloroquine sulfate [see Warnings and
Precautions (5.3), Drug Interactions (7), and Microbiology (12.4)].
Pregnancy
Inform patients to notify their healthcare provider in the event of a pregnancy [see Use in Specific
Populations (8.1)].
VEKLURY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks
referenced herein are the property of their respective owners.
© 202X Gilead Sciences, Inc. All rights reserved
45
Reference ID: 5499606
PATIENT INFORMATION
VEKLURY® (VEK-lur-ee)
VEKLURY® (VEK-lur-ee)
(remdesivir)
(remdesivir)
for injection
injection
What is VEKLURY?
VEKLURY is a prescription medicine used for the treatment of coronavirus disease 2019 (COVID-19) in adults and children
weighing at least 3 pounds (1.5 kg) who are:
•
Hospitalized, or
•
Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19,
including hospitalization or death.
It is not known if VEKLURY is safe and effective in children weighing less than 3 pounds (1.5 kg).
Do not take VEKLURY if you are allergic to remdesivir or any of the ingredients in VEKLURY. See the end of this
leaflet for a complete list of ingredients in VEKLURY.
Before receiving VEKLURY, tell your healthcare provider about all of your medical conditions, including if you:
•
have liver problems
•
are pregnant or plan to become pregnant. It is not known if VEKLURY may harm your unborn baby if taken during the
first trimester of pregnancy. Tell your healthcare provider right away if you are or if you become pregnant.
•
are breastfeeding or plan to breastfeed. VEKLURY can pass into your breast milk. Talk to your healthcare provider
about the best way to feed your baby.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements. VEKLURY may interact with other medicines.
Especially tell your healthcare provider if you are taking the medicines chloroquine phosphate or
hydroxychloroquine sulfate.
How will I receive VEKLURY?
•
Hospitalized: VEKLURY is given to you through a vein by intravenous (IV) infusion one time each day for up to 10
days. Your healthcare provider will decide how many doses you need.
•
Not hospitalized: VEKLURY is given to you through a vein by intravenous (IV) infusion one time each day for 3 days.
•
Your healthcare provider will do certain blood tests before starting and during treatment with VEKLURY.
What are the possible side effects of VEKLURY?
VEKLURY may cause serious side effects, including:
•
Allergic reactions. Allergic reactions can happen during or after infusion with VEKLURY. Your healthcare provider will
monitor you for signs and symptoms of allergic reactions during your infusion and for at least 1 hour after your infusion.
Tell your healthcare provider right away if you get any of the following signs and symptoms of an allergic reaction:
o
changes in your heart rate
o
rash
o
fever
o
nausea
o
shortness of breath, wheezing
o
sweating
o
swelling of the lips, face, or throat
o
shivering
•
Increase in liver enzymes. Increases in liver enzymes are common in people who have received VEKLURY and may
be a sign of liver injury. Your healthcare provider will do blood tests to check your liver enzymes before and during
treatment with VEKLURY as needed. Your healthcare provider may stop treatment with VEKLURY if you develop liver
problems.
The most common side effect of VEKLURY is nausea.
These are not all of the possible side effects of VEKLURY.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
1
Reference ID: 5499606
General information about the safe and effective use of VEKLURY.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your
pharmacist or healthcare provider for information about VEKLURY that is written for healthcare professionals.
What are the ingredients in VEKLURY?
Active ingredient: remdesivir
Inactive ingredients:
VEKLURY for injection: betadex sulfobutyl ether sodium and may include hydrochloric acid and/or sodium hydroxide for
pH adjustment.
VEKLURY injection: betadex sulfobutyl ether sodium, Water for Injection, USP, and may include hydrochloric acid and/or
sodium hydroxide for pH adjustment.
Manufactured and distributed by: Gilead Sciences, Inc., Foster City, CA 94404
VEKLURY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.
© 202X Gilead Sciences, Inc. All rights reserved.
214787-GS-01X
For more information, call 1-800-445-3235 or go to www.VEKLURY.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
2
Reference ID: 5499606
| custom-source | 2025-02-12T15:48:02.756877 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214787s029lbl.pdf', 'application_number': 214787, 'submission_type': 'SUPPL ', 'submission_number': 29} |
80,685 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HARVONI® safely and effectively. See full prescribing information
for HARVONI.
HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use
HARVONI® (ledipasvir and sofosbuvir) oral pellets
Initial U.S. Approval: 2014
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
See full prescribing information for complete boxed warning.
Hepatitis B virus (HBV) reactivation has been reported, in some
cases resulting in fulminant hepatitis, hepatic failure, and death.
(5.1)
-------------------------------INDICATIONS AND USAGE------------------------
HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus
(HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog
NS5B polymerase inhibitor, and is indicated for the treatment of
chronic hepatitis C virus (HCV) in adults and pediatric patients 3 years
of age and older:
• Genotype 1, 4, 5, or 6 infection without cirrhosis or with
compensated cirrhosis
• Genotype 1 infection with decompensated cirrhosis, in combination
with ribavirin
• Genotype 1 or 4 infection who are liver transplant recipients without
cirrhosis or with compensated cirrhosis, in combination with ribavirin.
(1)
------------------------DOSAGE AND ADMINISTRATION----------------------
• Testing prior to the initiation of therapy: Test all patients for HBV
infection by measuring HBsAg and anti-HBc. (2.1)
• Recommended treatment regimen and duration in patients 3 years
of age and older: (2.2)
HCV
Genotype
Patient Population
Regimen
and
Duration
Treatment-naïve without cirrhosis or
with compensated cirrhosis (Child-
Pugh A)
HARVONI
12 weeks
Genotype
1
Treatment-experienced without
cirrhosis
HARVONI
12 weeks
Treatment-experienced with
compensated cirrhosis (Child-Pugh A)
HARVONI
24 weeks
Treatment-naïve and treatment-
experienced with decompensated
cirrhosis (Child-Pugh B or C)
HARVONI
+ ribavirin
12 weeks
Genotype
1 or 4
Treatment-naïve and treatment-
experienced liver transplant recipients
without cirrhosis, or with compensated
cirrhosis (Child-Pugh A)
HARVONI
+ ribavirin
12 weeks
Genotype
4, 5, or 6
Treatment-naïve and treatment-
experienced without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
HARVONI
12 weeks
• Recommended dosage in adults: One tablet (90 mg of ledipasvir
and 400 mg of sofosbuvir) taken orally once daily with or without
food. (2.3)
• Recommended dosage in pediatric patients 3 years and older:
Recommended dosage of HARVONI in pediatric patients 3 years of
age and older is based on weight. Refer to Table 2 of the full
prescribing information for specific dosing guidelines based on body
weight. (2.4)
• Instructions for Use should be followed for preparation and
administration of HARVONI oral pellets. (2.5)
• HCV/HIV-1 coinfection: For adult and pediatric patients with
HCV/HIV-1 coinfection, follow the dosage recommendations in the
tables in the full prescribing information. (2.3, 2.4)
• If used in combination with ribavirin, follow the recommendations for
ribavirin dosing and dosage modifications. (2.3, 2.4)
• For patients with any degree of renal impairment, including end
stage renal disease on dialysis, no HARVONI dosage adjustment is
recommended. (2.6)
-----------------------DOSAGE FORMS AND STRENGTHS-------------------
• Tablets: 90 mg of ledipasvir and 400 mg of sofosbuvir; 45 mg of
ledipasvir and 200 mg of sofosbuvir. (3)
• Oral Pellets: 45 mg of ledipasvir and 200 mg of sofosbuvir; 33.75 mg
of ledipasvir and 150 mg of sofosbuvir. (3)
--------------------------------CONTRAINDICATIONS-----------------------------
If used in combination with ribavirin, all contraindications to ribavirin
also apply to HARVONI combination therapy. (4)
-------------------------WARNINGS AND PRECAUTIONS---------------------
• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence
of current or prior HBV infection before initiation of HCV treatment.
Monitor HCV/HBV coinfected patients for HBV reactivation and
hepatitis flare during HCV treatment and post-treatment follow-up.
Initiate appropriate patient management for HBV infection as
clinically indicated. (5.1)
• Bradycardia with amiodarone coadministration: Serious symptomatic
bradycardia may occur in patients taking amiodarone, particularly in
patients also receiving beta blockers, or those with underlying
cardiac comorbidities and/or advanced liver disease.
Coadministration of amiodarone with HARVONI is not
recommended. In patients without alternative, viable treatment
options, cardiac monitoring is recommended. (5.2, 6.2, 7.2)
-------------------------------ADVERSE REACTIONS----------------------------
• The most common adverse reactions (incidence greater than or
equal to 10%, all grades) observed with treatment with HARVONI
were fatigue, headache, and asthenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
---------------------------------DRUG INTERACTIONS--------------------------
• Coadministration with amiodarone may result in serious
symptomatic bradycardia. Use of HARVONI with amiodarone is not
recommended. (5.2, 6.2, 7.2)
• P-gp inducers (e.g., rifampin, St. John’s wort): May alter
concentrations of ledipasvir and sofosbuvir. Use of HARVONI with
P-gp inducers is not recommended. (5.3, 7, 12.3)
• Consult the full prescribing information prior to use for potential drug
interactions. (5.2, 5.3, 7, 12.3)
• Clearance of HCV infection with direct acting antivirals may lead to
changes in hepatic function, which may impact safe and effective
use of concomitant medications. Frequent monitoring of relevant
laboratory parameters (INR or blood glucose) and dose adjustments
of certain concomitant medications may be necessary. (7.2)
---------------------USE IN SPECIFIC POPULATIONS---------------------
• Pediatric Use: No data are available regarding the safety of
HARVONI in pediatric patients with renal impairment. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
Reference ID: 5499805
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
2.2 Recommended Treatment Regimen and Duration in
Patients 3 Years of Age and Older with Genotype 1, 4, 5, or
6 HCV
2.3 Recommended Dosage in Adults
2.4 Recommended Dosage in Pediatric Patients 3 Years of
Age and Older
2.5 Preparation and Administration of Oral Pellets
2.6 Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Hepatitis B Virus Reactivation in Patients
Coinfected with HCV and HBV
5.2 Serious Symptomatic Bradycardia When Coadministered
with Amiodarone
5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp
Inducers
5.4 Risks Associated with Ribavirin Combination Treatment
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Potential for Drug Interaction
7.2 Established and Potentially Significant Drug Interactions
7.3 Drugs without Clinically Significant Interactions with
HARVONI
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
14.2 Clinical Trials in Subjects with Genotype 1 HCV
14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV
14.4 Clinical Trials in Subjects Coinfected with HCV and HIV-1
14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with
Decompensated Cirrhosis
14.6 Clinical Trials in Adults with Severe Renal Impairment, Including
those Requiring Dialysis
14.7 Clinical Trial in Pediatric Subjects
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5499805
FULL PRESCRIBING INFORMATION
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
COINFECTED WITH HCV AND HBV
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection
before initiating treatment with HARVONI. HBV reactivation has been reported in
HCV/HBV coinfected patients who were undergoing or had completed treatment
with HCV direct acting antivirals and were not receiving HBV antiviral therapy.
Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation
during HCV treatment and post-treatment follow-up. Initiate appropriate patient
management for HBV infection as clinically indicated [see Warnings and
Precautions (5.1)].
1
INDICATIONS AND USAGE
HARVONI is indicated for the treatment of adults and pediatric patients 3 years of age
and older with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2 and
2.3) and Clinical Studies (14)]:
• genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
• genotype 1 infection with decompensated cirrhosis, for use in combination with
ribavirin
• genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or
with compensated cirrhosis, for use in combination with ribavirin
2
DOSAGE AND ADMINISTRATION
2.1
Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV
treatment with HARVONI [see Warnings and Precautions (5.1)].
2.2
Recommended Treatment Regimen and Duration in Patients 3 Years of Age
and Older with Genotype 1, 4, 5, or 6 HCV
Table 1 shows the recommended HARVONI treatment regimen and duration based on
patient population. Relapse rates are affected by baseline host and viral factors and
differ between treatment durations for certain subgroups [see Clinical Studies (14)].
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1
[see Clinical Studies (14)]. Refer to Drug Interactions (7) for dosage recommendations
for concomitant HIV-1 antiviral drugs.
Reference ID: 5499805
Table 1
Recommended Treatment Regimen and Duration for HARVONI in
Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV
HCV Genotype
Patient Population
Treatment Regimen and
Duration
Genotype 1
Treatment-naïve without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
HARVONI 12 weeksa
Treatment-experiencedb without cirrhosis
HARVONI 12 weeks
Treatment-experiencedb with
compensated cirrhosis (Child-Pugh A)
HARVONI 24 weeksc
Treatment-naïve and treatment
experiencedb with decompensated
cirrhosis (Child-Pugh B or C)
HARVONI + ribavirind 12 weeks
Genotype 1 or 4
Treatment-naïve and treatment
experiencedb liver transplant recipients
without cirrhosis, or with compensated
cirrhosis (Child-Pugh A)
HARVONI + ribavirind 12 weeks
Genotype 4, 5, or 6
Treatment-naïve and treatment
experiencedb, without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
HARVONI 12 weeks
a.
HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis
who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)].
b.
Treatment-experienced adult and pediatric subjects have failed a peginterferon alfa +/- ribavirin based
regimen with or without an HCV protease inhibitor.
c.
HARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients
with cirrhosis who are eligible for ribavirin [see Dosage and Administration (2.3 and 2.4) and Clinical
Studies (14.2)].
d.
See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations.
2.3
Recommended Dosage in Adults
The recommended dosage of HARVONI in adults with genotype 1, 4, 5, or 6 HCV is
one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or
without food [see Clinical Pharmacology (12.3)].
The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg
for those ≥75 kg) administered orally in two divided doses with food.
In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and
can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two
divided doses with food. If the starting dosage of ribavirin is not well tolerated, the
dosage should be reduced as clinically indicated based on hemoglobin levels.
For further information on ribavirin dosing and dosage modifications, refer to the
ribavirin prescribing information [see Dosage and Administration (2.4), Use in Specific
Populations (8.6), and Clinical Studies (14.5)].
Reference ID: 5499805
2.4
Recommended Dosage in Pediatric Patients 3 Years of Age and Older
The recommended dosage of HARVONI in pediatric patients 3 years of age and older
with genotype 1, 4, 5, or 6 HCV using HARVONI tablets or oral pellets is based on
weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in
combination with HARVONI for pediatric patients. Take HARVONI tablets or pellets
(with or without food) once daily [see Dosage and Administration (2.5), Clinical
Pharmacology (12.3), and Clinical Studies (14.7)]. HARVONI pellets can be taken in
pediatric patients who cannot swallow the tablet formulation.
Table 2
Dosing for Pediatric Patients 3 Years and Older Using HARVONI
Tablets or Oral Pellets
Body Weight
(kg)
Dosing of HARVONI Tablets or Oral Pellets
HARVONI Daily Dose
at least 35
one 90 mg/400 mg tablet once daily
or
two 45 mg/200 mg tablets once daily
or
two 45 mg/200 mg packets of pellets once daily
90 mg/400 mg per day
17 to less than
35
one 45 mg/200 mg tablet once daily
or
one 45 mg/200 mg packet of pellets once daily
45 mg/200 mg per day
less than 17
one 33.75 mg/150 mg packet of pellets once
daily
33.75 mg/150 mg per day
Table 3
Recommended Dosing for Ribavirin in Combination Therapy with
HARVONI for Pediatric Patients 3 Years and Older
Body Weight (kg)
Oral Ribavirin Daily Dosagea
less than 47
15 mg per kg per day
(divided dose AM and PM)
47–49
600 mg per day
(1 x 200 mg AM, 2 x 200 mg PM)
50–65
800 mg per day
(2 x 200 mg AM, 2 x 200 mg PM)
66–80
1000 mg per day
(2 x 200 mg AM, 3 x 200 mg PM)
greater than 80
1200 mg per day
(3 x 200 mg AM, 3 x 200 mg PM)
a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
Reference ID: 5499805
2.5
Preparation and Administration of Oral Pellets
See the HARVONI oral pellets full Instructions for Use for details on the preparation and
administration of HARVONI pellets.
Do not chew HARVONI pellets. If HARVONI pellets are administered with food, sprinkle
the pellets on one or more spoonfuls of non-acidic soft food at or below room
temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed
potato, and ice cream. Take HARVONI pellets within 30 minutes of gently mixing with
food and swallow the entire contents without chewing to avoid a bitter aftertaste.
2.6
Renal Impairment
No dosage adjustment of HARVONI is recommended in patients with any degree of
renal impairment, including end stage renal disease (ESRD) on dialysis [see Dosage
and Administration (2.3)]. Take HARVONI with or without ribavirin according to the
recommendations in Table 1 [see Adverse Reactions (6.1), Use in Specific Populations
(8.6), and Clinical Studies (14.6)]. Refer to ribavirin tablet prescribing information for
ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per
minute.
3
DOSAGE FORMS AND STRENGTHS
HARVONI is available as tablets or pellets for oral use. Each dosage form is available in
two dose strengths.
• 90 mg/400 mg Tablets: orange, diamond-shaped, film-coated tablet debossed
with “GSI” on one side and “7985” on the other side of the tablet. Each tablet
contains 90 mg ledipasvir and 400 mg sofosbuvir.
• 45 mg/200 mg Tablets: white, capsule-shaped, film-coated tablets, debossed
with “GSI” on one side and “HRV” on the other side. Each tablet contains 45 mg
ledipasvir and 200 mg sofosbuvir.
• 45 mg/200 mg Pellets: orange pellets in unit-dose packets. Each packet contains
45 mg ledipasvir and 200 mg sofosbuvir.
• 33.75 mg/150 mg Pellets: orange pellets in unit-dose packets. Each packet
contains 33.75 mg ledipasvir and 150 mg sofosbuvir.
4
CONTRAINDICATIONS
If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to
this combination regimen. Refer to the ribavirin prescribing information for a list of
contraindications for ribavirin [see Dosage and Administration (2.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and
HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients
who were undergoing or had completed treatment with HCV direct acting antivirals, and
Reference ID: 5499805
who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Cases have been reported in patients who are
HBsAg positive and also in patients with serologic evidence of resolved HBV infection
(i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported
in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk
of HBV reactivation associated with treatment with HCV direct-acting antivirals may be
increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting
as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection,
reappearance of HBsAg can occur. Reactivation of HBV replication may be
accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe
cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and
anti-HBc before initiating HCV treatment with HARVONI. In patients with serologic
evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or
HBV reactivation during HCV treatment with HARVONI and during post-treatment
follow-up. Initiate appropriate patient management for HBV infection as clinically
indicated.
5.2
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and
cases requiring pacemaker intervention, have been reported when amiodarone is
coadministered with HARVONI. Bradycardia has generally occurred within hours to
days, but cases have been observed up to 2 weeks after initiating HCV treatment.
Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or
advanced liver disease, may be at increased risk for symptomatic bradycardia with
coadministration of amiodarone. Bradycardia generally resolved after discontinuation of
HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with HARVONI is not recommended. For patients
taking amiodarone who have no other alternative, viable treatment options and who will
be coadministered HARVONI:
• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of
coadministration is recommended, after which outpatient or self-monitoring of the
heart rate should occur on a daily basis through at least the first 2 weeks of
treatment.
Patients who are taking HARVONI who need to start amiodarone therapy due to no
other alternative, viable treatment options should undergo similar cardiac monitoring as
outlined above.
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to
starting HARVONI should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation
immediately. Symptoms may include near-fainting or fainting, dizziness or
Reference ID: 5499805
lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest
pains, confusion, or memory problems [see Adverse Reactions (6.2), Drug Interactions
(7.2)].
5.3
Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
The concomitant use of HARVONI and P-gp inducers may significantly decrease
ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic
effect of HARVONI. Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin,
St. John’s wort) is not recommended [see Drug Interactions (7.2)].
5.4
Risks Associated with Ribavirin Combination Treatment
If HARVONI is administered with ribavirin, the warnings and precautions for ribavirin, in
particular the pregnancy avoidance warning, apply to this combination regimen. Refer to
the ribavirin prescribing information for a full list of the warnings and precautions for
ribavirin [see Dosage and Administration (2.2)].
6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in labeling:
• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see
Warnings and Precautions (5.2)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
If HARVONI is administered with ribavirin to adults, refer to the prescribing information
for ribavirin for a description of ribavirin-associated adverse reactions.
Clinical Trials in Adult Subjects
The safety assessment of HARVONI was based on pooled data from three randomized,
open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1
HCV with compensated liver disease (with and without cirrhosis) including 215, 539,
and 326 subjects who received HARVONI once daily by mouth for 8, 12, and 24 weeks,
respectively [see Clinical Studies (14)].
The proportion of subjects who permanently discontinued treatment due to adverse
events was 0%, less than 1%, and 1% for subjects receiving HARVONI for 8, 12, and
24 weeks, respectively.
The most common adverse reactions (at least 10%) were fatigue and headache in
subjects treated with 8, 12, or 24 weeks of HARVONI.
Table 4 lists adverse reactions (adverse events assessed as causally related by the
investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks
of treatment with HARVONI in clinical trials. The majority of adverse reactions
presented in Table 4 occurred at severity of grade 1. The side-by-side tabulation is to
Reference ID: 5499805
simplify presentation; direct comparison across trials should not be made due to
differing trial designs.
Table 4
Adverse Reactions (All Grades) Reported in ≥5% of Subjects
Receiving 8, 12, or 24 Weeks of Treatment with HARVONI
HARVONI
8 weeks
(N=215)
HARVONI
12 weeks
(N=539)
HARVONI
24 weeks
(N=326)
Fatigue
16%
13%
18%
Headache
11%
14%
17%
Nausea
6%
7%
9%
Diarrhea
4%
3%
7%
Insomnia
3%
5%
6%
The safety assessment of HARVONI was also based on pooled data from three open-
label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV
genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis)
[see Clinical Studies (14.3)]. The subjects received HARVONI once daily by mouth for
12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection
with compensated liver disease was similar to that observed in subjects with chronic
HCV genotype 1 infection with compensated liver disease. The most common adverse
reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%),
and fatigue (10%).
Adverse Reactions in Subjects with Cirrhosis
The safety assessment of HARVONI with or without ribavirin was based on a
randomized, double-blind and placebo-controlled trial in treatment-experienced
genotype 1 subjects with compensated cirrhosis and was compared to placebo in the
SIRIUS trial. Subjects were randomized to receive 24 weeks of HARVONI once daily by
mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI once
daily by mouth + ribavirin [see Clinical Studies (14.2)]. Table 5 presents the adverse
reactions, as defined above, that occurred with at least 5% greater frequency in
subjects treated with 24 weeks of HARVONI or 12 weeks of HARVONI + ribavirin,
compared to those reported for 12 weeks of placebo. The majority of the adverse
reactions presented in Table 5 were Grade 1 or 2 in severity.
Reference ID: 5499805
Table 5
Adverse Reactions with ≥5% Greater Frequency Reported in
Treatment-Experienced Subjects with Cirrhosis Receiving HARVONI
for 24 Weeks or HARVONI + Ribavirin for 12 Weeks Compared to
Placebo for 12 weeks
HARVONI
24 weeks
(N=78)
HARVONI + RBV
12 weeks
(N=76)
Placebo
12 weeks
(N=77)
Asthenia
31%
36%
23%
Headache
29%
13%
16%
Fatigue
18%
4%
1%
Cough
5%
11%
1%
Myalgia
9%
4%
0
Dyspnea
3%
9%
1%
Irritability
8%
7%
1%
Dizziness
5%
1%
0
RBV=ribavirin
Adverse Reactions in Subjects Coinfected with HIV-1
The safety assessment of HARVONI was based on an open-label clinical trial in
335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable
antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in
HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected
subjects. The most common adverse reactions occurring in at least 10% of subjects
were headache (20%) and fatigue (17%).
Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated
Cirrhosis
The safety assessment of HARVONI with ribavirin in liver transplant recipients and/or
those who had decompensated liver disease was based on pooled data from two Phase
2 open-label clinical trials including 336 subjects who received HARVONI plus ribavirin
for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were
excluded from the trials [see Clinical Studies (14.5)].
The adverse events observed were consistent with the expected clinical sequelae of
liver transplantation and/or decompensated liver disease, or the known safety profile of
HARVONI and/or ribavirin.
Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were
observed in 38% and 13% of subjects treated with HARVONI plus ribavirin for 12
weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated
with HARVONI plus ribavirin for 12 weeks.
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Liver Transplant Recipients with Compensated Liver Disease:
Among the 174 liver transplant recipients with compensated liver disease who received
HARVONI with ribavirin for 12 weeks, 2 (1%) subjects permanently discontinued
HARVONI due to an adverse event.
Subjects with Decompensated Liver Disease:
Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who
received HARVONI with ribavirin for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects
underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and
died during treatment or within 30 days after discontinuation of treatment. Because
these events occurred in patients with advanced liver disease who are at risk of
progression of liver disease including liver failure and death, it is not possible to reliably
assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects
permanently discontinued HARVONI due to an adverse event.
Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The
following adverse reactions occurred in less than 5% of subjects receiving HARVONI in
any one trial. These events have been included because of their seriousness or
assessment of potential causal relationship.
Psychiatric disorders: depression (including in subjects with pre-existing history of
psychiatric illness).
Depression (particularly in subjects with pre-existing history of psychiatric illness)
occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and
suicide have occurred in less than 1% of subjects treated with sofosbuvir in
combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.
Laboratory Abnormalities
Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in
3%, less than 1%, and 2% of subjects treated with HARVONI for 8, 12, and
24 weeks, respectively. Bilirubin elevations of greater than 1.5xULN were observed
in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo,
HARVONI + ribavirin for 12 weeks, and HARVONI for 24 weeks, respectively, in the
SIRIUS trial.
Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN
were observed in less than 1%, 2%, and 3% of subjects treated with HARVONI for 8,
12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater
than 3x ULN were observed in 1%, 3%, and 9% of subjects with compensated
cirrhosis treated with placebo, HARVONI + ribavirin for 12 weeks, and HARVONI for
24 weeks, respectively, in the SIRIUS trial.
Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1,
or ION-2 of HARVONI. Creatine kinase was assessed in the ION-4 trial. Isolated,
asymptomatic creatine kinase elevations of greater than or equal to 10xULN was
observed in 1% of subjects treated with HARVONI for 12 weeks in the ION-4 trial
Reference ID: 5499805
and has also been previously reported in subjects treated with sofosbuvir in
combination with ribavirin or peginterferon/ribavirin in other clinical trials.
Adverse Reactions in Adults with Severe Renal Impairment, Including those on Dialysis
In an open-label trial (Trial 0154) in which adults with HCV with compensated liver
disease (with or without cirrhosis) and severe renal impairment received HARVONI for
12 weeks (N=18), the most common adverse reaction was fatigue (17%) [see Clinical
Studies (14.6)].
In an open-label clinical trial, Trial 4063, a total of 95 adults with HCV with compensated
liver disease (with or without cirrhosis) and ESRD requiring dialysis received HARVONI
for 8 (n=45), 12 (n=31), or 24 (n=19) weeks. The most common adverse reactions were
insomnia and headache (each reported in 4% of subjects overall) [see Clinical Studies
(14.6)].
Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
The safety assessment of HARVONI in pediatric subjects 3 years of age and older is
based on data from a Phase 2, open-label clinical trial (Study 1116). In total, 226
subjects were enrolled, which included 223 subjects without cirrhosis or with
compensated cirrhosis who were treated with HARVONI for 12 weeks; one genotype 1
treatment-experienced subject with cirrhosis who was treated with HARVONI for 24
weeks; and two genotype 3 subjects who were treated with HARVONI + ribavirin for 24
weeks. The adverse reactions observed were consistent with those observed in clinical
studies of HARVONI in adults. Limited safety data are available in pediatric subjects
receiving HARVONI for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation
due to an adverse reaction was observed in those pediatric subjects receiving
HARVONI for 24 weeks [see Clinical Studies (14.7)].
In a 5-year follow-up study, 178 of the 226 subjects from the Phase 2 open-label clinical
trial (Study 1116) were followed for a median (Q1, Q3) duration of 239 (143, 244)
weeks. No notable effects on growth as assessed by changes from baseline through
end of study were observed for height, weight, BMI percentiles, and Z-scores for any
age group. No notable effects were observed on the development of secondary sexual
characteristics of subjects as assessed by changes from baseline through end of study
in Tanner pubertal stages [see Use in Specific Populations (8.4)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of
HARVONI. Because postmarketing reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Cardiac Disorders
Serious symptomatic bradycardia has been reported in patients taking amiodarone who
initiate treatment with HARVONI [see Warnings and Precautions (5.2), Drug Interactions
(7.2)].
Reference ID: 5499805
Skin and Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling
Angioedema
7
DRUG INTERACTIONS
7.1
Potential for Drug Interaction
As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been
identified with these agents individually may occur with HARVONI.
After oral administration of HARVONI, sofosbuvir is rapidly absorbed and subject to
extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir
and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic
analyses.
Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance
protein (BCRP) and may increase intestinal absorption of coadministered substrates for
these transporters.
Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while
GS-331007 is not. P-gp inducers (e.g., rifampin, St. John’s wort) may decrease
ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect
of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see
Warnings and Precautions (5.3)].
7.2
Established and Potentially Significant Drug Interactions
Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic
function, which may impact the safe and effective use of concomitant medications. For
example, altered blood glucose control resulting in serious symptomatic hypoglycemia
has been reported in diabetic patients in postmarketing case reports and published
epidemiological studies. Management of hypoglycemia in these cases required either
discontinuation or dose modification of concomitant medications used for diabetes
treatment.
Frequent monitoring of relevant laboratory parameters (e.g., International Normalized
Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug
concentrations of concomitant medications such as cytochrome P450 substrates with a
narrow therapeutic index (e.g., certain immunosuppressants) is recommended to
ensure safe and effective use. Dose adjustments of concomitant medications may be
necessary.
Table 6 provides a listing of established or potentially clinically significant drug
interactions. The drug interactions described are based on studies conducted with either
HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual
agents, or are predicted drug interactions that may occur with HARVONI [see Warnings
and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].
Reference ID: 5499805
Table 6
Potentially Significant Drug Interactions: Alteration in Dose or
Regimen May Be Recommended Based on Drug Interaction Studies
or Predicted Interactiona
Concomitant Drug
Class: Drug Name
Effect on
Concentrationb
Clinical Comment
Acid Reducing Agents:
↓ ledipasvir
Ledipasvir solubility decreases as pH increases. Drugs
that increase gastric pH are expected to decrease
concentration of ledipasvir.
Antacids (e.g., aluminum
and magnesium
hydroxide)
It is recommended to separate antacid and HARVONI
administration by 4 hours.
H2-receptor antagonistsc
H2-receptor antagonists may be administered
(e.g., famotidine)
simultaneously with or 12 hours apart from HARVONI at
a dose that does not exceed doses comparable to
famotidine 40 mg twice daily.
Proton-pump inhibitorsc
(e.g., omeprazole)
Proton-pump inhibitor doses comparable to omeprazole
20 mg or lower can be administered simultaneously with
HARVONI under fasted conditions.
Antiarrhythmics:
Effect on
Coadministration of amiodarone with HARVONI may
amiodarone
amiodarone,
ledipasvir, and
sofosbuvir
concentrations
unknown
result in serious symptomatic bradycardia. The
mechanism of this effect is unknown. Coadministration
of amiodarone with HARVONI is not recommended; if
coadministration is required, cardiac monitoring is
recommended [see Warnings and Precautions (5.2),
Adverse Reactions (6.2)].
digoxin
↑ digoxin
Coadministration of HARVONI with digoxin may
increase the concentration of digoxin. Therapeutic
concentration monitoring of digoxin is recommended
when coadministered with HARVONI.
Anticonvulsants:
↓ ledipasvir
Coadministration of HARVONI with carbamazepine,
carbamazepinec
↓ sofosbuvir
phenytoin, or phenobarbital is expected to decrease the
phenytoin
concentration of ledipasvir and sofosbuvir, leading to
phenobarbital
reduced therapeutic effect of HARVONI.
Coadministration is not recommended.
Antimycobacterials:
rifabutinc
rifampinc
rifapentine
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with rifampin, rifabutin, or
rifapentine is not recommended [see Warnings and
Precautions (5.3)].
HIV Antiretrovirals:
Regimens containing
↑ tenofovir
Monitor for tenofovir-associated adverse reactions in
tenofovir DF without an
patients receiving HARVONI concomitantly with a
HIV protease inhibitor/
regimen containing tenofovir DF without an HIV
ritonavir or cobicistat
protease inhibitor/ritonavir or cobicistat. Refer to
VIREAD or TRUVADA prescribing information for
recommendations on renal monitoring.
Regimens containing
tenofovir DF and an HIV
protease inhibitor/
ritonavir or cobicistat
• atazanavir/ritonavir or
cobicistat +
emtricitabine/tenofovir
DFc
• darunavir/ritonavir or
↑ tenofovir
The safety of increased tenofovir concentrations in the
setting of HARVONI and an HIV protease
inhibitor/ritonavir or cobicistat has not been established.
Consider alternative HCV or antiretroviral therapy to
avoid increases in tenofovir exposures. If
coadministration is necessary, monitor for tenofovir
associated adverse reactions. Refer to VIREAD or
TRUVADA prescribing information for recommendations
on renal monitoring.
Reference ID: 5499805
Concomitant Drug
Class: Drug Name
Effect on
Concentrationb
Clinical Comment
cobicistat +
emtricitabine/tenofovir
DFc
• lopinavir/ritonavir +
emtricitabine/tenofovir
DF
elvitegravir, cobicistat,
emtricitabine, tenofovir
DF
↑ tenofovir
The safety of increased tenofovir concentrations in the
setting of HARVONI and the combination of elvitegravir,
cobicistat, emtricitabine, and tenofovir DF has not been
established. Coadministration is not recommended.
tipranavir/ritonavir
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with tipranavir/ritonavir is
expected to decrease the concentration of ledipasvir and
sofosbuvir, leading to reduced therapeutic effect of
HARVONI. Coadministration is not recommended.
HCV Products:
simeprevirc
↑ ledipasvir
↑ simeprevir
Concentrations of ledipasvir and simeprevir are
increased when simeprevir is coadministered with
ledipasvir. Coadministration of HARVONI with
simeprevir is not recommended.
Herbal Supplements:
St. John’s wort
(Hypericum perforatum)
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with St. John’s wort, a P
gp inducer, is not recommended [see Warnings and
Precautions (5.3)].
HMG-CoA Reductase
Inhibitors:
rosuvastatin
↑ rosuvastatin
Coadministration of HARVONI with rosuvastatin may
significantly increase the concentration of rosuvastatin,
which is associated with increased risk of myopathy,
including rhabdomyolysis. Coadministration of
HARVONI with rosuvastatin is not recommended.
atorvastatin
↑ atorvastatin
Coadministration of HARVONI with atorvastatin may be
associated with increased risk of myopathy, including
rhabdomyolysis. Monitor closely for HMG-CoA
reductase inhibitor-associated adverse reactions, such
as myopathy and rhabdomyolysis.
tenofovir DF = tenofovir disoproxil fumarate
a.
This table is not all inclusive.
b.
↓ = decrease, ↑ = increase
c.
These interactions have been studied in healthy adults.
7.3
Drugs without Clinically Significant Interactions with HARVONI
Based on drug interaction studies conducted with the components of HARVONI
(ledipasvir or sofosbuvir) or HARVONI, no clinically significant drug interactions have
been either observed or are expected when HARVONI is used with the following drugs
[see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine,
darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives,
pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 6 for use of
HARVONI with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].
Reference ID: 5499805
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
If HARVONI is administered with ribavirin, the combination regimen is contraindicated in
pregnant women and in men whose female partners are pregnant. Refer to the ribavirin
prescribing information for more information on ribavirin-associated risks of use during
pregnancy.
No adequate human data are available to establish whether or not HARVONI poses a
risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse
developmental outcomes was observed with the components of HARVONI (ledipasvir or
sofosbuvir) at exposures greater than those in humans at the recommended human
dose (RHD) [see Data]. During organogenesis in the rat and rabbit, systemic exposures
(AUC) to ledipasvir were approximately 4 (rats) and 2 (rabbits) times the exposure in
humans at the RHD, while exposures to the predominant circulating metabolite of
sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at
the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC)
to ledipasvir and GS-331007 were approximately 5 and 7 times, respectively, the
exposure in humans at the RHD.
The background risk of major birth defects and miscarriage for the indicated population
is unknown. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
respectively.
Data
Animal Data
Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day)
and rabbits (up to 180 mg/kg/day) on gestation days 6 to 18 and 7 to 20, respectively,
and also to rats (oral doses up to 100 mg/kg/day) on gestation day 6 to lactation/post
partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal
(rats) development were observed at the highest doses tested. Systemic exposures
(AUC) to ledipasvir were ≥4 (rats) and 2 (rabbits) times the exposure in humans at the
RHD.
Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day)
and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively,
and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post
partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal
(rats) development were observed at the highest doses tested. Systemic exposures
(AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were
≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD, with exposures
increasing during gestation from approximately 3 to 6 (rats) and 7 to 17 (rabbits) times
the exposure in humans at the RHD.
Reference ID: 5499805
8.2
Lactation
Risk Summary
It is not known whether ledipasvir or sofosbuvir, the components of HARVONI, or their
metabolites are present in human breast milk, affect human milk production or have
effects on the breastfed infant. When administered to lactating rats, ledipasvir was
detected in the plasma of nursing pups likely due to the presence of ledipasvir in milk,
without clear effects on nursing pups [see Data]. The predominant circulating metabolite
of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating
rats, without effect on nursing pups.
The development and health benefits of breastfeeding should be considered along with
the mother’s clinical need for HARVONI and any potential adverse effects on the
breastfed child from HARVONI or from the underlying maternal condition.
If HARVONI is administered with ribavirin, the nursing mother’s information for ribavirin
also applies to this combination regimen. Refer to the ribavirin prescribing information
for more information on use during lactation.
Data
Ledipasvir: No effects of ledipasvir on growth and postnatal development were
observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure
(AUC) to ledipasvir was approximately 5 times the exposure in humans at the RHD.
Although not measured directly, ledipasvir was likely present in the milk of lactating rats,
since systemic exposure (AUC) to ledipasvir of approximately 25% that of maternal
exposure was observed in nursing pups on lactation day 10.
Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were
observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure
(AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was
approximately 7 times the exposure in humans at the RHD, with exposure of
approximately 2% that of maternal exposure observed in nursing pups on lactation day
10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted
into the milk of lactating rats following administration of a single oral dose of sofosbuvir
(20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of
maternal plasma concentrations observed 1 hour post-dose.
8.3
Females and Males of Reproductive Potential
If HARVONI is administered with ribavirin, the information for ribavirin with regard to
pregnancy testing, contraception, and infertility also applies to this combination regimen.
Refer to ribavirin prescribing information for additional information.
8.4
Pediatric Use
The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV
genotype 1 and 4 infection in treatment-naïve and treatment-experienced pediatric
patients 3 years of age and older without cirrhosis or with compensated cirrhosis have
been established in an open-label, multicenter clinical trial (Study 1116, N=226; 186
treatment-naïve, 40 treatment-experienced) and are comparable to that observed in
adults.
Reference ID: 5499805
The safety and efficacy of HARVONI for treatment of HCV genotypes 5 or 6 infection in
pediatric patients 3 years of age and older are supported by comparable ledipasvir,
sofosbuvir, and GS-331007 exposures between adults and pediatric patients [see
Dosage and Administration (2.2 and 2.4), Adverse Reactions (6.1), Clinical
Pharmacology (12.3), and Clinical Studies (14.3, 14.6, 14.7)]. Similar rationale is used
to support dosing recommendations for pediatric patients with HCV genotype 1 infection
who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients with
HCV genotype 1 and 4 infection who are liver transplant recipients without cirrhosis or
with compensated cirrhosis.
In patients with severe renal impairment, including those requiring dialysis, exposures of
GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical
Pharmacology (12.3)]. No data are available regarding the safety of HARVONI in
pediatric patients with renal impairment [see Use in Specific Populations (8.6)].
The safety and efficacy of HARVONI have not been established in pediatric patients
less than 3 years of age.
In a 5-year follow-up study, the long-term effects of HARVONI on pediatric growth were
assessed in 178 pediatric subjects 3 years of age and older treated with HARVONI in
Study 1116. No notable effects on growth from baseline through end of study were
observed [see Adverse Reactions (6.1)]. All subjects who had achieved SVR12
maintained SVR through end of study.
8.5
Geriatric Use
Clinical trials of HARVONI included 225 subjects aged 65 and over (9% of total number
of subjects in the clinical studies). No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out. No
dosage adjustment of HARVONI is warranted in geriatric patients [see Clinical
Pharmacology (12.3)].
8.6
Renal Impairment
No dosage adjustment of HARVONI is recommended for patients with mild, moderate,
or severe renal impairment, including ESRD requiring dialysis [see Dosage and
Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and
Clinical Studies (14.6)]. No safety data are available in subjects with both
decompensated cirrhosis and severe renal impairment, including those on dialysis.
Additionally, no safety data are available in pediatric patients with renal impairment [see
Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information
regarding use in patients with renal impairment.
8.7
Hepatic Impairment
No dosage adjustment of HARVONI is recommended for patients with mild, moderate,
or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and
Administration (2.3), Clinical Pharmacology (12.3) and Clinical Studies (14.5)].
Reference ID: 5499805
Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for
patients with decompensated cirrhosis receiving treatment with HARVONI and ribavirin
[see Adverse Reactions (6.1)].
10
OVERDOSAGE
No specific antidote is available for overdose with HARVONI. If overdose occurs, the
patient must be monitored for evidence of toxicity. Treatment of overdose with
HARVONI consists of general supportive measures including monitoring of vital signs
as well as observation of the clinical status of the patient. Hemodialysis is unlikely to
result in significant removal of ledipasvir since ledipasvir is highly bound to plasma
protein. Hemodialysis can efficiently remove the predominant circulating metabolite of
sofosbuvir, GS-331007, with an extraction ratio of 53%.
11
DESCRIPTION
Tablets
HARVONI tablets are fixed-dose combination tablets containing ledipasvir and
sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is
a nucleotide analog inhibitor of HCV NS5B polymerase.
Each 90 mg/400 mg tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The
tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone,
croscarmellose sodium, lactose monohydrate, magnesium stearate, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing
the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake,
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Each 45 mg/200 mg tablet contains 45 mg ledipasvir and 200 mg sofosbuvir. The
tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone,
croscarmellose sodium, lactose monohydrate, magnesium stearate, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing
the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and
titanium dioxide.
Pellets
HARVONI oral pellets are for oral administration, supplied as small, orange pellets in
unit-dose packets. Each unit-dose of HARVONI oral pellets contains either 45 mg
ledipasvir and 200 mg sofosbuvir or 33.75 mg ledipasvir and 150 mg sofosbuvir and the
following inactive ingredients: amino-methacrylate copolymer, colloidal silicon dioxide,
copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, iron oxide
red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, talc, and titanium dioxide.
Ledipasvir: The IUPAC name for ledipasvir is methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7
{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2
azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5
azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate.
Reference ID: 5499805
It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the
following structural formula:
O
O
F
F
H
N
H3CO
H
N
N
N
H
N
N
H
N
H
N
OCH3
O
O
Ledipasvir is practically insoluble (less than 0.1 mg/mL) across the pH range of 3.0–7.5
and is slightly soluble below pH 2.3 (1.1 mg/mL).
Sofosbuvir: The IUPAC name for sofosbuvir is (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5
(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2
yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
H
O
N
O
O
O
O
N
O
HN P O
O
HO
F
Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL
across the pH range of 2–7.7 at 37oC and is slightly soluble in water.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-
acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].
12.2 Pharmacodynamics
Cardiac Electrophysiology
Thorough QT studies have been conducted for ledipasvir and sofosbuvir.
The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended
dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose,
placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover thorough
QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the
maximum recommended dosage), ledipasvir does not prolong QTc interval to any
clinically relevant extent.
The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three
times the maximum recommended dosage) on QTc interval was evaluated in a
randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four-
period crossover thorough QT trial in 59 healthy subjects. At a dose three times the
maximum recommended dose, sofosbuvir does not prolong QTc to any clinically
relevant extent.
Reference ID: 5499805
12.3 Pharmacokinetics
Absorption
The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant
circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in
subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir
median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was
absorbed quickly and the peak median plasma concentration was observed ~0.8 to
1 hour post-dose. Median peak plasma concentration of GS-331007 was observed
between 3.5 to 4 hours post-dose.
Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric
mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and
GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL, respectively. Steady-
state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL,
respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult
subjects and subjects with HCV infection. Relative to healthy subjects (N=191),
ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in
HCV-infected subjects.
Effect of Food
Relative to fasting conditions, the administration of a single dose of HARVONI with a
moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal
increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect
sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the
presence of either meal type. The response rates in Phase 3 trials were similar in HCV-
infected subjects who received HARVONI with food or without food. HARVONI can be
administered without regard to food.
Distribution
Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg
dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity
ranged between 0.51 and 0.66.
Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding
is independent of drug concentration over the range of 1 microgram/mL to
20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a
single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of
14C-radioactivity was approximately 0.7.
Metabolism
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative
metabolism via an unknown mechanism has been observed. Following a single dose of
90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug
(greater than 98%). Unchanged ledipasvir is the major species present in feces.
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves
Reference ID: 5499805
sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A
(CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine
nucleotide biosynthesis pathway. Dephosphorylation results in the formation of
nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks
anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007
accounted for approximately greater than 90% of total systemic exposure.
Elimination
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the
[14C]-radioactivity in feces and urine was approximately 87%, with most of the
radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir
excreted in feces accounted for a mean of 70% of the administered dose and the
oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that
biliary excretion of unchanged ledipasvir is a major route of elimination, with renal
excretion being a minor pathway (approximately 1%). The median terminal half-life of
ledipasvir following administration of HARVONI was 47 hours.
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose
was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in
urine, feces, and expired air, respectively. The majority of the sofosbuvir dose
recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir.
These data indicate that renal clearance is the major elimination pathway for
GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following
administration of HARVONI were 0.5 and 27 hours, respectively.
Specific Populations
Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that
race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and
GS-331007.
Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated
that gender had no clinically relevant effect on the exposure of sofosbuvir and
GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in
females than males; however, the relationship between gender and ledipasvir
exposures was not considered clinically relevant, as high response rates
(SVR12 >90%) were achieved in male and female subjects across the Phase 3
studies and the safety profiles are similar in females and males.
Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007
were determined in HCV genotype 1, 3, or 4 infected pediatric subjects 3 years of
age and older receiving a daily dose of HARVONI as described below in Table 7.
Exposures in pediatric subjects were similar to those observed in adults.
Reference ID: 5499805
Table 7
Pharmacokinetic Properties of the Components of HARVONI in
HCV-Infected Pediatric Subjects 3 Years of Age and Oldera
Weight Group
Dose
PK Parameter
Geometric Mean (%CV)
Ledipasvir
Sofosbuvir
GS-331007
≥35 kgb
90/400 mg
AUCtau (ng•hr/mL)
11200 (45.7)
1350 (45.2)
13600 (18.9)
Cmax (ng/mL)
550 (44.2)
660 (51.1)
921 (17.8)
17 to <35 kgc
45/200 mg
AUCtau (ng•hr/mL)
8750 (46.6)
1420 (34.2)
10700 (30.9)
Cmax (ng/mL)
440 (42.7)
690 (24.8)
958 (26.1)
<17 kgd
33.75/150
mg
AUCtau (ng•hr/mL)
7460 (31.0)
1720 (23.2)
12200 (15.2)
Cmax (ng/mL)
405 (25.7)
791 (16.6)
1070 (13.0)
a. Population PK derived parameters
b. Ledipasvir N=100; Sofosbuvir N=72; GS-331007 N=100
c. Ledipasvir N=86; Sofosbuvir N=66; GS-331007 N=86
d. Ledipasvir N=9; Sofosbuvir N=9; GS-331007 N=9
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been
established in pediatric subjects less than 3 years of age [see Use in Specific
Populations (8.4) and Clinical Studies (14.7)].
Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects
showed that within the age range (18 to 80 years) analyzed, age did not have a
clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007
[see Use in Specific Populations (8.5)].
Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied
with a single dose of 90 mg ledipasvir in HCV negative subjects with severe renal
impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant
differences in ledipasvir pharmacokinetics were observed between healthy subjects
and subjects with severe renal impairment.
The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild
(eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to
less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than
30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a
single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function
(eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0-inf was 61%, 107%,
and 171% higher in mild, moderate, and severe renal impairment, while the
GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with
ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007
AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before
hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed
1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed
approximately 18% of administered dose [see Dosage and Administration (2.6) and
Use in Specific Populations (8.6)].
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in
HCV-infected subjects with severe renal impairment or ESRD requiring dialysis
Reference ID: 5499805
treated with HARVONI for 8, 12, or 24 weeks. The results were generally consistent
with those observed in HCV-negative subjects with ESRD requiring dialysis.
Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied
with a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic
impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar
in subjects with severe hepatic impairment and control subjects with normal hepatic
function. Population pharmacokinetics analysis in HCV-infected subjects indicated
that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on
the exposure of ledipasvir [see Use in Specific Populations (8.7)].
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg
sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment
(Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the
sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic
impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively.
Population pharmacokinetics analysis in HCV-infected subjects indicated that
cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the
exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) and
Clinical Studies (14.5)].
Drug Interaction Studies
Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while
GS-331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease
ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect
of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see
Warnings and Precautions (5.3)]. Coadministration with drugs that inhibit P-gp and/or
BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing
GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or
BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake
transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal
transporters, including organic anion transporter OAT1 or OAT3, or organic cation
transporter OCT2.
Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro,
no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary
excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a
substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with
HARVONI mediated by CYP or UGT1A1 enzymes are not expected.
The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and
GS-331007 are shown in Table 8 [see Drug Interactions (7)].
Reference ID: 5499805
Table 8
Drug Interactions: Changes in Pharmacokinetic Parameters for
Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite
GS-331007 in the Presence of the Coadministered Druga
Coadministered
Drug
Dose of
Coadminis
tered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
-buvir
Dose
(mg)
N
Mean Ratio (90% CI) of Ledipasvir,
Sofosbuvir, and GS-331007 PK With/Without
Coadministered Drug
No Effect=1.00
Cmax
AUC
Cmin
Atazanavir/
ritonavir +
emtricitabine/
tenofovir DFb,c
300/100 +
200/300
once daily
90
once
daily
400
once
daily
24
ledipasvir
1.68
(1.54, 1.84)
1.96
(1.74, 2.21)
2.18
(1.91, 2.50)
sofosbuvir
1.01
(0.88, 1.15)
1.11
(1.02, 1.21)
NA
GS-331007
1.17
(1.12, 1.23)
1.31
(1.25, 1.36)
1.42
(1.34, 1.49)
Carbamazepine
300 twice
daily
ND
400
single
dose
24
sofosbuvir
0.52
(0.43, 0.62)
0.52
(0.46, 0.59)
NA
GS-331007
1.04
(0.97, 1.11)
0.99
(0.94, 1.04)
NA
Cyclosporine
600 single
dose
ND
400
single
dose
19
sofosbuvir
2.54
(1.87, 3.45)
4.53
(3.26, 6.30)
NA
GS-331007
0.60
(0.53, 0.69)
1.04
(0.90, 1.20)
NA
Darunavir/ ritonavir
800/100
once daily
90
once
daily
ND
23
ledipasvir
1.45
(1.34, 1.56)
1.39
(1.28, 1.49)
1.39
(1.29, 1.51)
ND
400
single
dose
18
sofosbuvir
1.45
(1.10, 1.92)
1.34
(1.12, 1.59)
NA
GS-331007
0.97
(0.90, 1.05)
1.24
(1.18, 1.30)
NA
Darunavir/ ritonavir
+ emtricitabine/
tenofovir DFb
800/100 +
200/300
once daily
90
once
daily
400
once
daily
23
ledipasvir
1.11
(0.99, 1.24)
1.12
(1.00, 1.25)
1.17
(1.04, 1.31)
sofosbuvir
0.63
(0.52, 0.75)
0.73
(0.65, 0.82)
NA
GS-331007
1.10
(1.04, 1.16)
1.20
(1.16, 1.24)
1.26
(1.20, 1.32)
Efavirenz/
emtricitabine/
tenofovir DFd
600/200/300
once daily
90
once
daily
400
once
daily
14
ledipasvir
0.66
(0.59, 0.75)
0.66
(0.59, 0.75)
0.66
(0.57, 0.76)
sofosbuvir
1.03
(0.87, 1.23)
0.94
(0.81, 1.10)
NA
GS-331007
0.86
(0.76, 0.96)
0.90
(0.83, 0.97)
1.07
(1.02, 1.13)
Elvitegravir/
cobicistat/
emtricitabine/
tenofovir
alafenamide
150/150/200
/10 once
daily
90
once
daily
400
once
daily
30
ledipasvir
1.65
(1.53, 1.78)
1.79
(1.64, 1.96)
1.93
(1.74, 2.15)
sofosbuvir
1.28
(1.13, 1.47)
1.47
(1.35,1.59)
NA
GS-331007
1.29
(1.24, 1.35)
1.48
(1.44, 1.53)
1.66
(1.60, 1.73)
Reference ID: 5499805
Coadministered
Drug
Dose of
Coadminis
tered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
-buvir
Dose
(mg)
N
Mean Ratio (90% CI) of Ledipasvir,
Sofosbuvir, and GS-331007 PK With/Without
Coadministered Drug
No Effect=1.00
Cmax
AUC
Cmin
Famotidine
40 single
dose
simultaneou
sly with
HARVONI
90
single
dose
400
single
dose
12
ledipasvir
0.80
(0.69, 0.93)
0.89
(0.76, 1.06)
NA
sofosbuvir
1.15
(0.88, 1.50)
1.11
(1.00, 1.24)
NA
GS-331007
1.06
(0.97, 1.14)
1.06
(1.02, 1.11)
NA
40 single
dose 12
hours prior
to HARVONI
12
ledipasvir
0.83
(0.69, 1.00)
0.98
(0.80, 1.20)
NA
sofosbuvir
1.00
(0.76, 1.32)
0.95
(0.82, 1.10)
NA
GS-331007
1.13
(1.07, 1.20)
1.06
(1.01, 1.12)
NA
Methadone
30 to 130
daily
ND
400
once
daily
14
sofosbuvir
0.95
(0.68, 1.33)
1.30
(1.00, 1.69)
NA
GS-331007
0.73
(0.65, 0.83)
1.04
(0.89, 1.22)
NA
Omeprazole
20 once
daily
simultaneou
sly with
HARVONI
90
single
dose
400
single
dose
16
ledipasvir
0.89
(0.61, 1.30)
0.96
(0.66, 1.39)
NA
sofosbuvir
1.12
(0.88, 1.42)
1.00
(0.80, 1.25)
NA
GS-331007
1.14
(1.01, 1.29)
1.03
(0.96, 1.12)
NA
20 once
daily 2 hours
prior to
ledipasvir
30
single
dose
ND
17
ledipasvir
0.52
(0.41, 0.66)
0.58
(0.48, 0.71)
NA
Rifabutin
300 once
daily
ND
400
single
dose
20
sofosbuvir
0.64
(0.53, 0.77)
0.76
(0.63, 0.91)
NA
GS-331007
1.15
(1.03, 1.27)
1.03
(0.95, 1.12)
NA
Rifampin
600 once
daily
90
single
dosee
ND
31
ledipasvir
0.65
(0.56, 0.76)
0.41
(0.36, 0.48)
NA
ND
400
single
dose
17
sofosbuvir
0.23
(0.19, 0.29)
0.28
(0.24, 0.32)
NA
GS-331007
1.23
(1.14, 1.34)
0.95
(0.88, 1.03)
NA
Simeprevir
150 once
daily
30
once
daily
ND
22
ledipasvir
1.81
(1.69, 2.94)
1.92
(1.77, 2.07)
NA
Tacrolimus
5 single
dose
ND
400
single
dose
16
sofosbuvir
0.97
(0.65, 1.43)
1.13
(0.81, 1.57)
NA
GS-331007
0.97
(0.83, 1.14)
1.00
(0.87, 1.13)
NA
NA = not available/not applicable, ND = not dosed.
tenofovir DF = tenofovir disoproxil fumarate
a. All interaction studies conducted in healthy volunteers.
b. Data generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of
atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and HARVONI
provided similar results.
c. The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of
Reference ID: 5499805
emtricitabine/tenofovir DF.
d. Administered as ATRIPLA® (efavirenz, emtricitabine, tenofovir DF).
e. This study was conducted in the presence of two other investigational HCV direct-acting agents.
No effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007
was observed with raltegravir and the combination of abacavir and lamivudine;
emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine,
and tenofovir disoproxil fumarate.
Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein
(BCRP) and may increase intestinal absorption of coadministered substrates for these
transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP
only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor
of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug
interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp
and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic
circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007
are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1,
OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1
enzymes.
The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are
shown in Table 9 [see Drug Interactions (7)].
Table 9
Drug Interactions: Changes in Pharmacokinetic Parameters for
Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or
HARVONIa
Coadministered
Drug
Dose of
Coadministered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
buvir
Dose
(mg)
N
Mean Ratio (90% CI) of
Coadministered Drug PK
With/Without Ledipasvir, Sofosbuvir,
or HARVONI
No Effect=1.00
Cmax
AUC
Cmin
Atazanavir/
ritonavir +
emtricitabine
/tenofovir DFb,c,d
atazanavir 300 once
daily
90 once
daily
400
once
daily
24
1.07
(0.99,
1.14)
1.27
(1.18,
1.37)
1.63
(1.45,
1.84)
ritonavir 100 once daily
0.86
(0.79,
0.93)
0.97
(0.89,
1.05)
1.45
(1.27,
1.64)
tenofovir DF 300 once
daily
1.47
(1.37,
1.58)
1.35
(1.29,
1.42)
1.47
(1.38,
1.57)
Darunavir/
ritonavir +
emtricitabine/
tenofovir DFb,d
darunavir 800 once
daily
90 once
daily
400
once
daily
23
1.01
(0.96,
1.06)
1.04
(0.99,
1.08)
1.08
(0.98,
1.20)
ritonavir 100 once daily
1.17
(1.01,
1.35)
1.25
(1.15,
1.36)
1.48
(1.34,
1.63)
tenofovir DF 300 once
daily
1.64
(1.54,
1.74)
1.50
(1.42,
1.59)
1.59
(1.49,
1.70)
Reference ID: 5499805
Coadministered
Drug
Dose of
Coadministered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
buvir
Dose
(mg)
N
Mean Ratio (90% CI) of
Coadministered Drug PK
With/Without Ledipasvir, Sofosbuvir,
or HARVONI
No Effect=1.00
Cmax
AUC
Cmin
Elvitegravir/
cobicistat/
emtricitabine/
tenofovir
alafenamide
elvitegravir 150 once
daily
90 once
daily
400
once
daily
30
0.98
(0.90,
1.07)
1.11
(1.02,
1.20)
1.46
(1.28,
1.66)
cobicistat 150 once
daily
1.23
(1.15,
1.32)
1.53
(1.45,
1.62)
3.25
(2.88,
3.67)
tenofovir alafenamide
10 once daily
0.90
(0.73,
1.11)
0.86
(0.78,
0.95)
NA
Norelgestromin
norgestimate
0.180/0.215/0.25/ethinyl
estradiol 0.025 once
daily
90 once
daily
ND
15
1.02
(0.89,
1.16)
1.03
(0.90,
1.18)
1.09
(0.91,
1.31)
ND
400
once
daily
1.07
(0.94,
1.22)
1.06
(0.92,
1.21)
1.07
(0.89,
1.28)
Norgestrel
90 once
daily
ND
1.03
(0.87,
1.23)
0.99
(0.82,
1.20)
1.00
(0.81,
1.23)
ND
400
once
daily
1.18
(0.99,
1.41)
1.19
(0.98,
1.45)
1.23
(1.00,
1.51)
Ethinyl estradiol
90 once
daily
ND
1.40
(1.18,
1.66)
1.20
(1.04,
1.39)
0.98
(0.79,
1.22)
ND
400
once
daily
1.15
(0.97,
1.36)
1.09
(0.94,
1.26)
0.99
(0.80,
1.23)
Midazolam
2.5 single dose
90
single
dose
ND
30
1.07
(1.00,
1.14)
0.99
(0.95,
1.04)
NA
0.95
(0.87,
1.04)
0.89
(0.84,
0.95)
NA
Raltegravir
400 twice daily
90 once
daily
ND
28
0.82
(0.66,
1.02)
0.85
(0.70,
1.02)
1.15
(0.90,
1.46)
ND
400
single
dose
19
0.57
(0.44,
0.75)
0.73
(0.59,
0.91)
0.95
(0.81,
1.12)
Simeprevir
150 once daily
30 once
daily
ND
22
2.61
(2.39,
2.86)
2.69
(2.44,
2.96)
NA
Tacrolimus
5 single dose
ND
400
single
dose
16
0.73
(0.59,
0.90)
1.09
(0.84,
1.40)
NA
Tenofovir DF
300 once dailye
90 once
daily
400
once
daily
15
1.79
(1.56,
2.04)
1.98
(1.77,
2.23)
2.63
(2.32,
2.97)
NA = not available/not applicable, ND = not dosed.
tenofovir DF = tenofovir disoproxil fumarate
a. All interaction studies conducted in healthy volunteers.
b. Data generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of
atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and HARVONI
provided similar results.
Reference ID: 5499805
c. The effects of HARVONI on atazanavir and ritonavir are similar with or without the presence of
emtricitabine/tenofovir DF.
d. This magnitude of change in tenofovir exposure does not reflect the approximately 60–80% increase caused by
the effects of an HIV PI/ritonavir and the effect of food. Therefore, tenofovir exposure is approximately 130%
higher when administered as tenofovir DF + atazanavir/ritonavir + HARVONI or tenofovir DF + darunavir/ritonavir
+ HARVONI and with food as compared to the tenofovir exposure observed following fasted administration of
tenofovir DF-based regimens that do not contain an HIV PI/ritonavir and HARVONI.
e. Administered as ATRIPLA (efavirenz, emtricitabine, tenofovir DF). The effects of HARVONI on tenofovir
exposures are similar when tenofovir is administered as ATRIPLA, COMPLERA, or TRUVADA + dolutegravir.
No effect on the pharmacokinetic parameters of the following coadministered drugs was
observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir,
dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.
12.4 Microbiology
Mechanism of Action
Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication.
Resistance selection in cell culture and cross-resistance studies indicate ledipasvir
targets NS5A as its mode of action.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is
required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes
intracellular metabolism to form the pharmacologically active uridine analog
triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B
polymerase and acts as a chain terminator. In a biochemical assay, GS-461203
inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and
4a with IC50 values of 3.3 and 2.7 microM, respectively. GS-461203 is neither an
inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA
polymerase.
Antiviral Activity
In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from
genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50
values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical
isolates from treatment-naïve HCV-infected subjects were 0. 02 nM for genotype 1a
(range 0.007–1.0 nM; N=23) and 0.006 nM for genotype 1b (range 0.002–1.0 nM;
N=34). Ledipasvir had median EC50 values ranging between 0.002 nM to 0.16 nM
against 11 genotype 4 subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m, and 4t). The
median EC50 value for subtype 4b was 199.6 nM (range 0.66–1799 nM; N=3); the two
4b isolates with EC50 values greater than 100 nM had NS5A resistance-associated
polymorphisms L30S+M31M+P58S+Y93H. The median EC50 value of ledipasvir was
0.03 nM against genotype 5a isolates (range 0.008–0.081 nM; N=35). For genotype 6,
the EC50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC50
values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k, and 6m, the
median EC50 values ranged from 60.6 nM to 430.1 nM.
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from
genotypes 1a, 1b, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 5a
or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric
replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a
Reference ID: 5499805
(range 29–128 nM; N=67) and 102 nM for genotype 1b (range 45–170 nM; N=29). In
replication competent virus assays, the EC50 value of sofosbuvir against genotype 1a
was 30 nM. Evaluation of sofosbuvir in combination with ledipasvir showed no
antagonistic effect in reducing HCV RNA levels in replicon cells.
Resistance
In Cell Culture
HCV replicons with reduced susceptibility to ledipasvir have been selected in cell
culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated
with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b.
Additionally, a Q30E substitution emerged in genotype 1a replicons. Site-directed
mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E
substitution in genotype 1a, conferred high levels of reduced susceptibility to
ledipasvir (fold change in EC50 greater than 1000-fold).
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell
culture for multiple genotypes including 1b, 4a, 5a, and 6a. Reduced susceptibility to
sofosbuvir was associated with the NS5B substitution S282T in all replicon
genotypes examined. An M289L substitution developed along with the S282T
substitution in genotype 5 and 6 replicons. Site-directed mutagenesis of the S282T
substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility
to sofosbuvir.
In Clinical Trials
Genotype 1
In a pooled analysis of subjects who received HARVONI in Phase 3 trials (ION-3,
ION-1, and ION-2), 37 subjects (29 with genotype 1a HCV and 8 with genotype 1b
HCV) qualified for resistance analysis due to virologic failure (35 with virologic
relapse, 2 with breakthrough on-treatment due to documented non-adherence).
Post-baseline NS5A and NS5B deep nucleotide sequence analysis data (assay
sensitivity of 1%) were available for 37/37 and 36/37 subjects’ viruses, respectively.
Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus
with emergent NS5A resistance-associated substitutions K24R, M28T/V,
Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects’ viruses also had
baseline NS5A polymorphisms at resistance-associated amino acid positions. The
most common substitutions detected at failure were Q30R, Y93H or N, and L31M.
Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent
NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Virus from
three of these 7 subjects also had baseline NS5A polymorphisms at resistance-
associated positions. The most common substitution detected at failure was Y93H.
At failure, 38% (14/37) of virologic failure subjects’ viruses had 2 or more NS5A
substitutions at resistance-associated positions.
In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with
decompensated liver disease), there were 24 virologic failures with genotype 1
infection (20 relapsers and 4 subjects who discontinued treatment prior to achieving
Reference ID: 5499805
HCV RNA <LLOQ). Treatment-emergent NS5A resistance-associated substitutions
K24R, M28T, Q30R/H/K, L31V, H58D/P, and/or Y93H/C were detected in
14/17 (82%) genotype 1a virologic failure subjects, and R30Q, L31M, and/or Y93H/N
were detected in 6/7 (86%) genotype 1b virologic failure subjects.
In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A
resistance-associated substitutions at failure showed 20- to >243-fold reduced
susceptibility to ledipasvir.
Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously
associated with sofosbuvir failure were detected in the Phase 3 trials (ION-3, ION-1,
and ION-2). In addition, treatment-emergent NS5B substitutions at highly conserved
positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected
at low frequency by next generation sequencing in treatment failure subjects infected
with HCV genotype 1a. The D61G substitution was previously described in subjects
infected with HCV genotype 1a in a liver pre-transplant trial. The E237G substitution
was detected in 3 subjects infected with HCV GT1a in the SOLAR-1 and SOLAR-2
trials. The clinical significance of these substitutions is currently unknown. The
sofosbuvir-associated resistance substitution S282T in NS5B was not detected in
any failure isolate from the Phase 3 trials. NS5B substitutions S282T, L320V/I, and
V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected
in one subject at failure following 8 weeks of treatment with HARVONI in a Phase 2
trial.
Genotype 4, 5 or 6
Resistance analysis was performed for 6 relapse subjects infected with HCV
genotype 4 (Study 1119 and ION-4, N=3), genotype 5 (Study 1119, N=2) or
genotype 6 (ELECTRON-2, N=1) and treated with HARVONI for 12 weeks. All the
relapse subjects with NS5A sequencing data (5 of 6) had pretreatment NS5A
resistance-associated polymorphisms (single or combinations at positions 24, 28,
30, 31, and 58). NS5A resistance substitutions (Y93C or L28V) emerged in two of
the genotype 4 relapse subjects post-treatment who also had NS5A polymorphisms
pretreatment that were retained post-treatment. Two of the relapsers with genotype
4 HCV infection had an NS5B V321I substitution pretreatment, which was retained
post-treatment. Three of the relapse subjects (1 each for genotype 4, 5, and 6) had
virus with emergent sofosbuvir resistance-associated substitution S282T at relapse;
the genotype 5 relapse subject also had emergent nucleotide inhibitor substitution
M289I.
Persistence of Resistance-Associated Substitutions
Certain NS5A inhibitor resistance-associated substitutions have been found to persist
for >1 year in some patients. The long-term clinical impact of the emergence or
persistence of virus containing ledipasvir or sofosbuvir resistance-associated
substitutions is unknown.
Reference ID: 5499805
Effect of Baseline HCV Polymorphisms on Treatment Response
Adults
Genotype 1
Analyses were conducted to explore the association between pre-existing baseline
NS5A polymorphisms at resistance-associated positions and relapse rates. In the
pooled analysis of the Phase 3 trials, 23% (370/1589) of subjects’ virus had baseline
NS5A polymorphisms at resistance-associated positions (any change from reference
at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population
or analysis of deep nucleotide sequences with a 15% frequency threshold.
In treatment-naïve subjects whose virus had baseline NS5A polymorphisms at
resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6%
(3/48) after 8 weeks and 1% (1/113) after 12 weeks of treatment with HARVONI.
Relapse rates among subjects without baseline NS5A polymorphisms at resistance-
associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks
of treatment with HARVONI.
In treatment-experienced subjects in Study ION-2 whose virus had baseline NS5A
polymorphisms at resistance-associated positions, relapse rates were 22% (5/23)
after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. In another
study in treatment-experienced subjects (SIRIUS), 0/15 (0%) subjects with NS5A
polymorphisms at resistance-associated positions relapsed after 12 weeks of
treatment with HARVONI + ribavirin compared to 2/15 (13%) subjects treated with
24 weeks of HARVONI.
SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F;
and N=3 with N142T) who had baseline polymorphisms associated with resistance
to sofosbuvir and/or other NS5B nucleoside inhibitors. The NS5B S282T substitution
associated with resistance to sofosbuvir was not detected in the baseline NS5B
sequence of any subject in Phase 3 trials by population or deep nucleotide
sequence analysis.
In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with
decompensated liver disease), after 12 weeks of treatment with HARVONI and
ribavirin, relapse rates were 7% (5/71) and 5% (10/217) in genotype 1 subjects with
and without baseline NS5A polymorphisms at resistance-associated positions,
respectively.
In the Phase 3 trials and SOLAR trials, the specific baseline NS5A resistance-
associated polymorphisms observed among subjects who relapsed were M28T/V,
Q30H/R, L31M, H58D/P, and Y93H/N in genotype 1a, and L28M, L31M, A92T, and
Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-
associated positions appeared to have higher relapse rates.
Genotype 4, 5 or 6
Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study
1119 (N=44) and ION-4 (N=8) identified 7 HCV genotype 4 subtypes (4a, 4b, 4d, 4f,
4m, 4o, and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d
Reference ID: 5499805
(N=11; 21%); 1 to 3 subjects were infected with each of the other genotype 4
subtypes. There were 3 subjects with subtype 4r, 2 of whom experienced virologic
relapse, and both had a combination of 2 pretreatment NS5A resistance-associated
polymorphisms (L28M/V+L30R).
Phylogenetic analysis of HCV sequences from genotype 5-infected subjects in
Study 1119 showed almost all were subtype 5a (N=39) with one subject not having a
subtype identified at screening or by analysis.
Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in
ELECTRON-2 identified 7 HCV genotype 6 subtypes (6a, 6e, 6l, 6m, 6p, 6q, and 6r).
Thirty-two percent of the subjects had subtype 6a and 24% had subtype 6e. One to
three subjects were infected with the other subtypes 6l, 6m, 6p, 6q, or 6r. The one
subject who did not achieve SVR12 had subtype 6l.
Although the data are limited, baseline HCV NS5A resistance-associated
polymorphisms are not expected to impact the likelihood of achieving SVR when
HARVONI is used as recommended to treat HCV genotype 4, 5, or 6-infected
patients, based on the low virologic failure rate observed in Study 1119 and
ELECTRON-2. The specific baseline polymorphisms observed in subjects with
virologic failure were L28M/V, L30R, and P58T for genotype 4; L31M for genotype 5;
and Q24K, F28V, R30A, and T58P for genotype 6.
Relapse occurred in 2 of 3 genotype 4 subjects who had baseline NS5B V321I, a
polymorphism at a position associated with treatment failure to sofosbuvir and other
nucleoside inhibitors; these two subjects also had baseline NS5A resistance-
associated polymorphisms. For genotype 5 and 6, SVR12 was achieved in subjects
who had baseline NS5B polymorphisms at positions associated with resistance to
sofosbuvir and other nucleoside inhibitors (N=1 with N142T in genotype 5; N=1 with
M289I in genotype 5; N=15 with M289L/I in genotype 6). The sofosbuvir resistance-
associated substitution S282T was not detected in the baseline NS5B sequence of
any subject with genotype 4, 5, or 6 HCV in clinical trials by population or deep
nucleotide sequence analysis.
Pediatrics
In Study 1116, the presence of NS5A and NS5B resistance-associated
polymorphisms did not impact treatment outcome; all pediatric subjects 3 years of
age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-
associated polymorphisms (14%; 32/223) achieved SVR following 12 weeks
treatment with HARVONI.
Cross Resistance
Based on resistance patterns observed in cell culture replicon studies and HCV-infected
subjects, cross-resistance between ledipasvir and other NS5A inhibitors is expected.
Both sofosbuvir and ledipasvir were fully active against substitutions associated with
resistance to other classes of direct-acting antivirals with different mechanisms of
action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The
efficacy of ledipasvir/sofosbuvir has not been established in patients who have
previously failed treatment with other regimens that include an NS5A inhibitor.
Reference ID: 5499805
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays,
including bacterial mutagenicity, chromosome aberration using human peripheral blood
lymphocytes, and in vivo rat micronucleus assays.
Ledipasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to
300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in a 2-year rat study (up to
100 mg/kg/day in males and 30 mg/kg/day in females), resulting in exposures
approximately 10 and 4 times, respectively, higher than the exposure in humans at the
recommended human dose (RHD).
Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays,
including bacterial mutagenicity, chromosome aberration using human peripheral blood
lymphocytes, and in vivo mouse micronucleus assays.
Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males
and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day),
resulting in exposures of the predominant circulating metabolite GS-331007 of
approximately 4 and 18 times (in mice) and 8 and 10 times (in rats), in males and
females respectively, the exposure in humans at the RHD.
Impairment of Fertility
Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the
mean number of corpora lutea and implantation sites were reduced slightly at maternal
exposures approximately 3 times the exposure in humans at the RHD. At the highest
dose levels without effects, exposures of ledipasvir were approximately 5 and 2 times,
in males and females, respectively, the exposure in humans at the RHD.
Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when
evaluated in rats. At the highest dose tested, exposure to the predominant circulating
metabolite GS-331007 was approximately 5 times the exposure in humans at the RHD.
14
CLINICAL STUDIES
14.1 Description of Clinical Trials
The efficacy and safety of HARVONI were evaluated in four trials in genotype 1 HCV
mono-infected subjects including one trial exclusively in treatment-experienced subjects
with compensated cirrhosis (Child-Pugh A); one trial in genotype 1 or 4 HCV/HIV-1
coinfected subjects; two trials in genotype 4, 5, or 6 HCV mono-infected subjects; two
trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated
cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0-F3 fibrosis,
compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis
(FCH); two trials in subjects with severe renal impairment (one of which included
subjects requiring dialysis); and one trial in genotype 1 or 4 HCV pediatric subjects 3
years of age and older without cirrhosis or with compensated cirrhosis, as summarized
in Table 10 [see Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, and 14.7)]:
Reference ID: 5499805
Table 10
Trials Conducted with HARVONI with or without Ribavirin in
Subjects with Chronic HCV Genotype 1, 4, 5, or 6 Infection
Trial
Population
Study Arms
(Number of Subjects Treated)
ION-3 a
(NCT01851330)
GT1, TN without cirrhosis
HARVONI 8 weeks (215)
HARVONI + RBV 8 weeks (216)
HARVONI 12 weeks (216)
ION-1 a
(NCT01701401)
GT1, TN with or without cirrhosis
HARVONI 12 weeks (214)
HARVONI + RBV 12 weeks (217)
HARVONI 24 weeks (217)
HARVONI + RBV 24 weeks (217)
ION-2 a
(NCT01768286)
GT1, TEb with or without cirrhosis
HARVONI 12 weeks (109)
HARVONI + RBV 12 weeks (111)
HARVONI 24 weeks (109)
HARVONI + RBV 24 weeks (111)
SIRIUS c
(NCT01965535)
GT1, TEb with cirrhosis
HARVONI + RBV 12 Weeks (77)
HARVONI 24 weeks (77)
ION-4 a
(NCT02073656)
GT1 and GT4 HCV/HIV-1 coinfected
TN and TEb with or without cirrhosis
HARVONI 12 Weeks
(N=327 for GT1; N=8 for GT4)
1119 a
(NCT02081079)
GT4 and GT5, TN and TEb with or
without cirrhosis
HARVONI 12 Weeks
(N=44 for GT4; N=41 for GT5)
ELECTRON-2 a
(NCT01826981)
GT6, TN and TEb with or without
cirrhosis
HARVONI 12 Weeks (25)
SOLAR-1 a and
SOLAR-2 a
(NCT01938430
and
NCT02010255)
GT1 and GT4 pre-transplant with
decompensated cirrhosis or post-
transplant with Metavir F0-F3 fibrosis,
compensated cirrhosis,
decompensated cirrhosis, or FCH
HARVONI + RBV 12 Weeks (336)
HARVONI + RBV 24 weeks (334)
1116 a
(NCT02249182)
GT1 or 4 TN and TE with or without
cirrhosis in pediatric subjects
3 years of age and older
HARVONI 12 Weeks (223)
HARVONI 24 Weeks (1)
0154 a
(NCT01958281)
GT1 TN and TEb with severe RI
without dialysis
HARVONI 12 weeks (18)
4063 a
(NCT03036839)
GT1, 5, or 6 TN and TEd with or
without compensated cirrhosis, with
ESRD requiring dialysis
HARVONI 8 Weeks (45)
HARVONI 12 Weeks (12)
HARVONI 24 Weeks (6)
ESRD = End stage renal disease; RBV = ribavirin; RI = Renal impairment; TN = Treatment-naïve subjects.
a.
Open-label.
b.
TE = Treatment-experienced subjects including those who have failed a peginterferon alfa + RBV based regimen
with or without an HCV protease inhibitor.
c.
Double-blind, placebo-controlled.
d.
TE = Treatment experienced subjects including those who have failed either interferon/peginterferon alfa/ribavirin
based regimens or HCV-specific direct-acting antiviral regimens that do not include an NS5A polymerase
inhibitor.
Reference ID: 5499805
HARVONI was administered once daily by mouth in these trials. For subjects without
cirrhosis or with compensated cirrhosis who received ribavirin, the ribavirin dosage was
1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects
weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and
SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of
transplantation status. Ribavirin dose adjustments were performed according to the
ribavirin labeling.
Serum HCV RNA values were measured during the clinical trials using the COBAS
TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1,
ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test
(version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The
COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower
limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS
Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic
response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the
cessation of treatment, was the primary endpoint in studies in adults and the key
efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse
was a secondary endpoint, which was defined as HCV RNA greater than or equal to
LLOQ with 2 consecutive values or last available post-treatment measurement during
the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.
14.2 Clinical Trials in Subjects with Genotype 1 HCV
Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108)
ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with
genotype 1 HCV. Subjects were randomized in a 1:1:1 ratio to one of the following three
treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks,
HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks.
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the
subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV
RNA levels greater than or equal to 800,000 IU per mL; 80% had genotype 1a HCV
infection; 73% had non-C/C IL28B alleles (CT or TT).
Table 11 presents the SVR12 for the HARVONI treatment groups in the ION-3 trial after
8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the
SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not
presented in Table 11.
Reference ID: 5499805
Table 11
Study ION-3: SVR12 after 8 and 12 Weeks of Treatment in Treatment-
Naïve Non-Cirrhotic Subjects with Genotype 1 HCV
HARVONI
8 Weeks
(N=215)
HARVONI
12 Weeks
(N=216)
SVR12
94% (202/215)
96% (208/216)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
0/215
0/216
Relapsea
5% (11/215)
1% (3/216)
Otherb
1% (2/215)
2% (5/216)
SVR by Genotypec
Genotype 1a
93% (159/171)
96% (165/172)
Genotype 1b
98% (42/43)
98% (43/44)
a.
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b.
Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow
up).
c.
One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis.
The treatment difference between the 8-week treatment of HARVONI and 12-week
treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%). Among
subjects with a baseline HCV RNA less than 6 million IU per mL, the SVR12 was 97%
(119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week
treatment of HARVONI.
Relapse rates by baseline viral load are presented in Table 12.
Table 12
Study ION-3: Relapse Rates by Baseline Viral Load after 8 and
12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects
with Genotype 1 HCV
HARVONI
8 Weeks
(N=215)
HARVONI
12 Weeks
(N=216)
Number of Responders at End of Treatment
215
216
Baseline HCV RNAa
HCV RNA <6 million IU/mL
2% (2/123)
2% (2/131)
HCV RNA ≥6 million IU/mL
10% (9/92)
1% (1/85)
a. HCV RNA values were determined using the Roche TaqMan Assay; a subject’s HCV RNA may vary from visit to
visit.
Treatment-Naïve Adults with or without Cirrhosis ─ ION-1 (Study 0102)
ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment
with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1
HCV including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to
receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for
Reference ID: 5499805
24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the
presence or absence of cirrhosis and HCV genotype (1a vs 1b).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the
subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino;
mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV
RNA levels greater than or equal to 800,000 IU per mL; 67% had genotype 1a HCV
infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
Table 13 presents the SVR12 for the treatment group of HARVONI for 12 weeks in the
ION-1 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI.
Therefore, the HARVONI + ribavirin arm is not presented in Table 13.
Table 13
Study ION-1: SVR12 after 12 Weeks of Treatment in Treatment-Naïve
Subjects with Genotype 1 HCV with and without Cirrhosis
HARVONI 12 Weeks
(N=214)
SVR12a
99% (210/213)
Outcome for Subjects without SVR
On-Treatment Virologic Failurea
0/213
Relapsea,b
<1% (1/212)
Othera,c
1% (2/213)
a. Excluding one subject with genotype 4 infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow
up).
SVR12 for selected subgroups are presented in Table 14.
Table 14
Study ION-1: SVR12 for Selected Subgroups after 12 Weeks of
Treatment in Treatment-Naïve Subjects with Genotype 1 HCV with
and without Cirrhosis
HARVONI 12 Weeks
(N=214)
Genotypea
Genotype 1a
98% (142/145)
Genotype 1b
100% (67/67)
Cirrhosisb
No
99% (176/177)
Yes
94% (32/34)
a.
One subject without a confirmed subtype for genotype 1 infection and one subject with genotype 4 infection were
excluded from this subgroup analysis.
b.
Subjects with missing cirrhosis status were excluded from this subgroup analysis.
Reference ID: 5499805
Previously-Treated Adults with or without Cirrhosis ─ ION-2 (Study 0109)
ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment
with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or
without cirrhosis who failed prior therapy with an interferon-based regimen, including
regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1
ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI
for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the
presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV
therapy (relapse/breakthrough vs nonresponse).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the
subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV
RNA levels greater than or equal to 800,000 IU per mL; 79% had genotype 1a HCV
infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis.
Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon
and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were
non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of
pegylated interferon and ribavirin with an HCV protease inhibitor. Among these
subjects, 62% were relapse/breakthrough and 38% were non-responder.
Table 15 presents the SVR12 for the HARVONI treatment groups in the ION-2 trial.
Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the
HARVONI + ribavirin arms are not presented in Table 15.
Table 15
Study ION-2: SVR12 after 12 and 24 Weeks of Treatment in Subjects
with Genotype 1 HCV with or without Cirrhosis Who Failed Prior
Therapy
HARVONI
12 Weeks
(N=109)
HARVONI
24 Weeks
(N=109)
SVR12
94% (102/109)
99% (108/109)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
0/109
0/109
Relapsea
6% (7/108)
0/109
Otherb
0/109
1% (1/109)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow
up).
Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who
achieved SVR12 in the ION-2 study also achieved SVR24.
SVR12 and relapse rates for selected subgroups are presented in Tables 16 and 17.
Reference ID: 5499805
Table 16
Study ION-2: SVR12 for Selected Subgroups after 12 and 24 Weeks
of Treatment in Subjects with Genotype 1 HCV Who Failed Prior
Therapy
HARVONI
12 Weeks
(N=109)
HARVONI
24 Weeks
(N=109)
Genotype
Genotype 1a
95% (82/86)
99% (84/85)
Genotype 1b
87% (20/23)
100% (24/24)
Cirrhosisa
No
95% (83/87)
99% (85/86)
Yes
86% (19/22)
100% (22/22)
Prior HCV Therapy
Peg-IFN + RBV
93% (40/43)
100% (58/58)
HCV protease inhibitor + Peg-IFN + RBV
94% (62/66)
98% (49/50)
Response to Prior HCV Therapy
Relapse/Breakthrough
95% (57/60)
100% (60/60)
Non-responder
92% (45/49)
98% (48/49)
RBV = ribavirin.
a.
Subjects with missing cirrhosis status were excluded from this subgroup analysis.
Table 17
Study ION-2: Relapse Rates for Selected Subgroups after 12 and 24
Weeks of Treatment in Subjects with Genotype 1 HCV Who Failed
Prior Therapy
HARVONI
12 Weeks
(N=109)
HARVONI
24 Weeks
(N=109)
Number of Responders at End of Treatment
108
109
Cirrhosisa
No
5% (4/86)b
0% (0/86)
Yes
14% (3/22)
0% (0/22)
Presence of Baseline NS5A Resistance-Associated Polymorphismsc
No
2% (2/85)
0% (0/90)
Yes
22% (5/23)
0% (0/19)
IL28B Status
C/C
0% (0/10)
0% (0/16)
Non-C/C
7% (7/98)
0% (0/93)
a.
Subjects with missing cirrhosis status were excluded from this subgroup analysis.
b.
These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms.
c.
NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93.
Reference ID: 5499805
Previously-Treated Adults with Cirrhosis ─ SIRIUS (Study 0121)
SIRIUS was a randomized, double-blind and placebo-controlled trial that evaluated the
efficacy of HARVONI + ribavirin for 12 weeks or HARVONI without ribavirin for
24 weeks in genotype 1 HCV-infected subjects with compensated cirrhosis who failed
prior therapy with a Peg-IFN + ribavirin regimen followed by a subsequent Peg-IFN +
ribavirin + an HCV protease inhibitor regimen. Subjects were randomized in a 1:1 ratio
to receive placebo for 12 weeks followed by HARVONI + ribavirin for 12 weeks or
HARVONI for 24 weeks. Randomization was stratified by HCV genotype (1a vs 1b) and
response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved
HCV RNA less than LLOQ).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 155 randomized subjects, the median age was 56 years (range: 23 to 77); 74%
of the subjects were male; 97% were White; mean body mass index was 27 kg/m2
(range: 19 to 47 kg/m2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B
alleles (CT or TT). One subject discontinued therapy while on placebo, and was not
included in the efficacy analysis.
The SVR12 was 96% (74/77) and 97% (75/77) in subjects treated with HARVONI +
ribavirin for 12 weeks and HARVONI for 24 weeks without ribavirin, respectively. All
5 subjects who did not achieve SVR12 relapsed.
14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV
Below are trial descriptions, SVR12, and relapse data in the genotype 4, 5, and 6 HCV
populations. Trial results in the genotype 4, 5, and 6 HCV populations are based upon
limited number of subjects in some subgroups, particularly in subjects who have been
previously treated and subjects with cirrhosis.
Genotype 4
In two open-label studies (Study 1119 and ION-4), HARVONI was administered for
12 weeks to treatment-naïve and previously-treated adult subjects with genotype 4 HCV
infection. Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with
genotype 4 HCV, with or without cirrhosis. ION-4 enrolled 4 treatment-naïve and
4 previously-treated subjects with genotype 4 HCV infection who were coinfected with
HIV-1, none of whom had cirrhosis.
In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based
upon prior HCV treatment history and cirrhosis status. In ION-4, all 8 subjects achieved
SVR12.
Genotype 5
In the open-label 1119 trial, HARVONI was administered for 12 weeks to 41 treatment
naïve or previously treated adult subjects with genotype 5 HCV infection, with or without
cirrhosis. The overall SVR12 was 93% (38/41). SVR12 was similar based upon prior
HCV treatment history and cirrhosis status.
Reference ID: 5499805
Genotype 6
In the open-label ELECTRON-2 trial, HARVONI was administered for 12 weeks to
25 treatment-naïve or previously treated adult subjects with genotype 6 HCV infection,
with or without cirrhosis. The overall SVR12 was 96% (24/25). SVR12 was similar
based upon prior HCV treatment history and cirrhosis status. The single subject who
relapsed discontinued study treatment early (at approximately Week 8).
14.4 Clinical Trials in Subjects Coinfected with HCV and HIV-1
ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks
of treatment with HARVONI without ribavirin in HCV treatment-naïve and previously
treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV
1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + ribavirin,
Peg-IFN + ribavirin + an HCV protease inhibitor, or sofosbuvir + ribavirin. Subjects were
on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil
fumarate, administered with efavirenz, rilpivirine, or raltegravir.
Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the
subjects were male; 61% were White; 34% were Black; mean body mass index was
27 kg/m2 (range: 18 to 66 kg/m2); 75% had genotype 1a HCV infection; 2% had
genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had
compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-
experienced.
Table 18 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment.
Table 18
Study ION-4: SVR12 in Subjects with Genotype 1 or 4 HCV
Coinfected with HIV-1
HARVONI 12 Weeks
(N=335)
SVR12
96% (321/335)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
<1% (2/335)
Relapsea
3% (10/333)
Otherb
<1% (2/335)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b.
Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow
up).
SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects
who were previously treated and had cirrhosis. The relapse rate in the ION-4 trial in
Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none
in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection
studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-
Black subjects.
Reference ID: 5499805
No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not
change during treatment. Median CD4+ cell count increase of 29 cells/mm3 was
observed at the end of treatment with HARVONI for 12 weeks.
14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with
Decompensated Cirrhosis
SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of
treatment with HARVONI in combination with ribavirin in HCV treatment-naïve and
previously treated adult subjects with genotype 1 and 4 infection who had undergone
liver transplantation and/or who had decompensated liver disease. The two trials were
identical in study design. Subjects were enrolled in one of the seven groups in the trials
based on liver transplantation status and severity of hepatic impairment (see Table 19).
Subjects with a CPT score greater than 12 were excluded. Within each group, subjects
were randomized in a 1:1 ratio to receive HARVONI + ribavirin for 12 weeks or
HARVONI + ribavirin for 24 weeks. For subjects with decompensated cirrhosis in
SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day
regardless of transplantation status. Ribavirin dose adjustments were performed
according to the ribavirin labeling [see Clinical Studies (14.1)].
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the
subjects were male; 91% were White; mean body mass index was 28 kg/m2 (range:
18 to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of
the subjects failed a prior HCV therapy.
Table 19 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with
genotype 1 HCV treated with HARVONI + ribavirin for 12 weeks. The SVR12 rates
observed with 24 weeks of HARVONI + ribavirin were similar to the SVR12 rates
observed with 12 weeks of treatment. Therefore, the results for the HARVONI + ribavirin
24 weeks arm are not presented in Table 19.
Reference ID: 5499805
Table 19
Studies SOLAR-1 and SOLAR-2: SVR12 and Relapse Rates After
12 Weeks of Treatment with HARVONI and Ribavirin in Subjects with
Genotype 1 HCV Who Were Post Liver Transplant and/or Who Had
Decompensated Liver Disease
HARVONI + RBV 12 weeks
(N=307)
SVR12 (N=300)a,b
Relapse (N=288)a,b,c
Pre-transplant
CPT B
87% (45/52)
12% (6/51)
CPT C
88% (35/40)
5% (2/37)
Post-transplant
Metavir score F0-F3
95% (94/99)
3% (3/97)
CPT A
98% (55/56)
0% (0/55)
CPT B
89% (41/46)
2% (1/42)
CPT C
57% (4/7)
33% (2/6)
a.
Five subjects transplanted prior to post-treatment Week 12 with HCV RNA<LLOQ at last measurement prior to
transplant were excluded.
b.
Two subjects were excluded due to failure to meet the inclusion criteria for any of the treatment groups (i.e., did
not have decompensated cirrhosis and had also not received a liver transplant).
c.
Twelve subjects were excluded from relapse analysis because they died (N=11) or withdrew consent (N=1) prior
to reaching the 12-week post-treatment follow-up visit.
There were 7 subjects with fibrosing cholestatic hepatitis in the 12-week treatment arm,
and all subjects achieved SVR12.
In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated
cirrhosis treated with HARVONI + ribavirin for 12 weeks (N=12), the SVR12 rate was
similar to rates reported with genotype 1; no subjects relapsed. Available data in
subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver
transplantation) were insufficient for dosing recommendations; therefore, these results
are not presented.
14.6 Clinical Trials in Adults with Severe Renal Impairment, Including those
Requiring Dialysis
Trial 0154 was an open-label clinical trial that evaluated 12 weeks of treatment with
HARVONI in 18 treatment-naïve and treatment-experienced (subjects with prior
exposure to an HCV NS5B polymerase inhibitor were excluded) genotype 1 HCV-
infected adults with severe renal impairment not requiring dialysis. At baseline, two
subjects (11%) had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0 to 39.6).
The SVR rate was 100% (18/18).
As shown in the table below, Trial 4063 was an open-label three-arm clinical trial that
evaluated 8, 12, and 24 weeks of treatment with HARVONI in a total of 63 adults with
chronic HCV infection and ESRD requiring dialysis. Of the 63 subjects, 10% had
cirrhosis, 24% were treatment-experienced, 95% were on hemodialysis, and 5% were
on peritoneal dialysis; mean duration on dialysis was 12 years (range: 0.2 to 43 years).
The SVR rates for the 8, 12, and 24 week HARVONI treatment groups are shown in
Table 20.
Reference ID: 5499805
Table 20
Trial 4063: SVR12 after 8, 12, and 24 Weeks of Treatment in Adults
with HCV with or without Cirrhosis and with Severe Renal
Impairment Requiring Dialysis
HARVONI
8 Weeks
(N=45)
HARVONI
12 Weeks
(N=12)
HARVONI
24 Weeks
(N=6)
Population
Treatment-naïve,
GT 1 HCV
Non-cirrhotic
Treatment-naïve
and treatment
experienceda GT
1, 5, 6b HCV
Non-cirrhotic
Treatment-
experienced, GT 1
HCV with
compensated
cirrhosis
SVR12
93% (42/45)
100% (12/12)
83% (5/6)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
0/45
0/12
0/6
Relapse
0/44
0/12
0/6
Otherc
7% (3/45)
0/12
17% (1/6)
a.
Subjects with prior exposure to any HCV NS5A inhibitor were excluded.
b.
One subject had an indeterminant HCV GT.
c.
“Other” outcomes includes subjects who did not achieve SVR and did not meet virologic failure criteria. All
subjects who failed without virologic relapse or on-treatment virologic failure died prior to follow-up Week 12.
None of these deaths were assessed as treatment-related.
14.7 Clinical Trial in Pediatric Subjects
The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) in 224 HCV
treatment-naïve (N=186) and treatment-experienced (N=38) pediatric subjects 3 years
of age or older. This study evaluated 12 weeks of treatment with HARVONI once daily
in genotype 1 (N=183) or genotype 4 (N=3) treatment-naive subjects without cirrhosis or
with compensated cirrhosis; genotype 1 treatment-experienced subjects without
cirrhosis (N=37); and evaluated 24 weeks of treatment with HARVONI once daily in one
genotype 1 subject who was both treatment-experienced and cirrhotic.
Subjects 12 Years to <18 Years of Age: HARVONI was evaluated in 100 subjects 12
years to <18 years of age with HCV genotype 1 infection. Demographics and baseline
characteristics were balanced across treatment-naïve and treatment-experienced
subjects (patients had failed an interferon based regimen with or without ribavirin). The
median age was 15 years (range: 12 to 17); 63% of the subjects were female; 91%
were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body
mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range
33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to
800,000 IU/mL; 81% had genotype 1a HCV infection. One subject (treatment-naïve)
had known compensated cirrhosis. The majority of subjects (84%) had been infected
through vertical transmission.
Reference ID: 5499805
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and
100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment
virologic failure or relapse. Two subjects were lost to follow-up.
Subjects 6 Years to <12 Years of Age: HARVONI was evaluated in 90 subjects 6 years
to <12 years of age with HCV genotype 1 or 4 infection. Among these subjects, 72
(80%) were treatment-naïve and 18 (20%) were treatment-experienced. Eighty-nine of
the subjects (87 with genotype 1 HCV infection and 2 with genotype 4 HCV infection)
were treated with HARVONI for 12 weeks, 1 subject with genotype 1 HCV infection was
treated with HARVONI for 24 weeks. The median age was 9 years (range: 6 to 11);
59% of the subjects were male; 79% were White, 8% were Black, and 6% were Asian;
10% were Hispanic/Latino; mean body mass index was 18 kg/m2 (range: 13 to
31kg/m2); mean weight was 33 kg (range 18 to 76 kg); 59% had baseline HCV RNA
levels greater than or equal to 800,000 IU/mL; 86% had genotype 1a HCV infection; 2
subjects (1 treatment-naïve, 1 treatment-experienced) had known compensated
cirrhosis. The majority of subjects (97%) had been infected through vertical
transmission.
The SVR12 rate was 99% (86/87) in subjects with genotype 1 HCV infection, and 100%
(2/2) in subjects with genotype 4 HCV infection. The one genotype 1 subject treated
with HARVONI for 24 weeks also achieved SVR12. The one subject (genotype 1) who
did not achieve SVR12 and relapsed had been treated with HARVONI for 12 weeks.
Subjects 3 Years to <6 Years of Age: HARVONI was evaluated in 34 subjects 3 years to
<6 years of age with HCV genotype 1 (N = 33) or genotype 4 (N = 1) infection. All of the
subjects were treatment-naïve and treated with HARVONI for 12 weeks. The median
age was 5 years (range: 3 to 5); 71% of the subjects were female; 79% were White, 3%
were Black, and 6% were Asian; 18% were Hispanic/Latino; mean body mass index
was 17 kg/m2 (range: 13 to 25 kg/m2); mean weight was 19 kg (range 11 to 34 kg); 56%
had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 82% had
genotype 1a HCV infection; no subjects had known cirrhosis. All subjects (100%) had
been infected through vertical transmission.
The SVR12 rate was 97% (32/33) in subjects with genotype 1 HCV infection, and the
one subject with genotype 4 HCV infection also achieved SVR12. One subject
prematurely discontinued study treatment due to an adverse event.
16
HOW SUPPLIED/STORAGE AND HANDLING
Tablets
HARVONI tablets 90 mg/400 mg are orange, diamond-shaped, film-coated, debossed
with “GSI” on one side and “7985” on the other side of the tablet. Each bottle contains
28 tablets (NDC 61958-1801-1), a silica gel desiccant and polyester coil, and is closed
with a child-resistant closure.
HARVONI tablets, 45 mg/200 mg, are white, capsule-shaped, film-coated, debossed
with “GSI” on one side and “HRV” on the other side of the tablet. Each bottle contains
28 tablets (NDC 61958-1803-1), a silica gel desiccant and polyester coil, and is closed
with a child-resistant closure.
Reference ID: 5499805
• Store below 30 °C (86 °F).
• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing.
Oral Pellets
HARVONI pellets, 45 mg/200 mg, are orange pellets supplied as unit-dose packets in
cartons. Each carton contains 28 packets (NDC 61958-1804-1).
HARVONI pellets, 33.75 mg/150 mg, are orange pellets supplied as unit-dose packets
in cartons. Each carton contains 28 packets (NDC 61958-1805-1).
• Store below 30 °C (86 °F).
• Do not use if carton tamper-evident seal or packet seal is broken or damaged.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during
or after treatment of HCV infection. Advise patients to tell their healthcare provider if
they have a history of HBV infection [see Warnings and Precautions (5.1)].
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Advise patients to seek medical evaluation immediately for symptoms of bradycardia
such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness,
excessive tiredness, shortness of breath, chest pain, confusion, or memory problems
[see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions
(7.2)].
Drug Interactions
Inform patients that HARVONI may interact with other drugs. Advise patients to report to
their healthcare provider the use of any other prescription or nonprescription medication
or herbal products including St. John’s wort [see Warnings and Precautions (5.2, 5.3)
and Drug Interactions (7)].
Pregnancy
Advise patients to avoid pregnancy during combination treatment with HARVONI and
ribavirin and for 6 months after completion of treatment. Inform patients to notify their
healthcare provider immediately in the event of a pregnancy [see Use in Specific
Populations (8.1)].
Reference ID: 5499805
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus
during treatment or in the event of treatment failure should be taken.
Administration
Advise patients to take HARVONI every day at the regularly scheduled time with or
without food. Inform patients that it is important not to miss or skip doses and to take
HARVONI for the duration that is recommended by the physician.
For HARVONI oral pellets, advise patients or caregivers to read and follow the
Instructions for Use for preparing the correct dose.
Manufactured and distributed by:
Gilead Sciences, Inc.
Foster City, CA 94404
HARVONI, ATRIPLA, COMPLERA, TRUVADA and VIREAD are trademarks of Gilead
Sciences, Inc., or its related companies. All other trademarks referenced herein are the
property of their respective owners.
© 2024 Gilead Sciences, Inc. All rights reserved.
205834-GS-012
Reference ID: 5499805
Patient Information
HARVONI® (har-VOE-nee)
HARVONI® (har-VOE-nee)
(ledipasvir and sofosbuvir)
(ledipasvir and sofosbuvir)
tablets
oral pellets
Important: If you take HARVONI with ribavirin, you should also read the Medication Guide for ribavirin.
What is the most important information I should know about HARVONI?
HARVONI can cause serious side effects, including,
Hepatitis B virus reactivation: Before starting treatment with HARVONI, your healthcare provider will do blood tests
to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could
become active again during or after treatment of hepatitis C virus with HARVONI. Hepatitis B virus becoming active
again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider
will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking HARVONI.
For more information about side effects, see the section “What are the possible side effects of HARVONI?”
What is HARVONI?
HARVONI is a prescription medicine used to treat adults and children 3 years of age and older with chronic (lasting a
long time) hepatitis C virus (HCV):
•
genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
•
genotype 1 infection with advanced cirrhosis (decompensated) in combination with ribavirin
•
genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis who have had a liver transplant, in
combination with ribavirin
It is not known if HARVONI is safe and effective in children with HCV under 3 years of age.
Before taking HARVONI, tell your healthcare provider about all of your medical conditions, including if you:
•
have ever had hepatitis B virus infection
•
have liver problems other than hepatitis C infection
•
have had a liver transplant
•
have kidney problems or you are on dialysis
•
have HIV infection
•
are pregnant or plan to become pregnant. It is not known if HARVONI will harm your unborn baby.
o
Males and females who take HARVONI in combination with ribavirin should also read the ribavirin
Medication Guide for important pregnancy, contraception, and infertility information.
•
are breastfeeding or plan to breastfeed. It is not known if HARVONI passes into your breast milk.
o
Talk to your healthcare provider about the best way to feed your baby during treatment with HARVONI.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. HARVONI and other medicines may affect each other. This can cause
you to have too much or not enough HARVONI or other medicines in your body. This may affect the way HARVONI or
your other medicines work, or may cause side effects. Keep a list of your medicines to show your healthcare
provider and pharmacist.
•
You can ask your healthcare provider or pharmacist for a list of medicines that interact with HARVONI.
Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you
if it is safe to take HARVONI with other medicines.
How should I take HARVONI?
•
Take HARVONI exactly as your healthcare provider tells you to take it. Do not change your dose unless your
healthcare provider tells you to.
•
Do not stop taking HARVONI without first talking with your healthcare provider.
•
Take HARVONI tablets or oral pellets by mouth, with or without food.
•
It is important that you do not miss or skip doses of HARVONI during treatment.
•
For adults the usual dose of HARVONI is one 90/400 mg tablet each day.
•
For children 3 years of age and older your healthcare provider will prescribe the right dose of HARVONI tablets or
oral pellets based on your child’s body weight.
o
Tell your healthcare provider if your child has problems with swallowing tablets.
o
If your healthcare provider prescribes HARVONI oral pellets for your child, see “How should I give
HARVONI oral pellets to my child.”
Reference ID: 5499805
•
Do not miss a dose of HARVONI. Missing a dose lowers the amount of medicine in your blood. Refill your
HARVONI prescription before you run out of medicine.
If you take too much HARVONI, call your healthcare provider or go to the nearest hospital emergency room right
away.
How should I give HARVONI oral pellets to my child?
See the detailed Instructions for Use for information about how to give or take a dose of HARVONI oral
pellets.
•
Administer HARVONI oral pellets exactly as instructed by your healthcare provider.
•
Do not open the packet until ready to use.
•
Hold the HARVONI pellets packet with the cut line on top.
•
Shake the HARVONI pellets packet gently to settle the pellets.
•
Tear or cut the HARVONI packet along the cut line.
•
HARVONI oral pellets can be taken right in the mouth without chewing, or with food.
•
If HARVONI pellets are taken with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or
below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice
cream. Take HARVONI pellets within 30 minutes of gently mixing with food and swallow the entire contents
without chewing to avoid a bitter taste.
•
Do not store any leftover HARVONI mixture (oral pellets mixed with food) for use at a later time. Throw away any
unused portion.
What are the possible side effects of HARVONI?
HARVONI can cause serious side effects, including:
•
Hepatitis B virus reactivation. See “What is the most important information I should know about HARVONI?”
•
Slow heart rate (bradycardia). HARVONI treatment may result in slowing of the heart rate along with other
symptoms when taken with amiodarone (Cordarone®, Nexterone®, Pacerone®), a medicine used to treat certain
heart problems. In some cases bradycardia has led to death or the need for a heart pacemaker when amiodarone
is taken with HARVONI. Get medical help right away if you take amiodarone with HARVONI and get any of the
following symptoms:
•
fainting or near-fainting
•
weakness
•
chest pains
•
dizziness or lightheadedness
•
extreme tiredness
•
confusion
•
not feeling well
•
shortness of breath
•
memory problems
The most common side effects of HARVONI include:
•
tiredness
•
headache
•
weakness
These are not all the possible side effects of HARVONI. For more information, ask your healthcare provider or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store HARVONI?
•
Store HARVONI tablets or pellets below 86°F (30°C).
•
Keep HARVONI tablets in the original container.
•
Do not use HARVONI tablets if the seal over the bottle opening is broken or missing.
•
Do not use HARVONI pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or damaged.
Keep HARVONI and all medicines out of the reach of children.
General information about the safe and effective use of HARVONI
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
HARVONI for a condition for which it was not prescribed. Do not give HARVONI to other people, even if they have the
same symptoms you have. It may harm them.
You can ask your healthcare provider or pharmacist for information about HARVONI that is written for health
professionals.
What are the ingredients in HARVONI?
Active ingredients: ledipasvir and sofosbuvir
Inactive ingredients, Tablets 90/400 mg: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose
monohydrate, magnesium stearate, and microcrystalline cellulose.
The tablet film-coat contains: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl
alcohol, talc, and titanium dioxide.
Inactive ingredients, Tablets 45/200 mg: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose
monohydrate, magnesium stearate, and microcrystalline cellulose.
Reference ID: 5499805
The tablet film-coat contains: polyethylene glycol, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.
Inactive ingredients, Oral Pellets: amino-methacrylate copolymer, colloidal silicon dioxide, copovidone,
croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
Manufactured and distributed by:
Gilead Sciences, Inc., Foster City, CA 94404
For more information, call 1-800-445-3235 or go to www.HARVONI.com.
HARVONI is a trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.
©2024 Gilead Sciences, Inc. All rights reserved.
205834-GS-012
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 03/2020
Reference ID: 5499805
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INSTRUCTIONS FOR USE
HARVONI® (har-VOE-nee)
(ledipasvir and sofosbuvir)
pellets, for oral use
Read the Patient Information that comes with HARVONI oral pellets for important information about HARVONI.
This Instructions for Use contains information on how to take HARVONI oral pellets. Be sure you understand and follow
the instructions. If you have any questions, ask your healthcare provider or pharmacist.
Important Information You Need to Know Before Taking HARVONI oral pellets
•
For oral use only (take by mouth with or without food).
•
Do not open the HARVONI oral pellet packet(s) until ready to use.
•
HARVONI oral pellets are orange pellets supplied as single-use packets in cartons. Each carton contains 28
packets.
•
Do not use HARVONI oral pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or
damaged.
Preparing a dose of HARVONI oral pellets to be taken with food:
Before you prepare a dose of HARVONI oral pellets to be taken with food, gather the following supplies:
•
Daily HARVONI oral pellet packet(s), as prescribed by your healthcare provider
•
One or more spoonfuls of non-acidic soft food such as pudding, chocolate syrup, mashed potato, or ice cream
•
Bowl
•
Spoon
•
Scissors (optional)
Step 1: Add one or more spoonfuls of non-acidic soft food to the bowl first.
Step 2: Hold the HARVONI oral pellets packet
Step 3: Shake the packet gently to settle the
with the cut line on top (see Figure A).
pellets to the bottom of the packet (see Figure B).
Figure A
Figure B
Reference ID: 5499805
Step 4: Cut the packet along the cut line with scissors (see Figure C), or fold the packet back at the tear line (see
Figure D) and tear open (see Figure E).
OR
Figure C
Figure D
Figure E
Step 5: Carefully pour the entire contents of the prescribed number of HARVONI oral pellet packet(s) onto the food in
the bowl and gently mix with a spoon (see Figure F). Make sure that no HARVONI oral pellets remain in the packet(s).
Figure F
Step 6: Take the HARVONI oral pellets and food mixture within 30 minutes without chewing to avoid a bitter taste.
Ensure all of the HARVONI oral pellets are taken.
Preparing a dose of HARVONI oral pellets to be taken without food:
Before you prepare a dose of HARVONI oral pellets to be taken without food, gather the following supplies:
•
Daily HARVONI oral pellet packet(s), as prescribed by your healthcare provider
•
Scissors (optional)
•
Water (optional)
Reference ID: 5499805
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Step 1: Hold the HARVONI oral pellets packet
Step 2: Shake the packet gently to settle the
with the cut line on top (see Figure G).
pellets to the bottom of the packet (see Figure H).
Figure G
Figure H
Step 3: Cut the packet along the cut line with scissors (see Figure I), or fold the packet back at the tear line (see
Figure J) and tear open (see Figure K).
OR
Figure I
Figure J
Figure K
Reference ID: 5499805
Step 4: Pour the entire contents of the HARVONI oral pellets packet directly in the mouth and swallow without chewing to
avoid a bitter taste (see Figure L). Water may be taken after swallowing the pellets, if needed. Make sure that no HARVONI
oral pellets remain in the packet. If your healthcare provider prescribed more than one HARVONI oral pellets packet, repeat
Steps 1 through 4.
Figure L
Storing HARVONI oral pellets
•
Store HARVONI pellets below 86°F (30°C).
•
Keep HARVONI oral pellets and all medicines out of the reach of children.
Disposing of HARVONI oral pellets
•
Throw away any unused portion. Do not store and reuse any leftover HARVONI mixture (pellets mixed with food).
For more information, call 1-800-445-3235 or go to www.HARVONI.com.
Manufactured for and distributed by: Gilead Sciences, Inc., Foster City, CA 94404
HARVONI is a trademark of Gilead Sciences, Inc., or its related companies.
© 2024 Gilead Sciences, Inc. All rights reserved.
205834-GS-012
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: March 2020
Reference ID: 5499805
| custom-source | 2025-02-12T15:48:03.107203 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205834s036,212477s006lbl.pdf', 'application_number': 205834, 'submission_type': 'SUPPL ', 'submission_number': 36} |
80,692 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALYFTREK safely and effectively. See full prescribing information for
ALYFTREK.
ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor tablets), for oral
use
Initial U.S. Approval: 2024
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER
FAILURE
See full prescribing information for complete boxed warning.
Elevated transaminases have been observed in patients treated with
ALYFTREK (5.1, 6).
Cases of serious and potentially fatal drug-induced liver injury and
liver failure leading to transplantation and death were reported in
patients who were taking ELX/TEZ/IVA, a drug containing the same
or similar active ingredients as ALYFTREK (5.1).
Assess liver function tests (ALT, AST, alkaline phosphatase,
bilirubin) in all patients prior to initiating ALYFTREK, every month
for first 6 months, every 3 months for next 12 months, then at least
annually (2.1 5.1).
Interrupt ALYFTREK for significant elevations in LFTs or signs or
symptoms of liver injury. Follow patients closely with clinical and
laboratory monitoring until abnormalities resolve (5.1).
Resume ALYFTREK if abnormalities resolve and only if the benefit
is expected to outweigh the risk (5.1).
ALYFTREK should not be used in patients with severe hepatic
impairment (Child-Pugh Class C). ALYFTREK is not recommended
in patients with moderate hepatic impairment (Child-Pugh Class B)
(2.4, 5.1, 8.7, 12.3).
------------------------------INDICATIONS AND USAGE---------------------------
ALYFTREK is a combination of deutivacaftor, a CFTR potentiator, tezacaftor,
and vanzacaftor indicated for the treatment of cystic fibrosis (CF) in patients
aged 6 years and older who have at least one F508del mutation or another
responsive mutation in the CFTR gene. (1, 12.1)
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should
be used to confirm the presence of at least one indicated mutation. (1, 12.1)
-------------------------DOSAGE AND ADMINISTRATION-----------------------
Prior to initiating ALYFTREK obtain liver function tests (ALT, AST, alkaline
phosphatase, and bilirubin) in all patients. Monitor liver function tests every
month during the first 6 months of treatment, then every 3 months during the next
12 months, then at least annually thereafter. (2.1, 5.1)
Recommended Dosage for Adult and Pediatric Patients Aged 6 Years
and Older (with fat-containing food) (2.2)
Age
Weight
Once Daily Oral Dosage
6 to less
than
12 years old
Less
than 40 kg
Three tablets of vanzacaftor 4 mg/tezacaftor
20 mg/deutivacaftor 50 mg
Greater than
or equal
to 40 kg
Two tablets of vanzacaftor 10 mg/tezacaftor
50 mg/deutivacaftor 125 mg
12 years and
older
Any Weight
Two tablets of vanzacaftor 10 mg/tezacaftor
50 mg/deutivacaftor 125 mg
Should not be used in patients with severe hepatic impairment. Use not
recommended in patients with moderate hepatic impairment unless the benefit
outweighs the risk. If used, no dose adjustment is recommended. Liver function
tests should be closely monitored. (2.4, 5.1, 6.1, 8.7)
See full prescribing information for dosage modifications for concomitant use
of ALYFTREK with strong or moderate CYP3A inhibitors. (2.3, 5.5, 7.1)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
Tablets:
Fixed-dose combination containing vanzacaftor 4 mg, tezacaftor 20 mg,
and deutivacaftor 50 mg. (3)
Fixed-dose combination containing vanzacaftor 10 mg, tezacaftor 50 mg,
and deutivacaftor 125 mg. (3)
------------------------------CONTRAINDICATIONS-----------------------------
None. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
Drug-Induced Liver Injury and Liver Failure: Elevated transaminases have
been observed in patients treated with ALYFTREK. Cases of serious and
potentially fatal drug-induced liver injury and liver failure have been
reported with a drug that contains the same or similar active ingredients as
ALYFTREK. Assess liver function tests (ALT, AST, alkaline
phosphatase, and bilirubin) in all patients prior to initiating and throughout
treatment with ALYFTREK. Interrupt ALYFTREK in the event of
significant elevations in liver function tests or signs or symptoms of liver
injury. ALYFTREK should not be used in patients with severe hepatic
impairment (Child-Pugh Class C). ALYFTREK is not recommended in
patients with moderate hepatic impairment (Child-Pugh Class B). (2.4,
5.1, 8.7)
Hypersensitivity Reactions: Hypersensitivity reactions, including
anaphylaxis, have been reported in the postmarketing setting for drugs
containing elexacaftor, tezacaftor, and/or ivacaftor. If signs or symptoms
of serious hypersensitivity reactions develop during ALYFTREK
treatment, discontinue ALYFTREK and initiate appropriate therapy. (5.2)
Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or
Ivacaftor-Containing Drugs Due to Adverse Reactions: Consider benefits
and risks before using ALYFTREK in patients who discontinued or
interrupted elexacaftor-, tezacaftor-, or ivacaftor-containing drugs due to
adverse reactions. If ALYFTREK is used, closely monitor for adverse
reactions as clinically appropriate. (5.3)
Reduced Effectiveness in Patients with Concomitant Use with CYP3A
Inducers: Concomitant use with strong and moderate CYP3A inducers
decreased vanzacaftor, tezacaftor, and deutivacaftor exposure, which may
reduce ALYFTREK efficacy. Therefore, concomitant use is not
recommended. (5.4, 7.1)
Adverse Reactions with Concomitant Use with CYP3A Inhibitors:
Concomitant use with strong or moderate CYP3A inhibitors increased
vanzacaftor, tezacaftor, and deutivacaftor exposure, which may increase
the risk of ALYFTREK associated adverse reactions. Reduce the
ALYFTREK dosage with concomitant use. (2.3, 5.5, 7.1)
Cataracts: Non-congenital lens opacities/cataracts have been reported in
patients with CF aged 18 years or less treated with drugs containing
ivacaftor. Baseline and follow up ophthalmological examinations are
recommended in pediatric patients treated with ALYFTREK. (5.6, 8.4)
------------------------------ADVERSE REACTIONS-----------------------------
Most common adverse reactions to ALYFTREK (≥5% of patients and at a
frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis,
upper respiratory tract infection, headache, oropharyngeal pain, influenza,
fatigue, increased ALT, rash, increased AST, and sinus congestion. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Vertex
Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-----------------------------
Strong or moderate CYP3A inducers: Concomitant use with ALYFTREK
is not recommended. (5.4, 7.1)
Strong or moderate CYP3A inhibitors: Reduce ALYFTREK dosage with
concomitant use. Avoid food or drink containing grapefruit. (2.3, 5.5, 7.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
During Treatment
2.2 Recommended Dosage
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE
2.3 Dosage Modification for Strong or Moderate CYP3A Inhibitors
1
INDICATIONS AND USAGE
2.4 Recommended Dosage for Patients with Hepatic Impairment
2
DOSAGE AND ADMINISTRATION
2.5 Recommendations Regarding Missed Dose(s)
2.1 Recommended Laboratory Testing Prior to ALYFTREK Initiation and
3
DOSAGE FORMS AND STRENGTHS
1
Reference ID: 5500641
4
CONTRAINDICATIONS
8.4 Pediatric Use
5
WARNINGS AND PRECAUTIONS
8.5 Geriatric Use
5.1 Drug-Induced Liver Injury and Liver Failure
8.6 Renal Impairment
5.2 Hypersensitivity Reactions, Including Anaphylaxis
8.7 Hepatic Impairment
5.3 Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or
10 OVERDOSAGE
Ivacaftor-Containing Drugs Due to Adverse Reactions
11 DESCRIPTION
5.4 Reduced Effectiveness with Concomitant Use with CYP3A Inducers
12 CLINICAL PHARMACOLOGY
5.5 Adverse Reactions with Concomitant Use with CYP3A Inhibitors
12.1 Mechanism of Action
5.6 Cataracts
12.2 Pharmacodynamics
6
ADVERSE REACTIONS
12.3 Pharmacokinetics
6.1 Clinical Trials Experience
13 NONCLINICAL TOXICOLOGY
7
DRUG INTERACTIONS
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
7.1 Effect of Other Drugs and Grapefruit on ALYFTREK
14 CLINICAL STUDIES
7.2 Effect of ALYFTREK on Other Drugs
16 HOW SUPPLIED/STORAGE AND HANDLING
7.3 Drugs with No Clinically Significant Interactions with ALYFTREK
17 PATIENT COUNSELING INFORMATION
8
USE IN SPECIFIC POPULATIONS
*Sections or subsections omitted from the full prescribing information are not
8.1 Pregnancy
listed.
8.2 Lactation
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FULL PRESCRIBING INFORMATION
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE
Elevated transaminases have been observed in patients treated with ALYFTREK. Cases of serious and
potentially fatal drug-induced liver injury and liver failure were reported in patients who were taking a
fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor, which contains the same or
similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy
and up to 15 months following initiation of elexacaftor/tezacaftor/ivacaftor [see Warnings and Precautions
(5.1) and Adverse Reactions (6)].
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating
ALYFTREK, every month during the first 6 months of treatment, then every 3 months for the next
12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history
of liver disease or elevated liver function tests at baseline [see Dosage and Administration (2.1), Warnings and
Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.7)].
Interrupt ALYFTREK for significant elevations in liver function tests or in the event of signs or symptoms of
liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory
monitoring until abnormalities resolve. If abnormalities resolve, resume treatment only if the benefit is
expected to outweigh the risk. Closer monitoring is advised after resuming ALYFTREK [see Warnings and
Precautions (5.1)].
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C).
ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and
should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used,
monitor patients closely [see Dosage and Administration (2.4), Warnings and Precautions (5.1), Adverse
Reactions (6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
1
INDICATIONS AND USAGE
ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least
one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene (see Table 5) [see Clinical Pharmacology (12.1)].
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at
least one indicated mutation.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Laboratory Testing Prior to ALYFTREK Initiation and During Treatment
Prior to initiating ALYFTREK, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all
patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months for the
next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver
disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing
elexacaftor, tezacaftor, and/or ivacaftor [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].
2.2
Recommended Dosage
The recommended ALYFTREK dosage in adult and pediatric patients aged 6 years and older is provided in Table 1.
Administer ALYFTREK orally (swallow the tablets whole) with fat-containing food, once daily, at approximately the
same time each day [see Clinical Pharmacology (12.3)]. Examples of meals or snacks that contain fat are those
prepared with butter or oils or those containing eggs, peanut butter, cheeses, nuts, whole milk, or meats.
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Table 1: Recommended Dosage of ALYFTREK in Adult and Pediatric Patients Aged 6 Years and Older
Age
Weight
Once Daily Oral Dosage
6 to less
than 12
years old
Less than 40 kg
Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg (total dose
of vanzacaftor 12 mg/tezacaftor 60 mg/ deutivacaftor 150 mg)
Greater than or
equal to 40 kg
Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose
of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg)
12 years
and older
Any weight
Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose
of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg)
2.3
Dosage Modification for Strong or Moderate CYP3A Inhibitors
Table 2 describes the recommended dosage modification for ALYFTREK when used concomitantly with strong or
moderate CYP3A inhibitors [see Warnings and Precautions (5.5)]. Administer ALYFTREK orally (swallow the
tablets whole) with fat-containing food, once daily, at approximately the same time each day [see Clinical
Pharmacology (12.3)].
Table 2: Dosage Modification for Concomitant Use of ALYFTREK with Strong or Moderate CYP3A
Inhibitors in Adult and Pediatric Patients Aged 6 Years and Older
Age
Weight
Moderate CYP3A Inhibitors
Strong CYP3A Inhibitors
6 to less
than 12
years
old
Less
than 40 kg
Two tablets of vanzacaftor
4 mg/tezacaftor 20 mg/deutivacaftor
50 mg every other day (total dose of
vanzacaftor 8 mg/tezacaftor
40 mg/deutivacaftor 100 mg)
Two tablets of vanzacaftor 4 mg/tezacaftor
20 mg/deutivacaftor 50 mg once a week
(total dose of vanzacaftor 8 mg/tezacaftor
40 mg/deutivacaftor 100 mg)
Greater than
or equal
to 40 kg
One tablet of vanzacaftor
10 mg/tezacaftor 50 mg/deutivacaftor
125 mg every other day
One tablet of vanzacaftor 10 mg/tezacaftor
50 mg/deutivacaftor 125 mg once a week
12 years
and
older
Any weight
One tablet of vanzacaftor
10 mg/tezacaftor 50 mg/deutivacaftor
125 mg every other day
One tablet of vanzacaftor 10 mg/tezacaftor
50 mg/deutivacaftor 125 mg once a week
2.4
Recommended Dosage for Patients with Hepatic Impairment
Severe Hepatic Impairment (Child-Pugh Class C): ALYFTREK should not be used in patients with severe hepatic
impairment (HI) (Child-Pugh Class C).
Moderate Hepatic Impairment (Child-Pugh Class B): The use of ALYFTREK in patients with moderate HI
(Child-Pugh Class B) is not recommended. Use of ALYFTREK should only be considered in patients with
moderate HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended
dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests
should be closely monitored [see Dosage and Administration (2.1, 2.2)].
Mild Hepatic Impairment (Child-Pugh Class A): The recommended dosage of ALYFTREK in patients with mild
HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be
closely monitored [see Dosage and Administration (2.1, 2.2)].
2.5
Recommendations Regarding Missed Dose(s)
If 6 hours or less have passed since the missed dose, take the missed dose as soon as possible and continue on the
original schedule.
If more than 6 hours have passed since the missed dose, skip the missed dose, and continue on the original schedule the
next day.
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3
DOSAGE FORMS AND STRENGTHS
Tablets:
Fixed-dose combination containing vanzacaftor 4 mg (equivalent to 4.24 mg of vanzacaftor calcium dihydrate),
tezacaftor 20 mg, and deutivacaftor 50 mg. Each tablet is purple, round-shaped, film-coated, debossed with “V4”
on one side and plain on the other.
Fixed-dose combination containing vanzacaftor 10 mg (equivalent to 10.6 mg of vanzacaftor calcium dihydrate),
tezacaftor 50 mg, and deutivacaftor 125 mg. Each tablet is purple, oblong-shaped, film-coated, debossed with
“V10” on one side and plain on the other.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Drug-Induced Liver Injury and Liver Failure
Elevated transaminases have been observed in patients treated with ALYFTREK [Adverse Reactions (6.1)]. Cases of
serious and potentially fatal drug-induced liver injury and liver failure have been reported in patients with and without
a history of liver disease who were taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and
ivacaftor (ELX/TEZ/IVA), which contains the same or similar active ingredients as ALYFTREK. Liver injury has
been reported within the first month of therapy and up to 15 months following initiation of ELX/TEZ/IVA.
Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating
ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for
the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of
liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing
ELX, TEZ and/or IVA. [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].
Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:
Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit or normal (ULN) or ALT or
AST >3× ULN with bilirubin >2× ULN)
Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea,
vomiting, altered mental status, ascites)
Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until
abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK
treatment with close monitoring.
ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not
recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when
there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely [see Dosage and
Administration (2.4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
5.2
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting of drugs
containing ELX, TEZ, and/or IVA (the same or similar active ingredients in ALYFTREK). If signs or symptoms of
serious hypersensitivity reactions develop during ALYFTREK treatment, discontinue ALYFTREK and institute
appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment
with ALYFTREK.
5.3
Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs
Due to Adverse Reactions
There are no available safety data for ALYFTREK in patients who previously discontinued or interrupted treatment
with drugs containing elexacaftor, tezacaftor, or ivacaftor due to adverse reactions. Consider the benefits and risks
5
Reference ID: 5500641
before using ALYFTREK in these patients. If ALYFTREK is used in these patients, closely monitor for adverse
reactions as clinically appropriate.
5.4
Reduced Effectiveness with Concomitant Use with CYP3A Inducers
Following concomitant use of strong or moderate CYP3A inducers with ALYFTREK, exposures of vanzacaftor,
tezacaftor, and deutivacaftor were decreased, which may reduce ALYFTREK effectiveness. Concomitant use with
strong or moderate CYP3A inducers is not recommended [see Drug Interactions (7.1)].
5.5
Adverse Reactions with Concomitant Use with CYP3A Inhibitors
Following concomitant use of strong or moderate CYP3A inhibitors with ALYFTREK, exposures of vanzacaftor,
tezacaftor, and deutivacaftor were increased, which may increase the risk of ALYFTREK-associated adverse reactions.
Reduce the ALYFTREK dosage with concomitant use of strong or moderate CYP3A inhibitors [see Dosage and
Administration (2.3) and Drug Interactions (7.1)].
5.6
Cataracts
Cases of non-congenital lens opacities have been reported in pediatric patients treated with drugs containing ivacaftor
(which is similar to an active ingredient in ALYFTREK). Although other risk factors were present (such as
corticosteroid use, exposure to radiation) in some cases, a possible risk attributable to ivacaftor treatment cannot be
excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients treated with
ALYFTREK [see Use in Specific Populations (8.4)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
Drug-Induced Liver Injury and Liver Failure [see Warnings and Precautions (5.1)]
Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2)]
Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to
Adverse Reactions [see Warnings and Precautions (5.3)]
Cataracts [see Warnings and Precautions (5.6)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in clinical practice.
The adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF
with at least one responsive CFTR mutation who were able to tolerate ELX/TEZ/IVA. Adverse reactions data in
patients who previously discontinued or interrupted ELX/TEZ/IVA due to adverse reactions are not available.
Adverse Reactions in Patients Aged 12 Years and Older with CF
The safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one F508del
mutation or another responsive mutation in the CFTR gene in two, 52-week, active-controlled trials (Trials 1 and 2)
[see Clinical Studies (14)]. In both trials, patients received a fixed-dose combination drug containing elexacaftor,
tezacaftor, and ivacaftor (ELX/TEZ/IVA) in a 4-week run-in period and then were subsequently randomized to
continue ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg
in the evening) or receive ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg) once daily.
Patients with a history of prior intolerance to ELX/TEZ/IVA (i.e., patients who discontinued or interrupted treatment
due to adverse reactions) were excluded. Trials 1 and 2 were not designed to evaluate meaningful comparisons of the
incidence of adverse reactions between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional
information regarding ELX/TEZ/IVA adverse reactions, refer to ELX/TEZ/IVA Prescribing Information.
In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse
reactions were 3.8% and 3.7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively.
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Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA
treatment that occurred in 2 or more patients (≥0.4%) were influenza (1.5%), increased AST (0.4%), increased GGT
(0.4%), depression (0.4%), and syncope (0.4%).
Table 3: Adverse Reactions Occurring in ≥5% of ALYFTREK-Treated Patients and ≥1% Higher
than ELX/TEZ/IVA-Treated Patients Aged 12 Years and Older with CF Who Had at Least One
F508del Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2)
Adverse Reactions
ALYFTREK
N=480
ELX/TEZ/IVA
N=491
Cough*
120 (25%)
116 (24%)
Nasopharyngitis
102 (21%)
95 (19%)
Upper respiratory tract infection†
101 (21%)
97 (20%)
Headache
76 (16%)
63 (13%)
Oropharyngeal pain
69 (14%)
60 (12%)
Influenza
52 (11%)
26 (5%)
Fatigue
51 (11%)
46 (9%)
ALT increased
38 (8%)
29 (6%)
Rash
37 (8%)
22 (4%)
AST increased
33 (7%)
27 (5%)
Sinus congestion
32 (7%)
15 (3%)
* Cough is composed of several similar terms including productive cough
† Upper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor
Adverse events that occurred in ≥5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the
ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain,
pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis,
nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting.
Liver Function Test Elevations
The incidence of adverse reactions of transaminase elevations was 9% in ALYFTREK-treated patients and 7.1% in
ELX/TEZ/IVA-treated patients in Trials 1 and 2. In these trials, 1.5% of ALYFTREK-treated patients and 0.6% of
ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases. Table 4 shows the incidence of
maximum transaminase (ALT or AST) elevations in Trials 1 and 2.
Table 4: Number and Incidence of Maximum Transaminase Elevation in Patients Aged 12 Years and Older
with CF Who Had at Least One F508del Mutation or Responsive Mutation in the CFTR Gene
(Trials 1 and 2)
Maximum ALT or AST Elevation
ALYFTREK
N=480
ELX/TEZ/IVA*
N=491
>3× ULN
29 (6%)
15 (3.1%)
>5× ULN
12 (2.5%)
6 (1.2%)
>8× ULN
6 (1.3%)
1 (0.2%)
Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor.
* Trials 1 and 2 were not designed to evaluate meaningful comparisons of safety between the ALYFTREK and ELX/TEZ/IVA treatment
groups. For additional information regarding ELX/TEZ/IVA transaminase elevations, refer to ELX/TEZ/IVA Prescribing Information.
Rash
In Trials 1 and 2, the incidence of rash (e.g., rash, rash pruritic) was 11% in ALYFTREK-treated patients and 7.7% in
ELX/TEZ/IVA-treated patients. The rashes were generally mild to moderate in severity. The incidence of rash was
9.4% in males and 13% in females with ALYFTREK treatment and 7.6% in males and 7.9% in females with
ELX/TEZ/IVA treatment. A role of hormonal contraceptives in the occurrence of rash cannot be excluded [see Drug
Interactions (7.3)].
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Increased Creatine Phosphokinase
In Trials 1 and 2, the incidence of maximum creatine phosphokinase >5× the ULN was 7.9% with ALYFTREK
treatment and 6.5% with ELX/TEZ/IVA treatment. Discontinuation due to increased creatinine phosphokinase was
0.2% for ALYFTREK-treated patients and 0.2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without
renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug
containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK).
Increased Blood Pressure
Elevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination
drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). The proportion of patients
who had systolic blood pressure >140 mmHg and >10 mmHg increase from baseline on at least two occasions was
3.5% in ALYFTREK-treated patients and 3.3% in ELX/TEZ/IVA-treated patients. The proportion of patients who had
diastolic blood pressure >90 mmHg and >5 mmHg increase from baseline on at least two occasions was 1.7% in
ALYFTREK-treated patients and 1.8% in ELX/TEZ/IVA-treated patients. The mean systolic and diastolic blood
pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms.
Adverse Reactions in Pediatric Patients Aged 6 to Less Than 12 Years with CF
A 24-week, open-label trial of ALYFTREK was conducted in 78 patients with CF aged 6 to less than 12 years with at
least one mutation responsive to ELX/TEZ/IVA (Trial 3). In Trial 3, patients who weighed less than 40 kg received
ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg
or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily). Adverse
reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. In Trial 3, the incidence of
maximum transaminase (ALT or AST) >3×, >5×, and >8× ULN were 3.8%, 1.3%, and 0%, respectively.
7
DRUG INTERACTIONS
7.1
Effect of Other Drugs and Grapefruit on ALYFTREK
Strong or Moderate CYP3A Inducers
Concomitant use of ALYFTREK with strong or moderate CYP3A inducers is not recommended.
Vanzacaftor, tezacaftor, and deutivacaftor are substrates of CYP3A. Concomitant use of ALYFTREK with a strong or
moderate CYP3A inducer decreases vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology
(12.3)] which may reduce ALYFTREK effectiveness [see Warnings and Precautions (5.4)].
Strong or Moderate CYP3A Inhibitors
Reduce the ALYFTREK dosage when used concomitantly with a strong or moderate CYP3A inhibitor [see Dosage
and Administration (2.3)].
Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates. Concomitant use with a strong CYP3A inhibitor
increases vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology (12.3)], which may increase
the risk of ALYFTREK adverse reactions [see Warnings and Precautions (5.5)]. Concomitant use with a moderate
CYP3A inhibitor is predicted to increase vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical
Pharmacology (12.3)], which may increase the risk of ALYFTREK adverse reactions [see Warnings and Precautions
(5.5)].
Grapefruit
Food or drink containing grapefruit should be avoided during treatment with ALYFTREK. Concomitant use of
ALYFTREK with grapefruit juice which contains one or more components that moderately inhibit CYP3A may
increase exposure of vanzacaftor, tezacaftor and deutivacaftor.
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7.2
Effect of ALYFTREK on Other Drugs
P-glycoprotein (P-gp) Substrates
Unless otherwise recommended in the P-gp substrate Prescribing Information, monitor more frequently for adverse
reactions with concomitant use of ALYFTREK with P-gp substrates where minimal concentration changes may lead to
serious adverse reactions related to P-gp substrates.
Tezacaftor and deutivacaftor (components of ALYFTREK) are P-gp inhibitors. Administration of tezacaftor/ivacaftor
increases exposure of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse
reactions related to these substrates.
Breast Cancer Resistance Protein (BCRP) Substrates
Unless otherwise recommended in BCRP substrate Prescribing Information, monitor more frequently for adverse
reactions with concomitant use of ALYFTREK with BCRP substrate where minimal concentrations may lead to
serious adverse reactions related to BCRP substrates.
Vanzacaftor (VNZ) and deutivacaftor (D-IVA) (components of ALYFTREK) are inhibitors of BCRP in vitro.
Concomitant use of ALYFTREK with BCRP substrates may increase exposure of these substrates; however, this has
not been studied clinically [see Clinical Pharmacology (12.3)].
CYP2C9 Substrates
Use caution when ALYFTREK is used concomitantly with CYP2C9 substrates. Monitor the international normalized
ratio (INR) more frequently with concomitant use of ALYFTREK with warfarin.
This recommendation is based upon a mechanistic understanding of deutivacaftor pharmacokinetics (it is an inhibitor
of CYP2C9 in vitro) [see Clinical Pharmacology (12.3)]. Concomitant use of ALYFTREK with CYP2C9 substrates
may increase exposure of these substrates; however, this has not been studied clinically.
7.3
Drugs with No Clinically Significant Interactions with ALYFTREK
Ciprofloxacin
No clinically relevant effect on the exposure of tezacaftor was observed when tezacaftor/ivacaftor was used
concomitantly with ciprofloxacin [see Clinical Pharmacology (12.3)].
Hormonal Contraceptives
No clinically significant differences in the pharmacokinetics of ethinyl estradiol/norethindrone containing hormonal
contraceptives were observed when used concomitantly with tezacaftor in combination with ivacaftor and ivacaftor
alone [see Clinical Pharmacology (12.3)]. No clinically significant differences in the pharmacokinetics of ethinyl
estradiol/norethindrone containing hormonal contraceptives are expected when used in combination with ALYFTREK
based upon a mechanistic understanding of vanzacaftor, tezacaftor, and deutivacaftor pharmacokinetics [see Clinical
Pharmacology (12.3)]; however, this has not been studied clinically.
A role for hormonal contraceptives contributing to rash cannot be excluded [see Adverse Reactions (6.1)]. For patients
with CF taking hormonal contraceptives who develop rash, consider interrupting ALYFTREK and hormonal
contraceptives. Following the resolution of rash, consider resuming ALYFTREK without the hormonal contraceptives.
If rash does not recur, resumption of hormonal contraceptives can be considered.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no available data on ALYFTREK use in pregnant women to evaluate for a drug-associated risk of major
birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no animal reproduction
studies with the concomitant administration of vanzacaftor, tezacaftor, and deutivacaftor, separate reproductive and
developmental studies were conducted with vanzacaftor and tezacaftor in pregnant rats and rabbits. Deutivacaftor is a
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Reference ID: 5500641
deuterated isotopologue of ivacaftor with a toxicity profile similar to ivacaftor. Reproductive and development studies
were conducted with ivacaftor in pregnant rats and rabbits.
In animal embryo fetal development (EFD) studies, oral administration of vanzacaftor to pregnant rats and rabbits
during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to
approximately 30 times the exposure at the maximum recommended human dose (MRHD) in rats and 22 times the
MRHD in rabbits. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no
adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at
the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and the metabolite
M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse
developmental effects at doses that produced maternal exposures up to approximately 8 and 9 times the exposure at the
MRHD, respectively (based on AUC of ivacaftor for rats and rabbits). No adverse developmental effects were
observed after oral administration of vanzacaftor, tezacaftor, or ivacaftor to pregnant rats from the period of
organogenesis through lactation at doses that produced maternal exposures approximately 18 times, 1 time, and 8 times
the exposures at the MRHD, respectively (based on AUCs of vanzacaftor, tezacaftor and M1-TEZ, and ivacaftor) (see
Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All
pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and
15% to 20%, respectively.
Data
Animal Data
Vanzacaftor: In an EFD study, pregnant rats were administered vanzacaftor at oral doses of 2.5, 5, and 10 mg/kg/day
during the period of organogenesis from gestation Days 6-17. Vanzacaftor did not cause adverse effects to the fetus at
exposures up to 30 times the MRHD (based on AUC for vanzacaftor at maternal doses up to 10 mg/kg/day). In an EFD
study, pregnant rabbits were administered vanzacaftor at oral doses of 10, 40, and 70 mg/kg/day during the period of
organogenesis from gestation Days 7-20. Vanzacaftor did not cause adverse effects to the fetus at exposures up to
22 times the MRHD (based on AUC of vanzacaftor at maternal doses up to 40 mg/kg/day). The high dose of
70 mg/kg/day (71 times the exposure at the MRHD) produced maternal toxicity (i.e., mortality, abortion, decreased
mean body weight or body weight gains) and was associated with findings of increased post-implantation loss,
decreased live fetuses, decreased fetal body weight, and increased kidney malformations. In a pre- and postnatal
development (PPND) study in pregnant rats administered vanzacaftor at oral doses of 2.5, 5, and 10 mg/kg/day from
gestation Day 6 through lactation Day 18, vanzacaftor did not cause adverse developmental effects in pups at maternal
doses up to 10 mg/kg/day (approximately 18 times the exposure at the MRHD). Placental transfer of vanzacaftor was
observed in pregnant rats.
Tezacaftor: In an EFD study, pregnant rats were administered tezacaftor at oral doses of 25, 50, and 100 mg/kg/day
during the period of organogenesis from gestation Days 6-17. Tezacaftor did not cause adverse effects to the fetus at
exposures up to 3 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Maternal toxicity in rats was
observed at ≥50 mg/kg/day (approximately ≥1 time the MRHD). In an EFD study, pregnant rabbits were administered
tezacaftor at oral doses of 10, 25, and 50 mg/kg/day during the period of organogenesis from gestation Days 7-20.
Tezacaftor did not cause adverse effects to the fetus at exposures up to 0.2 times the MRHD (based on summed AUCs
of tezacaftor and M1-TEZ). Lower fetal body weights were observed in rabbits at a maternally toxic dose that
produced exposures approximately 1 time the MRHD (based on summed AUCs of tezacaftor and M1-TEZ at a
maternal dose of 50 mg/kg/day). In a PPND study, pregnant rats were administered tezacaftor at oral doses of 25, 50,
and 100 mg/kg/day from gestation Day 6 through lactation Day 18. Tezacaftor had no adverse developmental effects
on pups at an exposure of approximately 1 time the MRHD (based on summed AUCs for tezacaftor and M1-TEZ at a
maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment,
eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced
exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1-TEZ).
Placental transfer of tezacaftor was observed in pregnant rats.
10
Reference ID: 5500641
Deutivacaftor: Animal reproduction studies have not been conducted with deutivacaftor. However, as a deuterated
isotopologue of ivacaftor with a toxicity profile similar to ivacaftor based on a 13-week single-agent repeat dose
toxicity study, the reproductive and developmental toxicity data from ivacaftor can inform the developmental and
reproductive risks associated with deutivacaftor.
In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 200 mg/kg/day during the
period of organogenesis from gestation Days 7-17. Ivacaftor did not cause adverse effects to the fetus at exposures up
to 8 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies up to 200 mg/kg/day). In an EFD
study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, and 100 mg/kg/day during the period of
organogenesis from gestation Days 7-19. Ivacaftor did not cause adverse effects to the fetus at exposures up to 9 times
the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies). Maternal toxicity (i.e., death, decreased
food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was
observed at doses greater than or equal to 50 mg/kg/day (approximately 3 times the MRHD). In a PPND study,
pregnant rats were administered ivacaftor at oral doses of 50, 100, and 200 mg/kg/day from gestation Day 7 through
lactation Day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to
8 times the MRHD (based on AUC for ivacaftor at maternal oral doses up to 100 mg/kg/day). Decreased fetal body
weights were observed at a maternally toxic dose (200 mg/kg/day, 13 times the exposure at MHRD). Placental transfer
of ivacaftor was observed in pregnant rats and rabbits.
8.2
Lactation
Risk Summary
There are no data on the presence of vanzacaftor, tezacaftor, or deutivacaftor or their metabolites in human milk, the
effects on the breastfed infant, or the effects on milk production.
Vanzacaftor and tezacaftor are excreted into the milk of lactating female rats. Deutivacaftor has not been evaluated;
however, ivacaftor is excreted into the milk of lactating female rats (see Data). When a drug is present in animal milk,
it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should
be considered along with the mother’s clinical need for ALYFTREK and any potential adverse effects on the breastfed
child from ALYFTREK or from the underlying maternal condition.
Data
The concentration of vanzacaftor, tezacaftor, or deutivacaftor in animal milk does not necessarily predict the
concentration of drug in human milk.
Vanzacaftor: Lacteal excretion of vanzacaftor in rats was demonstrated following a single oral dose (10 mg/kg) of
14C-vanzacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-vanzacaftor in milk was
approximately 0.2 times the value observed in plasma (based on AUC0-72h).
Tezacaftor: Lacteal excretion of tezacaftor in rats was demonstrated following a single oral dose (30 mg/kg) of
14C-tezacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-tezacaftor in milk was
approximately 3.0 times higher than in plasma (based on AUC0-72h).
Deutivacaftor: Deutivacaftor has not been evaluated; however, ivacaftor is excreted into the milk of lactating female
rats. Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor
administered 9 to 10 days postpartum to lactating dams. Exposure of 14C-ivacaftor in milk was approximately 1.5 times
higher than in plasma (based on AUC0-24h).
8.4
Pediatric Use
The safety and effectiveness of ALYFTREK for the treatment of CF in pediatric patients aged 6 years and older who
have at least one F508del mutation or another responsive mutation in the CFTR gene have been established. Use of
ALYFTREK for this indication was supported by evidence from two adequate and well-controlled trials (Trials 1 and
2) in patients with CF aged 12 years and older who had at least one F508del mutation or another responsive mutation
in the CFTR gene and additional pharmacokinetic and safety data in pediatric patients with CF aged 6 to less than
11
Reference ID: 5500641
12 years who had at least one F508del mutation or another responsive mutation in the CFTR gene (Trial 3). In these
trials, a total of 145 patients with CF aged 6 to less than 18 years received ALYFTREK including:
In Trial 1, 26 adolescents aged 12 to less than 18 years who were heterozygous for F508del and a CFTR mutation
that is not responsive to ivacaftor or tezacaftor/ivacaftor (minimal function mutation) [see Adverse Reactions (6.1)
and Clinical Studies (14)].
In Trial 2, 41 adolescents aged 12 to less than 18 years who were homozygous for F508del mutation, heterozygous
for F508del mutation and either a gating or a residual function mutation, or with at least one mutation responsive
to ELX/TEZ/IVA with no F508del mutation [see Adverse Reactions (6.1) and Clinical Studies (14)].
In Trial 3, 78 pediatric patients with CF aged 6 to less than 12 years (mean age 9.1 years) with at least one
mutation that is responsive to ELX/TEZ/IVA [see Adverse Reactions (6.1)]. In Trial 3, patients who weighed less
than 40 kg patients received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily)
and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor
100 mg/deutivacaftor 250 mg once daily).
The efficacy of ALYFTREK in patients aged 6 to less than 12 years for this indication was extrapolated from patients
aged 12 years and older with support from population pharmacokinetic analyses showing vanzacaftor, tezacaftor, and
deutivacaftor exposure levels in patients aged 6 to less than 12 years to be within the range of exposures observed in
patients aged 12 years and older [see Clinical Pharmacology (12.3)].
Safety of ALYFTREK in patients aged 6 to less than 12 years for this indication was based on Trial 3. The overall
safety profile of patients in Trial 3 was generally similar to the safety data in adult and pediatric patients 12 years of
age and older observed in Trials 1 and 2 [see Adverse Reactions (6.1)].
There is a risk of cataracts in pediatric patients treated with ALYFTREK. Perform baseline and follow-up
ophthalmological examination in pediatric patients prior to and during treatment with ALYFTREK [see Warnings and
Precautions (5.6)].
The safety and effectiveness of ALYFTREK in patients younger than 6 years of age have not been established.
Juvenile Animal Toxicity Data
Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels
of 10 mg/kg/day and higher (0.21 time the MRHD based on systemic exposure of ivacaftor and its metabolites). This
finding has not been observed in older animals [see Warnings and Precautions (5.6)].
Studies were conducted with tezacaftor in juvenile rats starting at postnatal day (PND) 21 and ranging up to PNDs
35 to 49. Findings of convulsions and death were observed in juvenile rats that received a tezacaftor dose level of
100 mg/kg/day (approximately equivalent to 1.9 times the MRHD based on summed AUCs of tezacaftor and its
metabolite, M1-TEZ). A no effect dose level was identified at 30 mg/kg/day (approximately equivalent to 0.8 times the
MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). Findings were dose related and generally
more severe when dosing with tezacaftor was initiated earlier in the postnatal period (PND 7, which would be
approximately equivalent to a human neonate). Tezacaftor and its metabolite, M1-TEZ, are substrates for
P-glycoprotein. Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of
tezacaftor and M1-TEZ. These findings are not relevant for the indicated pediatric population 6 to 11 years of age, for
whom levels of P-glycoprotein activity are equivalent to levels observed in adults.
8.5
Geriatric Use
Clinical studies of ALYFTREK did not include a sufficient number of patients with CF aged 65 years and older
(n=2, 0.4% of patients treated with ALYFTREK in Trials 1 and 2) to determine whether they respond differently from
younger adult patients with CF.
8.6
Renal Impairment
The recommended ALYFTREK dosage in patients with CF with mild to moderate renal impairment (RI) (eGFR 30 to
< 90 mL/min/1.73 m2) is the same in patients with CF with normal kidney function. Use of ALYFTREK in patients
12
Reference ID: 5500641
with CF with severe RI (eGFR <30 mL/min/1.73 m2) or end-stage renal disease is recommended only if the benefits
are expected to outweigh the risks.
No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed
in patients with mild to moderate RI (eGFR 30 to <90 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)]. The
effect of severe RI (eGFR <30 mL/min/1.73 m2) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is
unknown [see Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
Severe Hepatic Impairment
ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). ALYFTREK
has not been studied in patients with CF with severe HI [see Warnings and Precautions (5.1) and Adverse Reactions
(6.1)].
Moderate Hepatic Impairment
The use of ALYFTREK is not recommended in patients with moderate HI (Child-Pugh Class B). Use of ALYFTREK
should only be considered in patients with HI when there is a clear medical need, and the benefit outweighs the risk. If
used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function.
Liver function tests should be closely monitored [see Dosage and Administration (2.2), Warnings and Precautions
(5.1) and Adverse Reactions (6.1)].
Mild Hepatic Impairment
The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients
with normal hepatic function. Liver function tests should be closely monitored [see Warnings and Precautions (5.1)
and Adverse Reactions (6.1)].
10
OVERDOSAGE
Treatment of overdosage consists of general supportive measures including monitoring of vital signs and observation
of the clinical status.
11
DESCRIPTION
ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor tablets) are fixed-dose combination tablets for oral use
available as:
10 mg of vanzacaftor (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), 50 mg of tezacaftor, 125 mg of
deutivacaftor or
4 mg of vanzacaftor (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), 20 mg of tezacaftor, 50 mg of
deutivacaftor.
The tablets contain the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate
succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating contains
Brilliant Blue FCF aluminum lake/FD&C Blue #1, carmine, hydroxypropyl cellulose, hypromellose, iron oxide red,
talc, and titanium dioxide.
The active ingredients of ALYFTREK are described below.
Vanzacaftor
Vanzacaftor is provided as a calcium salt. Vanzacaftor calcium dihydrate is a white solid that is practically insoluble in
water (< 0.1 mg/mL). Its chemical name is calcium bis((14S)-8-[3-(2-{dispiro[2.0.2⁴.1³]heptan-7-yl}ethoxy)pyrazol-1
yl]-12,12-dimethyl-2,2,4-trioxo-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1¹¹,¹⁴.0⁵,¹⁰]tetracosa-1(23),5,7,9,19,21
hexaen-3-ide) dihydrate. Its molecular formula is C32H38N7O4SꞏCa0.5ꞏH2O and its molecular weight is 654.82.
Vanzacaftor calcium dihydrate has the following structural formula:
13
Reference ID: 5500641
~~
ll.ANJJ
H
OH
CD6□3
CD3
Tezacaftor
Tezacaftor is a white to off-white solid that is practically insoluble in water (< 5 microgram/mL). Its chemical name is
1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2
yl)-1H-indol-5-yl}cyclopropane-1-carboxamide. Its molecular formula is C26H27N2F3O6 and its molecular weight is
520.50. Tezacaftor has the following structural formula:
Deutivacaftor
Deutivacaftor is a white to off-white solid that is practically insoluble in water (< 0.1 mg/mL). Pharmacologically, it is
a CFTR potentiator. Its chemical name is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3
d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. Its molecular formula is C24H19D9N2O3 and its molecular
weight is 401.55. Deutivacaftor has the following structural formula:
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Vanzacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the
cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount
of CFTR protein delivered to the cell surface compared to either molecule alone. Deutivacaftor potentiates the channel
open probability (or gating) of the CFTR protein at the cell surface.
The combined effect of vanzacaftor, tezacaftor and deutivacaftor is increased quantity and function of CFTR at the cell
surface, resulting in increased CFTR activity as measured both by CFTR mediated chloride transport in vitro and by
sweat chloride in patients with CF.
CFTR Chloride Transport Assay in Fischer Rat Thyroid Cells Expressing Mutant CFTR Protein
Effects of vanzacaftor/tezacaftor/deutivacaftor on chloride transport for mutant CFTR protein was determined in
Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing
CFTR protein from individual mutations. Vanzacaftor/tezacaftor/deutivacaftor increased chloride transport in FRT
cells expressing select CFTR mutations, as identified in Table 5.
The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be
considered responsive is ≥10% of normal over baseline. This threshold was used because it is expected to predict
clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride
transport in vitro is not correlated with the magnitude of clinical response.
14
Reference ID: 5500641
CFTR Chloride Transport Assay in Human Bronchial Epithelial Cells Expressing Mutant CFTR Protein
Homozygous and heterozygous N1303K- Human Bronchial Epithelial (HBE) cells showed greater chloride transport in
the presence of vanzacaftor/tezacaftor/deutivacaftor than F508del/F508del-HBE cells treated with tezacaftor/ivacaftor
which has shown clinical benefit in people homozygous for F508del.
Patient Selection
Select patients 6 years of age and older for treatment of CF with ALYFTREK based on the presence of at least one
F508del mutation or another responsive mutation in the CFTR gene (see Table 5) [see Indications and Usage (1)].
Table 5 lists CFTR mutations responsive to ALYFTREK based on clinical response, and/or in vitro data in FRT or
HBE cells, or based on extrapolation of efficacy [see Clinical Studies (14)].
Table 5: List of CFTR Gene Mutations Responsive to ALYFTREK
Based on Clinical Data*
A455E
G551D
L1077P†
R352Q
S549N
V754M
D1152H
G85E†
L206W
R75Q
S549R
W1098C†
F508del†
H1054D
M1101K†
S1159F
S945L
W1282R
G1244E
I336K
R1066H
S1251N
V562I
Y563N†
Based on in vitro Data‡
1507_1515del9
E116Q
G424S
I556V
P140S
R334L
T1053I
2183A→G
E193K
G463V
I601F
P205S
R334Q
T1086I
3141del9
E292K
G480C
I618T
P499A
R347H
T1246I
3195del6
E403D
G480S
I807M
P5L
R347L
T1299I
3199del6
E474K
G551A
I980K
P574H
R347P
T338I
546insCTA
E56K
G551S
K1060T
P67L
R352W
T351I
A1006E
E588V
G576A
K162E
P750L
R516G
T604I
A1067P
E60K
G576A;R668C§
K464E
P99L
R516S
V1153E
A1067T
E822K
G622D
L1011S
Q1100P
R553Q
V1240G
A107G
E92K
G628R
L102R
Q1291R
R555G
V1293G
A120T
F1016S
G91R
L1065P
Q1313K
R560S
V201M
A234D
F1052V
G970D
L1324P
Q237E
R560T
V232D
A309D
F1074L
G970S
L1335P
Q237H
R668C
V392G
A349V
F1099L
H1085P
L137P
Q359R
R709Q
V456A
A46D
F1107L
H1085R
L1480P
Q372H
R74Q
V456F
A554E
F191V
H1375P
L15P
Q452P
R74W
V520F
A559T
F200I
H139R
L165S
Q493R
R74W;D1270N§
V603F
A559V
F311del
H199R
L320V
Q552P
R74W;V201M§
W361R
A561E
F311L
H199Y
L333F
Q98R
R74W;V201M;D
1270N§
Y1014C
A613T
F508C
H609R
L333H
R1048G
R75L
Y1032C
A62P
F508C;S1251N§
H620P
L346P
R1066C
R751L
Y109N
A72D
F575Y
H620Q
L441P
R1066L
R792G
Y161D
C491R
F587I
H939R
L453S
R1066M
R933G
Y161S
D110E
G1047R
H939R;H949L
L619S
R1070Q
S1045Y
Y301C
D110H
G1061R
I1027T
L967S
R1070W
S108F
Y569C
D1270N
G1069R
I105N
L997F
R1162L
S1118F
Y913C
D1445N
G1123R
I1139V
M1101R
R117C
S1159P
D192G
G1247R
I1234Vdel6aa
M1137V
R117C;G576A;R
668C
S1235R
D443Y
G1249R
I125T
M150K
R117G
S1255P
D443Y;G576A;R
668C§
G126D
I1269N
M152V
R117H
S13F
D513G
G1349D
I331N
M265R
R117L
S341P
D565G
G149R
I1366N
M952I
R117P
S364P
D579G
G178E
I1398S
M952T
R1283M
S492F
D614G
G178R
I148N
N1088D
R1283S
S549I
D836Y
G194R
I148T
N1303I
R170H
S589N
D924N
G194V
I175V
N1303K‡
R258G
S737F
D979V
G27E
I502T
N186K
R297Q
S912L
D993Y
G27R
I506L
N187K
R31C
S977F
15
Reference ID: 5500641
E116K
G314E
I506T
N418S
R31L
T1036N
Based on Extrapolation¶
1341G→A
2789+2insA
3041-15T→G
3849+10kbC→T
3850-3T→G
5T;TG13
711+3A→G
1898+3A→G
2789+5G→A
3272-26A→G
3849+4A→G
4005+2T→C
621+3A→G
E831X
2752-26A→G
296+28A→G
3600G→A
3849+40A→G
5T;TG12
* Clinical data is obtained from Trials 1 and 2.
† This mutation is also predicted to be responsive by FRT assay with ALYFTREK.
‡ The N1303K mutation is predicted to be responsive only by HBE assay. All other mutations predicted to be responsive with in vitro data
are supported by FRT assay.
§ Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of
mutations on the other allele.
¶ Efficacy is extrapolated to certain non-canonical splice mutations because clinical trials in all mutations in this subgroup are infeasible
and these mutations are not amenable to interrogation by FRT system.
12.2
Pharmacodynamics
Effects on Sweat Chloride
In patients with CF heterozygous for F508del and a CFTR mutation that results in a protein that is not responsive to
ivacaftor or tezacaftor/ivacaftor [minimal function mutation] (Trial 1) the treatment difference of ALYFTREK
compared to ELX/TEZ/IVA for mean absolute change in sweat chloride from baseline through Week 24
was -8.4 mmol/L (95% CI: -10.5, -6.3; P <0.0001).
In patients with CF homozygous for the F508del mutation, heterozygous for the F508del mutation and either a
gating or a residual function mutation, or at least one mutation responsive to ELX/TEZ/IVA with no F508del
mutation (Trial 2), the treatment difference of ALYFTREK compared to ELX/TEZ/IVA for mean absolute change
in sweat chloride from baseline through Week 24 was -2.8 mmol/L (95% CI: -4.7, -0.9; P = 0.0034).
In an open label trial in patients with CF aged 6 to less than 12 years with at least one mutation that is responsive to
ELX/TEZ/IVA (Trial 3) [see Adverse Reactions (6.1)], the mean absolute change in sweat chloride from baseline
through Week 24 was -8.6 mmol/L (95% CI: -11.0, -6.3).
The clinical relevance of these differences in sweat chloride has not been established in interventional clinical trials.
Cardiac Electrophysiology
At approximately 6 times the maximum recommended dose of vanzacaftor, clinically significant QTc interval
prolongation was not observed. Similarly, in separate studies of tezacaftor and ivacaftor evaluating up to 3 times the
respective maximum recommended doses, clinically significant QTc interval prolongation was not observed.
12.3
Pharmacokinetics
The pharmacokinetic parameters for vanzacaftor, tezacaftor, and deutivacaftor in patients with CF aged 12 years and
older are provided in Table 6 as mean (SD) unless otherwise specified. No clinically significant differences in the
pharmacokinetics of vanzacaftor, tezacaftor, and deutivacaftor were observed between healthy adult subjects and
patients with CF.
Table 6: Pharmacokinetics Parameters of ALYFTREK Components
Vanzacaftor
Tezacaftor
Deutivacaftor
Exposure
Cmax,ss (mcg/mL)
0.812 (0.344)
6.77 (1.24)
2.33 (0.637)
AUC0-24h,ss (mcg∙h/mL)
18.6 (8.08)
89.5 (28.0)
39.0 (15.3)
Time to steady state
within 20 days
within 8 days
within 8 days
AUC Accumulation
Ratio
6.09 (1.81)
1.92 (0.337)
1.74 (0.497)
Absorption
Tmax * (hours)
7.80 (3.70, 11.9)
1.60 (1.40, 1.70)
3.7 (2.7, 11.4)
Effect of food
AUCinf†
Increase 4- (low-fat meal)
to 6- (high-fat meal) fold
No clinically significant
change
Increase 3- (low-fat meal) to
4- (high-fat meal) fold
Distribution‡
16
Reference ID: 5500641
Apparent (oral) volume
of distribution (L)
121 (28.6)
73.1 (13.3)
159 (26.1)
Protein Binding§
> 99%
Approximately 99%
> 99%
Elimination
Effective Half-life
(hours)¶
92.8 (30.2)
22.5 (5.85)
19.2 (8.71)
Apparent (oral)
Clearance (L/hours)
1.34 (0.819)
1.22 (0.390)
7.29 (2.68)
Metabolism
Primary Pathway
CYP3A4/5
CYP3A4/5
CYP3A4/5
Active metabolites
None
M1-TEZ
M1-D-IVA
Metabolite potency
(relative to parent)
Not applicable
Similar
Approximately 20%
Excretion #
Feces
91.6%
(primarily metabolites)
72% (unchanged or M2-TEZ)
[0.79% as unchanged drug]
Not available
Urine
0.50%
13.7%
Not available
Abbreviations: AUC: area under the concentration versus time curve; SD: Standard Deviation; Cmax: maximum observed concentration; Tmax: time of
maximum concentration; ss: steady state
* Median (range)
† When administered with fat-containing meals relative to fasted conditions. Note: The high-fat meal was approximately 800-1000 calories with 50% fat.
The low-fat meal was approximately 400-500 calories with 25% fat.
‡ Vanzacaftor, tezacaftor, deutivacaftor do not partition preferentially into human red blood cells.
§ Vanzacaftor and deutivacaftor bind primarily to albumin and alpha 1-acid glycoprotein. Tezacaftor binds primarily to albumin.
¶ The mean (SD) terminal half-lives of vanzacaftor, tezacaftor, and deutivacaftor are 54.0 (10.1) hours, 92.4 (23.1) hours and 17.3 (2.67) hours,
respectively based on a single dose of vanzacaftor/tezacaftor/deutivacaftor tablets in healthy subjects in the fed state.
# Following radiolabeled doses.
Specific Populations
No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed
based on age, sex, race, CFTR genotype, or mild to moderate renal impairment (eGFR 30 to <90 mL/min/1.73m2 as
estimated by modification of diet in renal disease (MDRD) equation). The effect of severe renal impairment (eGFR
less than 30 mL/min/1.73m2) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown.
Weight was identified as the key covariate having a clinically meaningful impact on pharmacokinetics of vanzacaftor,
tezacaftor, and deutivacaftor.
Pediatric Patients Aged 6 to Less Than 18 Years
Vanzacaftor, tezacaftor and deutivacaftor exposures observed in clinical trials are presented by age group and dosage
administered in Table 7. No clinically significant differences in vanzacaftor, tezacaftor, and deutivacaftor exposures
were observed in patients with CF aged 6 to less than 18 years compared to adults following the recommended
dosages.
Table 7: Mean (SD) Vanzacaftor, Tezacaftor and Deutivacaftor Exposures by Age Group
Age group
Weight
Dosage (once daily)
AUC0-24h (mcg∙h/mL)
Vanzacaftor
Tezacaftor
Deutivacaftor
6 to <12 years
<40 kg
(N = 70)
vanzacaftor 12 mg
tezacaftor 60 mg
deutivacaftor 150 mg
13.0 (4.90)
69.1 (20.7)
30.2 (11.6)
≥40 kg
(N = 8)
vanzacaftor 20 mg
tezacaftor 100 mg
deutivacaftor 250 mg
18.6 (7.49)
101 (33.7)
48.5 (18.7)
12 to <18 years
-
(N = 66)
vanzacaftor 20 mg
tezacaftor 100 mg
deutivacaftor 250 mg
15.8 (6.52)
93.0 (32.5)
37.1 (15.3)
≥18 years
-
(N = 414)
19.0 (8.22)
89.0 (27.2)
39.3 (15.3)
Abbreviations: SD: Standard Deviation; AUC0-24h: Area Under the Concentration versus time curve at steady state
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Patients with Hepatic Impairment
Vanzacaftor AUC was approximately 30% lower, tezacaftor AUC was comparable, and deutivacaftor AUC was
approximately 20% lower in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects
with normal liver function matched for demographics [see Use in Specific Populations (8.7)].
The effect of mild hepatic impairment (Child-Pugh Class A) or severe hepatic impairment (Child-Pugh Class C) on
vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Exposure changes associated with concomitant use of vanzacaftor, tezacaftor, ivacaftor and/or deutivacaftor with other
drugs are shown in Table 8.
Table 8: Observed or Predicted Exposure Changes Associated with Concomitant Use of Vanzacaftor,
Tezacaftor, Ivacaftor and/or Deutivacaftor with Other Drugs
Dosage
Effected Drug
Geometric Mean Ratio (90% CI)
No Effect = 1.0
AUC
Cmax
Itraconazole
200 mg q12h on
Day 1, followed by
200 mg daily
TEZ 25 mg daily + IVA
50 mg daily
Tezacaftor
4.02
(3.71, 4.63)
2.83
(2.62, 3.07)
Itraconazole
200 mg daily
ELX 20 mg + TEZ 50 mg
+ D-IVA 50 mg single
dose
Tezacaftor
4.51
(3.85, 5.29)
1.48
(1.33, 1.65)
Deutivacaftor
11.1
(8.72, 14.1)
1.96
(1.70, 2.26)
Itraconazole
200 mg daily*
VNZ 5 mg single dose
Vanzacaftor
6.37
(5.53, 7.35)
1.55
(1.41, 1.70)
Ciprofloxacin†
750 mg twice daily
TEZ 50 mg q12h + IVA
150 mg q12h
Tezacaftor
1.08
(1.03, 1.13)
1.05
(0.99, 1.11)
Digoxin 0.5 mg
single dose
TEZ 25 mg daily +
IVA 50 mg daily
Digoxin
1.3
(1.17, 1.45)
1.32
(1.07, 1.64)
Fluconazole
200 mg daily
VNZ 20 mg qd + TEZ
100 mg + D-IVA 250 mg
qd
Vanzacaftor
2.55
(2.12, 3.12)‡
2.48
(2.04, 3.01)‡
Deutivacaftor
3.13
(2.44, 3.95)‡
2.27
(1.82, 2.93)‡
Erythromycin
500 mg four times
daily
VNZ 20 mg qd + TEZ
100 mg + D-IVA 250 mg
qd
Vanzacaftor
3.29
(1.62, 7.55)‡
3.19
(1.60, 7.29)‡
Deutivacaftor
4.13
(1.80, 9.73)‡
2.89
(1.52, 6.97)‡
Verapamil
80 mg three times
daily
VNZ 20 mg qd + TEZ
100 mg + D-IVA 250 mg
qd
Vanzacaftor
3.93
(1.84, 8.75)‡
3.80
(1.78, 8.33)‡
Deutivacaftor
5.11
(2.06, 12.5)‡
3.43
(1.64, 7.65)‡
Rifampin
600 mg daily
VNZ 20 mg qd + TEZ
100 mg + D-IVA 250 mg
qd
Vanzacaftor
0.18
(0.10, 0.34)‡
0.22
(0.12, 0.38)‡
Deutivacaftor
0.10
(0.04, 0.26)‡
0.20
(0.08, 0.44)‡
Carbamazepine
400 mg twice daily
Vanzacaftor
0.44
(0.28, 0.61)‡
0.46
(0.31, 0.64)‡
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Table 8: Observed or Predicted Exposure Changes Associated with Concomitant Use of Vanzacaftor,
Tezacaftor, Ivacaftor and/or Deutivacaftor with Other Drugs
Dosage
VNZ 20 mg qd + TEZ
100 mg + D-IVA 250 mg
qd
Effected Drug
Geometric Mean Ratio (90% CI)
No Effect = 1.0
AUC
Cmax
Deutivacaftor
0.24
(0.11, 0.47)‡
0.32
(0.17, 0.57)‡
Efavirenz
600 mg daily
VNZ 20 mg qd + TEZ
100 mg + D-IVA 250 mg
qd
Vanzacaftor
0.31
(0.16, 0.57)‡
0.35
(0.19, 0.59)‡
Deutivacaftor
0.27
(0.11, 0.50)‡
0.44
(0.23, 0.68)‡
Abbreviations: CI = Confidence Interval; ELX = elexacaftor; VNZ = vanzacaftor; TEZ = tezacaftor; IVA = ivacaftor; D-IVA = deutivacaftor;
PK = Pharmacokinetics; qd = once daily
* The itraconazole dosing (200 mg qd for14 days) did not fully cover the elimination of vanzacaftor. A 10.5-fold increase in vanzacaftor AUC is predicted by
physiologically based pharmacokinetic modeling and simulations when itraconazole fully covers the elimination.
† Effect is not clinically significant [see Drug Interactions (7.3)].
‡ Predicted by physiologically based pharmacokinetic modeling and simulations. Data presented as geometric mean ratio and 5th to 95th percentiles of
individuals in the simulated population [see Drug Interactions (7.1)].
Other Drugs: No clinically significant differences in tezacaftor pharmacokinetics were observed when
tezacaftor/ivacaftor was used concomitantly with ciprofloxacin. No clinically significant differences in the
pharmacokinetics of the following drugs were observed when used concomitantly with tezacaftor/ivacaftor: midazolam
(CYP3A4 substrate) or ethinyl estradiol/norethindrone containing hormonal contraceptives.
In Vitro Studies
CYP450 Enzymes: Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates. Deutivacaftor inhibits CYP2C8,
CYP2C9, and CYP3A4. Vanzacaftor and tezacaftor do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
CYP2D6, and CYP3A4. Vanzacaftor, tezacaftor, and deutivacaftor do not induce CYP3A4.
Transporter Systems: Tezacaftor and deutivacaftor are substrates of P-gp, but vanzacaftor is not a substrate of P-gp.
Tezacaftor is a substrate of BCRP, OATP1B1, but not OATP1B3. Vanzacaftor and deutivacaftor are not substrates for
OATP1B1 or OATP1B3. Vanzacaftor and deutivacaftor are BCRP inhibitors. Vanzacaftor, tezacaftor and deutivacaftor
are P-gp inhibitors. Vanzacaftor, tezacaftor, and deutivacaftor do not inhibit OATP1B1 nor OATP1B3.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with the combination of
vanzacaftor, tezacaftor, and deutivacaftor; however, separate studies of vanzacaftor, tezacaftor, deutivacaftor, and
ivacaftor are described below.
Vanzacaftor
A 6-month study in Tg.rasH2 mice showed no evidence of tumorigenicity at 30 mg/kg/day dose, the highest dose
tested.
Vanzacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro
micronucleus assay in TK6 cells, and in vivo rat micronucleus assay.
Administration of oral vanzacaftor had no effects on fertility and early embryonic development in male and female rats
at up to 12.5 and 10 mg/kg/day, respectively (approximately 19 times for males and 30 times for females the exposure
at the MRHD based on AUCs of vanzacaftor).
Tezacaftor
A two-year study in Sprague-Dawley rats and a 6-month study in Tg.rasH2 transgenic mice were conducted to assess
the carcinogenic potential of tezacaftor. No evidence of tumorigenicity from tezacaftor was observed in male and
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female rats at oral doses up to 50 and 75 mg/kg/day (approximately 2 and 4 times the MRHD based on summed AUCs
of tezacaftor and M1-TEZ in males and females, respectively). No evidence of tumorigenicity was observed in male
and female Tg.rasH2 transgenic mice at tezacaftor doses up to 500 mg/kg/day.
Tezacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro
chromosomal aberration assay in Chinese hamster ovary cells and in vivo mouse micronucleus test.
There were no effects on male or female fertility and early embryonic development in rats at oral tezacaftor doses up to
100 mg/kg/day (approximately 3 times the MRHD based on summed AUC of tezacaftor and M1-TEZ).
Deutivacaftor
Deutivacaftor is a deuterated isotopologue of ivacaftor with an established toxicity profile similar to ivacaftor based on
a 13-week single-agent repeat dose toxicity study; therefore, reproductive and developmental toxicity data and
carcinogenicity data from ivacaftor are expected to be equivalent to deutivacaftor.
Ivacaftor
Two-year studies were conducted in CD-1 mice and Sprague-Dawley rats to assess the carcinogenic potential of
ivacaftor. No evidence of tumorigenicity from ivacaftor was observed in mice or rats at oral doses up to 200 mg/kg/day
and 50 mg/kg/day, respectively (approximately equivalent to 3 and 11 times MRHD, respectively, based on summed
AUCs of ivacaftor).
Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro
chromosomal aberration assay in Chinese hamster ovary cells and in vivo mouse micronucleus test.
Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day
(approximately 15 and 13 times, respectively, the MRHD based on AUCs of ivacaftor). Increases in prolonged diestrus
were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos
and decreased corpora lutea, implantations and viable embryos in rats at 200 mg/kg/day when dams were dosed prior
to and during early pregnancy. Slight decreases of the seminal vesicle weights were observed in males at
200 mg/kg/day dose (approximately 15 times the MRHD based on summed AUCs of IVA). These impairments of
fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity.
14
CLINICAL STUDIES
The efficacy of ALYFTREK in patients aged 12 years and older with cystic fibrosis (CF) who have at least one
F508del mutation or a responsive mutation in the CFTR gene was evaluated in two 52-week randomized, double-blind,
active-controlled trials comparing ALYFTREK and a fixed-dose combination drug containing elexacaftor, tezacaftor,
and ivacaftor (ELX/TEZ/IVA) (Trial 1, NCT05033080 and Trial 2, NCT05076149). The two trials enrolled a total of
971 patients aged 12 years and older with CF who have at least one F508del mutation or other
ELX/TEZ/IVA-responsive mutations in the CFTR gene. Because patients in Trial 1 and Trial 2 would receive
ELX/TEZ/IVA, patients with a history of intolerance to ELX/TEZ/IVA were excluded from these trials.
Trial 1 enrolled patients with CF heterozygous for F508del and a CFTR mutation that results in a protein that was
not responsive to ivacaftor or tezacaftor/ivacaftor (minimal function mutation). A total of 398 patients with CF
aged 12 years and older received a daily oral dosage of ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor
100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening) during a 4-week run-in period and
were then randomized to receive ALYFTREK (total once daily oral dosage of vanzacaftor 20 mg/tezacaftor
100 mg/deutivacaftor 250 mg) or ELX/TEZ/IVA (same dosage as in the run-in period) during the 52-week
treatment period. Patients had a mean age of 30.8 years (range: 12.2 to 71.6 years), were 59% male, 97.5% White,
1.3% Black/African American, 0.3% Asian, 0.3% Other race, and 6% Hispanic or Latino ethnicity. After the
4₋week run-in, the mean ppFEV1 at baseline was 67.1 percentage points (range: 28.0, 108.6) and the mean sweat
chloride at baseline was 53.9 mmol/L (range: 10.0 mmol/L, 113.5 mmol/L).
Trial 2 enrolled patients with CF who had one of the following genotypes: homozygous for the F508del mutation,
heterozygous for the F508del mutation and either a gating or a residual function mutation, at least one mutation
responsive to ELX/TEZ/IVA with no F508del mutation. A total of 573 patients with CF aged 12 years and older
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received a daily oral dosage of ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the
morning and ivacaftor 150 mg in the evening) during a 4-week run-in period and were then randomized to receive
ALYFTREK (total once daily oral dosage of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) or
ELX/TEZ/IVA (same dosage as during the run-in period) during the 52-week treatment period. Patients had a
mean age of 33.7 years (range: 12.2 to 71.2 years), were 51.1% male, 92.8% White, 0% Black/African American,
0.3% Asian, 0.2% American Indian or Alaska Native, 0.3% Other race, and 1.6% Hispanic or Latino ethnicity.
After the 4-week run-in, the mean ppFEV1 at baseline was 66.8 percentage points (range: 36.4, 112.5) and the
mean sweat chloride at baseline was 42.8 mmol/L (range: 10.0 mmol/L, 113.3 mmol/L).
Efficacy Endpoints
In both trials, the primary endpoint evaluated non-inferiority in mean absolute change in ppFEV1 from baseline
through Week 24 and a key secondary endpoint evaluated the mean absolute change from baseline in sweat chloride
through Week 24 in the ALYFTREK and ELX/TEZ/IVA treatment groups.
Trials 1 and 2 also assessed other secondary endpoints including pulmonary exacerbation rate and change in Cystic
Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score from baseline.
Efficacy Results
In Trial 1, treatment with ALYFTREK resulted in an LS mean difference of 0.2 percentage points (95% CI: -0.7,
1.1) in absolute change in ppFEV1 from baseline through Week 24 compared to ELX/TEZ/IVA.
In Trial 2, treatment with ALYFTREK resulted in an LS mean difference of 0.2 percentage points (95% CI: -0.5,
0.9) in absolute change in ppFEV1 from baseline through Week 24 compared to ELX/TEZ/IVA.
As the lower bounds of the 95% CI of the LS mean difference in absolute change from baseline in ppFEV1 through
Week 24 were greater than -3.0 percentage points (the pre-specified non-inferiority margin) in Trial 1 and Trial 2,
these results demonstrate non-inferiority of ALYFTREK to ELX/TEZ/IVA.
Table 9 provides the primary and key secondary efficacy endpoints results for Trials 1 and 2.
Table 9: Efficacy Results in Patients Aged 12 Years and Older with CF Who Had at Least One F508del
Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2)
Analysis*
Statistic
Trial 1
Trial 2
ALYFTREK
N = 196
ELX/TEZ/IVA
N = 202
ALYFTREK
N = 284
ELX/TEZ/IVA
N = 289
Primary Endpoint
Absolute change
from baseline in
ppFEV1 through
Week 24
(percentage
points)
n
187
193
268
276
LS mean (SE)
0.5 (0.3)
0.3 (0.3)
0.2 (0.3)
0.0 (0.2)
LS mean difference,
95% CI§
0.2 (-0.7, 1.1)
0.2 (-0.5, 0.9)
Key Secondary Endpoint
Absolute change
from baseline in
SwCl through
Week 24
(mmol/L)
n
185
194
270
276
LS mean (SE)
-7.5 (0.8)
0.9 (0.8)
-5.1 (0.7)
-2.3 (0.7)
LS mean difference,
95% CI
-8.4 (-10.5, -6.3)
-2.8 (-4.7, -0.9)
P-value (2-sided)
< 0.0001
0.0034
ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SE: Standard Error; SwCl: sweat chloride
Note: Analyses were based on the full analysis set (FAS). FAS was defined as all randomized subjects who carry the intended CFTR allele mutation and
received at least 1 dose of study drug.
* A 4-week ELX/TEZ/IVA run-in-period was performed to establish an on-treatment baseline.
§ The pre-specified non-inferiority margin was -3.0 percentage points.
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The trials were not designed to demonstrate a difference between the treatment groups or to support non-inferiority of
the other secondary endpoints. In Trial 1 and Trial 2, mean absolute change from baseline ppFEV1 through Week 52,
the rate in pulmonary exacerbations through Week 52, and the absolute change from baseline in the CFQ-R RD
through Week 24 were similar between the ALYFTREK-treated and the ELX/TEZ/IVA-treated patients. The results
were not tested for statistical significance as they were not in the pre-specified multiple testing procedure.
16
HOW SUPPLIED/STORAGE AND HANDLING
ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor) tablets are supplied as follows:
Table 10: ALYFTREK Tablets and Package Configuration
Strengths
Tablet Description
Package Configuration
NDC
4 mg of vanzacaftor/
20 mg of tezacaftor /
50 mg of deutivacaftor
purple, round-shaped,
film-coated, debossed with “V4”
on one side and plain on the
other
84-count carton containing 4 wallets,
each wallet containing 21 tablets in
blister packs
NDC 51167-135-01
10 mg of vanzacaftor/
50 mg of tezacaftor /
125 mg of deutivacaftor
purple, oblong-shaped,
film-coated, debossed with
“V10” on one side and plain on
the other
56-count carton containing 4 wallets,
each wallet containing 14 tablets in
blister packs
NDC 51167-121-01
Store at 20ºC - 25ºC (68ºF - 77ºF); excursions permitted to 15ºC - 30ºC (59ºF - 86ºF) [see USP Controlled Room
Temperature].
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Drug-Induced Liver Injury and Liver Failure
Inform patients that elevations of transaminases have occurred in patients with CF treated with ALYFTREK and that
cases of drug-induced liver injury and failure have been observed with fixed-dose combination drug containing
elexacaftor, tezacaftor, and ivacaftor, which contains the same or similar active ingredients as ALYFTREK.
Advise all patients that liver function tests should be assessed prior to initiating ALYFTREK, and then assessed every
month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually
thereafter. Inform patients with a history of liver disease or liver function test elevations at baseline that more frequent
monitoring may be necessary. Instruct patients to interrupt treatment with ALYFTREK if symptoms of liver injury
occur (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) and notify their
healthcare provider immediately [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Adverse
Reactions (6.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Hypersensitivity Reactions, Including Anaphylaxis
Inform patients that hypersensitivity reactions including anaphylaxis have been reported in patients who received drugs
containing elexacaftor, tezacaftor, and/or ivacaftor (the same or similar active ingredients as ALYFTREK). Instruct
patients to discontinue ALYFTREK and notify their healthcare provider if they experience signs and symptoms of a
hypersensitivity reaction, including rash, hives, itching, facial swelling, tightness of the chest and wheezing [see
Warnings and Precautions (5.2)].
Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse
Reactions
Inform patients that there is no available safety data for ALYFTREK in patients who previously discontinued or
interrupted treatment with elexacaftor-, tezacaftor-, or ivacaftor-containing drugs due to adverse reactions. These
patients who start treatment with ALYFTREK may require closer and more frequent monitoring [see Warnings and
Precautions (5.3)].
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•
VERTEX
Drug Interactions with CYP3A Inducers and Inhibitors
Inform patients that certain medications, herbal supplements, or vitamins, when used concomitantly with ALYFTREK,
may reduce the effectiveness of ALYFTREK or increase the risk of adverse reactions associated with ALYFTREK.
Instruct patients to report all concomitant medications, herbal supplements, or vitamins, to their healthcare providers
while taking ALYFTREK [see Dosage and Administration (2.3), Warnings and Precautions (5.4, 5.5) and Drug
Interactions (7.1)].
Instruct patients to avoid food or drink containing grapefruit when using ALYFTREK [see Drug Interactions (7.1)].
Cataracts
Inform patients that abnormality of the eye lens (cataract) has been noted in some pediatric patients receiving drugs
containing ivacaftor (which is similar to an active ingredient in ALYFTREK) and baseline and follow-up
ophthalmological examinations are needed in pediatric patients receiving ALYFTREK [see Warnings and Precautions
(5.6) and Nonclinical Toxicology (13.1)].
Administration
Inform patients that ALYFTREK is best absorbed by the body when taken with food that contains fat. Examples
include eggs, butter, peanut butter, whole-milk dairy products (such as whole milk, cheese and yogurt), etc. [see
Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Inform patients of the following if they miss an ALYFTREK dose [see Dosage and Administration (2.5)]:
If 6 hours or less have passed since the missed dose is usually taken, patients with CF should be instructed to take
the prescribed dose with fat-containing food as soon as possible.
If more than 6 hours have passed since the missed dose, patients with CF should be instructed to skip the missed
dose and continue on the original schedule the next day.
Manufactured for
Vertex Pharmaceuticals Incorporated
50 Northern Avenue
Boston, MA 02210
ALYFTREK, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated.
All other trademarks referenced herein are the property of their respective owners.
©2024 Vertex Pharmaceuticals Incorporated
All Rights Reserved
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Reference ID: 5500641
MEDICATION GUIDE
ALYFTREK® (ah-LIF-trek)
(vanzacaftor, tezacaftor, and deutivacaftor tablets), tablets for oral use
What is the most important information I should know about ALYFTREK?
Elevated liver enzymes have been observed in patients taking ALYFTREK. Cases of serious liver damage
and liver failure leading to transplantation and death have been seen in some people with or without a history of
liver problems taking elexacaftor/tezacaftor/ivacaftor (TRIKAFTA®), a medicine which has the same or similar
active ingredients as ALYFTREK.
Your healthcare provider will do blood tests to check your liver:
o
before you start ALYFTREK
o
every month during your first 6 months of taking ALYFTREK
o
then every 3 months during the next 12 months of taking ALYFTREK
o
then at least every year while you are taking ALYFTREK
Your healthcare provider may do blood tests to check the liver more often if you have had high liver enzymes
in your blood in the past or are experiencing signs or symptoms of liver injury.
Stop taking ALYFTREK and call your healthcare provider right away if you have any of the following
symptoms of liver problems:
o
pain, swelling, or discomfort in the upper right
o nausea or vomiting
stomach (abdominal) area
o dark, amber-colored urine
o
yellowing of your skin or the white part of your eyes
o loss of appetite
o
mental changes
o have fluid in your stomach area (ascites)
What is ALYFTREK?
ALYFTREK is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 6 years
and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene.
Talk to your healthcare provider to learn if you have an indicated CF gene mutation.
It is not known if ALYFTREK is safe and effective in children under 6 years of age.
What should I tell my healthcare provider before taking ALYFTREK?
Before taking ALYFTREK, tell your healthcare provider about all of your medical conditions, including if
you:
have or have had liver problems.
are allergic to ALYFTREK or any ingredients in ALYFTREK. See the end of this medication guide for a
complete list of ingredients in ALYFTREK.
have taken another medicine with elexacaftor, tezacaftor, or ivacaftor before and temporarily or
permanently stopped because of side effects. Your healthcare provider may want to see you more often.
have kidney problems.
are pregnant or plan to become pregnant. It is not known if ALYFTREK will harm your unborn baby. You
and your healthcare provider should decide if you will take ALYFTREK while you are pregnant.
are breastfeeding or planning to breastfeed. It is not known if ALYFTREK passes into your breast milk.
You and your healthcare provider should decide if you will take ALYFTREK while you are breastfeeding.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Reference ID: 5500641
ALYFTREK may affect the way other medicines work and other medicines may affect how ALYFTREK works.
The dose of ALYFTREK may need to be adjusted when taken with certain medicines. Ask your healthcare
provider or pharmacist for a list of these medicines if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you
get a new medicine.
How should I take ALYFTREK?
Take ALYFTREK exactly as your healthcare provider tells you to take it.
Take ALYFTREK by mouth only.
Always take ALYFTREK tablets with food that contains fat. Examples of fat-containing foods include
butter, oil, eggs, peanut butter, nuts, meat, and whole-milk dairy products such as whole milk, cheese, and
yogurt.
ALYFTREK tablets (age 6 to less than 12 years weighing less than 88 pounds (40 kg)):
o
The purple round-shaped tablet is marked with ‘V4’ and each tablet contains the medicines vanzacaftor,
tezacaftor, and deutivacaftor. Take 3 tablets at the same time each day.
AYLFTREK tablets (age 6 to less than 12 years weighing 88 pounds (40 kg) or more, or 12 years and older):
o
The purple oblong-shaped tablet is marked with ‘V10’ and each tablet contains the medicines
vanzacaftor, tezacaftor, and deutivacaftor. Take 2 tablets at the same time each day.
Take ALYFTREK tablets whole.
Take the doses about the same time every day.
If you miss a dose of ALYFTREK and:
o
it is 6 hours or less from the time you usually take the dose, take the missed dose with food that
contains fat as soon as you can. Then take your next dose at your usual time.
o
it is more than 6 hours from the time you usually take the dose, do not take the missed dose. Take
your dose the next day at your usual time.
o
Do not take more than your usual dose of ALYFTREK to make up for a missed dose.
If you are not sure about your dosing, call your healthcare provider.
What should I avoid while taking ALYFTREK?
Avoid food or drink that contains grapefruit while you are taking ALYFTREK.
What are the possible or reasonably likely side effects of ALYFTREK?
ALYFTREK can cause serious side effects, including:
See "What is the most important information I should know about ALYFTREK?"
Serious Allergic Reactions can happen to people who are treated with ALYFTREK. Call your healthcare
provider or go to the emergency room right away if you have any symptoms of an allergic reaction.
Symptoms of an allergic reaction may include:
o
rash or hives
o
tightness of the chest or throat or difficulty breathing
o
light-headedness or dizziness
Reference ID: 5500641
...
VERTEX
-
Abnormality of the eye lens (cataract) has happened in some children and adolescents treated with
ALYFTREK. If you are a child or adolescent, your healthcare provider should perform eye examinations
before and during treatment with ALYFTREK to look for cataracts.
The most common side effects of ALYFTREK include:
cough
mouth or throat pain
pain or swelling of your nose or throat
flu (influenza)
(nasopharyngitis)
tiredness
upper respiratory tract infection (common
increase in liver enzymes
cold) including stuffy and runny nose
rash
headache
sinus congestion
Your healthcare provider should monitor you during treatment with ALYFTREK. You may require additional
monitoring if your treatment with a medicine that works like ALYFTREK has been previously stopped or
interrupted because of side effects.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of ALYFTREK. For more information, ask your healthcare provider
or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ALYFTREK?
Store ALYFTREK at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
Keep ALYFTREK and all medicines out of the reach of children.
General information about the safe and effective use of ALYFTREK.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
ALYFTREK for a condition for which it was not prescribed. Do not give ALYFTREK to other people, even if they
have the same symptoms that you have. It may harm them.
You can ask your pharmacist or healthcare provider for information about ALYFTREK that is written for health
professionals.
What are the ingredients in ALYFTREK?
Active ingredients: vanzacaftor, tezacaftor, and deutivacaftor.
Inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium
stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains Brilliant Blue FCF
aluminum lake/FD&C Blue #1, carmine, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium
dioxide.
Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210
ALYFTREK, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated.
All other trademarks referenced herein are the property of their respective owners.
©2024 Vertex Pharmaceuticals Incorporated
For more information, go to www.alyftrek.com or call 1-877-752-5933.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: 12/2024
Reference ID: 5500641
| custom-source | 2025-02-12T15:48:03.380575 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218730s000lbl.pdf', 'application_number': 218730, 'submission_type': 'ORIG ', 'submission_number': 1} |
80,695 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SKYCLARYS safely and effectively. See full prescribing
information for SKYCLARYS.
SKYCLARYS® (omaveloxolone) capsules, for oral use
Initial U.S. Approval: 2023
-----------------------------RECENT MAJOR CHANGES-------------------------
Dosage and Administration (2.2)
12/2024
-----------------------------INDICATIONS AND USAGE---------------------------
SKYCLARYS is indicated for the treatment of Friedreich’s ataxia in
adults and adolescents aged 16 years and older. (1)
------------------------DOSAGE AND ADMINISTRATION-----------------------
• Obtain alanine aminotransferase (ALT), aspartate aminotransferase
(AST), bilirubin, B-type natriuretic peptide (BNP), and lipid
parameters prior to initiating SKYCLARYS and during treatment.
(2.1, 5.1, 5.2, 5.3)
• Recommended dosage is 150 mg (3 capsules) taken orally once
daily. (2.2)
• Administer SKYCLARYS on an empty stomach, at least 1 hour
before or 2 hours after eating. (2.2)
• Swallow SKYCLARYS capsules whole or open and sprinkle the
entire contents of both halves of the capsule onto applesauce and
mix. Do not crush or chew capsules. (2.2)
• Moderate and Severe Hepatic Impairment: The recommended
dosage of SKYCLARYS is 100 mg once daily for patients with
moderate hepatic impairment. If adverse reactions emerge, further
reduce the dosage to 50 mg once daily. Avoid use in patients with
severe hepatic impairment. (2.5, 8.6, 12.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Capsules: 50 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
None. (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
• Elevation of Aminotransferases: Monitor ALT, AST, and total
bilirubin prior to initiation, every month for the first 3 months of
treatment, and periodically thereafter. (2.1, 5.1)
• Elevation of B-type Natriuretic Peptide (BNP): Advise patients of
signs and symptoms of fluid overload. (2.1, 5.2)
• Lipid Abnormalities: Monitor cholesterol periodically during
treatment. (2.1, 5.3)
-------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions (incidence ≥20% and greater than
placebo) are elevated liver enzymes (AST/ALT), headache, nausea,
abdominal pain, fatigue, diarrhea, and musculoskeletal pain. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Biogen at
1-844-987-3224- or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS--------------------------------
• Moderate or Strong CYP3A4 Inhibitors: Avoid concomitant use.
Consider SKYCLARYS dosage reduction with monitoring if use is
unavoidable. (2.4, 7.1)
• Moderate or Strong CYP3A4 Inducers: Avoid concomitant use. (7.1)
----------------------------USE IN SPECIFIC POPULATIONS-------------------
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Testing Before Initiating SKYCLARYS and
Monitoring to Assess Safety
2.2 Recommended Dosage
2.3 Missed Doses
2.4 Recommendations for Concomitant Use with Strong or
Moderate CYP3A4 Inhibitors and Inducers
2.5 Recommended Dosage for Patients with Hepatic Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Elevation of Aminotransferases
5.2 Elevation of B-Type Natriuretic Peptide
5.3 Lipid Abnormalities
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on SKYCLARYS
7.2 Effect of SKYCLARYS on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 5500338
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
SKYCLARYS is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged
16 years and older.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Testing Before Initiating SKYCLARYS and Monitoring to Assess Safety
Obtain ALT, AST, bilirubin, BNP, and lipid parameters prior to initiating SKYCLARYS and during
treatment [see Warnings and Precautions (5.1, 5.2, 5.3)].
2.2 Recommended Dosage
The recommended dosage of SKYCLARYS is 150 mg (3 capsules) taken orally once daily.
• Administer SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after eating
[see Clinical Pharmacology (12.3)].
• Swallow SKYCLARYS capsules whole. Do not crush or chew.
• For patients who are unable to swallow whole capsules:
o SKYCLARYS capsules may be opened and the entire contents of both halves of the
capsule sprinkled onto 2 tablespoons (30 mL) of applesauce [see Clinical Pharmacology
(12.3)].
o Stir the mixture until homogenous.
o Swallow all the drug/applesauce mixture immediately.
o Do not store the mixture for future use.
o Contents of the SKYCLARYS capsules should not be mixed with milk or orange juice.
o Not for enteral feeding tube administration.
2.3 Missed Doses
If a dose of SKYCLARYS is missed, take the next dose at its scheduled time the following day. A
double dose should not be taken to make up for a missed dose.
2.4 Recommendations for Concomitant Use with Strong or Moderate CYP3A4 Inhibitors and
Inducers
The recommended dosage for concomitant use of SKYCLARYS with cytochrome P450 (CYP) 3A4
inhibitors and inducers are described in Table 1 [see Drug Interactions (7.1) and Clinical
Pharmacology (12.3)].
Reference ID: 5500338
Table 1: Recommended Dosage of SKYCLARYS with Concomitant Use of CYP3A4 Inhibitors
and Inducers
Concomitant Drug Class
Dosage
Strong CYP3A4 inhibitor
Recommended to avoid concomitant use.
If coadministration cannot be avoided:
• Reduce the dosage of SKYCLARYS to 50 mg
once daily with close monitoring for adverse
reactions.
• If adverse reactions emerge, coadministration
with strong CYP3A4 inhibitors should be
discontinued.
Moderate CYP3A4 inhibitor
Recommended to avoid concomitant use.
If coadministration cannot be avoided:
• Reduce the dosage of SKYCLARYS to 100
mg once daily with close monitoring for
adverse reactions.
• If adverse reactions emerge, further reduce
the dosage of SKYCLARYS to 50 mg once
daily.
Strong or Moderate CYP3A4 inducer
Recommended to avoid concomitant use.
2.5 Recommended Dosage for Patients with Hepatic Impairment
The recommended dosage for patients with hepatic impairment are described in Table 2 [see Use in
Specific Populations (8.6)].
Table 2: Recommended Dosage in Patients with Hepatic Impairment
Impairment Classification (Child-Pugh)
Dosage
Severe (Child-Pugh Class C)
Avoid use
Moderate (Child-Pugh Class B)
• 100 mg once daily with close monitoring for
adverse reactions
• Consider lowering to 50 mg once daily if
adverse reactions emerge
Mild (Child-Pugh Class A)
150 mg once daily
Reference ID: 5500338
3 DOSAGE FORMS AND STRENGTHS
SKYCLARYS capsules contain 50 mg of omaveloxolone, and are supplied as opaque hard capsules
having a light green body and blue cap, imprinted with “RTA 408” in white ink on the body and “50” in
white ink on the cap.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Elevation of Aminotransferases
Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (ALT and AST). In
Study 1 [see Clinical Studies (14)], the incidence of elevations of ALT or AST above 5 times and 3
times the upper limit of normal (ULN) was 16% and 31%, respectively, in patients treated with
SKYCLARYS. There were no cases of concomitant elevation of transaminases and total bilirubin
observed in Study 1. Maximum increases in ALT and AST occurred within 12 weeks after starting
SKYCLARYS. Increases in serum aminotransferases were generally asymptomatic and reversible
following discontinuation of SKYCLARYS. Patients with clinically significant liver disease were
excluded from Study 1.
Monitor ALT, AST, and total bilirubin prior to initiation of SKYCLARYS, every month for the first 3
months of treatment, and periodically thereafter. If transaminases increase to levels greater than 5
times the ULN, or greater than 3 times the ULN with evidence of liver dysfunction (e.g., elevated
bilirubin), immediately discontinue SKYCLARYS and repeat liver function tests as soon as possible. If
transaminase levels stabilize or resolve, SKYCLARYS may be reinitiated with an appropriate
increased frequency of monitoring of liver function [see Adverse Reactions (6.1) and Use in Specific
Populations (8.6)].
5.2 Elevation of B-Type Natriuretic Peptide
Treatment with SKYCLARYS can cause an increase in BNP, a marker of cardiac function. In Study 1,
a total of 14% of patients treated with SKYCLARYS had an increase from baseline in BNP and a BNP
above the ULN (100 pg/mL), compared to 4% of patients who received placebo. The incidence of
elevation of BNP above 200 pg/mL was 4% in patients treated with SKYCLARYS. Cardiomyopathy
and cardiac failure are common in patients with Friedreich’s ataxia. Patients were excluded from
Study 1 if they had BNP levels > 200 pg/mL prior to study entry, or a history of clinically significant
left-sided heart disease and/or clinically significant cardiac disease, with the exception of mild to
moderate cardiomyopathy associated with Friedreich’s ataxia [see Adverse Reactions (6.1)]. Whether
the elevations in BNP in Study 1 are related to SKYCLARYS or cardiac disease associated with
Friedreich’s ataxia is unclear.
Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function.
Check BNP prior to initiation of SKYCLARYS. Monitor patients for the signs and symptoms of fluid
overload, such as sudden weight gain (3 pounds or more of weight gain in one day, or 5 pounds or
Reference ID: 5500338
more of weight gain in a week), peripheral edema, palpitations, and shortness of breath. If signs and
symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac
function, and manage appropriately. Management of fluid overload and heart failure may require
discontinuation of SKYCLARYS.
5.3 Lipid Abnormalities
Treatment with SKYCLARYS can cause changes in cholesterol. In Study 1, 29% of patients treated
with SKYCLARYS reported elevated cholesterol above ULN at one or more time points. Mean
increases were observed within 2 weeks of initiation of SKYCLARYS and returned to baseline within
4 weeks of discontinuing treatment. A total of 16% of patients treated with SKYCLARYS had an
increase in low-density lipoprotein cholesterol (LDL-C) from baseline, compared to 8% of patients
who received placebo. The mean increase in LDL-C for all SKYCLARYS-treated patients was 23.5
mg/dL at 48 weeks. A total of 6% of patients treated with SKYCLARYS had decreases in high-density
lipoprotein cholesterol (HDL-C) from baseline compared to 4% of patients who received placebo. The
mean decrease in HDL-C for all SKYCLARYS-treated patients was 5.3 mg/dL at 48 weeks.
Assess lipid parameters prior to initiation of SKYCLARYS and monitor periodically during treatment.
Manage lipid abnormalities according to clinical guidelines.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described in greater detail in other labeling
sections:
• Elevation of aminotransferases [see Warnings and Precautions (5.1)]
• Elevation of BNP [see Warnings and Precautions (5.2)]
• Lipid abnormalities [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of
another drug and may not reflect the rates observed in clinical practice.
The safety of SKYCLARYS 150 mg once daily has been evaluated in 165 patients with Friedreich’s
ataxia, including 137 patients exposed for at least 48 weeks, and 125 patients exposed for at least 96
weeks.
The most common adverse reactions in Study 1 (≥20% and greater than placebo) were elevated liver
enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.
Table 3 shows the adverse reactions that occurred in 10% or more of patients treated with
SKYCLARYS and greater than placebo.
Reference ID: 5500338
Table 3:
Adverse Reactions Reported in 10% or More of Patients Treated with
SKYCLARYS and Greater than Placebo (Study 1)
Adverse Reactions
SKYCLARYS
150 mg
(N = 51)
%
Placebo
(N = 52)
%
Elevated liver enzymes (AST/ALT)
37
2
Headache
37
25
Nausea
33
13
Abdominal pain
29
6
Fatigue
24
14
Diarrhea
20
10
Musculoskeletal pain
20
15
Oropharyngeal pain
18
6
Influenza
16
6
Vomiting
16
12
Muscle spasms
14
6
Back pain
13
8
Decreased appetite
12
4
Rash
10
4
Laboratory Abnormalities
In addition to elevated liver enzymes, additional laboratory abnormalities include elevation of BNP
and lipid abnormalities [see Warnings and Precautions (5.1, 5.2, 5.3)].
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of SKYCLARYS.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: hypersensitivity (urticaria, rash)
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on SKYCLARYS
CYP3A4 Inhibitors
Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong
CYP3A4 inhibitors is expected to result in clinically significant increased exposure of omaveloxolone
Reference ID: 5500338
[see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions. Avoid
concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors. If use cannot be
avoided, dosage modifications are recommended [see Dosage and Administration (2.4)].
CYP3A4 Inducers
Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong
CYP3A4 inducers is expected to result in clinically significant decreased exposure of omaveloxolone
[see Clinical Pharmacology (12.3)], which may reduce the effectiveness of SKYCLARYS. Avoid
concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers.
7.2 Effect of SKYCLARYS on Other Drugs
CYP3A4 and CYP2C8 Substrates
Omaveloxolone is a weak inducer of CYP3A4 and CYP2C8. Concomitant use with SKYCLARYS can
reduce the exposure of CYP3A4 and CYP2C8 substrates which may reduce the activity of these
substrates [see Clinical Pharmacology (12.3)]. Refer to the prescribing information of substrates of
CYP3A4 and CYP2C8 for dosing instructions if used concomitantly with SKYCLARYS and monitor for
lack of efficacy of the concomitant treatment.
Hormonal Contraceptives
Omaveloxolone is a weak CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use with
SKYCLARYS may reduce the efficacy of hormonal contraceptives. Advise patients to avoid
concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and
progestin only pills [see Use in Specific Populations (8.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
SKYCLARYS during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or
pregnant women may register themselves in the program by calling 1-866-609-1785 or by sending an
email to SkyclarysPregnancySurveillance@ppd.com.
Risk Summary
There are no adequate data on the developmental risks associated with the use of SKYCLARYS in
pregnant women. In animal studies, administration of omaveloxolone during pregnancy or throughout
pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and
growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at
plasma exposures similar to or less than exposures in humans (see Animal Data). In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically
Reference ID: 5500338
recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major
birth defects and miscarriage for the indicated population is unknown.
Data
Animal Data
Oral administration of omaveloxolone (0, 1, 3, or 10 mg/kg/day) to pregnant rats throughout
organogenesis resulted in no adverse effects on embryofetal development; however, in a dose range-
finding study, oral administration of omaveloxolone at doses up to 30 mg/kg/day to pregnant rats
throughout organogenesis produced increases in post-implantation loss and resorptions, resulting in
a decrease in viable fetuses, and reduced fetal weight at the highest dose tested. At the highest dose
tested in the pivotal study (10 mg/kg/day), plasma exposure (AUC) was approximately 5 times that in
humans at the recommended human dose (RHD) of 150 mg/day.
Oral administration of omaveloxolone (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits throughout
organogenesis resulted in increased embryofetal mortality and skeletal variations and reduced fetal
weight at the highest dose tested, which was associated with maternal toxicity. At the no-effect dose
for adverse effects on embryofetal development (10 mg/kg/day), plasma exposure was less than that
in humans at the RHD.
Oral administration of omaveloxolone (0, 1, 3, or 10 mg/kg/day) to rats throughout pregnancy and
lactation resulted in an increase in stillbirths and impaired neurobehavioral function (increased
locomotor activity and learning and memory deficits) in offspring at all doses, reduced body weight in
offspring at all but the lowest dose tested, and delayed sexual maturation (males), increased
postnatal mortality, and impaired reproductive performance in offspring at the highest dose tested. A
no-effect dose for adverse effects on pre- and postnatal development was not identified. Plasma
exposure (AUC) at the lowest dose tested was less than that in humans at the RHD.
8.2 Lactation
Risk Summary
There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on
milk production and the breastfed infant are unknown. Omaveloxolone was excreted in the milk of
lactating rats following oral administration. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for SKYCLARYS and any potential
adverse effects on the breastfed infant from SKYCLARYS or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
SKYCLARYS may decrease the efficacy of hormonal contraceptives [see Drug Interactions (7.2) and
Clinical Pharmacology (12.3)]. Advise patients to avoid concomitant use with combined hormonal
contraceptives (e.g., pill, patch, ring), implants, and progestin only pills. Counsel females using
hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonal intrauterine
system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 28
days after discontinuation of SKYCLARYS.
Reference ID: 5500338
8.4 Pediatric Use
The safety and effectiveness of SKYCLARYS for the treatment of Friedreich's ataxia have been
established in pediatric patients aged 16 years and older. Use of SKYCLARYS for this indication is
supported by evidence from one adequate and well-controlled study (Study 1) in adults and in
pediatric patients aged 16 years and older [see Clinical Studies (14)].
Safety and effectiveness of SKYCLARYS have not been established in pediatric patients less than 16
years of age.
8.5 Geriatric Use
Clinical studies of SKYCLARYS in Friedreich’s ataxia did not include patients aged 65 and over. No
data are available to determine whether they respond differently than younger adult patients.
8.6 Hepatic Impairment
Omaveloxolone plasma exposure is increased in patients with moderate or severe hepatic
impairment (Child-Pugh Class B and C) [see Clinical Pharmacology (12.3)]. Avoid treatment with
SKYCLARYS in patients with severe hepatic impairment, including those who develop severe hepatic
impairment. If hepatic function improves to moderate impairment, mild impairment, or normal function,
initiation of SKYCLARYS treatment at the approved recommended dosage may be considered. For
patients with moderate hepatic impairment, a reduced dosage is recommended with close monitoring
for adverse reactions [see Dosage and Administration (2.5)]. For patients with mild hepatic
impairment (Child-Pugh Class A), no dose adjustments are recommended.
11 DESCRIPTION
SKYCLARYS contains omaveloxolone in immediate release capsules for oral administration available
in a 50 mg strength. The chemical name of omaveloxolone is N-(2-cyano-3,12-dioxo-28-noroleana-
1,9(11)-dien-17-yl)-2,2-difluoro-propanamide. Omaveloxolone is a white to off-white amorphous solid.
The molecular formula is C33H44F2N2O3. Molecular weight is 554.72 g/mol. The chemical structure is:
Reference ID: 5500338
Omaveloxolone has a pKa of 7.26 and is practically insoluble in water across the physiological pH
range. Capsule contents include the following inactive ingredients: croscarmellose sodium,
magnesium stearate, pregelatinized starch, and silicified microcrystalline cellulose. The hard capsule
shells contain FD&C Blue #1, ferric oxide yellow, hypromellose, titanium dioxide, and white ink.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with
Friedreich’s ataxia is unknown. Omaveloxolone has been shown to activate the Nuclear factor
(erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2
pathway is involved in the cellular response to oxidative stress.
12.2 Pharmacodynamics
Cardiac Electrophysiology
Clinically significant QTc interval prolongation was not observed in healthy subjects with
administration of SKYCLARYS at a supratherapeutic dose of 450 mg (3 times the recommended
dosage) with a high fat meal.
12.3 Pharmacokinetics
Absorption
The median (range) time to achieve peak plasma concentration (Tmax) was 7 to 14 (1 to 24) hours.
The total plasma omaveloxolone exposure based on area under the concentration-time curve (AUC)
increased in a dose-dependent and dose proportional manner over a dose range of 50 mg (0.33
times the recommended dosage) to 150 mg, but maximum omaveloxolone plasma concentration
(Cmax) increased in a less than dose proportional manner over the dose range in healthy fasted
subjects.
Effect of Food
Omaveloxolone Cmax and AUC0-inf increased by approximately 350% and 15%, respectively, with a
high-fat meal (800-1000 calories, approximately 150, 250, and 500 to 600 calories from protein,
carbohydrate, and fat, respectively) compared to fasted conditions [see Dosage and Administration
(2.2)].
Omaveloxolone Cmax and AUC0-inf were similar when capsule contents were sprinkled on applesauce
or when administered as intact capsules. The median Tmax of omaveloxolone was shortened from
approximately 10 to 6 hours when sprinkled on applesauce [see Dosage and Administration (2.2)].
Distribution
The mean apparent volume of distribution of omaveloxolone is 7361 L (105 L/kg for a 70 kg person).
Protein binding of omaveloxolone is 97%.
Elimination
Reference ID: 5500338
The mean (range) terminal half-life of omaveloxolone is 57 hours (32 to 90 hours). The mean
apparent plasma clearance of omaveloxolone is 109 L/hr.
Metabolism
Omaveloxolone is primarily metabolized by CYP3A with minor metabolism by CYP2C8 and CYP2J2.
Excretion
Following administration of a single oral dose of radiolabeled omaveloxolone 150 mg to healthy
subjects, approximately 92% of the dose was recovered in feces (approximately 91% within 96 hours
after administration) and 0.1% in urine.
Specific Populations
There were no clinically significant differences in the pharmacokinetics of omaveloxolone based on
age (16 to 71 years of age), sex, race, or body weight (41 to 128 kg).
Patients with Renal Impairment
Population pharmacokinetic analysis demonstrated that estimated glomerular filtration rate (eGFR)
values ≥ 63 mL/min/1.73 m2 did not have a significant effect on the pharmacokinetics of
omaveloxolone. Therefore, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m2) is not expected
to have a significant effect on the pharmacokinetics of omaveloxolone. The effect of moderate or
severe renal impairment (eGFR ≤59 mL/min/1.73m2) on the pharmacokinetics of omaveloxolone is
unknown.
Patients with Hepatic Impairment
There were no clinically significant differences in the pharmacokinetics of omaveloxolone in subjects
with mild hepatic impairment (Child-Pugh Class A). In subjects with moderate and severe hepatic
impairment (Child-Pugh Class B and C), omaveloxolone clearance was reduced, resulting in higher
plasma exposure of omaveloxolone. The omaveloxolone AUC increased up to 1.65-fold and Cmax
increased up to 1.83-fold in subjects with moderate hepatic impairment. The omaveloxolone AUC
increased up to 2.17-fold in subjects with severe hepatic impairment; however, this change was
variable [see Use in Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
Strong CYP3A Inhibitors: After single dose administration, omaveloxolone Cmax increased 3-fold and
AUC 4-fold following concomitant use with itraconazole (strong CYP3A inhibitor) [see Drug
Interactions (7.1)].
Moderate CYP3A Inhibitors: After single dose administration, omaveloxolone Cmax and AUC
increased approximately 1.25-fold following concomitant use with verapamil (moderate CYP3A4 and
P-gp inhibitor) [see Drug Interactions (7.1)].
Reference ID: 5500338
Moderate CYP3A Inducers: After single dose administration, omaveloxolone Cmax and AUC
decreased 38% and 48%, respectively, following concomitant use with efavirenz (moderate CYP3A4
inducer) [see Drug Interactions (7.1)].
Certain CYP450 Enzymes or Transporter Substrates: Omaveloxolone decreased the AUC of
midazolam (CYP3A4 substrate) by approximately 45%, AUC of repaglinide (CYP2C8 substrate) by
approximately 35%, and AUC of rosuvastatin (BCRP and OATP1B1 substrate) by approximately 30%
[see Drug Interactions (7.2)]. There were no clinically significant differences in the pharmacokinetics
of digoxin (P-gp substrate) or metformin [(organic cation transporter (OCT)1 substrate] when co-
administered with omaveloxolone.
Other Drugs: No clinically significant differences in the pharmacokinetics of omaveloxolone are
expected following concomitant use with weak CYP3A4 inhibitors or strong CYP2C8 inhibitors.
In Vitro Studies
CYP Enzymes: Omaveloxolone is an inducer of CYP3A4 and CYP2C19. Omaveloxolone is not an
inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Omaveloxolone is not an inducer
of CYP1A2, CYP2B6, CYP2C8, and CYP2C9.
Drug Transporters: Omaveloxolone is not an inhibitor of BCRP, BSEP, OAT3, OATP1B1, OATP1B3,
OCT2, MATE1, and MATE2-K. Omaveloxolone inhibited the renal transporter OAT1.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In a 26-week carcinogenicity study in transgenic (Tg.rasH2) mice, oral administration of
omaveloxolone (0, 5, 10, or 30 mg/kg/day in males; 0, 20, 50, or 100 mg/kg/day in females) resulted
in no increase in tumors.
Mutagenesis
Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a
chromosomal aberration assay in human peripheral blood lymphocytes but negative in the in vivo rat
micronucleus assay and the in vitro comet assay.
Impairment of Fertility
Oral administration of omaveloxolone (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and
during mating and continuing in females to gestation day 7 produced an increase in pre-and post-
implantation loss and resorptions, resulting in a decrease in viable embryos at the highest dose
tested. The no-effect dose (3 mg/kg/day) for adverse effects on fertility and reproductive function was
associated with plasma exposures (AUC) approximately 2 times that in humans at the recommended
human dose of 150 mg/day.
Reference ID: 5500338
14 CLINICAL STUDIES
The efficacy of SKYCLARYS was evaluated in a 48-week, randomized, double-blind, placebo-
controlled study in patients 16 to 40 years of age with Friedreich’s Ataxia (Study 1; NCT02255435).
A total of 103 patients were randomized (1:1) to receive SKYCLARYS 150 mg once daily (n=51) or
placebo (n=52).
Enrolled patients had to have a stable modified Friedreich’s Ataxia Rating Scale (mFARS) score
between 20 and 80, be able to complete maximal exercise testing, and have a left ventricular ejection
fraction of at least 40%. In Study 1, 53% of enrolled patients were male, 97% were White, and the
mean age was 24 years at study entry. Patients with or without pes cavus were included in Study 1.
Pes cavus was defined as having a loss of lateral support and was determined if light from a flashlight
could be seen under the patient’s arch when barefoot and weight bearing.
The prespecified primary analysis was the change from baseline in the mFARS score compared to
placebo at Week 48 in the Full Analysis Population of patients without pes cavus (n=82). The mFARS
is a clinical assessment tool to assess patient function, which consists of 4 domains to evaluate
bulbar function, upper limb coordination, lower limb coordination, and upright stability. The mFARS
has a maximum score of 99, with a lower score on the mFARS signifying lesser physical impairment.
Treatment with SKYCLARYS resulted in statistically significant lower mFARS scores (less
impairment) relative to placebo (see Table 4) at Week 48.
Table 4: Primary Analysis in Full Analysis Population: mFARS Least Squares (LS) Mean
Change from Baseline at Week 48
Mean (SD)
Baseline mFARS
Total Score
LS Mean
Change from
Baseline at Week
48
Treatment difference
SKYCLARYS-
placebo (95% CI)
p-value
SKYCLARYS
(n = 40)
40.95 (10.39)
-1.56
-2.41
(-4.32, -0.51)
0.0138
Placebo
(n = 42)
38.78 (11.03)
0.85
SD = Standard Deviation; LS = Least Squares; CI = Confidence Interval
The All Randomized Population (N=103), which included all patients regardless of pes cavus status,
demonstrated similar results to the Full Analysis Population of lower mFARS scores in patients
treated with SKYCLARYS compared to placebo, with a nominally significant least squares mean
difference between treatment groups of ‑1.94 (95% CI: -3.71, -0.16, p=0.0331).
In a post hoc, propensity-matched analysis, lower mFARS scores were observed in patients treated
with SKYCLARYS after 3 years relative to a matched set of untreated patients from a natural history
study. These exploratory analyses should be interpreted cautiously given the limitations of data
collected outside of a controlled study, which may be subject to confounding.
Reference ID: 5500338
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
SKYCLARYS (omaveloxolone) capsules, 50 mg, are supplied as opaque, hard capsules having a
light green body and blue cap imprinted with “RTA 408” in white ink on the body and “50” in white ink
on the cap. SKYCLARYS is supplied in high density polyethylene bottles that contain 90 capsules,
with a foil induction seal and child-resistant closure (NDC 64406-250-90).
16.2 Storage and Handling
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F to 86°F)
[see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Elevation of Aminotransferases
Inform patients that elevation in aminotransferases have occurred in patients treated with
SKYCLARYS. Liver function tests will be performed prior to initiating SKYCLARYS, every month for
the first 3 months of treatment, and periodically thereafter as needed [see Warnings and Precautions
(5.1)].
Fluid Overload
Inform patients that elevations in BNP, a marker of cardiac function, have occurred in patients treated
with SKYCLARYS. BNP will be performed prior to initiating SKYCLARYS and if signs and symptoms
of fluid overload occur, such as sudden weight gain, peripheral edema, palpitations, and shortness of
breath. Advise patients to contact their healthcare provider if signs and symptoms of fluid overload
develop [see Warnings and Precautions (5.2)].
Lipid Abnormalities
Inform patients that treatment with SKYCLARYS has been associated with increases in LDL
cholesterol and decreases in HDL cholesterol. Cholesterol will be assessed prior to starting
SKYCLARYS and monitored periodically during treatment [see Warnings and Precautions (5.3)].
Drug Interactions
Advise patients to discuss all medications they are taking, including other prescription medications,
non-prescription medications, or herbal products (e.g., St. John’s Wort) with their healthcare provider
[see Drug Interactions (7)].
Pregnancy
Advise women to notify their healthcare provider if they become pregnant or intend to become
pregnant during SKYCLARYS therapy. Inform patients that there is a pregnancy exposure registry
Reference ID: 5500338
that monitors pregnancy outcomes in women exposed to SKYCLARYS during pregnancy [see Use in
Specific Populations (8.1)].
Females of Reproductive Potential
Counsel females using hormonal contraceptives to use an alternative contraceptive method (e.g.,
non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during
concomitant use and for 28 days after discontinuation of SKYCLARYS [see Drug Interactions (7.2)
and Use in Specific Populations (8.3)].
Administration
Advise patients to take SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after
eating [see Dosage and Administration (2.2)].
Advise patients to swallow SKYCLARYS capsules whole or to open the capsules and sprinkle the
entire contents of both halves onto 2 tablespoons (30 mL) of applesauce, then stir the mixture. If
sprinkled, advise patients to swallow the drug/applesauce mixture immediately and not to store for
future use. Do not crush or chew the capsules. Inform patients that the contents of the SKYCLARYS
capsules should not be mixed with milk or orange juice. Advise patients to not administer
SKYCLARYS by an enteral feeding tube [see Dosage and Administration (2.2)].
Advise patients that if a dose of SKYCLARYS is missed to not to double their dose or take more than
the prescribed dose [see Dosage and Administration (2.3)].
Advise patients to avoid grapefruit juice and grapefruit while they are taking SKYCLARYS [see Drug
Interactions (7.1)].
59564-03
Manufactured for Biogen U.S. Corporation, Cambridge, MA
© Biogen 2024
All rights reserved
Reference ID: 5500338
PATIENT INFORMATION
SKYCLARYS® (skye klar’ is)
(omaveloxolone)
capsules, for oral use
What is SKYCLARYS?
SKYCLARYS is used for the treatment of Friedreich's ataxia in adults and children aged 16 years and
older.
It is not known if SKYCLARYS is safe and effective for use in children younger than 16 years of age.
Before taking SKYCLARYS, tell your healthcare provider about all of your medical conditions,
including if you:
• have liver problems.
• have a history of heart problems, including heart failure.
• have a high level of fat in your blood (high blood cholesterol).
• are pregnant or plan to become pregnant.
o It is not known if SKYCLARYS will harm your unborn baby.
o Women who use hormonal birth control should use another form of birth control such as a non-
hormonal intrauterine system or an extra non-hormonal birth control such as condoms while
using SKYCLARYS and for 28 days after stopping SKYCLARYS.
o Pregnancy exposure registry: There is a pregnancy registry for women who are pregnant and are
taking SKYCLARYS. The purpose of this registry is to collect information about the health of you
and your baby. Your healthcare provider can enroll you or you may enroll yourself by calling 1-
866-609-1785 or by sending an email to SkyclarysPregnancySurveillance@ppd.com.
• are breastfeeding or plan to breastfeed. It is not known if SKYCLARYS passes into your breast milk.
Talk to your healthcare provider about the best way to feed your baby if you take SKYCLARYS.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements such as St. John’s Wort.
Taking SKYCLARYS with other medicines can cause serious side effects.
SKYCLARYS may affect the way other medicines work, and other medicines may affect how
SKYCLARYS works.
Know the medicines you take. Keep a list of them to show to your healthcare provider and
pharmacist when you get a new medicine.
How should I take SKYCLARYS?
• Take SKYCLARYS exactly as your healthcare provider tells you to take it.
• Take SKYCLARYS capsules on an empty stomach, at least 1 hour before or 2 hours after eating.
• Swallow SKYCLARYS capsules whole. Do not crush or chew.
• If SKYCLARYS capsules cannot be swallowed whole, the capsules may be opened and the entire
contents of both halves sprinkled onto 2 tablespoonfuls (30 mL) of applesauce.
o Stir the mixture.
o Swallow all the mixture of medicine and applesauce right away. Do not store the mixture of
medicine and applesauce to use at a later time.
o The contents of the SKYCLARYS capsules should not be mixed with milk or orange juice.
o Do not administer SKYCLARYS by an enteral feeding tube.
• If you miss a dose, then you should skip the missed dose and take the next dose at the regular time
the next day. Do not double your next dose or take more than the prescribed dose.
What should I avoid while taking SKYCLARYS?
Do not drink grapefruit juice or eat grapefruit. These may change the amount of SKYCLARYS in your
blood.
What are the possible side effects of SKYCLARYS?
SKYCLARYS may cause serious side effects, including:
• increase in blood liver enzymes. Some people taking SKYCLARYS have had an increase in the
level of liver enzymes in their blood. Your healthcare provider will do liver function tests
o
before you start taking SKYCLARYS
Reference ID: 5500338
o
every month for the first 3 months after starting your treatment with SKYCLARYS
o
during certain times as needed while taking SKYCLARYS
If your liver enzymes increase, your healthcare provider may change your dose during treatment, stop
treatment for some time, or completely stop treatment with SKYCLARYS.
• increase in a blood protein called B-Type Natriuretic Peptide (BNP). BNP tells how well your
heart is working. Your healthcare provider will check your BNP levels before your treatment with
SKYCLARYS. Tell your healthcare provider if you have signs and symptoms of your heart not
working well such as too much fluid in your body (fluid overload). Signs and symptoms may include:
o sudden weight gain (3 pounds or more of weight gain in 1 day, or 5 pounds or more of weight
gain in 1 week)
o swelling in your arms, hands, legs, or feet (peripheral edema)
o fast heartbeat (palpitations)
o shortness of breath
If you have symptoms of fluid overload that is considered a side effect of SKYCLARYS, your healthcare
provider may stop treatment with SKYCLARYS.
• changes in cholesterol levels. Increases in low density lipoprotein cholesterol (LDL-C) or bad
cholesterol and decreases in high density lipoprotein cholesterol (HDL-C) or good cholesterol have
happened during treatment with SKYCLARYS.
Your healthcare provider will check your cholesterol levels before and during your treatment with
SKYCLARYS.
The most common side effects of SKYCLARYS include:
• increased liver enzymes (ALT/AST)
• headache
• nausea
• stomach pain
• tiredness
• diarrhea
• muscle pain
These are not all the possible side effects of SKYCLARYS.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA-1088.
How should I store SKYCLARYS?
• Store SKYCLARYS at room temperature between 68°F to 77°F (20°C to 25°C)
Keep SKYCLARYS and all medicines out of the reach of children.
General information about the safe and effective use of SKYCLARYS.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use SKYCLARYS for a condition for which it was not prescribed. Do not give
SKYCLARYS to other people, even if they have the same symptoms you have. It may harm them. You
can ask your healthcare provider or pharmacist for information about SKYCLARYS that is written for
health professionals.
What are the ingredients in SKYCLARYS?
Active ingredient: omaveloxolone
Inactive ingredients: croscarmellose sodium, magnesium stearate, pregelatinized starch, silicified
microcrystalline cellulose. The hard capsule shells contain FD&C Blue #1, ferric oxide yellow,
hypromellose, titanium dioxide, and white edible ink.
Manufactured for Biogen U.S. Corporation, Cambridge, MA
© Biogen 2024
All rights reserved
For more information about SKYCLARYS®, go to www.SKYCLARYS.com or call Biogen.at 1-844-987-3224.
This Patient Information has been approved by the U.S. Food and Drug Administration Approved: 12/2024
Reference ID: 5500338
| custom-source | 2025-02-12T15:48:03.909598 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216718s008s009lbl.pdf', 'application_number': 216718, 'submission_type': 'SUPPL ', 'submission_number': 8} |
80,696 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SKYCLARYS safely and effectively. See full prescribing
information for SKYCLARYS.
SKYCLARYS® (omaveloxolone) capsules, for oral use
Initial U.S. Approval: 2023
-----------------------------RECENT MAJOR CHANGES-------------------------
Dosage and Administration (2.2)
12/2024
-----------------------------INDICATIONS AND USAGE---------------------------
SKYCLARYS is indicated for the treatment of Friedreich’s ataxia in
adults and adolescents aged 16 years and older. (1)
------------------------DOSAGE AND ADMINISTRATION-----------------------
• Obtain alanine aminotransferase (ALT), aspartate aminotransferase
(AST), bilirubin, B-type natriuretic peptide (BNP), and lipid
parameters prior to initiating SKYCLARYS and during treatment.
(2.1, 5.1, 5.2, 5.3)
• Recommended dosage is 150 mg (3 capsules) taken orally once
daily. (2.2)
• Administer SKYCLARYS on an empty stomach, at least 1 hour
before or 2 hours after eating. (2.2)
• Swallow SKYCLARYS capsules whole or open and sprinkle the
entire contents of both halves of the capsule onto applesauce and
mix. Do not crush or chew capsules. (2.2)
• Moderate and Severe Hepatic Impairment: The recommended
dosage of SKYCLARYS is 100 mg once daily for patients with
moderate hepatic impairment. If adverse reactions emerge, further
reduce the dosage to 50 mg once daily. Avoid use in patients with
severe hepatic impairment. (2.5, 8.6, 12.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Capsules: 50 mg (3)
-------------------------------CONTRAINDICATIONS-------------------------------
None. (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
• Elevation of Aminotransferases: Monitor ALT, AST, and total
bilirubin prior to initiation, every month for the first 3 months of
treatment, and periodically thereafter. (2.1, 5.1)
• Elevation of B-type Natriuretic Peptide (BNP): Advise patients of
signs and symptoms of fluid overload. (2.1, 5.2)
• Lipid Abnormalities: Monitor cholesterol periodically during
treatment. (2.1, 5.3)
-------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions (incidence ≥20% and greater than
placebo) are elevated liver enzymes (AST/ALT), headache, nausea,
abdominal pain, fatigue, diarrhea, and musculoskeletal pain. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Biogen at
1-844-987-3224- or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS--------------------------------
• Moderate or Strong CYP3A4 Inhibitors: Avoid concomitant use.
Consider SKYCLARYS dosage reduction with monitoring if use is
unavoidable. (2.4, 7.1)
• Moderate or Strong CYP3A4 Inducers: Avoid concomitant use. (7.1)
----------------------------USE IN SPECIFIC POPULATIONS-------------------
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Testing Before Initiating SKYCLARYS and
Monitoring to Assess Safety
2.2 Recommended Dosage
2.3 Missed Doses
2.4 Recommendations for Concomitant Use with Strong or
Moderate CYP3A4 Inhibitors and Inducers
2.5 Recommended Dosage for Patients with Hepatic Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Elevation of Aminotransferases
5.2 Elevation of B-Type Natriuretic Peptide
5.3 Lipid Abnormalities
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on SKYCLARYS
7.2 Effect of SKYCLARYS on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 5500338
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
SKYCLARYS is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged
16 years and older.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Testing Before Initiating SKYCLARYS and Monitoring to Assess Safety
Obtain ALT, AST, bilirubin, BNP, and lipid parameters prior to initiating SKYCLARYS and during
treatment [see Warnings and Precautions (5.1, 5.2, 5.3)].
2.2 Recommended Dosage
The recommended dosage of SKYCLARYS is 150 mg (3 capsules) taken orally once daily.
• Administer SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after eating
[see Clinical Pharmacology (12.3)].
• Swallow SKYCLARYS capsules whole. Do not crush or chew.
• For patients who are unable to swallow whole capsules:
o SKYCLARYS capsules may be opened and the entire contents of both halves of the
capsule sprinkled onto 2 tablespoons (30 mL) of applesauce [see Clinical Pharmacology
(12.3)].
o Stir the mixture until homogenous.
o Swallow all the drug/applesauce mixture immediately.
o Do not store the mixture for future use.
o Contents of the SKYCLARYS capsules should not be mixed with milk or orange juice.
o Not for enteral feeding tube administration.
2.3 Missed Doses
If a dose of SKYCLARYS is missed, take the next dose at its scheduled time the following day. A
double dose should not be taken to make up for a missed dose.
2.4 Recommendations for Concomitant Use with Strong or Moderate CYP3A4 Inhibitors and
Inducers
The recommended dosage for concomitant use of SKYCLARYS with cytochrome P450 (CYP) 3A4
inhibitors and inducers are described in Table 1 [see Drug Interactions (7.1) and Clinical
Pharmacology (12.3)].
Reference ID: 5500338
Table 1: Recommended Dosage of SKYCLARYS with Concomitant Use of CYP3A4 Inhibitors
and Inducers
Concomitant Drug Class
Dosage
Strong CYP3A4 inhibitor
Recommended to avoid concomitant use.
If coadministration cannot be avoided:
• Reduce the dosage of SKYCLARYS to 50 mg
once daily with close monitoring for adverse
reactions.
• If adverse reactions emerge, coadministration
with strong CYP3A4 inhibitors should be
discontinued.
Moderate CYP3A4 inhibitor
Recommended to avoid concomitant use.
If coadministration cannot be avoided:
• Reduce the dosage of SKYCLARYS to 100
mg once daily with close monitoring for
adverse reactions.
• If adverse reactions emerge, further reduce
the dosage of SKYCLARYS to 50 mg once
daily.
Strong or Moderate CYP3A4 inducer
Recommended to avoid concomitant use.
2.5 Recommended Dosage for Patients with Hepatic Impairment
The recommended dosage for patients with hepatic impairment are described in Table 2 [see Use in
Specific Populations (8.6)].
Table 2: Recommended Dosage in Patients with Hepatic Impairment
Impairment Classification (Child-Pugh)
Dosage
Severe (Child-Pugh Class C)
Avoid use
Moderate (Child-Pugh Class B)
• 100 mg once daily with close monitoring for
adverse reactions
• Consider lowering to 50 mg once daily if
adverse reactions emerge
Mild (Child-Pugh Class A)
150 mg once daily
Reference ID: 5500338
3 DOSAGE FORMS AND STRENGTHS
SKYCLARYS capsules contain 50 mg of omaveloxolone, and are supplied as opaque hard capsules
having a light green body and blue cap, imprinted with “RTA 408” in white ink on the body and “50” in
white ink on the cap.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Elevation of Aminotransferases
Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (ALT and AST). In
Study 1 [see Clinical Studies (14)], the incidence of elevations of ALT or AST above 5 times and 3
times the upper limit of normal (ULN) was 16% and 31%, respectively, in patients treated with
SKYCLARYS. There were no cases of concomitant elevation of transaminases and total bilirubin
observed in Study 1. Maximum increases in ALT and AST occurred within 12 weeks after starting
SKYCLARYS. Increases in serum aminotransferases were generally asymptomatic and reversible
following discontinuation of SKYCLARYS. Patients with clinically significant liver disease were
excluded from Study 1.
Monitor ALT, AST, and total bilirubin prior to initiation of SKYCLARYS, every month for the first 3
months of treatment, and periodically thereafter. If transaminases increase to levels greater than 5
times the ULN, or greater than 3 times the ULN with evidence of liver dysfunction (e.g., elevated
bilirubin), immediately discontinue SKYCLARYS and repeat liver function tests as soon as possible. If
transaminase levels stabilize or resolve, SKYCLARYS may be reinitiated with an appropriate
increased frequency of monitoring of liver function [see Adverse Reactions (6.1) and Use in Specific
Populations (8.6)].
5.2 Elevation of B-Type Natriuretic Peptide
Treatment with SKYCLARYS can cause an increase in BNP, a marker of cardiac function. In Study 1,
a total of 14% of patients treated with SKYCLARYS had an increase from baseline in BNP and a BNP
above the ULN (100 pg/mL), compared to 4% of patients who received placebo. The incidence of
elevation of BNP above 200 pg/mL was 4% in patients treated with SKYCLARYS. Cardiomyopathy
and cardiac failure are common in patients with Friedreich’s ataxia. Patients were excluded from
Study 1 if they had BNP levels > 200 pg/mL prior to study entry, or a history of clinically significant
left-sided heart disease and/or clinically significant cardiac disease, with the exception of mild to
moderate cardiomyopathy associated with Friedreich’s ataxia [see Adverse Reactions (6.1)]. Whether
the elevations in BNP in Study 1 are related to SKYCLARYS or cardiac disease associated with
Friedreich’s ataxia is unclear.
Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function.
Check BNP prior to initiation of SKYCLARYS. Monitor patients for the signs and symptoms of fluid
overload, such as sudden weight gain (3 pounds or more of weight gain in one day, or 5 pounds or
Reference ID: 5500338
more of weight gain in a week), peripheral edema, palpitations, and shortness of breath. If signs and
symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac
function, and manage appropriately. Management of fluid overload and heart failure may require
discontinuation of SKYCLARYS.
5.3 Lipid Abnormalities
Treatment with SKYCLARYS can cause changes in cholesterol. In Study 1, 29% of patients treated
with SKYCLARYS reported elevated cholesterol above ULN at one or more time points. Mean
increases were observed within 2 weeks of initiation of SKYCLARYS and returned to baseline within
4 weeks of discontinuing treatment. A total of 16% of patients treated with SKYCLARYS had an
increase in low-density lipoprotein cholesterol (LDL-C) from baseline, compared to 8% of patients
who received placebo. The mean increase in LDL-C for all SKYCLARYS-treated patients was 23.5
mg/dL at 48 weeks. A total of 6% of patients treated with SKYCLARYS had decreases in high-density
lipoprotein cholesterol (HDL-C) from baseline compared to 4% of patients who received placebo. The
mean decrease in HDL-C for all SKYCLARYS-treated patients was 5.3 mg/dL at 48 weeks.
Assess lipid parameters prior to initiation of SKYCLARYS and monitor periodically during treatment.
Manage lipid abnormalities according to clinical guidelines.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described in greater detail in other labeling
sections:
• Elevation of aminotransferases [see Warnings and Precautions (5.1)]
• Elevation of BNP [see Warnings and Precautions (5.2)]
• Lipid abnormalities [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of
another drug and may not reflect the rates observed in clinical practice.
The safety of SKYCLARYS 150 mg once daily has been evaluated in 165 patients with Friedreich’s
ataxia, including 137 patients exposed for at least 48 weeks, and 125 patients exposed for at least 96
weeks.
The most common adverse reactions in Study 1 (≥20% and greater than placebo) were elevated liver
enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.
Table 3 shows the adverse reactions that occurred in 10% or more of patients treated with
SKYCLARYS and greater than placebo.
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Table 3:
Adverse Reactions Reported in 10% or More of Patients Treated with
SKYCLARYS and Greater than Placebo (Study 1)
Adverse Reactions
SKYCLARYS
150 mg
(N = 51)
%
Placebo
(N = 52)
%
Elevated liver enzymes (AST/ALT)
37
2
Headache
37
25
Nausea
33
13
Abdominal pain
29
6
Fatigue
24
14
Diarrhea
20
10
Musculoskeletal pain
20
15
Oropharyngeal pain
18
6
Influenza
16
6
Vomiting
16
12
Muscle spasms
14
6
Back pain
13
8
Decreased appetite
12
4
Rash
10
4
Laboratory Abnormalities
In addition to elevated liver enzymes, additional laboratory abnormalities include elevation of BNP
and lipid abnormalities [see Warnings and Precautions (5.1, 5.2, 5.3)].
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of SKYCLARYS.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: hypersensitivity (urticaria, rash)
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on SKYCLARYS
CYP3A4 Inhibitors
Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong
CYP3A4 inhibitors is expected to result in clinically significant increased exposure of omaveloxolone
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[see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions. Avoid
concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors. If use cannot be
avoided, dosage modifications are recommended [see Dosage and Administration (2.4)].
CYP3A4 Inducers
Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong
CYP3A4 inducers is expected to result in clinically significant decreased exposure of omaveloxolone
[see Clinical Pharmacology (12.3)], which may reduce the effectiveness of SKYCLARYS. Avoid
concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers.
7.2 Effect of SKYCLARYS on Other Drugs
CYP3A4 and CYP2C8 Substrates
Omaveloxolone is a weak inducer of CYP3A4 and CYP2C8. Concomitant use with SKYCLARYS can
reduce the exposure of CYP3A4 and CYP2C8 substrates which may reduce the activity of these
substrates [see Clinical Pharmacology (12.3)]. Refer to the prescribing information of substrates of
CYP3A4 and CYP2C8 for dosing instructions if used concomitantly with SKYCLARYS and monitor for
lack of efficacy of the concomitant treatment.
Hormonal Contraceptives
Omaveloxolone is a weak CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use with
SKYCLARYS may reduce the efficacy of hormonal contraceptives. Advise patients to avoid
concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and
progestin only pills [see Use in Specific Populations (8.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
SKYCLARYS during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or
pregnant women may register themselves in the program by calling 1-866-609-1785 or by sending an
email to SkyclarysPregnancySurveillance@ppd.com.
Risk Summary
There are no adequate data on the developmental risks associated with the use of SKYCLARYS in
pregnant women. In animal studies, administration of omaveloxolone during pregnancy or throughout
pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and
growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at
plasma exposures similar to or less than exposures in humans (see Animal Data). In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically
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recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major
birth defects and miscarriage for the indicated population is unknown.
Data
Animal Data
Oral administration of omaveloxolone (0, 1, 3, or 10 mg/kg/day) to pregnant rats throughout
organogenesis resulted in no adverse effects on embryofetal development; however, in a dose range-
finding study, oral administration of omaveloxolone at doses up to 30 mg/kg/day to pregnant rats
throughout organogenesis produced increases in post-implantation loss and resorptions, resulting in
a decrease in viable fetuses, and reduced fetal weight at the highest dose tested. At the highest dose
tested in the pivotal study (10 mg/kg/day), plasma exposure (AUC) was approximately 5 times that in
humans at the recommended human dose (RHD) of 150 mg/day.
Oral administration of omaveloxolone (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits throughout
organogenesis resulted in increased embryofetal mortality and skeletal variations and reduced fetal
weight at the highest dose tested, which was associated with maternal toxicity. At the no-effect dose
for adverse effects on embryofetal development (10 mg/kg/day), plasma exposure was less than that
in humans at the RHD.
Oral administration of omaveloxolone (0, 1, 3, or 10 mg/kg/day) to rats throughout pregnancy and
lactation resulted in an increase in stillbirths and impaired neurobehavioral function (increased
locomotor activity and learning and memory deficits) in offspring at all doses, reduced body weight in
offspring at all but the lowest dose tested, and delayed sexual maturation (males), increased
postnatal mortality, and impaired reproductive performance in offspring at the highest dose tested. A
no-effect dose for adverse effects on pre- and postnatal development was not identified. Plasma
exposure (AUC) at the lowest dose tested was less than that in humans at the RHD.
8.2 Lactation
Risk Summary
There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on
milk production and the breastfed infant are unknown. Omaveloxolone was excreted in the milk of
lactating rats following oral administration. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for SKYCLARYS and any potential
adverse effects on the breastfed infant from SKYCLARYS or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
SKYCLARYS may decrease the efficacy of hormonal contraceptives [see Drug Interactions (7.2) and
Clinical Pharmacology (12.3)]. Advise patients to avoid concomitant use with combined hormonal
contraceptives (e.g., pill, patch, ring), implants, and progestin only pills. Counsel females using
hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonal intrauterine
system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 28
days after discontinuation of SKYCLARYS.
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8.4 Pediatric Use
The safety and effectiveness of SKYCLARYS for the treatment of Friedreich's ataxia have been
established in pediatric patients aged 16 years and older. Use of SKYCLARYS for this indication is
supported by evidence from one adequate and well-controlled study (Study 1) in adults and in
pediatric patients aged 16 years and older [see Clinical Studies (14)].
Safety and effectiveness of SKYCLARYS have not been established in pediatric patients less than 16
years of age.
8.5 Geriatric Use
Clinical studies of SKYCLARYS in Friedreich’s ataxia did not include patients aged 65 and over. No
data are available to determine whether they respond differently than younger adult patients.
8.6 Hepatic Impairment
Omaveloxolone plasma exposure is increased in patients with moderate or severe hepatic
impairment (Child-Pugh Class B and C) [see Clinical Pharmacology (12.3)]. Avoid treatment with
SKYCLARYS in patients with severe hepatic impairment, including those who develop severe hepatic
impairment. If hepatic function improves to moderate impairment, mild impairment, or normal function,
initiation of SKYCLARYS treatment at the approved recommended dosage may be considered. For
patients with moderate hepatic impairment, a reduced dosage is recommended with close monitoring
for adverse reactions [see Dosage and Administration (2.5)]. For patients with mild hepatic
impairment (Child-Pugh Class A), no dose adjustments are recommended.
11 DESCRIPTION
SKYCLARYS contains omaveloxolone in immediate release capsules for oral administration available
in a 50 mg strength. The chemical name of omaveloxolone is N-(2-cyano-3,12-dioxo-28-noroleana-
1,9(11)-dien-17-yl)-2,2-difluoro-propanamide. Omaveloxolone is a white to off-white amorphous solid.
The molecular formula is C33H44F2N2O3. Molecular weight is 554.72 g/mol. The chemical structure is:
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Omaveloxolone has a pKa of 7.26 and is practically insoluble in water across the physiological pH
range. Capsule contents include the following inactive ingredients: croscarmellose sodium,
magnesium stearate, pregelatinized starch, and silicified microcrystalline cellulose. The hard capsule
shells contain FD&C Blue #1, ferric oxide yellow, hypromellose, titanium dioxide, and white ink.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with
Friedreich’s ataxia is unknown. Omaveloxolone has been shown to activate the Nuclear factor
(erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2
pathway is involved in the cellular response to oxidative stress.
12.2 Pharmacodynamics
Cardiac Electrophysiology
Clinically significant QTc interval prolongation was not observed in healthy subjects with
administration of SKYCLARYS at a supratherapeutic dose of 450 mg (3 times the recommended
dosage) with a high fat meal.
12.3 Pharmacokinetics
Absorption
The median (range) time to achieve peak plasma concentration (Tmax) was 7 to 14 (1 to 24) hours.
The total plasma omaveloxolone exposure based on area under the concentration-time curve (AUC)
increased in a dose-dependent and dose proportional manner over a dose range of 50 mg (0.33
times the recommended dosage) to 150 mg, but maximum omaveloxolone plasma concentration
(Cmax) increased in a less than dose proportional manner over the dose range in healthy fasted
subjects.
Effect of Food
Omaveloxolone Cmax and AUC0-inf increased by approximately 350% and 15%, respectively, with a
high-fat meal (800-1000 calories, approximately 150, 250, and 500 to 600 calories from protein,
carbohydrate, and fat, respectively) compared to fasted conditions [see Dosage and Administration
(2.2)].
Omaveloxolone Cmax and AUC0-inf were similar when capsule contents were sprinkled on applesauce
or when administered as intact capsules. The median Tmax of omaveloxolone was shortened from
approximately 10 to 6 hours when sprinkled on applesauce [see Dosage and Administration (2.2)].
Distribution
The mean apparent volume of distribution of omaveloxolone is 7361 L (105 L/kg for a 70 kg person).
Protein binding of omaveloxolone is 97%.
Elimination
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The mean (range) terminal half-life of omaveloxolone is 57 hours (32 to 90 hours). The mean
apparent plasma clearance of omaveloxolone is 109 L/hr.
Metabolism
Omaveloxolone is primarily metabolized by CYP3A with minor metabolism by CYP2C8 and CYP2J2.
Excretion
Following administration of a single oral dose of radiolabeled omaveloxolone 150 mg to healthy
subjects, approximately 92% of the dose was recovered in feces (approximately 91% within 96 hours
after administration) and 0.1% in urine.
Specific Populations
There were no clinically significant differences in the pharmacokinetics of omaveloxolone based on
age (16 to 71 years of age), sex, race, or body weight (41 to 128 kg).
Patients with Renal Impairment
Population pharmacokinetic analysis demonstrated that estimated glomerular filtration rate (eGFR)
values ≥ 63 mL/min/1.73 m2 did not have a significant effect on the pharmacokinetics of
omaveloxolone. Therefore, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m2) is not expected
to have a significant effect on the pharmacokinetics of omaveloxolone. The effect of moderate or
severe renal impairment (eGFR ≤59 mL/min/1.73m2) on the pharmacokinetics of omaveloxolone is
unknown.
Patients with Hepatic Impairment
There were no clinically significant differences in the pharmacokinetics of omaveloxolone in subjects
with mild hepatic impairment (Child-Pugh Class A). In subjects with moderate and severe hepatic
impairment (Child-Pugh Class B and C), omaveloxolone clearance was reduced, resulting in higher
plasma exposure of omaveloxolone. The omaveloxolone AUC increased up to 1.65-fold and Cmax
increased up to 1.83-fold in subjects with moderate hepatic impairment. The omaveloxolone AUC
increased up to 2.17-fold in subjects with severe hepatic impairment; however, this change was
variable [see Use in Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
Strong CYP3A Inhibitors: After single dose administration, omaveloxolone Cmax increased 3-fold and
AUC 4-fold following concomitant use with itraconazole (strong CYP3A inhibitor) [see Drug
Interactions (7.1)].
Moderate CYP3A Inhibitors: After single dose administration, omaveloxolone Cmax and AUC
increased approximately 1.25-fold following concomitant use with verapamil (moderate CYP3A4 and
P-gp inhibitor) [see Drug Interactions (7.1)].
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Moderate CYP3A Inducers: After single dose administration, omaveloxolone Cmax and AUC
decreased 38% and 48%, respectively, following concomitant use with efavirenz (moderate CYP3A4
inducer) [see Drug Interactions (7.1)].
Certain CYP450 Enzymes or Transporter Substrates: Omaveloxolone decreased the AUC of
midazolam (CYP3A4 substrate) by approximately 45%, AUC of repaglinide (CYP2C8 substrate) by
approximately 35%, and AUC of rosuvastatin (BCRP and OATP1B1 substrate) by approximately 30%
[see Drug Interactions (7.2)]. There were no clinically significant differences in the pharmacokinetics
of digoxin (P-gp substrate) or metformin [(organic cation transporter (OCT)1 substrate] when co-
administered with omaveloxolone.
Other Drugs: No clinically significant differences in the pharmacokinetics of omaveloxolone are
expected following concomitant use with weak CYP3A4 inhibitors or strong CYP2C8 inhibitors.
In Vitro Studies
CYP Enzymes: Omaveloxolone is an inducer of CYP3A4 and CYP2C19. Omaveloxolone is not an
inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Omaveloxolone is not an inducer
of CYP1A2, CYP2B6, CYP2C8, and CYP2C9.
Drug Transporters: Omaveloxolone is not an inhibitor of BCRP, BSEP, OAT3, OATP1B1, OATP1B3,
OCT2, MATE1, and MATE2-K. Omaveloxolone inhibited the renal transporter OAT1.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In a 26-week carcinogenicity study in transgenic (Tg.rasH2) mice, oral administration of
omaveloxolone (0, 5, 10, or 30 mg/kg/day in males; 0, 20, 50, or 100 mg/kg/day in females) resulted
in no increase in tumors.
Mutagenesis
Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a
chromosomal aberration assay in human peripheral blood lymphocytes but negative in the in vivo rat
micronucleus assay and the in vitro comet assay.
Impairment of Fertility
Oral administration of omaveloxolone (0, 1, 3, and 10 mg/kg/day) to male and female rats prior to and
during mating and continuing in females to gestation day 7 produced an increase in pre-and post-
implantation loss and resorptions, resulting in a decrease in viable embryos at the highest dose
tested. The no-effect dose (3 mg/kg/day) for adverse effects on fertility and reproductive function was
associated with plasma exposures (AUC) approximately 2 times that in humans at the recommended
human dose of 150 mg/day.
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14 CLINICAL STUDIES
The efficacy of SKYCLARYS was evaluated in a 48-week, randomized, double-blind, placebo-
controlled study in patients 16 to 40 years of age with Friedreich’s Ataxia (Study 1; NCT02255435).
A total of 103 patients were randomized (1:1) to receive SKYCLARYS 150 mg once daily (n=51) or
placebo (n=52).
Enrolled patients had to have a stable modified Friedreich’s Ataxia Rating Scale (mFARS) score
between 20 and 80, be able to complete maximal exercise testing, and have a left ventricular ejection
fraction of at least 40%. In Study 1, 53% of enrolled patients were male, 97% were White, and the
mean age was 24 years at study entry. Patients with or without pes cavus were included in Study 1.
Pes cavus was defined as having a loss of lateral support and was determined if light from a flashlight
could be seen under the patient’s arch when barefoot and weight bearing.
The prespecified primary analysis was the change from baseline in the mFARS score compared to
placebo at Week 48 in the Full Analysis Population of patients without pes cavus (n=82). The mFARS
is a clinical assessment tool to assess patient function, which consists of 4 domains to evaluate
bulbar function, upper limb coordination, lower limb coordination, and upright stability. The mFARS
has a maximum score of 99, with a lower score on the mFARS signifying lesser physical impairment.
Treatment with SKYCLARYS resulted in statistically significant lower mFARS scores (less
impairment) relative to placebo (see Table 4) at Week 48.
Table 4: Primary Analysis in Full Analysis Population: mFARS Least Squares (LS) Mean
Change from Baseline at Week 48
Mean (SD)
Baseline mFARS
Total Score
LS Mean
Change from
Baseline at Week
48
Treatment difference
SKYCLARYS-
placebo (95% CI)
p-value
SKYCLARYS
(n = 40)
40.95 (10.39)
-1.56
-2.41
(-4.32, -0.51)
0.0138
Placebo
(n = 42)
38.78 (11.03)
0.85
SD = Standard Deviation; LS = Least Squares; CI = Confidence Interval
The All Randomized Population (N=103), which included all patients regardless of pes cavus status,
demonstrated similar results to the Full Analysis Population of lower mFARS scores in patients
treated with SKYCLARYS compared to placebo, with a nominally significant least squares mean
difference between treatment groups of ‑1.94 (95% CI: -3.71, -0.16, p=0.0331).
In a post hoc, propensity-matched analysis, lower mFARS scores were observed in patients treated
with SKYCLARYS after 3 years relative to a matched set of untreated patients from a natural history
study. These exploratory analyses should be interpreted cautiously given the limitations of data
collected outside of a controlled study, which may be subject to confounding.
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16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
SKYCLARYS (omaveloxolone) capsules, 50 mg, are supplied as opaque, hard capsules having a
light green body and blue cap imprinted with “RTA 408” in white ink on the body and “50” in white ink
on the cap. SKYCLARYS is supplied in high density polyethylene bottles that contain 90 capsules,
with a foil induction seal and child-resistant closure (NDC 64406-250-90).
16.2 Storage and Handling
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F to 86°F)
[see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Elevation of Aminotransferases
Inform patients that elevation in aminotransferases have occurred in patients treated with
SKYCLARYS. Liver function tests will be performed prior to initiating SKYCLARYS, every month for
the first 3 months of treatment, and periodically thereafter as needed [see Warnings and Precautions
(5.1)].
Fluid Overload
Inform patients that elevations in BNP, a marker of cardiac function, have occurred in patients treated
with SKYCLARYS. BNP will be performed prior to initiating SKYCLARYS and if signs and symptoms
of fluid overload occur, such as sudden weight gain, peripheral edema, palpitations, and shortness of
breath. Advise patients to contact their healthcare provider if signs and symptoms of fluid overload
develop [see Warnings and Precautions (5.2)].
Lipid Abnormalities
Inform patients that treatment with SKYCLARYS has been associated with increases in LDL
cholesterol and decreases in HDL cholesterol. Cholesterol will be assessed prior to starting
SKYCLARYS and monitored periodically during treatment [see Warnings and Precautions (5.3)].
Drug Interactions
Advise patients to discuss all medications they are taking, including other prescription medications,
non-prescription medications, or herbal products (e.g., St. John’s Wort) with their healthcare provider
[see Drug Interactions (7)].
Pregnancy
Advise women to notify their healthcare provider if they become pregnant or intend to become
pregnant during SKYCLARYS therapy. Inform patients that there is a pregnancy exposure registry
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that monitors pregnancy outcomes in women exposed to SKYCLARYS during pregnancy [see Use in
Specific Populations (8.1)].
Females of Reproductive Potential
Counsel females using hormonal contraceptives to use an alternative contraceptive method (e.g.,
non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during
concomitant use and for 28 days after discontinuation of SKYCLARYS [see Drug Interactions (7.2)
and Use in Specific Populations (8.3)].
Administration
Advise patients to take SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after
eating [see Dosage and Administration (2.2)].
Advise patients to swallow SKYCLARYS capsules whole or to open the capsules and sprinkle the
entire contents of both halves onto 2 tablespoons (30 mL) of applesauce, then stir the mixture. If
sprinkled, advise patients to swallow the drug/applesauce mixture immediately and not to store for
future use. Do not crush or chew the capsules. Inform patients that the contents of the SKYCLARYS
capsules should not be mixed with milk or orange juice. Advise patients to not administer
SKYCLARYS by an enteral feeding tube [see Dosage and Administration (2.2)].
Advise patients that if a dose of SKYCLARYS is missed to not to double their dose or take more than
the prescribed dose [see Dosage and Administration (2.3)].
Advise patients to avoid grapefruit juice and grapefruit while they are taking SKYCLARYS [see Drug
Interactions (7.1)].
59564-03
Manufactured for Biogen U.S. Corporation, Cambridge, MA
© Biogen 2024
All rights reserved
Reference ID: 5500338
PATIENT INFORMATION
SKYCLARYS® (skye klar’ is)
(omaveloxolone)
capsules, for oral use
What is SKYCLARYS?
SKYCLARYS is used for the treatment of Friedreich's ataxia in adults and children aged 16 years and
older.
It is not known if SKYCLARYS is safe and effective for use in children younger than 16 years of age.
Before taking SKYCLARYS, tell your healthcare provider about all of your medical conditions,
including if you:
• have liver problems.
• have a history of heart problems, including heart failure.
• have a high level of fat in your blood (high blood cholesterol).
• are pregnant or plan to become pregnant.
o It is not known if SKYCLARYS will harm your unborn baby.
o Women who use hormonal birth control should use another form of birth control such as a non-
hormonal intrauterine system or an extra non-hormonal birth control such as condoms while
using SKYCLARYS and for 28 days after stopping SKYCLARYS.
o Pregnancy exposure registry: There is a pregnancy registry for women who are pregnant and are
taking SKYCLARYS. The purpose of this registry is to collect information about the health of you
and your baby. Your healthcare provider can enroll you or you may enroll yourself by calling 1-
866-609-1785 or by sending an email to SkyclarysPregnancySurveillance@ppd.com.
• are breastfeeding or plan to breastfeed. It is not known if SKYCLARYS passes into your breast milk.
Talk to your healthcare provider about the best way to feed your baby if you take SKYCLARYS.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements such as St. John’s Wort.
Taking SKYCLARYS with other medicines can cause serious side effects.
SKYCLARYS may affect the way other medicines work, and other medicines may affect how
SKYCLARYS works.
Know the medicines you take. Keep a list of them to show to your healthcare provider and
pharmacist when you get a new medicine.
How should I take SKYCLARYS?
• Take SKYCLARYS exactly as your healthcare provider tells you to take it.
• Take SKYCLARYS capsules on an empty stomach, at least 1 hour before or 2 hours after eating.
• Swallow SKYCLARYS capsules whole. Do not crush or chew.
• If SKYCLARYS capsules cannot be swallowed whole, the capsules may be opened and the entire
contents of both halves sprinkled onto 2 tablespoonfuls (30 mL) of applesauce.
o Stir the mixture.
o Swallow all the mixture of medicine and applesauce right away. Do not store the mixture of
medicine and applesauce to use at a later time.
o The contents of the SKYCLARYS capsules should not be mixed with milk or orange juice.
o Do not administer SKYCLARYS by an enteral feeding tube.
• If you miss a dose, then you should skip the missed dose and take the next dose at the regular time
the next day. Do not double your next dose or take more than the prescribed dose.
What should I avoid while taking SKYCLARYS?
Do not drink grapefruit juice or eat grapefruit. These may change the amount of SKYCLARYS in your
blood.
What are the possible side effects of SKYCLARYS?
SKYCLARYS may cause serious side effects, including:
• increase in blood liver enzymes. Some people taking SKYCLARYS have had an increase in the
level of liver enzymes in their blood. Your healthcare provider will do liver function tests
o
before you start taking SKYCLARYS
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o
every month for the first 3 months after starting your treatment with SKYCLARYS
o
during certain times as needed while taking SKYCLARYS
If your liver enzymes increase, your healthcare provider may change your dose during treatment, stop
treatment for some time, or completely stop treatment with SKYCLARYS.
• increase in a blood protein called B-Type Natriuretic Peptide (BNP). BNP tells how well your
heart is working. Your healthcare provider will check your BNP levels before your treatment with
SKYCLARYS. Tell your healthcare provider if you have signs and symptoms of your heart not
working well such as too much fluid in your body (fluid overload). Signs and symptoms may include:
o sudden weight gain (3 pounds or more of weight gain in 1 day, or 5 pounds or more of weight
gain in 1 week)
o swelling in your arms, hands, legs, or feet (peripheral edema)
o fast heartbeat (palpitations)
o shortness of breath
If you have symptoms of fluid overload that is considered a side effect of SKYCLARYS, your healthcare
provider may stop treatment with SKYCLARYS.
• changes in cholesterol levels. Increases in low density lipoprotein cholesterol (LDL-C) or bad
cholesterol and decreases in high density lipoprotein cholesterol (HDL-C) or good cholesterol have
happened during treatment with SKYCLARYS.
Your healthcare provider will check your cholesterol levels before and during your treatment with
SKYCLARYS.
The most common side effects of SKYCLARYS include:
• increased liver enzymes (ALT/AST)
• headache
• nausea
• stomach pain
• tiredness
• diarrhea
• muscle pain
These are not all the possible side effects of SKYCLARYS.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA-1088.
How should I store SKYCLARYS?
• Store SKYCLARYS at room temperature between 68°F to 77°F (20°C to 25°C)
Keep SKYCLARYS and all medicines out of the reach of children.
General information about the safe and effective use of SKYCLARYS.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use SKYCLARYS for a condition for which it was not prescribed. Do not give
SKYCLARYS to other people, even if they have the same symptoms you have. It may harm them. You
can ask your healthcare provider or pharmacist for information about SKYCLARYS that is written for
health professionals.
What are the ingredients in SKYCLARYS?
Active ingredient: omaveloxolone
Inactive ingredients: croscarmellose sodium, magnesium stearate, pregelatinized starch, silicified
microcrystalline cellulose. The hard capsule shells contain FD&C Blue #1, ferric oxide yellow,
hypromellose, titanium dioxide, and white edible ink.
Manufactured for Biogen U.S. Corporation, Cambridge, MA
© Biogen 2024
All rights reserved
For more information about SKYCLARYS®, go to www.SKYCLARYS.com or call Biogen.at 1-844-987-3224.
This Patient Information has been approved by the U.S. Food and Drug Administration Approved: 12/2024
Reference ID: 5500338
| custom-source | 2025-02-12T15:48:03.939112 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216718s008s009lbl.pdf', 'application_number': 216718, 'submission_type': 'SUPPL ', 'submission_number': 9} |
80,698 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SYFOVRE safely and effectively. See full prescribing information for
SYFOVRE.
SYFOVRE ® (pegcetacoplan injection), for intravitreal use
Initial U.S. Approval: 2021
---------------------------RECENT MAJOR CHANGES --------------------------
Contraindications, Hypersensitivity (4.3)
12/2024
---------------------------INDICATIONS AND USAGE --------------------------
SYFOVRE is a complement inhibitor indicated for the treatment of
geographic atrophy (GA) secondary to age-related macular degeneration
(AMD). (1)
-----------------------DOSAGE AND ADMINISTRATION----------------------
The recommended dose for SYFOVRE is 15 mg (0.1 mL of 150 mg/mL
solution) administered by intravitreal injection to each affected eye once every
25 to 60 days. (2.2)
---------------------DOSAGE FORMS AND STRENGTHS --------------------
Injection: 150 mg/mL in a single-dose vial. (3)
------------------------------CONTRAINDICATIONS -----------------------------
• Ocular or Periocular Infections (4.1)
• Active Intraocular Inflammation (4.2)
• Hypersensitivity (4.3)
-----------------------WARNINGS AND PRECAUTIONS ----------------------
• Endophthalmitis and Retinal Detachments (5.1)
• Retinal Vasculitis and/or Retinal Vascular Occlusion (5.2)
• Neovascular AMD (5.3)
• Intraocular inflammation (5.4)
• Increased Intraocular Pressure (5.5)
------------------------------ADVERSE REACTIONS -----------------------------
Most common adverse reactions (incidence ≥5%) are ocular discomfort,
neovascular age-related macular degeneration, vitreous floaters, and
conjunctival hemorrhage. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Apellis
Pharmaceuticals, Inc. at 1-833-866-3346 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Information
2.2
Recommended Dosage
2.3
Preparation for Administration
2.4
Injection Procedure
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1
Ocular or Periocular Infections
4.2
Active Intraocular Inflammation
4.3
Hypersensitivity
5
WARNINGS AND PRECAUTIONS
5.1
Endophthalmitis and Retinal Detachments
5.2
Retinal Vasculitis and/or Retinal Vascular Occlusion
5.3
Neovascular AMD
5.4
Intraocular Inflammation
5.5
Increased Intraocular Pressure
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.6
Immunogenicity
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5500518
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
SYFOVRE is indicated for the treatment of geographic atrophy (GA) secondary to age-related macular
degeneration (AMD).
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
SYFOVRE must be administered by a qualified physician.
2.2 Recommended Dosage
The recommended dose for SYFOVRE is 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal
injection to each affected eye once every 25 to 60 days.
2.3 Preparation for Administration
Store SYFOVRE in the refrigerator between 2°C to 8°C (36°F to 46°F);
Keep the vial in the original carton to protect from light.
Remove the carton from the refrigerator. Keep the vial in the original
carton at room temperature 20°C to 25°C (68°F to 77°F), for at least
15 minutes prior to injection, but no longer than 8 hours. Fill the syringe
immediately prior to the injection.
Do not shake the vial.
The vial is for use in a single eye.
Reference ID: 5500518
Inspect the solution. It is a clear, colorless to light yellow aqueous solution.
Do not use if:
• particulates, cloudiness, or discoloration are visible,
• the vial shows signs of damage or tampering,
• or if the expiration date has passed
STEP 1
Gather the supplies needed:
• One SYFOVRE vial (included)
• One sterile 5-micron filter needle (not included)
• One sterile 1-mL Luer-lock syringe with a 0.1 mL dose mark (not included)
• One sterile ½ inch: 29-gauge thin-wall injection needle with Luer-lock hub or a 27-gauge needle with
Luer-lock hub (not included)
Note: Increased injection forces and/or increased injection time could be experienced if a smaller
diameter injection needle is used (e.g., 30-gauge)
• Alcohol swab (not included)
Use aseptic technique to carry out the following preparation steps:
STEP 2
Remove the flip-off cap from the vial (see Figure 1a) and clean the vial septum with an alcohol swab and wait
for the alcohol to dry out (see Figure 1b).
Figure 1a:
Figure 1b:
STEP 3
Attach the 5-micron filter needle onto a 1-mL Luer-lock syringe (see Figure 2) by twisting it onto the Luer-lock
syringe tip.
Reference ID: 5500518
Figure 2:
STEP 4
Push the filter needle into the center of the vial septum until the needle is submerged in the drug product to
prevent withdrawal of air (see Figure 3a). To withdraw the entire contents of the vial into the syringe, hold the
vial at a slightly inclined position. Withdraw the drug product slowly to prevent air bubbles. Continue to tilt the
vial during withdrawal keeping the bevel of the filter needle submerged in the liquid until all of the fluid is
withdrawn from the vial (see Figure 3b). *Do not tap the syringe to remove air bubbles. While maintaining the
filter needle within the vial, invert the syringe and move the plunger down and up until bubbles move to the top
(see Figure 3c).
Figure 3a:
Figure 3b:
Reference ID: 5500518
Figure 3c:
STEP 5
Using aseptic technique, disconnect the filter needle from the syringe and dispose of it.
Do not use the filter needle for injection.
STEP 6
Aseptically and firmly attach the injection needle onto the 1-mL Luer-lock syringe (see Figure 4).
Figure 4:
STEP 7
Check for air bubbles by holding the syringe with the needle pointing up. *Do not tap the syringe to remove air
bubbles.
If there are any air bubbles, remove the needle cap and with the needle end facing up gently advance the
plunger to the 0.1 mL dose mark (see Figure 5).
Only 0.1 mL (15 mg of SYFOVRE) should be administered to deliver a single dose. Any excess volume should
be disposed.
The syringe is ready for injection.
Reference ID: 5500518
Figure 5:
2.4 Injection Procedure
Only 0.1 mL (15 mg of SYFOVRE) should be administered to deliver a single dose. Any excess volume should
be disposed. Ensure that the injection is given immediately after the preparation of the dose.
Prior to the intravitreal injection, patients should be monitored for elevated intraocular pressure (IOP) using
tonometry [see Warnings and Precautions (5.4)]. If necessary, ocular hypotensive medication can be given to
lower the IOP.
The intravitreal injection procedure should be carried out under aseptic conditions, which includes the use of
surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate
anesthesia and a broad-spectrum topical microbicide to disinfect the periocular skin, eyelid, and ocular surface
should be administered prior to the injection.
Inject slowly until the rubber stopper reaches the end of the syringe to deliver the volume of 0.1 mL. Confirm
delivery of the full dose by checking that the rubber stopper has reached the end of the syringe barrel.
Immediately following the intravitreal injection, patients should be monitored for elevations in IOP. Additional
evaluation may include checking for perfusion of the optic nerve head and tonometry.
Following intravitreal injection patients should be instructed to report any symptoms suggestive of
endophthalmitis (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay [see Patient
Counseling Information (17)].
Each vial should only be used for the treatment of a single eye. If the fellow eye requires treatment, a new
sterile, vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection
needles should be changed before SYFOVRE administration. Repeat same procedure steps as above.
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.
3 DOSAGE FORMS AND STRENGTHS
Injection: 150 mg/mL, clear, colorless to light yellow aqueous solution in a single-dose vial for administration
of a single 0.1 mL dose.
4 CONTRAINDICATIONS
4.1 Ocular or Periocular Infections
SYFOVRE is contraindicated in patients with ocular or periocular infections [see Warnings and Precautions
(5.1)].
Reference ID: 5500518
4.2 Active Intraocular Inflammation
SYFOVRE is contraindicated in patients with active intraocular inflammation.
4.3 Hypersensitivity
SYFOVRE is contraindicated in patients with hypersensitivity to pegcetacoplan or to any of the
excipients in SYFOVRE. Systemic hypersensitivity reactions (e.g., anaphylaxis, rash, urticaria) have occurred
in patients treated with SYFOVRE [see Adverse Reactions (6.2)].
5 WARNINGS AND PRECAUTIONS
5.1 Endophthalmitis and Retinal Detachments
Intravitreal injections, including those with SYFOVRE, may be associated with endophthalmitis and retinal
detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must always be used when
administering SYFOVRE in order to minimize the risk of endophthalmitis [see Dosage and Administration
(2.4)]. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment
without delay and should be managed appropriately.
5.2 Retinal Vasculitis and/or Retinal Vascular Occlusion
Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have
been reported with the use of SYFOVRE [see Adverse Reactions (6.2)]. Cases may occur with the first dose of
SYFOVRE and may result in severe vision loss. Discontinue treatment with SYFOVRE in patients who develop
these events. Patients should be instructed to report any change in vision without delay.
5.3 Neovascular AMD
In clinical trials, use of SYFOVRE was associated with increased rates of neovascular (wet) AMD or choroidal
neovascularization (12% when administered monthly, 7% when administered every other month and 3% in the
control group) by Month 24. Patients receiving SYFOVRE should be monitored for signs of neovascular AMD.
In case anti-Vascular Endothelial Growth Factor (anti-VEGF) is required, it should be given separately from
SYFOVRE administration.
5.4 Intraocular Inflammation
In clinical trials, use of SYFOVRE was associated with episodes of intraocular inflammation including: vitritis,
vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, and anterior chamber flare. After inflammation
resolves patients may resume treatment with SYFOVRE.
5.5 Increased Intraocular Pressure
Acute increase in IOP may occur within minutes of any intravitreal injection, including with SYFOVRE.
Perfusion of the optic nerve head should be monitored following the injection and managed as needed [see
Dosage and Administration (2.4)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Ocular and periocular infections [see Contraindications (4.1)]
• Active intraocular inflammation [see Contraindications (4.2)]
• Hypersensitivity [see Contraindications (4.3)]
• Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)]
• Retinal Vasculitis and/or Retinal Vascular Occlusion [see Warnings and Precautions (5.2)]
• Neovascular AMD [see Warnings and Precautions (5.3)]
• Intraocular inflammation [see Warnings and Precautions (5.4)]
Reference ID: 5500518
• Increased intraocular pressure [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
A total of 839 patients with GA in two Phase 3 studies (OAKS and DERBY) were treated with intravitreal
SYFOVRE, 15 mg (0.1 mL of 150 mg/mL solution). Four hundred nineteen (419) of these patients were treated
in the affected eye monthly and 420 were treated in the affected eye every other month. Four hundred seventeen
(417) patients were assigned to sham.
The most common adverse reactions (≥5%) reported in patients receiving SYFOVRE were ocular discomfort,
neovascular age-related macular degeneration, vitreous floaters, and conjunctival hemorrhage.
Table 1: Adverse Reactions in Study Eye Reported in ≥2% of Patients Treated with SYFOVRE Through Month
24 in Studies OAKS and DERBY
Adverse Reactions
PM
(N = 419)
%
PEOM
(N = 420)
%
Sham Pooled
(N = 417)
%
Ocular discomfort*
13
10
11
Neovascular age-related macular
degeneration*
12
7
3
Vitreous floaters
10
7
1
Conjunctival hemorrhage
8
8
4
Vitreous detachment
4
6
3
Retinal hemorrhage
4
5
3
Punctate keratitis*
5
3
<1
Posterior capsule opacification
4
4
3
Intraocular inflammation*
4
2
<1
Intraocular pressure increased
2
3
<1
PM: SYFOVRE monthly; PEOM: SYFOVRE every other month
*The following reported terms were combined:
Ocular discomfort included: eye pain, eye irritation, foreign body sensation in eyes, ocular discomfort, abnormal sensation in eye
Neovascular age-related macular degeneration included: exudative age-related macular degeneration, choroidal neovascularization
Punctate keratitis included: punctate keratitis, keratitis
Intraocular inflammation included: vitritis, vitreal cells, iridocyclitis, uveitis, anterior chamber cells, iritis, anterior chamber flare
Endophthalmitis, retinal detachment, hyphema and retinal tears were reported in less than 1% of patients.
Optic ischemic neuropathy was reported in 1.7% of patients treated monthly, 0.2% of patients treated every
other month and 0.0% of patients assigned to sham. Deaths were reported in 6.7% of patients treated monthly,
3.6% of patients treated every other month and 3.8% of patients assigned to sham. The rates and causes of death
were consistent with the elderly study population.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of SYFOVRE. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Eye disorders: retinal vasculitis with or without retinal vascular occlusion.
Systemic reactions: anaphylaxis, rash, and urticaria.
Reference ID: 5500518
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no adequate and well-controlled studies of SYFOVRE administration in pregnant women to inform a
drug-associated risk. The use of SYFOVRE may be considered following an assessment of the risks and
benefits.
Systemic exposure of SYFOVRE following ocular administration is low [see Clinical Pharmacology (12.3)].
Subcutaneous administration of pegcetacoplan to pregnant monkeys from the mid gestation period through birth
resulted in increased incidences of abortions and stillbirths at systemic exposures 1040-fold higher than that
observed in humans at the maximum recommended human ophthalmic dose (MRHOD) of SYFOVRE (based
on the area under the curve (AUC) systemically measured levels). No adverse maternal or fetal effects were
observed in monkeys at systemic exposures approximately 470-fold higher than that observed in humans at the
MRHOD (see Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
In embryofetal development studies, subcutaneous administration of pegcetacoplan to pregnant cynomolgus
monkeys from the mid gestation period through birth produced increased incidences of abortions and stillbirths
at doses of 28 mg/kg/day [approximately 1040-fold higher than the MRHOD based on exposure (AUC)].
Pegcetacoplan was not maternally toxic and did not produce adverse embryofetal effects in the monkey at
subcutaneous doses of 7 mg/kg/day. (approximately 470-fold higher than the MRHOD). No developmental
effects were observed in infants up to 6 months postpartum. Minimal systemic exposure to pegcetacoplan (less
than 1%, not pharmacologically significant) was detected in fetuses from monkeys treated subcutaneously with
28 mg/kg/day from the period of organogenesis through the second trimester.
8.2 Lactation
Risk Summary
It is not known whether intravitreal administered pegcetacoplan is secreted in human milk or whether there is
potential for absorption and harm to the infant. Animal data suggest that the risk of clinically relevant exposure
to the infant following maternal intravitreal treatment is minimal (see Data). Because many drugs are excreted
in human milk, and because the potential for absorption and harm to infant growth and development exists,
caution should be exercised when SYFOVRE is administered to a nursing woman.
Data
Animal Data
Pegcetacoplan was detectable in milk of lactating monkeys after subcutaneous administration at less than 1%
concentration of serum levels but was not detectable in the serum of nursing infants.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Reference ID: 5500518
}-i "--- F
~3 ~3
I
It is recommended that women of childbearing potential use effective contraception methods to prevent
pregnancy during treatment with intravitreal pegcetacoplan. Advise female patients of reproductive potential to
use effective contraception during treatment with SYFOVRE and for 40 days after the last dose. For women
planning to become pregnant, the use of SYFOVRE may be considered following an assessment of the risks and
benefits.
8.4 Pediatric Use
The safety and effectiveness of SYFOVRE in pediatric patients have not been established.
8.5 Geriatric Use
In clinical studies, approximately 97% (813/839) of patients randomized to treatment with SYFOVRE were
≥ 65 years of age and approximately 72% (607/839) were ≥ 75 years of age. No significant differences in
efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is
recommended based on age.
11 DESCRIPTION
SYFOVRE contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule
composed of two identical pentadecapeptides covalently bound to the ends of a linear 40 kiloDalton (kDa)
polyethylene glycol (PEG) molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan
(Trp(Me)) in position 4 and amino (ethoxyethoxy) acetic acid (AEEA) in position 14.
The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is
C1970H3848N50O947S4. The structure of pegcetacoplan is shown below.
O
H
Ac
Ile
Cys
Val
Trp(Me)
Gln
Asp
Trp
Gly
Ala
His
Arg
Cys
Thr AEEA N
NH2 H
N
O
O
O
O 899
Ac
Ile
Cys
Val
Trp(Me)
Gln
Asp
Trp Gly
Ala
His
Arg
Cys
Thr AEEA N
H
NH2 H
N
O
O
SYFOVRE (pegcetacoplan injection) is a sterile, clear, colorless to light yellow aqueous solution in a single-
dose vial for intravitreal use. Each vial allows for the delivery of 0.1 mL of solution containing 15 mg
pegcetacoplan, trehalose dihydrate (5.95 mg), glacial acetic acid (0.0895 mg), sodium acetate trihydrate
(0.0353 mg), and Water for Injection. SYFOVRE may also contain sodium hydroxide and/or additional glacial
acetic acid for adjustment to a target pH of 5.0. SYFOVRE does not contain an anti-microbial preservative.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity thereby
regulating the cleavage of C3 and the generation of downstream effectors of complement activation
12.2 Pharmacodynamics
Cardiac Electrophysiology
Reference ID: 5500518
Subcutaneous (SC) dosing of pegcetacoplan did not result in QT prolongation. Systemic exposures following
intravitreal (IVT) administration are much lower than with SC administration, therefore QT prolongation
following IVT pegcetacoplan is not expected.
12.3 Pharmacokinetics
SYFOVRE is administered directly into the vitreous to exert local effects in the eye.
Following repeat intravitreal administration of pegcetacoplan at a dose of 15 mg, geometric mean (%CV) serum
Cmax value at steady state was 2.2 μg/mL (28.7%) and 1.5 μg/mL (58.1%) for GA patients dosed monthly and
every other month, respectively. The steady state geometric mean (%CV) serum trough concentrations were
1.0 μg/mL (52.3%) and 0.2 μg/mL (89.6%) for patients treated monthly and every other month, respectively.
Absorption
Following intravitreal administration of pegcetacoplan, the systemic median Tmax of pegcetacoplan is between 7
and 14 days. Following intravitreal treatment, systemic exposure of pegcetacoplan increases approximately
proportionally over a dosage range from 4 to 20 mg.
Distribution
The geometric mean (95%CI) volume of distribution of pegcetacoplan is approximately 1.85 L (1.62 - 2.12) in
patients with GA following intravitreal administration.
Elimination
The estimated geometric mean (%CV) of clearance (CL) is 0.284 L/day (21.1%) and geometric mean half-life
of elimination (t1/2) is 4.5 days (21.1%) in patients with GA.
Metabolism
Pegcetacoplan is expected to be metabolized into small peptides and amino acids by catabolic pathways.
Specific Populations
There were no clinically significant differences on the pharmacokinetics of pegcetacoplan intravitreal
administration based on age (60 to 97 years old), gender, renal impairment, and hepatic function as evaluated by
total bilirubin (0.05-1.7 mg/dL), albumin (2.96-5.38 g/dL), aspartate aminotransferase (8.7-101 IU/L), or
alanine aminotransferase (5.9-136 IU/L).
12.6 Immunogenicity
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of
the assay. Difference in assay methods preclude meaningful comparisons of the incidence of ADA in the studies
described below with the incidence of ADA in other studies.
In the 24-month period in studies OAKS and DERBY, the incidence of anti-pegcetacoplan peptide antibodies in
patients treated with pegcetacoplan was 4% (18/415 evaluable patients) and 2.5% (10/404 evaluable patients),
respectively. Because of the low incidence of anti-pegcetacoplan peptide antibodies, the effect of these
antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of pegcetacoplan is
unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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Carcinogenesis
Animal carcinogenicity studies of pegcetacoplan have not been conducted.
Mutagenesis
Pegcetacoplan was not mutagenic when tested in in vitro bacterial reverse mutation (Ames) assays and was not
genotoxic in an in vitro assay in human TK6 cells or in an in vivo micronucleus assay in mice.
Impairment of Fertility
There are no fertility data in humans or animals. There were no microscopic abnormalities in male or female
reproductive organs in toxicity studies in rabbits and monkeys indicative of an impact of pegcetacoplan on
fertility.
14 CLINICAL STUDIES
The safety and efficacy of SYFOVRE were assessed in two multi-center, randomized, sham-controlled studies
in patients with GA (atrophic nonexudative age-related macular degeneration), with or without subfoveal
involvement, secondary to AMD in a total of 1258 randomized patients (SYFOVRE 839 patients, sham 419
patients). Studies OAKS (APL2-304; NCT03525613) and DERBY (APL2-303; NCT03525600) were 24
months in duration, in which patients received treatment for the entire length of the study.
Patient ages ranged from 60 to 100 years with a mean of 78.7 years. Mean (standard deviation) total area of GA
lesions(s) at baseline in the study eye (in mm2) were 8.23 (3.83) and 8.29 (4.11) for OAKS and DERBY
respectively.
In each study, patients were randomly assigned in a 2:2:1:1 ratio to 1 of 4 dosing regimens:
•
1) SYFOVRE administered at 15 mg/0.1 mL monthly;
•
2) SYFOVRE administered at 15 mg/0.1 mL every other month;
•
3) sham administered monthly;
•
4) sham administered every other month.
In OAKS, 31% of patients in the monthly group, 21% of patients in the every other month and 25% of the
patients assigned to sham discontinued treatment prior to Month 24. In DERBY, 29% of patients in the monthly
group, 22% of patients in the every other month and 21% of the patients assigned to sham discontinued
treatment prior to Month 24.
There was a reduction in the mean rate of GA lesion growth observed in both studies.
Detailed results are shown in Table 2 and Figures 1 and 2.
Table 2: Analysis of Change from Baseline in Study Eye GA Lesion Area Measured by FAF in Studies OAKS and
DERBY
Time Period
Group
Rate of GA Lesion Area Growth (mm2) ‡
Slope (SE)
Difference
(95% CI) in Slope from
Sham Pooled
Percent Difference
from Sham Pooled
OAKS (PM: N=202; PEOM: N=205; Sham Pooled: N=207)
Baseline to
Month 24*
PM
3.11 (0.148)
−0.87
(−1.27 to −0.47)
−21.9%
PEOM
3.26 (0.134)
−0.72
(−1.10 to −0.33)
−18.1%
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Time Period
Group
Rate of GA Lesion Area Growth (mm2) ‡
Slope (SE)
Difference
(95% CI) in Slope from
Sham Pooled
Percent Difference
from Sham Pooled
Sham Pooled
3.98 (0.143)
NA
Baseline to
Month 6
PM
0.76 (0.046)
−0.22
(−0.35 to −0.09)
−22.7%
PEOM
0.82 (0.043)
−0.16
(−0.29 to −0.04)
−16.4%
Sham Pooled
0.98 (0.047)
NA
Month 6 to
Month 12
PM
0.78 (0.060)
−0.19
(−0.34 to −0.03)
−19.2%
PEOM
0.82 (0.057)
−0.15
(−0.30 to −0.00)
−15.7%
Sham Pooled
0.97 (0.052)
NA
Month 12 to
Month 18
PM
0.80 (0.050)
−0.23
(−0.37 to −0.08)
−22.1%
PEOM
0.87 (0.050)
−0.16
(−0.30 to −0.02)
−15.4%
Sham Pooled
1.03 (0.053)
NA
Month 18 to
Month 24
PM
0.76 (0.067)
−0.23
(−0.41 to −0.06)
−23.5%
PEOM
0.75 (0.044)
−0.25
(−0.39 to −0.10)
−24.7%
Sham Pooled
1.00 (0.058)
NA
DERBY (PM: N=201; PEOM: N=201; Sham Pooled: N=195)
Baseline to
Month 24*
PM
3.28 (0.125)
−0.73
(−1.14 to −0.31)
−18.1%
PEOM
3.31 (0.129)
−0.70
(−1.11 to −0.28)
−17.4%
Sham Pooled
4.00 (0.169)
NA
Baseline to
Month 6
PM
0.91 (0.048)
−0.05
(−0.19 to 0.08)
−5.7%
PEOM
0.88 (0.047)
−0.08
(−0.21 to 0.05)
−8.2%
Sham Pooled
0.96 (0.050)
NA
Month 6 to
Month 12
PM
0.84 (0.051)
−0.17
(−0.33 to −0.02)
−17.0%
PEOM
0.85 (0.051)
−0.17
(−0.32 to −0.01)
−16.4%
Sham Pooled
1.01 (0.060)
NA
Month 12 to
Month 18
PM
0.90 (0.049)
−0.14
(−0.29 to 0.00)
−13.8%
PEOM
0.88 (0.051)
−0.17
(−0.32 to −0.02)
−16.0%
Reference ID: 5500518
I---
- --- .
-----k---·
Time Period
Group
Rate of GA Lesion Area Growth (mm2) ‡
Slope (SE)
Difference
(95% CI) in Slope from
Sham Pooled
Percent Difference
from Sham Pooled
Sham Pooled
1.05 (0.056)
NA
Month 18 to
Month 24
PM
0.63 (0.068)
−0.35
(−0.52 to −0.18)
−36.1%
PEOM
0.69 (0.053)
−0.28
(−0.43 to −0.14)
−29.1%
Sham Pooled
0.98 (0.055)
NA
GA: Geographic atrophy; FAF: fundus autofluorescence; PM: SYFOVRE monthly; PEOM: SYFOVRE every other month; SE:
standard error; CI: confidence interval
‡Based on a mixed effects model for repeated measures assuming a piecewise linear trend in time with knots at Month 6, Month 12,
and Month 18. The model included effects for treatment, baseline GA lesion area (<7.5 mm2 or ≥7.5 mm2), time terms, presence of
choroidal neovascularization in the fellow eye (yes or no), time terms by treatment interactions, and time terms by baseline GA lesion
area (<7.5 mm2 or ≥7.5 mm2) interactions. Time terms include a linear effect of time for each 6-month time period.
*Slope for baseline to Month 24 is an average of slope of baseline to Month 6, Month 6 to Month 12, Month 12 to Month 18, and
Month 18 to Month 24.
Figure 1: Mean Rate of Change from Baseline in Study Eye GA Lesion Area Measured by FAF in OAKS
PEOM: -18.1%
PM: -21.9%
Mean Rate of Change (±SE) from Bas eline in
GA Les ion (mm²)
0
1
2
3
4
Bas eline
M6
M12
M18
M24
Vis it (Month)
PM (N=202)
PEOM (N=205)
Sham Pooled (N=207)
GA: Geographic atrophy; FAF: fundus autofluorescence; PM: SYFOVRE monthly; PEOM: SYFOVRE every other month; SE:
standard error.
Based on a mixed effects model for repeated measures assuming a piecewise linear trend in time with knots at Month 6, Month 12,
and Month 18. The model included effects for treatment, baseline GA lesion area (<7.5 mm2 or ≥7.5 mm2), time terms, presence of
choroidal neovascularization in the fellow eye (yes or no), time terms by treatment interactions, and time terms by baseline GA lesion
area (<7.5 mm2 or ≥7.5 mm2) interactions. Time terms include a linear effect of time for each 6-month time period.
Reference ID: 5500518
I---
- --- .
-----k---·
Figure 2: Mean Rate of Change from Baseline in Study Eye GA Lesion Area Measured by FAF in DERBY
Mean Rate of Change (±SE) from Bas eline in
GA Les ion (mm²)
0
1
2
3
4
Bas eline
M6
M12
M18
M24
Vis it (Month)
PEOM: -17.4%
PM: -18.1%
PM (N=201)
PEOM (N=201)
Sham Pooled (N=195)
GA: Geographic atrophy; FAF: fundus autofluorescence; PM: SYFOVRE monthly; PEOM: SYFOVRE every other month; SE:
standard error.
Based on a mixed effects model for repeated measures assuming a piecewise linear trend in time with knots at Month 6, Month 12,
and Month 18. The model included effects for treatment, baseline GA lesion area (<7.5 mm2 or ≥7.5 mm2), time terms, presence of
choroidal neovascularization in the fellow eye (yes or no), time terms by treatment interactions, and time terms by baseline GA lesion
area (<7.5 mm2 or ≥7.5 mm2) interactions. Time terms include a linear effect of time for each 6-month time period.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
SYFOVRE (pegcetacoplan injection) is supplied as a clear, colorless to light yellow aqueous solution. Each
SYFOVRE carton (NDC 73606-020-01) contains one single-dose glass vial. Each glass vial contains an overfill
amount to allow for administration of a single 0.1 mL dose of solution containing 15 mg of SYFOVRE.
16.2
Storage and Handling
Refrigerate SYFOVRE between 2°C to 8°C (36°F to 46°F). Store the vial in the original carton to protect from
light.
Do not use beyond the expiration date on the carton.
Do not shake.
17 PATIENT COUNSELING INFORMATION
Advise patients that following SYFOVRE administration, patients are at risk of developing endophthalmitis,
retinal detachments, retinal vasculitis with or without retinal vascular occlusion and neovascular AMD. If the
eye becomes red, sensitive to light, painful, or if a patient develops any change in vision such as flashing lights,
blurred vision or metamorphopsia, instruct the patient to seek immediate care from an ophthalmologist [see
Warnings and Precautions (5.1, 5.2, 5.3)].
Reference ID: 5500518
Patients may experience temporary visual disturbances associated either with the intravitreal injection with
SYFOVRE or the eye examination [see Adverse Reactions (6.1)]. Advise patients not to drive or use machinery
until visual function has recovered sufficiently.
Manufactured for:
Apellis Pharmaceuticals, Inc.
100 Fifth Avenue
Waltham, MA 02451
For patent information: www.apellis.com/productpatent
Copyright © YYYY Apellis Pharmaceuticals, Inc. All rights reserved.
SYFOVRE is a registered trademark of Apellis Pharmaceuticals, Inc.
SYF-PI-DDMonthYYYY-X.0
Reference ID: 5500518
| custom-source | 2025-02-12T15:48:05.367305 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217171s002lbl.pdf', 'application_number': 217171, 'submission_type': 'SUPPL ', 'submission_number': 2} |
80,686 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HARVONI® safely and effectively. See full prescribing information
for HARVONI.
HARVONI® (ledipasvir and sofosbuvir) tablets, for oral use
HARVONI® (ledipasvir and sofosbuvir) oral pellets
Initial U.S. Approval: 2014
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
See full prescribing information for complete boxed warning.
Hepatitis B virus (HBV) reactivation has been reported, in some
cases resulting in fulminant hepatitis, hepatic failure, and death.
(5.1)
-------------------------------INDICATIONS AND USAGE------------------------
HARVONI is a fixed-dose combination of ledipasvir, a hepatitis C virus
(HCV) NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog
NS5B polymerase inhibitor, and is indicated for the treatment of
chronic hepatitis C virus (HCV) in adults and pediatric patients 3 years
of age and older:
• Genotype 1, 4, 5, or 6 infection without cirrhosis or with
compensated cirrhosis
• Genotype 1 infection with decompensated cirrhosis, in combination
with ribavirin
• Genotype 1 or 4 infection who are liver transplant recipients without
cirrhosis or with compensated cirrhosis, in combination with ribavirin.
(1)
------------------------DOSAGE AND ADMINISTRATION----------------------
• Testing prior to the initiation of therapy: Test all patients for HBV
infection by measuring HBsAg and anti-HBc. (2.1)
• Recommended treatment regimen and duration in patients 3 years
of age and older: (2.2)
HCV
Genotype
Patient Population
Regimen
and
Duration
Treatment-naïve without cirrhosis or
with compensated cirrhosis (Child-
Pugh A)
HARVONI
12 weeks
Genotype
1
Treatment-experienced without
cirrhosis
HARVONI
12 weeks
Treatment-experienced with
compensated cirrhosis (Child-Pugh A)
HARVONI
24 weeks
Treatment-naïve and treatment-
experienced with decompensated
cirrhosis (Child-Pugh B or C)
HARVONI
+ ribavirin
12 weeks
Genotype
1 or 4
Treatment-naïve and treatment-
experienced liver transplant recipients
without cirrhosis, or with compensated
cirrhosis (Child-Pugh A)
HARVONI
+ ribavirin
12 weeks
Genotype
4, 5, or 6
Treatment-naïve and treatment-
experienced without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
HARVONI
12 weeks
• Recommended dosage in adults: One tablet (90 mg of ledipasvir
and 400 mg of sofosbuvir) taken orally once daily with or without
food. (2.3)
• Recommended dosage in pediatric patients 3 years and older:
Recommended dosage of HARVONI in pediatric patients 3 years of
age and older is based on weight. Refer to Table 2 of the full
prescribing information for specific dosing guidelines based on body
weight. (2.4)
• Instructions for Use should be followed for preparation and
administration of HARVONI oral pellets. (2.5)
• HCV/HIV-1 coinfection: For adult and pediatric patients with
HCV/HIV-1 coinfection, follow the dosage recommendations in the
tables in the full prescribing information. (2.3, 2.4)
• If used in combination with ribavirin, follow the recommendations for
ribavirin dosing and dosage modifications. (2.3, 2.4)
• For patients with any degree of renal impairment, including end
stage renal disease on dialysis, no HARVONI dosage adjustment is
recommended. (2.6)
-----------------------DOSAGE FORMS AND STRENGTHS-------------------
• Tablets: 90 mg of ledipasvir and 400 mg of sofosbuvir; 45 mg of
ledipasvir and 200 mg of sofosbuvir. (3)
• Oral Pellets: 45 mg of ledipasvir and 200 mg of sofosbuvir; 33.75 mg
of ledipasvir and 150 mg of sofosbuvir. (3)
--------------------------------CONTRAINDICATIONS-----------------------------
If used in combination with ribavirin, all contraindications to ribavirin
also apply to HARVONI combination therapy. (4)
-------------------------WARNINGS AND PRECAUTIONS---------------------
• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence
of current or prior HBV infection before initiation of HCV treatment.
Monitor HCV/HBV coinfected patients for HBV reactivation and
hepatitis flare during HCV treatment and post-treatment follow-up.
Initiate appropriate patient management for HBV infection as
clinically indicated. (5.1)
• Bradycardia with amiodarone coadministration: Serious symptomatic
bradycardia may occur in patients taking amiodarone, particularly in
patients also receiving beta blockers, or those with underlying
cardiac comorbidities and/or advanced liver disease.
Coadministration of amiodarone with HARVONI is not
recommended. In patients without alternative, viable treatment
options, cardiac monitoring is recommended. (5.2, 6.2, 7.2)
-------------------------------ADVERSE REACTIONS----------------------------
• The most common adverse reactions (incidence greater than or
equal to 10%, all grades) observed with treatment with HARVONI
were fatigue, headache, and asthenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
---------------------------------DRUG INTERACTIONS--------------------------
• Coadministration with amiodarone may result in serious
symptomatic bradycardia. Use of HARVONI with amiodarone is not
recommended. (5.2, 6.2, 7.2)
• P-gp inducers (e.g., rifampin, St. John’s wort): May alter
concentrations of ledipasvir and sofosbuvir. Use of HARVONI with
P-gp inducers is not recommended. (5.3, 7, 12.3)
• Consult the full prescribing information prior to use for potential drug
interactions. (5.2, 5.3, 7, 12.3)
• Clearance of HCV infection with direct acting antivirals may lead to
changes in hepatic function, which may impact safe and effective
use of concomitant medications. Frequent monitoring of relevant
laboratory parameters (INR or blood glucose) and dose adjustments
of certain concomitant medications may be necessary. (7.2)
---------------------USE IN SPECIFIC POPULATIONS---------------------
• Pediatric Use: No data are available regarding the safety of
HARVONI in pediatric patients with renal impairment. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
Reference ID: 5499805
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
2.2 Recommended Treatment Regimen and Duration in
Patients 3 Years of Age and Older with Genotype 1, 4, 5, or
6 HCV
2.3 Recommended Dosage in Adults
2.4 Recommended Dosage in Pediatric Patients 3 Years of
Age and Older
2.5 Preparation and Administration of Oral Pellets
2.6 Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Hepatitis B Virus Reactivation in Patients
Coinfected with HCV and HBV
5.2 Serious Symptomatic Bradycardia When Coadministered
with Amiodarone
5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp
Inducers
5.4 Risks Associated with Ribavirin Combination Treatment
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Potential for Drug Interaction
7.2 Established and Potentially Significant Drug Interactions
7.3 Drugs without Clinically Significant Interactions with
HARVONI
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
14.2 Clinical Trials in Subjects with Genotype 1 HCV
14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV
14.4 Clinical Trials in Subjects Coinfected with HCV and HIV-1
14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with
Decompensated Cirrhosis
14.6 Clinical Trials in Adults with Severe Renal Impairment, Including
those Requiring Dialysis
14.7 Clinical Trial in Pediatric Subjects
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5499805
FULL PRESCRIBING INFORMATION
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
COINFECTED WITH HCV AND HBV
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection
before initiating treatment with HARVONI. HBV reactivation has been reported in
HCV/HBV coinfected patients who were undergoing or had completed treatment
with HCV direct acting antivirals and were not receiving HBV antiviral therapy.
Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation
during HCV treatment and post-treatment follow-up. Initiate appropriate patient
management for HBV infection as clinically indicated [see Warnings and
Precautions (5.1)].
1
INDICATIONS AND USAGE
HARVONI is indicated for the treatment of adults and pediatric patients 3 years of age
and older with chronic hepatitis C virus (HCV) [see Dosage and Administration (2.2 and
2.3) and Clinical Studies (14)]:
• genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
• genotype 1 infection with decompensated cirrhosis, for use in combination with
ribavirin
• genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or
with compensated cirrhosis, for use in combination with ribavirin
2
DOSAGE AND ADMINISTRATION
2.1
Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV
treatment with HARVONI [see Warnings and Precautions (5.1)].
2.2
Recommended Treatment Regimen and Duration in Patients 3 Years of Age
and Older with Genotype 1, 4, 5, or 6 HCV
Table 1 shows the recommended HARVONI treatment regimen and duration based on
patient population. Relapse rates are affected by baseline host and viral factors and
differ between treatment durations for certain subgroups [see Clinical Studies (14)].
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1
[see Clinical Studies (14)]. Refer to Drug Interactions (7) for dosage recommendations
for concomitant HIV-1 antiviral drugs.
Reference ID: 5499805
Table 1
Recommended Treatment Regimen and Duration for HARVONI in
Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV
HCV Genotype
Patient Population
Treatment Regimen and
Duration
Genotype 1
Treatment-naïve without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
HARVONI 12 weeksa
Treatment-experiencedb without cirrhosis
HARVONI 12 weeks
Treatment-experiencedb with
compensated cirrhosis (Child-Pugh A)
HARVONI 24 weeksc
Treatment-naïve and treatment
experiencedb with decompensated
cirrhosis (Child-Pugh B or C)
HARVONI + ribavirind 12 weeks
Genotype 1 or 4
Treatment-naïve and treatment
experiencedb liver transplant recipients
without cirrhosis, or with compensated
cirrhosis (Child-Pugh A)
HARVONI + ribavirind 12 weeks
Genotype 4, 5, or 6
Treatment-naïve and treatment
experiencedb, without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
HARVONI 12 weeks
a.
HARVONI for 8 weeks can be considered in treatment-naïve genotype 1 patients without cirrhosis
who have pretreatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14.2)].
b.
Treatment-experienced adult and pediatric subjects have failed a peginterferon alfa +/- ribavirin based
regimen with or without an HCV protease inhibitor.
c.
HARVONI + ribavirin for 12 weeks can be considered in treatment-experienced genotype 1 patients
with cirrhosis who are eligible for ribavirin [see Dosage and Administration (2.3 and 2.4) and Clinical
Studies (14.2)].
d.
See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations.
2.3
Recommended Dosage in Adults
The recommended dosage of HARVONI in adults with genotype 1, 4, 5, or 6 HCV is
one tablet (90 mg ledipasvir and 400 mg sofosbuvir) taken orally once daily with or
without food [see Clinical Pharmacology (12.3)].
The daily dosage of ribavirin is weight-based (1000 mg for patients <75 kg and 1200 mg
for those ≥75 kg) administered orally in two divided doses with food.
In patients with decompensated cirrhosis, the starting dosage of ribavirin is 600 mg and
can be titrated up to 1000 mg for patients <75 kg and 1200 mg for those ≥75 kg in two
divided doses with food. If the starting dosage of ribavirin is not well tolerated, the
dosage should be reduced as clinically indicated based on hemoglobin levels.
For further information on ribavirin dosing and dosage modifications, refer to the
ribavirin prescribing information [see Dosage and Administration (2.4), Use in Specific
Populations (8.6), and Clinical Studies (14.5)].
Reference ID: 5499805
2.4
Recommended Dosage in Pediatric Patients 3 Years of Age and Older
The recommended dosage of HARVONI in pediatric patients 3 years of age and older
with genotype 1, 4, 5, or 6 HCV using HARVONI tablets or oral pellets is based on
weight (Table 2). Table 3 provides the weight-based dosage of ribavirin when used in
combination with HARVONI for pediatric patients. Take HARVONI tablets or pellets
(with or without food) once daily [see Dosage and Administration (2.5), Clinical
Pharmacology (12.3), and Clinical Studies (14.7)]. HARVONI pellets can be taken in
pediatric patients who cannot swallow the tablet formulation.
Table 2
Dosing for Pediatric Patients 3 Years and Older Using HARVONI
Tablets or Oral Pellets
Body Weight
(kg)
Dosing of HARVONI Tablets or Oral Pellets
HARVONI Daily Dose
at least 35
one 90 mg/400 mg tablet once daily
or
two 45 mg/200 mg tablets once daily
or
two 45 mg/200 mg packets of pellets once daily
90 mg/400 mg per day
17 to less than
35
one 45 mg/200 mg tablet once daily
or
one 45 mg/200 mg packet of pellets once daily
45 mg/200 mg per day
less than 17
one 33.75 mg/150 mg packet of pellets once
daily
33.75 mg/150 mg per day
Table 3
Recommended Dosing for Ribavirin in Combination Therapy with
HARVONI for Pediatric Patients 3 Years and Older
Body Weight (kg)
Oral Ribavirin Daily Dosagea
less than 47
15 mg per kg per day
(divided dose AM and PM)
47–49
600 mg per day
(1 x 200 mg AM, 2 x 200 mg PM)
50–65
800 mg per day
(2 x 200 mg AM, 2 x 200 mg PM)
66–80
1000 mg per day
(2 x 200 mg AM, 3 x 200 mg PM)
greater than 80
1200 mg per day
(3 x 200 mg AM, 3 x 200 mg PM)
a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
Reference ID: 5499805
2.5
Preparation and Administration of Oral Pellets
See the HARVONI oral pellets full Instructions for Use for details on the preparation and
administration of HARVONI pellets.
Do not chew HARVONI pellets. If HARVONI pellets are administered with food, sprinkle
the pellets on one or more spoonfuls of non-acidic soft food at or below room
temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed
potato, and ice cream. Take HARVONI pellets within 30 minutes of gently mixing with
food and swallow the entire contents without chewing to avoid a bitter aftertaste.
2.6
Renal Impairment
No dosage adjustment of HARVONI is recommended in patients with any degree of
renal impairment, including end stage renal disease (ESRD) on dialysis [see Dosage
and Administration (2.3)]. Take HARVONI with or without ribavirin according to the
recommendations in Table 1 [see Adverse Reactions (6.1), Use in Specific Populations
(8.6), and Clinical Studies (14.6)]. Refer to ribavirin tablet prescribing information for
ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per
minute.
3
DOSAGE FORMS AND STRENGTHS
HARVONI is available as tablets or pellets for oral use. Each dosage form is available in
two dose strengths.
• 90 mg/400 mg Tablets: orange, diamond-shaped, film-coated tablet debossed
with “GSI” on one side and “7985” on the other side of the tablet. Each tablet
contains 90 mg ledipasvir and 400 mg sofosbuvir.
• 45 mg/200 mg Tablets: white, capsule-shaped, film-coated tablets, debossed
with “GSI” on one side and “HRV” on the other side. Each tablet contains 45 mg
ledipasvir and 200 mg sofosbuvir.
• 45 mg/200 mg Pellets: orange pellets in unit-dose packets. Each packet contains
45 mg ledipasvir and 200 mg sofosbuvir.
• 33.75 mg/150 mg Pellets: orange pellets in unit-dose packets. Each packet
contains 33.75 mg ledipasvir and 150 mg sofosbuvir.
4
CONTRAINDICATIONS
If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to
this combination regimen. Refer to the ribavirin prescribing information for a list of
contraindications for ribavirin [see Dosage and Administration (2.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and
HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients
who were undergoing or had completed treatment with HCV direct acting antivirals, and
Reference ID: 5499805
who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Cases have been reported in patients who are
HBsAg positive and also in patients with serologic evidence of resolved HBV infection
(i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported
in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk
of HBV reactivation associated with treatment with HCV direct-acting antivirals may be
increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting
as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection,
reappearance of HBsAg can occur. Reactivation of HBV replication may be
accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe
cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and
anti-HBc before initiating HCV treatment with HARVONI. In patients with serologic
evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or
HBV reactivation during HCV treatment with HARVONI and during post-treatment
follow-up. Initiate appropriate patient management for HBV infection as clinically
indicated.
5.2
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and
cases requiring pacemaker intervention, have been reported when amiodarone is
coadministered with HARVONI. Bradycardia has generally occurred within hours to
days, but cases have been observed up to 2 weeks after initiating HCV treatment.
Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or
advanced liver disease, may be at increased risk for symptomatic bradycardia with
coadministration of amiodarone. Bradycardia generally resolved after discontinuation of
HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with HARVONI is not recommended. For patients
taking amiodarone who have no other alternative, viable treatment options and who will
be coadministered HARVONI:
• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of
coadministration is recommended, after which outpatient or self-monitoring of the
heart rate should occur on a daily basis through at least the first 2 weeks of
treatment.
Patients who are taking HARVONI who need to start amiodarone therapy due to no
other alternative, viable treatment options should undergo similar cardiac monitoring as
outlined above.
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to
starting HARVONI should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation
immediately. Symptoms may include near-fainting or fainting, dizziness or
Reference ID: 5499805
lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest
pains, confusion, or memory problems [see Adverse Reactions (6.2), Drug Interactions
(7.2)].
5.3
Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
The concomitant use of HARVONI and P-gp inducers may significantly decrease
ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic
effect of HARVONI. Therefore, the use of HARVONI with P-gp inducers (e.g., rifampin,
St. John’s wort) is not recommended [see Drug Interactions (7.2)].
5.4
Risks Associated with Ribavirin Combination Treatment
If HARVONI is administered with ribavirin, the warnings and precautions for ribavirin, in
particular the pregnancy avoidance warning, apply to this combination regimen. Refer to
the ribavirin prescribing information for a full list of the warnings and precautions for
ribavirin [see Dosage and Administration (2.2)].
6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in labeling:
• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see
Warnings and Precautions (5.2)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
If HARVONI is administered with ribavirin to adults, refer to the prescribing information
for ribavirin for a description of ribavirin-associated adverse reactions.
Clinical Trials in Adult Subjects
The safety assessment of HARVONI was based on pooled data from three randomized,
open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of subjects with genotype 1
HCV with compensated liver disease (with and without cirrhosis) including 215, 539,
and 326 subjects who received HARVONI once daily by mouth for 8, 12, and 24 weeks,
respectively [see Clinical Studies (14)].
The proportion of subjects who permanently discontinued treatment due to adverse
events was 0%, less than 1%, and 1% for subjects receiving HARVONI for 8, 12, and
24 weeks, respectively.
The most common adverse reactions (at least 10%) were fatigue and headache in
subjects treated with 8, 12, or 24 weeks of HARVONI.
Table 4 lists adverse reactions (adverse events assessed as causally related by the
investigator, all grades) observed in at least 5% of subjects receiving 8, 12, or 24 weeks
of treatment with HARVONI in clinical trials. The majority of adverse reactions
presented in Table 4 occurred at severity of grade 1. The side-by-side tabulation is to
Reference ID: 5499805
simplify presentation; direct comparison across trials should not be made due to
differing trial designs.
Table 4
Adverse Reactions (All Grades) Reported in ≥5% of Subjects
Receiving 8, 12, or 24 Weeks of Treatment with HARVONI
HARVONI
8 weeks
(N=215)
HARVONI
12 weeks
(N=539)
HARVONI
24 weeks
(N=326)
Fatigue
16%
13%
18%
Headache
11%
14%
17%
Nausea
6%
7%
9%
Diarrhea
4%
3%
7%
Insomnia
3%
5%
6%
The safety assessment of HARVONI was also based on pooled data from three open-
label trials (Study 1119, ION-4, and ELECTRON-2) in 118 subjects with chronic HCV
genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis)
[see Clinical Studies (14.3)]. The subjects received HARVONI once daily by mouth for
12 weeks. The safety profile in subjects with chronic HCV genotype 4, 5, or 6 infection
with compensated liver disease was similar to that observed in subjects with chronic
HCV genotype 1 infection with compensated liver disease. The most common adverse
reactions occurring in at least 10% of subjects were asthenia (18%), headache (14%),
and fatigue (10%).
Adverse Reactions in Subjects with Cirrhosis
The safety assessment of HARVONI with or without ribavirin was based on a
randomized, double-blind and placebo-controlled trial in treatment-experienced
genotype 1 subjects with compensated cirrhosis and was compared to placebo in the
SIRIUS trial. Subjects were randomized to receive 24 weeks of HARVONI once daily by
mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI once
daily by mouth + ribavirin [see Clinical Studies (14.2)]. Table 5 presents the adverse
reactions, as defined above, that occurred with at least 5% greater frequency in
subjects treated with 24 weeks of HARVONI or 12 weeks of HARVONI + ribavirin,
compared to those reported for 12 weeks of placebo. The majority of the adverse
reactions presented in Table 5 were Grade 1 or 2 in severity.
Reference ID: 5499805
Table 5
Adverse Reactions with ≥5% Greater Frequency Reported in
Treatment-Experienced Subjects with Cirrhosis Receiving HARVONI
for 24 Weeks or HARVONI + Ribavirin for 12 Weeks Compared to
Placebo for 12 weeks
HARVONI
24 weeks
(N=78)
HARVONI + RBV
12 weeks
(N=76)
Placebo
12 weeks
(N=77)
Asthenia
31%
36%
23%
Headache
29%
13%
16%
Fatigue
18%
4%
1%
Cough
5%
11%
1%
Myalgia
9%
4%
0
Dyspnea
3%
9%
1%
Irritability
8%
7%
1%
Dizziness
5%
1%
0
RBV=ribavirin
Adverse Reactions in Subjects Coinfected with HIV-1
The safety assessment of HARVONI was based on an open-label clinical trial in
335 genotype 1 or 4 subjects with HCV/HIV-1 coinfection who were on stable
antiretroviral therapy in Study ION-4 [see Clinical Studies (14.4)]. The safety profile in
HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected
subjects. The most common adverse reactions occurring in at least 10% of subjects
were headache (20%) and fatigue (17%).
Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated
Cirrhosis
The safety assessment of HARVONI with ribavirin in liver transplant recipients and/or
those who had decompensated liver disease was based on pooled data from two Phase
2 open-label clinical trials including 336 subjects who received HARVONI plus ribavirin
for 12 weeks. Subjects with Child-Pugh-Turcotte (CPT) scores greater than 12 were
excluded from the trials [see Clinical Studies (14.5)].
The adverse events observed were consistent with the expected clinical sequelae of
liver transplantation and/or decompensated liver disease, or the known safety profile of
HARVONI and/or ribavirin.
Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were
observed in 38% and 13% of subjects treated with HARVONI plus ribavirin for 12
weeks, respectively. Ribavirin was permanently discontinued in 11% of subjects treated
with HARVONI plus ribavirin for 12 weeks.
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Liver Transplant Recipients with Compensated Liver Disease:
Among the 174 liver transplant recipients with compensated liver disease who received
HARVONI with ribavirin for 12 weeks, 2 (1%) subjects permanently discontinued
HARVONI due to an adverse event.
Subjects with Decompensated Liver Disease:
Among the 162 subjects with decompensated liver disease (pre- or post-transplant) who
received HARVONI with ribavirin for 12 weeks, 7 (4%) subjects died, 4 (2%) subjects
underwent liver transplantation, and 1 subject (<1%) underwent liver transplantation and
died during treatment or within 30 days after discontinuation of treatment. Because
these events occurred in patients with advanced liver disease who are at risk of
progression of liver disease including liver failure and death, it is not possible to reliably
assess the contribution of drug effect to outcomes. A total of 4 (2%) subjects
permanently discontinued HARVONI due to an adverse event.
Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The
following adverse reactions occurred in less than 5% of subjects receiving HARVONI in
any one trial. These events have been included because of their seriousness or
assessment of potential causal relationship.
Psychiatric disorders: depression (including in subjects with pre-existing history of
psychiatric illness).
Depression (particularly in subjects with pre-existing history of psychiatric illness)
occurred in subjects receiving sofosbuvir containing regimens. Suicidal ideation and
suicide have occurred in less than 1% of subjects treated with sofosbuvir in
combination with ribavirin or pegylated interferon/ribavirin in other clinical trials.
Laboratory Abnormalities
Bilirubin Elevations: Bilirubin elevations of greater than 1.5xULN were observed in
3%, less than 1%, and 2% of subjects treated with HARVONI for 8, 12, and
24 weeks, respectively. Bilirubin elevations of greater than 1.5xULN were observed
in 3%, 11%, and 3% of subjects with compensated cirrhosis treated with placebo,
HARVONI + ribavirin for 12 weeks, and HARVONI for 24 weeks, respectively, in the
SIRIUS trial.
Lipase Elevations: Transient, asymptomatic lipase elevations of greater than 3xULN
were observed in less than 1%, 2%, and 3% of subjects treated with HARVONI for 8,
12, and 24 weeks, respectively. Transient, asymptomatic lipase elevations of greater
than 3x ULN were observed in 1%, 3%, and 9% of subjects with compensated
cirrhosis treated with placebo, HARVONI + ribavirin for 12 weeks, and HARVONI for
24 weeks, respectively, in the SIRIUS trial.
Creatine Kinase: Creatine kinase was not assessed in Phase 3 trials ION-3, ION-1,
or ION-2 of HARVONI. Creatine kinase was assessed in the ION-4 trial. Isolated,
asymptomatic creatine kinase elevations of greater than or equal to 10xULN was
observed in 1% of subjects treated with HARVONI for 12 weeks in the ION-4 trial
Reference ID: 5499805
and has also been previously reported in subjects treated with sofosbuvir in
combination with ribavirin or peginterferon/ribavirin in other clinical trials.
Adverse Reactions in Adults with Severe Renal Impairment, Including those on Dialysis
In an open-label trial (Trial 0154) in which adults with HCV with compensated liver
disease (with or without cirrhosis) and severe renal impairment received HARVONI for
12 weeks (N=18), the most common adverse reaction was fatigue (17%) [see Clinical
Studies (14.6)].
In an open-label clinical trial, Trial 4063, a total of 95 adults with HCV with compensated
liver disease (with or without cirrhosis) and ESRD requiring dialysis received HARVONI
for 8 (n=45), 12 (n=31), or 24 (n=19) weeks. The most common adverse reactions were
insomnia and headache (each reported in 4% of subjects overall) [see Clinical Studies
(14.6)].
Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
The safety assessment of HARVONI in pediatric subjects 3 years of age and older is
based on data from a Phase 2, open-label clinical trial (Study 1116). In total, 226
subjects were enrolled, which included 223 subjects without cirrhosis or with
compensated cirrhosis who were treated with HARVONI for 12 weeks; one genotype 1
treatment-experienced subject with cirrhosis who was treated with HARVONI for 24
weeks; and two genotype 3 subjects who were treated with HARVONI + ribavirin for 24
weeks. The adverse reactions observed were consistent with those observed in clinical
studies of HARVONI in adults. Limited safety data are available in pediatric subjects
receiving HARVONI for 24 weeks. No Grade 3 or 4 adverse reactions or discontinuation
due to an adverse reaction was observed in those pediatric subjects receiving
HARVONI for 24 weeks [see Clinical Studies (14.7)].
In a 5-year follow-up study, 178 of the 226 subjects from the Phase 2 open-label clinical
trial (Study 1116) were followed for a median (Q1, Q3) duration of 239 (143, 244)
weeks. No notable effects on growth as assessed by changes from baseline through
end of study were observed for height, weight, BMI percentiles, and Z-scores for any
age group. No notable effects were observed on the development of secondary sexual
characteristics of subjects as assessed by changes from baseline through end of study
in Tanner pubertal stages [see Use in Specific Populations (8.4)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of
HARVONI. Because postmarketing reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Cardiac Disorders
Serious symptomatic bradycardia has been reported in patients taking amiodarone who
initiate treatment with HARVONI [see Warnings and Precautions (5.2), Drug Interactions
(7.2)].
Reference ID: 5499805
Skin and Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling
Angioedema
7
DRUG INTERACTIONS
7.1
Potential for Drug Interaction
As HARVONI contains ledipasvir and sofosbuvir, any interactions that have been
identified with these agents individually may occur with HARVONI.
After oral administration of HARVONI, sofosbuvir is rapidly absorbed and subject to
extensive first-pass hepatic extraction. In clinical pharmacology studies, both sofosbuvir
and the inactive metabolite GS-331007 were monitored for purposes of pharmacokinetic
analyses.
Ledipasvir is an inhibitor of the drug transporters P-gp and breast cancer resistance
protein (BCRP) and may increase intestinal absorption of coadministered substrates for
these transporters.
Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while
GS-331007 is not. P-gp inducers (e.g., rifampin, St. John’s wort) may decrease
ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect
of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see
Warnings and Precautions (5.3)].
7.2
Established and Potentially Significant Drug Interactions
Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic
function, which may impact the safe and effective use of concomitant medications. For
example, altered blood glucose control resulting in serious symptomatic hypoglycemia
has been reported in diabetic patients in postmarketing case reports and published
epidemiological studies. Management of hypoglycemia in these cases required either
discontinuation or dose modification of concomitant medications used for diabetes
treatment.
Frequent monitoring of relevant laboratory parameters (e.g., International Normalized
Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug
concentrations of concomitant medications such as cytochrome P450 substrates with a
narrow therapeutic index (e.g., certain immunosuppressants) is recommended to
ensure safe and effective use. Dose adjustments of concomitant medications may be
necessary.
Table 6 provides a listing of established or potentially clinically significant drug
interactions. The drug interactions described are based on studies conducted with either
HARVONI, the components of HARVONI (ledipasvir and sofosbuvir) as individual
agents, or are predicted drug interactions that may occur with HARVONI [see Warnings
and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].
Reference ID: 5499805
Table 6
Potentially Significant Drug Interactions: Alteration in Dose or
Regimen May Be Recommended Based on Drug Interaction Studies
or Predicted Interactiona
Concomitant Drug
Class: Drug Name
Effect on
Concentrationb
Clinical Comment
Acid Reducing Agents:
↓ ledipasvir
Ledipasvir solubility decreases as pH increases. Drugs
that increase gastric pH are expected to decrease
concentration of ledipasvir.
Antacids (e.g., aluminum
and magnesium
hydroxide)
It is recommended to separate antacid and HARVONI
administration by 4 hours.
H2-receptor antagonistsc
H2-receptor antagonists may be administered
(e.g., famotidine)
simultaneously with or 12 hours apart from HARVONI at
a dose that does not exceed doses comparable to
famotidine 40 mg twice daily.
Proton-pump inhibitorsc
(e.g., omeprazole)
Proton-pump inhibitor doses comparable to omeprazole
20 mg or lower can be administered simultaneously with
HARVONI under fasted conditions.
Antiarrhythmics:
Effect on
Coadministration of amiodarone with HARVONI may
amiodarone
amiodarone,
ledipasvir, and
sofosbuvir
concentrations
unknown
result in serious symptomatic bradycardia. The
mechanism of this effect is unknown. Coadministration
of amiodarone with HARVONI is not recommended; if
coadministration is required, cardiac monitoring is
recommended [see Warnings and Precautions (5.2),
Adverse Reactions (6.2)].
digoxin
↑ digoxin
Coadministration of HARVONI with digoxin may
increase the concentration of digoxin. Therapeutic
concentration monitoring of digoxin is recommended
when coadministered with HARVONI.
Anticonvulsants:
↓ ledipasvir
Coadministration of HARVONI with carbamazepine,
carbamazepinec
↓ sofosbuvir
phenytoin, or phenobarbital is expected to decrease the
phenytoin
concentration of ledipasvir and sofosbuvir, leading to
phenobarbital
reduced therapeutic effect of HARVONI.
Coadministration is not recommended.
Antimycobacterials:
rifabutinc
rifampinc
rifapentine
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with rifampin, rifabutin, or
rifapentine is not recommended [see Warnings and
Precautions (5.3)].
HIV Antiretrovirals:
Regimens containing
↑ tenofovir
Monitor for tenofovir-associated adverse reactions in
tenofovir DF without an
patients receiving HARVONI concomitantly with a
HIV protease inhibitor/
regimen containing tenofovir DF without an HIV
ritonavir or cobicistat
protease inhibitor/ritonavir or cobicistat. Refer to
VIREAD or TRUVADA prescribing information for
recommendations on renal monitoring.
Regimens containing
tenofovir DF and an HIV
protease inhibitor/
ritonavir or cobicistat
• atazanavir/ritonavir or
cobicistat +
emtricitabine/tenofovir
DFc
• darunavir/ritonavir or
↑ tenofovir
The safety of increased tenofovir concentrations in the
setting of HARVONI and an HIV protease
inhibitor/ritonavir or cobicistat has not been established.
Consider alternative HCV or antiretroviral therapy to
avoid increases in tenofovir exposures. If
coadministration is necessary, monitor for tenofovir
associated adverse reactions. Refer to VIREAD or
TRUVADA prescribing information for recommendations
on renal monitoring.
Reference ID: 5499805
Concomitant Drug
Class: Drug Name
Effect on
Concentrationb
Clinical Comment
cobicistat +
emtricitabine/tenofovir
DFc
• lopinavir/ritonavir +
emtricitabine/tenofovir
DF
elvitegravir, cobicistat,
emtricitabine, tenofovir
DF
↑ tenofovir
The safety of increased tenofovir concentrations in the
setting of HARVONI and the combination of elvitegravir,
cobicistat, emtricitabine, and tenofovir DF has not been
established. Coadministration is not recommended.
tipranavir/ritonavir
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with tipranavir/ritonavir is
expected to decrease the concentration of ledipasvir and
sofosbuvir, leading to reduced therapeutic effect of
HARVONI. Coadministration is not recommended.
HCV Products:
simeprevirc
↑ ledipasvir
↑ simeprevir
Concentrations of ledipasvir and simeprevir are
increased when simeprevir is coadministered with
ledipasvir. Coadministration of HARVONI with
simeprevir is not recommended.
Herbal Supplements:
St. John’s wort
(Hypericum perforatum)
↓ ledipasvir
↓ sofosbuvir
Coadministration of HARVONI with St. John’s wort, a P
gp inducer, is not recommended [see Warnings and
Precautions (5.3)].
HMG-CoA Reductase
Inhibitors:
rosuvastatin
↑ rosuvastatin
Coadministration of HARVONI with rosuvastatin may
significantly increase the concentration of rosuvastatin,
which is associated with increased risk of myopathy,
including rhabdomyolysis. Coadministration of
HARVONI with rosuvastatin is not recommended.
atorvastatin
↑ atorvastatin
Coadministration of HARVONI with atorvastatin may be
associated with increased risk of myopathy, including
rhabdomyolysis. Monitor closely for HMG-CoA
reductase inhibitor-associated adverse reactions, such
as myopathy and rhabdomyolysis.
tenofovir DF = tenofovir disoproxil fumarate
a.
This table is not all inclusive.
b.
↓ = decrease, ↑ = increase
c.
These interactions have been studied in healthy adults.
7.3
Drugs without Clinically Significant Interactions with HARVONI
Based on drug interaction studies conducted with the components of HARVONI
(ledipasvir or sofosbuvir) or HARVONI, no clinically significant drug interactions have
been either observed or are expected when HARVONI is used with the following drugs
[see Clinical Pharmacology (12.3)]: abacavir, atazanavir/ritonavir, cyclosporine,
darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives,
pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil. See Table 6 for use of
HARVONI with certain HIV antiretroviral regimens [see Drug Interactions (7.2)].
Reference ID: 5499805
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
If HARVONI is administered with ribavirin, the combination regimen is contraindicated in
pregnant women and in men whose female partners are pregnant. Refer to the ribavirin
prescribing information for more information on ribavirin-associated risks of use during
pregnancy.
No adequate human data are available to establish whether or not HARVONI poses a
risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse
developmental outcomes was observed with the components of HARVONI (ledipasvir or
sofosbuvir) at exposures greater than those in humans at the recommended human
dose (RHD) [see Data]. During organogenesis in the rat and rabbit, systemic exposures
(AUC) to ledipasvir were approximately 4 (rats) and 2 (rabbits) times the exposure in
humans at the RHD, while exposures to the predominant circulating metabolite of
sofosbuvir (GS-331007) were ≥3 (rats) and 7 (rabbits) times the exposure in humans at
the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC)
to ledipasvir and GS-331007 were approximately 5 and 7 times, respectively, the
exposure in humans at the RHD.
The background risk of major birth defects and miscarriage for the indicated population
is unknown. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
respectively.
Data
Animal Data
Ledipasvir: Ledipasvir was administered orally to pregnant rats (up to 100 mg/kg/day)
and rabbits (up to 180 mg/kg/day) on gestation days 6 to 18 and 7 to 20, respectively,
and also to rats (oral doses up to 100 mg/kg/day) on gestation day 6 to lactation/post
partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal
(rats) development were observed at the highest doses tested. Systemic exposures
(AUC) to ledipasvir were ≥4 (rats) and 2 (rabbits) times the exposure in humans at the
RHD.
Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day)
and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively,
and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post
partum day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal
(rats) development were observed at the highest doses tested. Systemic exposures
(AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) were
≥3 (rats) and 7 (rabbits) times the exposure in humans at the RHD, with exposures
increasing during gestation from approximately 3 to 6 (rats) and 7 to 17 (rabbits) times
the exposure in humans at the RHD.
Reference ID: 5499805
8.2
Lactation
Risk Summary
It is not known whether ledipasvir or sofosbuvir, the components of HARVONI, or their
metabolites are present in human breast milk, affect human milk production or have
effects on the breastfed infant. When administered to lactating rats, ledipasvir was
detected in the plasma of nursing pups likely due to the presence of ledipasvir in milk,
without clear effects on nursing pups [see Data]. The predominant circulating metabolite
of sofosbuvir (GS-331007) was the primary component observed in the milk of lactating
rats, without effect on nursing pups.
The development and health benefits of breastfeeding should be considered along with
the mother’s clinical need for HARVONI and any potential adverse effects on the
breastfed child from HARVONI or from the underlying maternal condition.
If HARVONI is administered with ribavirin, the nursing mother’s information for ribavirin
also applies to this combination regimen. Refer to the ribavirin prescribing information
for more information on use during lactation.
Data
Ledipasvir: No effects of ledipasvir on growth and postnatal development were
observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure
(AUC) to ledipasvir was approximately 5 times the exposure in humans at the RHD.
Although not measured directly, ledipasvir was likely present in the milk of lactating rats,
since systemic exposure (AUC) to ledipasvir of approximately 25% that of maternal
exposure was observed in nursing pups on lactation day 10.
Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were
observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure
(AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007) was
approximately 7 times the exposure in humans at the RHD, with exposure of
approximately 2% that of maternal exposure observed in nursing pups on lactation day
10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were excreted
into the milk of lactating rats following administration of a single oral dose of sofosbuvir
(20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of
maternal plasma concentrations observed 1 hour post-dose.
8.3
Females and Males of Reproductive Potential
If HARVONI is administered with ribavirin, the information for ribavirin with regard to
pregnancy testing, contraception, and infertility also applies to this combination regimen.
Refer to ribavirin prescribing information for additional information.
8.4
Pediatric Use
The safety, pharmacokinetics, and efficacy of HARVONI for treatment of HCV
genotype 1 and 4 infection in treatment-naïve and treatment-experienced pediatric
patients 3 years of age and older without cirrhosis or with compensated cirrhosis have
been established in an open-label, multicenter clinical trial (Study 1116, N=226; 186
treatment-naïve, 40 treatment-experienced) and are comparable to that observed in
adults.
Reference ID: 5499805
The safety and efficacy of HARVONI for treatment of HCV genotypes 5 or 6 infection in
pediatric patients 3 years of age and older are supported by comparable ledipasvir,
sofosbuvir, and GS-331007 exposures between adults and pediatric patients [see
Dosage and Administration (2.2 and 2.4), Adverse Reactions (6.1), Clinical
Pharmacology (12.3), and Clinical Studies (14.3, 14.6, 14.7)]. Similar rationale is used
to support dosing recommendations for pediatric patients with HCV genotype 1 infection
who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients with
HCV genotype 1 and 4 infection who are liver transplant recipients without cirrhosis or
with compensated cirrhosis.
In patients with severe renal impairment, including those requiring dialysis, exposures of
GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical
Pharmacology (12.3)]. No data are available regarding the safety of HARVONI in
pediatric patients with renal impairment [see Use in Specific Populations (8.6)].
The safety and efficacy of HARVONI have not been established in pediatric patients
less than 3 years of age.
In a 5-year follow-up study, the long-term effects of HARVONI on pediatric growth were
assessed in 178 pediatric subjects 3 years of age and older treated with HARVONI in
Study 1116. No notable effects on growth from baseline through end of study were
observed [see Adverse Reactions (6.1)]. All subjects who had achieved SVR12
maintained SVR through end of study.
8.5
Geriatric Use
Clinical trials of HARVONI included 225 subjects aged 65 and over (9% of total number
of subjects in the clinical studies). No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out. No
dosage adjustment of HARVONI is warranted in geriatric patients [see Clinical
Pharmacology (12.3)].
8.6
Renal Impairment
No dosage adjustment of HARVONI is recommended for patients with mild, moderate,
or severe renal impairment, including ESRD requiring dialysis [see Dosage and
Administration (2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and
Clinical Studies (14.6)]. No safety data are available in subjects with both
decompensated cirrhosis and severe renal impairment, including those on dialysis.
Additionally, no safety data are available in pediatric patients with renal impairment [see
Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information
regarding use in patients with renal impairment.
8.7
Hepatic Impairment
No dosage adjustment of HARVONI is recommended for patients with mild, moderate,
or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and
Administration (2.3), Clinical Pharmacology (12.3) and Clinical Studies (14.5)].
Reference ID: 5499805
Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for
patients with decompensated cirrhosis receiving treatment with HARVONI and ribavirin
[see Adverse Reactions (6.1)].
10
OVERDOSAGE
No specific antidote is available for overdose with HARVONI. If overdose occurs, the
patient must be monitored for evidence of toxicity. Treatment of overdose with
HARVONI consists of general supportive measures including monitoring of vital signs
as well as observation of the clinical status of the patient. Hemodialysis is unlikely to
result in significant removal of ledipasvir since ledipasvir is highly bound to plasma
protein. Hemodialysis can efficiently remove the predominant circulating metabolite of
sofosbuvir, GS-331007, with an extraction ratio of 53%.
11
DESCRIPTION
Tablets
HARVONI tablets are fixed-dose combination tablets containing ledipasvir and
sofosbuvir for oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is
a nucleotide analog inhibitor of HCV NS5B polymerase.
Each 90 mg/400 mg tablet contains 90 mg ledipasvir and 400 mg sofosbuvir. The
tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone,
croscarmellose sodium, lactose monohydrate, magnesium stearate, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing
the following inactive ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake,
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Each 45 mg/200 mg tablet contains 45 mg ledipasvir and 200 mg sofosbuvir. The
tablets include the following inactive ingredients: colloidal silicon dioxide, copovidone,
croscarmellose sodium, lactose monohydrate, magnesium stearate, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing
the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and
titanium dioxide.
Pellets
HARVONI oral pellets are for oral administration, supplied as small, orange pellets in
unit-dose packets. Each unit-dose of HARVONI oral pellets contains either 45 mg
ledipasvir and 200 mg sofosbuvir or 33.75 mg ledipasvir and 150 mg sofosbuvir and the
following inactive ingredients: amino-methacrylate copolymer, colloidal silicon dioxide,
copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, iron oxide
red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, talc, and titanium dioxide.
Ledipasvir: The IUPAC name for ledipasvir is methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7
{2-[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2
azabicyclo[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5
azaspiro[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]carbamate.
Reference ID: 5499805
It has a molecular formula of C49H54F2N8O6 and a molecular weight of 889.00. It has the
following structural formula:
O
O
F
F
H
N
H3CO
H
N
N
N
H
N
N
H
N
H
N
OCH3
O
O
Ledipasvir is practically insoluble (less than 0.1 mg/mL) across the pH range of 3.0–7.5
and is slightly soluble below pH 2.3 (1.1 mg/mL).
Sofosbuvir: The IUPAC name for sofosbuvir is (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5
(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2
yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
H
O
N
O
O
O
O
N
O
HN P O
O
HO
F
Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL
across the pH range of 2–7.7 at 37oC and is slightly soluble in water.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
HARVONI is a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-
acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].
12.2 Pharmacodynamics
Cardiac Electrophysiology
Thorough QT studies have been conducted for ledipasvir and sofosbuvir.
The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended
dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose,
placebo-, and active-controlled (moxifloxacin 400 mg) three-period crossover thorough
QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the
maximum recommended dosage), ledipasvir does not prolong QTc interval to any
clinically relevant extent.
The effect of sofosbuvir 400 mg (maximum recommended dosage) and 1200 mg (three
times the maximum recommended dosage) on QTc interval was evaluated in a
randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four-
period crossover thorough QT trial in 59 healthy subjects. At a dose three times the
maximum recommended dose, sofosbuvir does not prolong QTc to any clinically
relevant extent.
Reference ID: 5499805
12.3 Pharmacokinetics
Absorption
The pharmacokinetic properties of ledipasvir, sofosbuvir, and the predominant
circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in
subjects with chronic hepatitis C. Following oral administration of HARVONI, ledipasvir
median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was
absorbed quickly and the peak median plasma concentration was observed ~0.8 to
1 hour post-dose. Median peak plasma concentration of GS-331007 was observed
between 3.5 to 4 hours post-dose.
Based on the population pharmacokinetic analysis in HCV-infected subjects, geometric
mean steady-state AUC0-24 for ledipasvir (N=2113), sofosbuvir (N=1542), and
GS-331007 (N=2113) were 7290, 1320, and 12,000 ng•hr/mL, respectively. Steady-
state Cmax for ledipasvir, sofosbuvir, and GS-331007 were 323, 618, and 707 ng/mL,
respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult
subjects and subjects with HCV infection. Relative to healthy subjects (N=191),
ledipasvir AUC0-24 and Cmax were 24% lower and 32% lower, respectively, in
HCV-infected subjects.
Effect of Food
Relative to fasting conditions, the administration of a single dose of HARVONI with a
moderate fat (~600 kcal, 25% to 30% fat) or high fat (~1000 kcal, 50% fat) meal
increased sofosbuvir AUC0-inf by approximately 2-fold, but did not significantly affect
sofosbuvir Cmax. The exposures of GS-331007 and ledipasvir were not altered in the
presence of either meal type. The response rates in Phase 3 trials were similar in HCV-
infected subjects who received HARVONI with food or without food. HARVONI can be
administered without regard to food.
Distribution
Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg
dose of [14C]-ledipasvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity
ranged between 0.51 and 0.66.
Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding
is independent of drug concentration over the range of 1 microgram/mL to
20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a
single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of
14C-radioactivity was approximately 0.7.
Metabolism
In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Evidence of slow oxidative
metabolism via an unknown mechanism has been observed. Following a single dose of
90 mg [14C]-ledipasvir, systemic exposure was almost exclusively to the parent drug
(greater than 98%). Unchanged ledipasvir is the major species present in feces.
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves
Reference ID: 5499805
sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A
(CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine
nucleotide biosynthesis pathway. Dephosphorylation results in the formation of
nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks
anti-HCV activity in vitro. After a single 400 mg oral dose of [14C]-sofosbuvir, GS-331007
accounted for approximately greater than 90% of total systemic exposure.
Elimination
Following a single 90 mg oral dose of [14C]-ledipasvir, mean total recovery of the
[14C]-radioactivity in feces and urine was approximately 87%, with most of the
radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir
excreted in feces accounted for a mean of 70% of the administered dose and the
oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that
biliary excretion of unchanged ledipasvir is a major route of elimination, with renal
excretion being a minor pathway (approximately 1%). The median terminal half-life of
ledipasvir following administration of HARVONI was 47 hours.
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose
was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in
urine, feces, and expired air, respectively. The majority of the sofosbuvir dose
recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir.
These data indicate that renal clearance is the major elimination pathway for
GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following
administration of HARVONI were 0.5 and 27 hours, respectively.
Specific Populations
Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that
race had no clinically relevant effect on the exposure of ledipasvir, sofosbuvir, and
GS-331007.
Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated
that gender had no clinically relevant effect on the exposure of sofosbuvir and
GS-331007. AUC and Cmax of ledipasvir were 77% and 58% higher, respectively, in
females than males; however, the relationship between gender and ledipasvir
exposures was not considered clinically relevant, as high response rates
(SVR12 >90%) were achieved in male and female subjects across the Phase 3
studies and the safety profiles are similar in females and males.
Pediatric Patients: The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007
were determined in HCV genotype 1, 3, or 4 infected pediatric subjects 3 years of
age and older receiving a daily dose of HARVONI as described below in Table 7.
Exposures in pediatric subjects were similar to those observed in adults.
Reference ID: 5499805
Table 7
Pharmacokinetic Properties of the Components of HARVONI in
HCV-Infected Pediatric Subjects 3 Years of Age and Oldera
Weight Group
Dose
PK Parameter
Geometric Mean (%CV)
Ledipasvir
Sofosbuvir
GS-331007
≥35 kgb
90/400 mg
AUCtau (ng•hr/mL)
11200 (45.7)
1350 (45.2)
13600 (18.9)
Cmax (ng/mL)
550 (44.2)
660 (51.1)
921 (17.8)
17 to <35 kgc
45/200 mg
AUCtau (ng•hr/mL)
8750 (46.6)
1420 (34.2)
10700 (30.9)
Cmax (ng/mL)
440 (42.7)
690 (24.8)
958 (26.1)
<17 kgd
33.75/150
mg
AUCtau (ng•hr/mL)
7460 (31.0)
1720 (23.2)
12200 (15.2)
Cmax (ng/mL)
405 (25.7)
791 (16.6)
1070 (13.0)
a. Population PK derived parameters
b. Ledipasvir N=100; Sofosbuvir N=72; GS-331007 N=100
c. Ledipasvir N=86; Sofosbuvir N=66; GS-331007 N=86
d. Ledipasvir N=9; Sofosbuvir N=9; GS-331007 N=9
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 have not been
established in pediatric subjects less than 3 years of age [see Use in Specific
Populations (8.4) and Clinical Studies (14.7)].
Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects
showed that within the age range (18 to 80 years) analyzed, age did not have a
clinically relevant effect on the exposure to ledipasvir, sofosbuvir, and GS-331007
[see Use in Specific Populations (8.5)].
Patients with Renal Impairment: The pharmacokinetics of ledipasvir were studied
with a single dose of 90 mg ledipasvir in HCV negative subjects with severe renal
impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant
differences in ledipasvir pharmacokinetics were observed between healthy subjects
and subjects with severe renal impairment.
The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild
(eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to
less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than
30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a
single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function
(eGFR greater than 80 mL/min/1.73 m2), the sofosbuvir AUC0-inf was 61%, 107%,
and 171% higher in mild, moderate, and severe renal impairment, while the
GS-331007 AUC0-inf was 55%, 88%, and 451% higher, respectively. In subjects with
ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007
AUC0-inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before
hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed
1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed
approximately 18% of administered dose [see Dosage and Administration (2.6) and
Use in Specific Populations (8.6)].
The pharmacokinetics of ledipasvir, sofosbuvir, and GS-331007 were studied in
HCV-infected subjects with severe renal impairment or ESRD requiring dialysis
Reference ID: 5499805
treated with HARVONI for 8, 12, or 24 weeks. The results were generally consistent
with those observed in HCV-negative subjects with ESRD requiring dialysis.
Patients with Hepatic Impairment: The pharmacokinetics of ledipasvir were studied
with a single dose of 90 mg ledipasvir in HCV negative subjects with severe hepatic
impairment (Child-Pugh Class C). Ledipasvir plasma exposure (AUC0-inf) was similar
in subjects with severe hepatic impairment and control subjects with normal hepatic
function. Population pharmacokinetics analysis in HCV-infected subjects indicated
that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on
the exposure of ledipasvir [see Use in Specific Populations (8.7)].
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg
sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment
(Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the
sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic
impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively.
Population pharmacokinetics analysis in HCV-infected subjects indicated that
cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the
exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) and
Clinical Studies (14.5)].
Drug Interaction Studies
Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while
GS-331007 is not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease
ledipasvir and sofosbuvir plasma concentrations, leading to reduced therapeutic effect
of HARVONI, and the use with P-gp inducers is not recommended with HARVONI [see
Warnings and Precautions (5.3)]. Coadministration with drugs that inhibit P-gp and/or
BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing
GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or
BCRP inhibitors. Neither ledipasvir nor sofosbuvir is a substrate for hepatic uptake
transporters OCT1, OATP1B1, or OATP1B3. GS-331007 is not a substrate for renal
transporters, including organic anion transporter OAT1 or OAT3, or organic cation
transporter OCT2.
Ledipasvir is subject to slow oxidative metabolism via an unknown mechanism. In vitro,
no detectable metabolism of ledipasvir by CYP enzymes has been observed. Biliary
excretion of unchanged ledipasvir is a major route of elimination. Sofosbuvir is not a
substrate for CYP and UGT1A1 enzymes. Clinically significant drug interactions with
HARVONI mediated by CYP or UGT1A1 enzymes are not expected.
The effects of coadministered drugs on the exposure of ledipasvir, sofosbuvir, and
GS-331007 are shown in Table 8 [see Drug Interactions (7)].
Reference ID: 5499805
Table 8
Drug Interactions: Changes in Pharmacokinetic Parameters for
Ledipasvir, Sofosbuvir, and the Predominant Circulating Metabolite
GS-331007 in the Presence of the Coadministered Druga
Coadministered
Drug
Dose of
Coadminis
tered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
-buvir
Dose
(mg)
N
Mean Ratio (90% CI) of Ledipasvir,
Sofosbuvir, and GS-331007 PK With/Without
Coadministered Drug
No Effect=1.00
Cmax
AUC
Cmin
Atazanavir/
ritonavir +
emtricitabine/
tenofovir DFb,c
300/100 +
200/300
once daily
90
once
daily
400
once
daily
24
ledipasvir
1.68
(1.54, 1.84)
1.96
(1.74, 2.21)
2.18
(1.91, 2.50)
sofosbuvir
1.01
(0.88, 1.15)
1.11
(1.02, 1.21)
NA
GS-331007
1.17
(1.12, 1.23)
1.31
(1.25, 1.36)
1.42
(1.34, 1.49)
Carbamazepine
300 twice
daily
ND
400
single
dose
24
sofosbuvir
0.52
(0.43, 0.62)
0.52
(0.46, 0.59)
NA
GS-331007
1.04
(0.97, 1.11)
0.99
(0.94, 1.04)
NA
Cyclosporine
600 single
dose
ND
400
single
dose
19
sofosbuvir
2.54
(1.87, 3.45)
4.53
(3.26, 6.30)
NA
GS-331007
0.60
(0.53, 0.69)
1.04
(0.90, 1.20)
NA
Darunavir/ ritonavir
800/100
once daily
90
once
daily
ND
23
ledipasvir
1.45
(1.34, 1.56)
1.39
(1.28, 1.49)
1.39
(1.29, 1.51)
ND
400
single
dose
18
sofosbuvir
1.45
(1.10, 1.92)
1.34
(1.12, 1.59)
NA
GS-331007
0.97
(0.90, 1.05)
1.24
(1.18, 1.30)
NA
Darunavir/ ritonavir
+ emtricitabine/
tenofovir DFb
800/100 +
200/300
once daily
90
once
daily
400
once
daily
23
ledipasvir
1.11
(0.99, 1.24)
1.12
(1.00, 1.25)
1.17
(1.04, 1.31)
sofosbuvir
0.63
(0.52, 0.75)
0.73
(0.65, 0.82)
NA
GS-331007
1.10
(1.04, 1.16)
1.20
(1.16, 1.24)
1.26
(1.20, 1.32)
Efavirenz/
emtricitabine/
tenofovir DFd
600/200/300
once daily
90
once
daily
400
once
daily
14
ledipasvir
0.66
(0.59, 0.75)
0.66
(0.59, 0.75)
0.66
(0.57, 0.76)
sofosbuvir
1.03
(0.87, 1.23)
0.94
(0.81, 1.10)
NA
GS-331007
0.86
(0.76, 0.96)
0.90
(0.83, 0.97)
1.07
(1.02, 1.13)
Elvitegravir/
cobicistat/
emtricitabine/
tenofovir
alafenamide
150/150/200
/10 once
daily
90
once
daily
400
once
daily
30
ledipasvir
1.65
(1.53, 1.78)
1.79
(1.64, 1.96)
1.93
(1.74, 2.15)
sofosbuvir
1.28
(1.13, 1.47)
1.47
(1.35,1.59)
NA
GS-331007
1.29
(1.24, 1.35)
1.48
(1.44, 1.53)
1.66
(1.60, 1.73)
Reference ID: 5499805
Coadministered
Drug
Dose of
Coadminis
tered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
-buvir
Dose
(mg)
N
Mean Ratio (90% CI) of Ledipasvir,
Sofosbuvir, and GS-331007 PK With/Without
Coadministered Drug
No Effect=1.00
Cmax
AUC
Cmin
Famotidine
40 single
dose
simultaneou
sly with
HARVONI
90
single
dose
400
single
dose
12
ledipasvir
0.80
(0.69, 0.93)
0.89
(0.76, 1.06)
NA
sofosbuvir
1.15
(0.88, 1.50)
1.11
(1.00, 1.24)
NA
GS-331007
1.06
(0.97, 1.14)
1.06
(1.02, 1.11)
NA
40 single
dose 12
hours prior
to HARVONI
12
ledipasvir
0.83
(0.69, 1.00)
0.98
(0.80, 1.20)
NA
sofosbuvir
1.00
(0.76, 1.32)
0.95
(0.82, 1.10)
NA
GS-331007
1.13
(1.07, 1.20)
1.06
(1.01, 1.12)
NA
Methadone
30 to 130
daily
ND
400
once
daily
14
sofosbuvir
0.95
(0.68, 1.33)
1.30
(1.00, 1.69)
NA
GS-331007
0.73
(0.65, 0.83)
1.04
(0.89, 1.22)
NA
Omeprazole
20 once
daily
simultaneou
sly with
HARVONI
90
single
dose
400
single
dose
16
ledipasvir
0.89
(0.61, 1.30)
0.96
(0.66, 1.39)
NA
sofosbuvir
1.12
(0.88, 1.42)
1.00
(0.80, 1.25)
NA
GS-331007
1.14
(1.01, 1.29)
1.03
(0.96, 1.12)
NA
20 once
daily 2 hours
prior to
ledipasvir
30
single
dose
ND
17
ledipasvir
0.52
(0.41, 0.66)
0.58
(0.48, 0.71)
NA
Rifabutin
300 once
daily
ND
400
single
dose
20
sofosbuvir
0.64
(0.53, 0.77)
0.76
(0.63, 0.91)
NA
GS-331007
1.15
(1.03, 1.27)
1.03
(0.95, 1.12)
NA
Rifampin
600 once
daily
90
single
dosee
ND
31
ledipasvir
0.65
(0.56, 0.76)
0.41
(0.36, 0.48)
NA
ND
400
single
dose
17
sofosbuvir
0.23
(0.19, 0.29)
0.28
(0.24, 0.32)
NA
GS-331007
1.23
(1.14, 1.34)
0.95
(0.88, 1.03)
NA
Simeprevir
150 once
daily
30
once
daily
ND
22
ledipasvir
1.81
(1.69, 2.94)
1.92
(1.77, 2.07)
NA
Tacrolimus
5 single
dose
ND
400
single
dose
16
sofosbuvir
0.97
(0.65, 1.43)
1.13
(0.81, 1.57)
NA
GS-331007
0.97
(0.83, 1.14)
1.00
(0.87, 1.13)
NA
NA = not available/not applicable, ND = not dosed.
tenofovir DF = tenofovir disoproxil fumarate
a. All interaction studies conducted in healthy volunteers.
b. Data generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of
atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and HARVONI
provided similar results.
c. The effects of atazanavir/ritonavir on ledipasvir and sofosbuvir are similar with or without the presence of
Reference ID: 5499805
emtricitabine/tenofovir DF.
d. Administered as ATRIPLA® (efavirenz, emtricitabine, tenofovir DF).
e. This study was conducted in the presence of two other investigational HCV direct-acting agents.
No effect on the pharmacokinetic parameters of ledipasvir, sofosbuvir, and GS-331007
was observed with raltegravir and the combination of abacavir and lamivudine;
emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; or dolutegravir, emtricitabine,
and tenofovir disoproxil fumarate.
Ledipasvir is an inhibitor of drug transporter P-gp and breast cancer resistance protein
(BCRP) and may increase intestinal absorption of coadministered substrates for these
transporters. Ledipasvir is an inhibitor of transporters OATP1B1, OATP1B3, and BSEP
only at concentrations exceeding those achieved in clinic. Ledipasvir is not an inhibitor
of transporters MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, and OCT1. The drug-drug
interaction potential of ledipasvir is primarily limited to the intestinal inhibition of P-gp
and BCRP. Clinically relevant transporter inhibition by ledipasvir in the systemic
circulation is not expected due to its high protein binding. Sofosbuvir and GS-331007
are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1,
OATP1B3, and OCT1, and GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Ledipasvir, sofosbuvir, and GS-331007 are not inhibitors or inducers of CYP or UGT1A1
enzymes.
The effects of ledipasvir or sofosbuvir on the exposure of coadministered drugs are
shown in Table 9 [see Drug Interactions (7)].
Table 9
Drug Interactions: Changes in Pharmacokinetic Parameters for
Coadministered Drug in the Presence of Ledipasvir, Sofosbuvir, or
HARVONIa
Coadministered
Drug
Dose of
Coadministered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
buvir
Dose
(mg)
N
Mean Ratio (90% CI) of
Coadministered Drug PK
With/Without Ledipasvir, Sofosbuvir,
or HARVONI
No Effect=1.00
Cmax
AUC
Cmin
Atazanavir/
ritonavir +
emtricitabine
/tenofovir DFb,c,d
atazanavir 300 once
daily
90 once
daily
400
once
daily
24
1.07
(0.99,
1.14)
1.27
(1.18,
1.37)
1.63
(1.45,
1.84)
ritonavir 100 once daily
0.86
(0.79,
0.93)
0.97
(0.89,
1.05)
1.45
(1.27,
1.64)
tenofovir DF 300 once
daily
1.47
(1.37,
1.58)
1.35
(1.29,
1.42)
1.47
(1.38,
1.57)
Darunavir/
ritonavir +
emtricitabine/
tenofovir DFb,d
darunavir 800 once
daily
90 once
daily
400
once
daily
23
1.01
(0.96,
1.06)
1.04
(0.99,
1.08)
1.08
(0.98,
1.20)
ritonavir 100 once daily
1.17
(1.01,
1.35)
1.25
(1.15,
1.36)
1.48
(1.34,
1.63)
tenofovir DF 300 once
daily
1.64
(1.54,
1.74)
1.50
(1.42,
1.59)
1.59
(1.49,
1.70)
Reference ID: 5499805
Coadministered
Drug
Dose of
Coadministered Drug
(mg)
Ledi
pasvir
Dose
(mg)
Sofos
buvir
Dose
(mg)
N
Mean Ratio (90% CI) of
Coadministered Drug PK
With/Without Ledipasvir, Sofosbuvir,
or HARVONI
No Effect=1.00
Cmax
AUC
Cmin
Elvitegravir/
cobicistat/
emtricitabine/
tenofovir
alafenamide
elvitegravir 150 once
daily
90 once
daily
400
once
daily
30
0.98
(0.90,
1.07)
1.11
(1.02,
1.20)
1.46
(1.28,
1.66)
cobicistat 150 once
daily
1.23
(1.15,
1.32)
1.53
(1.45,
1.62)
3.25
(2.88,
3.67)
tenofovir alafenamide
10 once daily
0.90
(0.73,
1.11)
0.86
(0.78,
0.95)
NA
Norelgestromin
norgestimate
0.180/0.215/0.25/ethinyl
estradiol 0.025 once
daily
90 once
daily
ND
15
1.02
(0.89,
1.16)
1.03
(0.90,
1.18)
1.09
(0.91,
1.31)
ND
400
once
daily
1.07
(0.94,
1.22)
1.06
(0.92,
1.21)
1.07
(0.89,
1.28)
Norgestrel
90 once
daily
ND
1.03
(0.87,
1.23)
0.99
(0.82,
1.20)
1.00
(0.81,
1.23)
ND
400
once
daily
1.18
(0.99,
1.41)
1.19
(0.98,
1.45)
1.23
(1.00,
1.51)
Ethinyl estradiol
90 once
daily
ND
1.40
(1.18,
1.66)
1.20
(1.04,
1.39)
0.98
(0.79,
1.22)
ND
400
once
daily
1.15
(0.97,
1.36)
1.09
(0.94,
1.26)
0.99
(0.80,
1.23)
Midazolam
2.5 single dose
90
single
dose
ND
30
1.07
(1.00,
1.14)
0.99
(0.95,
1.04)
NA
0.95
(0.87,
1.04)
0.89
(0.84,
0.95)
NA
Raltegravir
400 twice daily
90 once
daily
ND
28
0.82
(0.66,
1.02)
0.85
(0.70,
1.02)
1.15
(0.90,
1.46)
ND
400
single
dose
19
0.57
(0.44,
0.75)
0.73
(0.59,
0.91)
0.95
(0.81,
1.12)
Simeprevir
150 once daily
30 once
daily
ND
22
2.61
(2.39,
2.86)
2.69
(2.44,
2.96)
NA
Tacrolimus
5 single dose
ND
400
single
dose
16
0.73
(0.59,
0.90)
1.09
(0.84,
1.40)
NA
Tenofovir DF
300 once dailye
90 once
daily
400
once
daily
15
1.79
(1.56,
2.04)
1.98
(1.77,
2.23)
2.63
(2.32,
2.97)
NA = not available/not applicable, ND = not dosed.
tenofovir DF = tenofovir disoproxil fumarate
a. All interaction studies conducted in healthy volunteers.
b. Data generated from simultaneous dosing with HARVONI. Staggered administration (12 hours apart) of
atazanavir/ritonavir + emtricitabine/tenofovir DF or darunavir/ritonavir + emtricitabine/tenofovir DF and HARVONI
provided similar results.
Reference ID: 5499805
c. The effects of HARVONI on atazanavir and ritonavir are similar with or without the presence of
emtricitabine/tenofovir DF.
d. This magnitude of change in tenofovir exposure does not reflect the approximately 60–80% increase caused by
the effects of an HIV PI/ritonavir and the effect of food. Therefore, tenofovir exposure is approximately 130%
higher when administered as tenofovir DF + atazanavir/ritonavir + HARVONI or tenofovir DF + darunavir/ritonavir
+ HARVONI and with food as compared to the tenofovir exposure observed following fasted administration of
tenofovir DF-based regimens that do not contain an HIV PI/ritonavir and HARVONI.
e. Administered as ATRIPLA (efavirenz, emtricitabine, tenofovir DF). The effects of HARVONI on tenofovir
exposures are similar when tenofovir is administered as ATRIPLA, COMPLERA, or TRUVADA + dolutegravir.
No effect on the pharmacokinetic parameters of the following coadministered drugs was
observed with ledipasvir or sofosbuvir: abacavir, cyclosporine, darunavir/ritonavir,
dolutegravir, efavirenz, emtricitabine, lamivudine, methadone, or rilpivirine.
12.4 Microbiology
Mechanism of Action
Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication.
Resistance selection in cell culture and cross-resistance studies indicate ledipasvir
targets NS5A as its mode of action.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is
required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes
intracellular metabolism to form the pharmacologically active uridine analog
triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B
polymerase and acts as a chain terminator. In a biochemical assay, GS-461203
inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b and
4a with IC50 values of 3.3 and 2.7 microM, respectively. GS-461203 is neither an
inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA
polymerase.
Antiviral Activity
In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from
genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50
values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical
isolates from treatment-naïve HCV-infected subjects were 0. 02 nM for genotype 1a
(range 0.007–1.0 nM; N=23) and 0.006 nM for genotype 1b (range 0.002–1.0 nM;
N=34). Ledipasvir had median EC50 values ranging between 0.002 nM to 0.16 nM
against 11 genotype 4 subtypes (4a, 4d, 4n, 4r, 4o, 4c, 4f, 4k, 4l, 4m, and 4t). The
median EC50 value for subtype 4b was 199.6 nM (range 0.66–1799 nM; N=3); the two
4b isolates with EC50 values greater than 100 nM had NS5A resistance-associated
polymorphisms L30S+M31M+P58S+Y93H. The median EC50 value of ledipasvir was
0.03 nM against genotype 5a isolates (range 0.008–0.081 nM; N=35). For genotype 6,
the EC50 values for ledipasvir varied by subtype. Subtypes 6a and 6h had median EC50
values of 0.55 and 0.17 nM, respectively. For subtypes 6e, 6l, 6n, 6q, 6k, and 6m, the
median EC50 values ranged from 60.6 nM to 430.1 nM.
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from
genotypes 1a, 1b, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 5a
or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric
replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a
Reference ID: 5499805
(range 29–128 nM; N=67) and 102 nM for genotype 1b (range 45–170 nM; N=29). In
replication competent virus assays, the EC50 value of sofosbuvir against genotype 1a
was 30 nM. Evaluation of sofosbuvir in combination with ledipasvir showed no
antagonistic effect in reducing HCV RNA levels in replicon cells.
Resistance
In Cell Culture
HCV replicons with reduced susceptibility to ledipasvir have been selected in cell
culture for genotypes 1a and 1b. Reduced susceptibility to ledipasvir was associated
with the primary NS5A amino acid substitution Y93H in both genotypes 1a and 1b.
Additionally, a Q30E substitution emerged in genotype 1a replicons. Site-directed
mutagenesis of the Y93H in both genotypes 1a and 1b, as well as the Q30E
substitution in genotype 1a, conferred high levels of reduced susceptibility to
ledipasvir (fold change in EC50 greater than 1000-fold).
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell
culture for multiple genotypes including 1b, 4a, 5a, and 6a. Reduced susceptibility to
sofosbuvir was associated with the NS5B substitution S282T in all replicon
genotypes examined. An M289L substitution developed along with the S282T
substitution in genotype 5 and 6 replicons. Site-directed mutagenesis of the S282T
substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility
to sofosbuvir.
In Clinical Trials
Genotype 1
In a pooled analysis of subjects who received HARVONI in Phase 3 trials (ION-3,
ION-1, and ION-2), 37 subjects (29 with genotype 1a HCV and 8 with genotype 1b
HCV) qualified for resistance analysis due to virologic failure (35 with virologic
relapse, 2 with breakthrough on-treatment due to documented non-adherence).
Post-baseline NS5A and NS5B deep nucleotide sequence analysis data (assay
sensitivity of 1%) were available for 37/37 and 36/37 subjects’ viruses, respectively.
Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus
with emergent NS5A resistance-associated substitutions K24R, M28T/V,
Q30R/H/K/L, L31M, or Y93H/N at failure. Five of these 16 subjects’ viruses also had
baseline NS5A polymorphisms at resistance-associated amino acid positions. The
most common substitutions detected at failure were Q30R, Y93H or N, and L31M.
Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent
NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Virus from
three of these 7 subjects also had baseline NS5A polymorphisms at resistance-
associated positions. The most common substitution detected at failure was Y93H.
At failure, 38% (14/37) of virologic failure subjects’ viruses had 2 or more NS5A
substitutions at resistance-associated positions.
In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with
decompensated liver disease), there were 24 virologic failures with genotype 1
infection (20 relapsers and 4 subjects who discontinued treatment prior to achieving
Reference ID: 5499805
HCV RNA <LLOQ). Treatment-emergent NS5A resistance-associated substitutions
K24R, M28T, Q30R/H/K, L31V, H58D/P, and/or Y93H/C were detected in
14/17 (82%) genotype 1a virologic failure subjects, and R30Q, L31M, and/or Y93H/N
were detected in 6/7 (86%) genotype 1b virologic failure subjects.
In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A
resistance-associated substitutions at failure showed 20- to >243-fold reduced
susceptibility to ledipasvir.
Treatment-emergent NS5B substitutions L159 (n=1) and V321 (n=2) previously
associated with sofosbuvir failure were detected in the Phase 3 trials (ION-3, ION-1,
and ION-2). In addition, treatment-emergent NS5B substitutions at highly conserved
positions D61G (n=3), A112T (n=2), E237G (n=2), and S473T (n=1) were detected
at low frequency by next generation sequencing in treatment failure subjects infected
with HCV genotype 1a. The D61G substitution was previously described in subjects
infected with HCV genotype 1a in a liver pre-transplant trial. The E237G substitution
was detected in 3 subjects infected with HCV GT1a in the SOLAR-1 and SOLAR-2
trials. The clinical significance of these substitutions is currently unknown. The
sofosbuvir-associated resistance substitution S282T in NS5B was not detected in
any failure isolate from the Phase 3 trials. NS5B substitutions S282T, L320V/I, and
V321I in combination with NS5A substitutions L31M, Y93H, and Q30L were detected
in one subject at failure following 8 weeks of treatment with HARVONI in a Phase 2
trial.
Genotype 4, 5 or 6
Resistance analysis was performed for 6 relapse subjects infected with HCV
genotype 4 (Study 1119 and ION-4, N=3), genotype 5 (Study 1119, N=2) or
genotype 6 (ELECTRON-2, N=1) and treated with HARVONI for 12 weeks. All the
relapse subjects with NS5A sequencing data (5 of 6) had pretreatment NS5A
resistance-associated polymorphisms (single or combinations at positions 24, 28,
30, 31, and 58). NS5A resistance substitutions (Y93C or L28V) emerged in two of
the genotype 4 relapse subjects post-treatment who also had NS5A polymorphisms
pretreatment that were retained post-treatment. Two of the relapsers with genotype
4 HCV infection had an NS5B V321I substitution pretreatment, which was retained
post-treatment. Three of the relapse subjects (1 each for genotype 4, 5, and 6) had
virus with emergent sofosbuvir resistance-associated substitution S282T at relapse;
the genotype 5 relapse subject also had emergent nucleotide inhibitor substitution
M289I.
Persistence of Resistance-Associated Substitutions
Certain NS5A inhibitor resistance-associated substitutions have been found to persist
for >1 year in some patients. The long-term clinical impact of the emergence or
persistence of virus containing ledipasvir or sofosbuvir resistance-associated
substitutions is unknown.
Reference ID: 5499805
Effect of Baseline HCV Polymorphisms on Treatment Response
Adults
Genotype 1
Analyses were conducted to explore the association between pre-existing baseline
NS5A polymorphisms at resistance-associated positions and relapse rates. In the
pooled analysis of the Phase 3 trials, 23% (370/1589) of subjects’ virus had baseline
NS5A polymorphisms at resistance-associated positions (any change from reference
at NS5A amino acid positions 24, 28, 30, 31, 58, 92, or 93) identified by population
or analysis of deep nucleotide sequences with a 15% frequency threshold.
In treatment-naïve subjects whose virus had baseline NS5A polymorphisms at
resistance-associated positions in Studies ION-1 and ION-3, relapse rates were 6%
(3/48) after 8 weeks and 1% (1/113) after 12 weeks of treatment with HARVONI.
Relapse rates among subjects without baseline NS5A polymorphisms at resistance-
associated positions were 5% (8/167) after 8 weeks and 1% (3/306) after 12 weeks
of treatment with HARVONI.
In treatment-experienced subjects in Study ION-2 whose virus had baseline NS5A
polymorphisms at resistance-associated positions, relapse rates were 22% (5/23)
after 12 weeks and 0% (0/19) after 24 weeks of treatment with HARVONI. In another
study in treatment-experienced subjects (SIRIUS), 0/15 (0%) subjects with NS5A
polymorphisms at resistance-associated positions relapsed after 12 weeks of
treatment with HARVONI + ribavirin compared to 2/15 (13%) subjects treated with
24 weeks of HARVONI.
SVR was achieved in all 24 subjects (N=20 with L159F+C316N; N=1 with L159F;
and N=3 with N142T) who had baseline polymorphisms associated with resistance
to sofosbuvir and/or other NS5B nucleoside inhibitors. The NS5B S282T substitution
associated with resistance to sofosbuvir was not detected in the baseline NS5B
sequence of any subject in Phase 3 trials by population or deep nucleotide
sequence analysis.
In the SOLAR-1 and SOLAR-2 trials (liver transplant recipients or subjects with
decompensated liver disease), after 12 weeks of treatment with HARVONI and
ribavirin, relapse rates were 7% (5/71) and 5% (10/217) in genotype 1 subjects with
and without baseline NS5A polymorphisms at resistance-associated positions,
respectively.
In the Phase 3 trials and SOLAR trials, the specific baseline NS5A resistance-
associated polymorphisms observed among subjects who relapsed were M28T/V,
Q30H/R, L31M, H58D/P, and Y93H/N in genotype 1a, and L28M, L31M, A92T, and
Y93H in genotype 1b. Subjects with multiple NS5A polymorphisms at resistance-
associated positions appeared to have higher relapse rates.
Genotype 4, 5 or 6
Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in Study
1119 (N=44) and ION-4 (N=8) identified 7 HCV genotype 4 subtypes (4a, 4b, 4d, 4f,
4m, 4o, and 4r). Most subjects were infected with subtype 4a (N=32; 62%) or 4d
Reference ID: 5499805
(N=11; 21%); 1 to 3 subjects were infected with each of the other genotype 4
subtypes. There were 3 subjects with subtype 4r, 2 of whom experienced virologic
relapse, and both had a combination of 2 pretreatment NS5A resistance-associated
polymorphisms (L28M/V+L30R).
Phylogenetic analysis of HCV sequences from genotype 5-infected subjects in
Study 1119 showed almost all were subtype 5a (N=39) with one subject not having a
subtype identified at screening or by analysis.
Phylogenetic analysis of HCV sequences from genotype 6-infected subjects in
ELECTRON-2 identified 7 HCV genotype 6 subtypes (6a, 6e, 6l, 6m, 6p, 6q, and 6r).
Thirty-two percent of the subjects had subtype 6a and 24% had subtype 6e. One to
three subjects were infected with the other subtypes 6l, 6m, 6p, 6q, or 6r. The one
subject who did not achieve SVR12 had subtype 6l.
Although the data are limited, baseline HCV NS5A resistance-associated
polymorphisms are not expected to impact the likelihood of achieving SVR when
HARVONI is used as recommended to treat HCV genotype 4, 5, or 6-infected
patients, based on the low virologic failure rate observed in Study 1119 and
ELECTRON-2. The specific baseline polymorphisms observed in subjects with
virologic failure were L28M/V, L30R, and P58T for genotype 4; L31M for genotype 5;
and Q24K, F28V, R30A, and T58P for genotype 6.
Relapse occurred in 2 of 3 genotype 4 subjects who had baseline NS5B V321I, a
polymorphism at a position associated with treatment failure to sofosbuvir and other
nucleoside inhibitors; these two subjects also had baseline NS5A resistance-
associated polymorphisms. For genotype 5 and 6, SVR12 was achieved in subjects
who had baseline NS5B polymorphisms at positions associated with resistance to
sofosbuvir and other nucleoside inhibitors (N=1 with N142T in genotype 5; N=1 with
M289I in genotype 5; N=15 with M289L/I in genotype 6). The sofosbuvir resistance-
associated substitution S282T was not detected in the baseline NS5B sequence of
any subject with genotype 4, 5, or 6 HCV in clinical trials by population or deep
nucleotide sequence analysis.
Pediatrics
In Study 1116, the presence of NS5A and NS5B resistance-associated
polymorphisms did not impact treatment outcome; all pediatric subjects 3 years of
age and older with baseline NS5A or NS5B nucleoside inhibitor resistance-
associated polymorphisms (14%; 32/223) achieved SVR following 12 weeks
treatment with HARVONI.
Cross Resistance
Based on resistance patterns observed in cell culture replicon studies and HCV-infected
subjects, cross-resistance between ledipasvir and other NS5A inhibitors is expected.
Both sofosbuvir and ledipasvir were fully active against substitutions associated with
resistance to other classes of direct-acting antivirals with different mechanisms of
action, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The
efficacy of ledipasvir/sofosbuvir has not been established in patients who have
previously failed treatment with other regimens that include an NS5A inhibitor.
Reference ID: 5499805
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays,
including bacterial mutagenicity, chromosome aberration using human peripheral blood
lymphocytes, and in vivo rat micronucleus assays.
Ledipasvir was not carcinogenic in a 6-month rasH2 transgenic mouse study (up to
300 mg/kg/day). Similarly, ledipasvir was not carcinogenic in a 2-year rat study (up to
100 mg/kg/day in males and 30 mg/kg/day in females), resulting in exposures
approximately 10 and 4 times, respectively, higher than the exposure in humans at the
recommended human dose (RHD).
Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays,
including bacterial mutagenicity, chromosome aberration using human peripheral blood
lymphocytes, and in vivo mouse micronucleus assays.
Sofosbuvir was not carcinogenic in a 2-year mouse study (up to 200 mg/kg/day in males
and 600 mg/kg/day in females) and in a 2-year rat study (up to 750 mg/kg/day),
resulting in exposures of the predominant circulating metabolite GS-331007 of
approximately 4 and 18 times (in mice) and 8 and 10 times (in rats), in males and
females respectively, the exposure in humans at the RHD.
Impairment of Fertility
Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the
mean number of corpora lutea and implantation sites were reduced slightly at maternal
exposures approximately 3 times the exposure in humans at the RHD. At the highest
dose levels without effects, exposures of ledipasvir were approximately 5 and 2 times,
in males and females, respectively, the exposure in humans at the RHD.
Sofosbuvir: Sofosbuvir had no effects on embryo-fetal viability or on fertility when
evaluated in rats. At the highest dose tested, exposure to the predominant circulating
metabolite GS-331007 was approximately 5 times the exposure in humans at the RHD.
14
CLINICAL STUDIES
14.1 Description of Clinical Trials
The efficacy and safety of HARVONI were evaluated in four trials in genotype 1 HCV
mono-infected subjects including one trial exclusively in treatment-experienced subjects
with compensated cirrhosis (Child-Pugh A); one trial in genotype 1 or 4 HCV/HIV-1
coinfected subjects; two trials in genotype 4, 5, or 6 HCV mono-infected subjects; two
trials in genotype 1 or 4 HCV infected pretransplant subjects with decompensated
cirrhosis (Child-Pugh B and C) or post-transplant with Metavir F0-F3 fibrosis,
compensated cirrhosis, decompensated cirrhosis, or fibrosing cholestatic hepatitis
(FCH); two trials in subjects with severe renal impairment (one of which included
subjects requiring dialysis); and one trial in genotype 1 or 4 HCV pediatric subjects 3
years of age and older without cirrhosis or with compensated cirrhosis, as summarized
in Table 10 [see Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, and 14.7)]:
Reference ID: 5499805
Table 10
Trials Conducted with HARVONI with or without Ribavirin in
Subjects with Chronic HCV Genotype 1, 4, 5, or 6 Infection
Trial
Population
Study Arms
(Number of Subjects Treated)
ION-3 a
(NCT01851330)
GT1, TN without cirrhosis
HARVONI 8 weeks (215)
HARVONI + RBV 8 weeks (216)
HARVONI 12 weeks (216)
ION-1 a
(NCT01701401)
GT1, TN with or without cirrhosis
HARVONI 12 weeks (214)
HARVONI + RBV 12 weeks (217)
HARVONI 24 weeks (217)
HARVONI + RBV 24 weeks (217)
ION-2 a
(NCT01768286)
GT1, TEb with or without cirrhosis
HARVONI 12 weeks (109)
HARVONI + RBV 12 weeks (111)
HARVONI 24 weeks (109)
HARVONI + RBV 24 weeks (111)
SIRIUS c
(NCT01965535)
GT1, TEb with cirrhosis
HARVONI + RBV 12 Weeks (77)
HARVONI 24 weeks (77)
ION-4 a
(NCT02073656)
GT1 and GT4 HCV/HIV-1 coinfected
TN and TEb with or without cirrhosis
HARVONI 12 Weeks
(N=327 for GT1; N=8 for GT4)
1119 a
(NCT02081079)
GT4 and GT5, TN and TEb with or
without cirrhosis
HARVONI 12 Weeks
(N=44 for GT4; N=41 for GT5)
ELECTRON-2 a
(NCT01826981)
GT6, TN and TEb with or without
cirrhosis
HARVONI 12 Weeks (25)
SOLAR-1 a and
SOLAR-2 a
(NCT01938430
and
NCT02010255)
GT1 and GT4 pre-transplant with
decompensated cirrhosis or post-
transplant with Metavir F0-F3 fibrosis,
compensated cirrhosis,
decompensated cirrhosis, or FCH
HARVONI + RBV 12 Weeks (336)
HARVONI + RBV 24 weeks (334)
1116 a
(NCT02249182)
GT1 or 4 TN and TE with or without
cirrhosis in pediatric subjects
3 years of age and older
HARVONI 12 Weeks (223)
HARVONI 24 Weeks (1)
0154 a
(NCT01958281)
GT1 TN and TEb with severe RI
without dialysis
HARVONI 12 weeks (18)
4063 a
(NCT03036839)
GT1, 5, or 6 TN and TEd with or
without compensated cirrhosis, with
ESRD requiring dialysis
HARVONI 8 Weeks (45)
HARVONI 12 Weeks (12)
HARVONI 24 Weeks (6)
ESRD = End stage renal disease; RBV = ribavirin; RI = Renal impairment; TN = Treatment-naïve subjects.
a.
Open-label.
b.
TE = Treatment-experienced subjects including those who have failed a peginterferon alfa + RBV based regimen
with or without an HCV protease inhibitor.
c.
Double-blind, placebo-controlled.
d.
TE = Treatment experienced subjects including those who have failed either interferon/peginterferon alfa/ribavirin
based regimens or HCV-specific direct-acting antiviral regimens that do not include an NS5A polymerase
inhibitor.
Reference ID: 5499805
HARVONI was administered once daily by mouth in these trials. For subjects without
cirrhosis or with compensated cirrhosis who received ribavirin, the ribavirin dosage was
1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects
weighing at least 75 kg. For subjects with decompensated cirrhosis in SOLAR-1 and
SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day regardless of
transplantation status. Ribavirin dose adjustments were performed according to the
ribavirin labeling.
Serum HCV RNA values were measured during the clinical trials using the COBAS
TaqMan HCV test (version 2.0), for use with the High Pure System in ION-3, ION-1,
ION-2, SIRIUS, and ION-4 studies or the COBAS AmpliPrep/COBAS Taqman HCV test
(version 2.0) in ELECTRON-2, 1119, SOLAR-1, SOLAR-2, and 1116 studies. The
COBAS TaqMan HCV test (version 2.0) for use with the High Pure System has a lower
limit of quantification (LLOQ) of 25 IU per mL and the COBAS AmpliPrep/COBAS
Taqman HCV test (version 2.0) has a LLOQ of 15 IU per mL. Sustained virologic
response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the
cessation of treatment, was the primary endpoint in studies in adults and the key
efficacy endpoint in the study in pediatric subjects 12 years of age and older. Relapse
was a secondary endpoint, which was defined as HCV RNA greater than or equal to
LLOQ with 2 consecutive values or last available post-treatment measurement during
the post-treatment period after achieving HCV RNA less than LLOQ at end of treatment.
14.2 Clinical Trials in Subjects with Genotype 1 HCV
Treatment-Naïve Adults without Cirrhosis ─ ION-3 (Study 0108)
ION-3 was a randomized, open-label trial in treatment-naïve non-cirrhotic subjects with
genotype 1 HCV. Subjects were randomized in a 1:1:1 ratio to one of the following three
treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI for 8 weeks,
HARVONI for 12 weeks, or HARVONI + ribavirin for 8 weeks.
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 647 treated subjects, the median age was 55 years (range: 20 to 75); 58% of the
subjects were male; 78% were White; 19% were Black; 6% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 18 to 56 kg/m2); 81% had baseline HCV
RNA levels greater than or equal to 800,000 IU per mL; 80% had genotype 1a HCV
infection; 73% had non-C/C IL28B alleles (CT or TT).
Table 11 presents the SVR12 for the HARVONI treatment groups in the ION-3 trial after
8 and 12 weeks of HARVONI treatment. Ribavirin was not shown to increase the
SVR12 observed with HARVONI. Therefore, the HARVONI + ribavirin arm is not
presented in Table 11.
Reference ID: 5499805
Table 11
Study ION-3: SVR12 after 8 and 12 Weeks of Treatment in Treatment-
Naïve Non-Cirrhotic Subjects with Genotype 1 HCV
HARVONI
8 Weeks
(N=215)
HARVONI
12 Weeks
(N=216)
SVR12
94% (202/215)
96% (208/216)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
0/215
0/216
Relapsea
5% (11/215)
1% (3/216)
Otherb
1% (2/215)
2% (5/216)
SVR by Genotypec
Genotype 1a
93% (159/171)
96% (165/172)
Genotype 1b
98% (42/43)
98% (43/44)
a.
The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b.
Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow
up).
c.
One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis.
The treatment difference between the 8-week treatment of HARVONI and 12-week
treatment of HARVONI was –2.3% (97.5% confidence interval –7.2% to 2.5%). Among
subjects with a baseline HCV RNA less than 6 million IU per mL, the SVR12 was 97%
(119/123) with 8-week treatment of HARVONI and 96% (126/131) with 12-week
treatment of HARVONI.
Relapse rates by baseline viral load are presented in Table 12.
Table 12
Study ION-3: Relapse Rates by Baseline Viral Load after 8 and
12 Weeks of Treatment in Treatment-Naïve Non-Cirrhotic Subjects
with Genotype 1 HCV
HARVONI
8 Weeks
(N=215)
HARVONI
12 Weeks
(N=216)
Number of Responders at End of Treatment
215
216
Baseline HCV RNAa
HCV RNA <6 million IU/mL
2% (2/123)
2% (2/131)
HCV RNA ≥6 million IU/mL
10% (9/92)
1% (1/85)
a. HCV RNA values were determined using the Roche TaqMan Assay; a subject’s HCV RNA may vary from visit to
visit.
Treatment-Naïve Adults with or without Cirrhosis ─ ION-1 (Study 0102)
ION-1 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment
with HARVONI with or without ribavirin in 865 treatment-naïve subjects with genotype 1
HCV including those with cirrhosis. Subjects were randomized in a 1:1:1:1 ratio to
receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI for
Reference ID: 5499805
24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the
presence or absence of cirrhosis and HCV genotype (1a vs 1b).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 865 treated subjects, the median age was 54 years (range: 18 to 80); 59% of the
subjects were male; 85% were White; 12% were Black; 12% were Hispanic or Latino;
mean body mass index was 27 kg/m2 (range: 18 to 48 kg/m2); 79% had baseline HCV
RNA levels greater than or equal to 800,000 IU per mL; 67% had genotype 1a HCV
infection; 70% had non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.
Table 13 presents the SVR12 for the treatment group of HARVONI for 12 weeks in the
ION-1 trial. Ribavirin was not shown to increase SVR12 observed with HARVONI.
Therefore, the HARVONI + ribavirin arm is not presented in Table 13.
Table 13
Study ION-1: SVR12 after 12 Weeks of Treatment in Treatment-Naïve
Subjects with Genotype 1 HCV with and without Cirrhosis
HARVONI 12 Weeks
(N=214)
SVR12a
99% (210/213)
Outcome for Subjects without SVR
On-Treatment Virologic Failurea
0/213
Relapsea,b
<1% (1/212)
Othera,c
1% (2/213)
a. Excluding one subject with genotype 4 infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow
up).
SVR12 for selected subgroups are presented in Table 14.
Table 14
Study ION-1: SVR12 for Selected Subgroups after 12 Weeks of
Treatment in Treatment-Naïve Subjects with Genotype 1 HCV with
and without Cirrhosis
HARVONI 12 Weeks
(N=214)
Genotypea
Genotype 1a
98% (142/145)
Genotype 1b
100% (67/67)
Cirrhosisb
No
99% (176/177)
Yes
94% (32/34)
a.
One subject without a confirmed subtype for genotype 1 infection and one subject with genotype 4 infection were
excluded from this subgroup analysis.
b.
Subjects with missing cirrhosis status were excluded from this subgroup analysis.
Reference ID: 5499805
Previously-Treated Adults with or without Cirrhosis ─ ION-2 (Study 0109)
ION-2 was a randomized, open-label trial that evaluated 12 and 24 weeks of treatment
with HARVONI with or without ribavirin in genotype 1 HCV-infected subjects with or
without cirrhosis who failed prior therapy with an interferon-based regimen, including
regimens containing an HCV protease inhibitor. Subjects were randomized in a 1:1:1:1
ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin for 12 weeks, HARVONI
for 24 weeks, or HARVONI + ribavirin for 24 weeks. Randomization was stratified by the
presence or absence of cirrhosis, HCV genotype (1a vs 1b) and response to prior HCV
therapy (relapse/breakthrough vs nonresponse).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 440 treated subjects, the median age was 57 years (range: 24 to 75); 65% of the
subjects were male; 81% were White; 18% were Black; 9% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 19 to 50 kg/m2); 89% had baseline HCV
RNA levels greater than or equal to 800,000 IU per mL; 79% had genotype 1a HCV
infection; 88% had non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis.
Forty-seven percent (47%) of the subjects failed a prior therapy of pegylated interferon
and ribavirin. Among these subjects, 49% were relapse/breakthrough and 51% were
non-responder. Fifty-three percent (53%) of the subjects failed a prior therapy of
pegylated interferon and ribavirin with an HCV protease inhibitor. Among these
subjects, 62% were relapse/breakthrough and 38% were non-responder.
Table 15 presents the SVR12 for the HARVONI treatment groups in the ION-2 trial.
Ribavirin was not shown to increase SVR12 observed with HARVONI. Therefore, the
HARVONI + ribavirin arms are not presented in Table 15.
Table 15
Study ION-2: SVR12 after 12 and 24 Weeks of Treatment in Subjects
with Genotype 1 HCV with or without Cirrhosis Who Failed Prior
Therapy
HARVONI
12 Weeks
(N=109)
HARVONI
24 Weeks
(N=109)
SVR12
94% (102/109)
99% (108/109)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
0/109
0/109
Relapsea
6% (7/108)
0/109
Otherb
0/109
1% (1/109)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow
up).
Among the subjects with available SVR12 and SVR24 data (206/218), all subjects who
achieved SVR12 in the ION-2 study also achieved SVR24.
SVR12 and relapse rates for selected subgroups are presented in Tables 16 and 17.
Reference ID: 5499805
Table 16
Study ION-2: SVR12 for Selected Subgroups after 12 and 24 Weeks
of Treatment in Subjects with Genotype 1 HCV Who Failed Prior
Therapy
HARVONI
12 Weeks
(N=109)
HARVONI
24 Weeks
(N=109)
Genotype
Genotype 1a
95% (82/86)
99% (84/85)
Genotype 1b
87% (20/23)
100% (24/24)
Cirrhosisa
No
95% (83/87)
99% (85/86)
Yes
86% (19/22)
100% (22/22)
Prior HCV Therapy
Peg-IFN + RBV
93% (40/43)
100% (58/58)
HCV protease inhibitor + Peg-IFN + RBV
94% (62/66)
98% (49/50)
Response to Prior HCV Therapy
Relapse/Breakthrough
95% (57/60)
100% (60/60)
Non-responder
92% (45/49)
98% (48/49)
RBV = ribavirin.
a.
Subjects with missing cirrhosis status were excluded from this subgroup analysis.
Table 17
Study ION-2: Relapse Rates for Selected Subgroups after 12 and 24
Weeks of Treatment in Subjects with Genotype 1 HCV Who Failed
Prior Therapy
HARVONI
12 Weeks
(N=109)
HARVONI
24 Weeks
(N=109)
Number of Responders at End of Treatment
108
109
Cirrhosisa
No
5% (4/86)b
0% (0/86)
Yes
14% (3/22)
0% (0/22)
Presence of Baseline NS5A Resistance-Associated Polymorphismsc
No
2% (2/85)
0% (0/90)
Yes
22% (5/23)
0% (0/19)
IL28B Status
C/C
0% (0/10)
0% (0/16)
Non-C/C
7% (7/98)
0% (0/93)
a.
Subjects with missing cirrhosis status were excluded from this subgroup analysis.
b.
These 4 non-cirrhotic relapsers all had baseline NS5A resistance-associated polymorphisms.
c.
NS5A resistance-associated polymorphisms include any change at NS5A positions 24, 28, 30, 31, 58, 92, or 93.
Reference ID: 5499805
Previously-Treated Adults with Cirrhosis ─ SIRIUS (Study 0121)
SIRIUS was a randomized, double-blind and placebo-controlled trial that evaluated the
efficacy of HARVONI + ribavirin for 12 weeks or HARVONI without ribavirin for
24 weeks in genotype 1 HCV-infected subjects with compensated cirrhosis who failed
prior therapy with a Peg-IFN + ribavirin regimen followed by a subsequent Peg-IFN +
ribavirin + an HCV protease inhibitor regimen. Subjects were randomized in a 1:1 ratio
to receive placebo for 12 weeks followed by HARVONI + ribavirin for 12 weeks or
HARVONI for 24 weeks. Randomization was stratified by HCV genotype (1a vs 1b) and
response to prior HCV therapy (never achieved HCV RNA less than LLOQ vs achieved
HCV RNA less than LLOQ).
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 155 randomized subjects, the median age was 56 years (range: 23 to 77); 74%
of the subjects were male; 97% were White; mean body mass index was 27 kg/m2
(range: 19 to 47 kg/m2); 63% had genotype 1a HCV infection; 94% had non-C/C IL28B
alleles (CT or TT). One subject discontinued therapy while on placebo, and was not
included in the efficacy analysis.
The SVR12 was 96% (74/77) and 97% (75/77) in subjects treated with HARVONI +
ribavirin for 12 weeks and HARVONI for 24 weeks without ribavirin, respectively. All
5 subjects who did not achieve SVR12 relapsed.
14.3 Clinical Trials in Subjects with Genotype 4, 5, or 6 HCV
Below are trial descriptions, SVR12, and relapse data in the genotype 4, 5, and 6 HCV
populations. Trial results in the genotype 4, 5, and 6 HCV populations are based upon
limited number of subjects in some subgroups, particularly in subjects who have been
previously treated and subjects with cirrhosis.
Genotype 4
In two open-label studies (Study 1119 and ION-4), HARVONI was administered for
12 weeks to treatment-naïve and previously-treated adult subjects with genotype 4 HCV
infection. Study 1119 enrolled 44 treatment-naïve or previously-treated subjects with
genotype 4 HCV, with or without cirrhosis. ION-4 enrolled 4 treatment-naïve and
4 previously-treated subjects with genotype 4 HCV infection who were coinfected with
HIV-1, none of whom had cirrhosis.
In Study 1119, the overall SVR12 rate was 93% (41/44). SVR12 was similar based
upon prior HCV treatment history and cirrhosis status. In ION-4, all 8 subjects achieved
SVR12.
Genotype 5
In the open-label 1119 trial, HARVONI was administered for 12 weeks to 41 treatment
naïve or previously treated adult subjects with genotype 5 HCV infection, with or without
cirrhosis. The overall SVR12 was 93% (38/41). SVR12 was similar based upon prior
HCV treatment history and cirrhosis status.
Reference ID: 5499805
Genotype 6
In the open-label ELECTRON-2 trial, HARVONI was administered for 12 weeks to
25 treatment-naïve or previously treated adult subjects with genotype 6 HCV infection,
with or without cirrhosis. The overall SVR12 was 96% (24/25). SVR12 was similar
based upon prior HCV treatment history and cirrhosis status. The single subject who
relapsed discontinued study treatment early (at approximately Week 8).
14.4 Clinical Trials in Subjects Coinfected with HCV and HIV-1
ION-4 was an open-label clinical trial that evaluated the safety and efficacy of 12 weeks
of treatment with HARVONI without ribavirin in HCV treatment-naïve and previously
treated adult subjects with genotype 1 or 4 HCV infection who were coinfected with HIV
1. Treatment-experienced subjects had failed prior treatment with Peg-IFN + ribavirin,
Peg-IFN + ribavirin + an HCV protease inhibitor, or sofosbuvir + ribavirin. Subjects were
on a stable HIV-1 antiretroviral therapy that included emtricitabine + tenofovir disoproxil
fumarate, administered with efavirenz, rilpivirine, or raltegravir.
Of the 335 treated subjects, the median age was 52 years (range: 26 to 72); 82% of the
subjects were male; 61% were White; 34% were Black; mean body mass index was
27 kg/m2 (range: 18 to 66 kg/m2); 75% had genotype 1a HCV infection; 2% had
genotype 4 infection; 76% had non-C/C IL28B alleles (CT or TT); and 20% had
compensated cirrhosis. Fifty-five percent (55%) of the subjects were treatment-
experienced.
Table 18 presents the SVR12 in the ION-4 trial after 12 weeks of HARVONI treatment.
Table 18
Study ION-4: SVR12 in Subjects with Genotype 1 or 4 HCV
Coinfected with HIV-1
HARVONI 12 Weeks
(N=335)
SVR12
96% (321/335)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
<1% (2/335)
Relapsea
3% (10/333)
Otherb
<1% (2/335)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b.
Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to follow
up).
SVR12 rates were 94% (63/67) in subjects with cirrhosis and 98% (46/47) in subjects
who were previously treated and had cirrhosis. The relapse rate in the ION-4 trial in
Black subjects was 9% (10/115), all of whom were IL28B non-CC genotype, and none
in non-Black subjects (0/220). In the ION-1, ION-2, and ION-3 HCV mono-infection
studies, relapse rates were 3% (10/305) in Black subjects and 2% (26/1637) in non-
Black subjects.
Reference ID: 5499805
No subject had HIV-1 rebound during the study. The percentage of CD4+ cells did not
change during treatment. Median CD4+ cell count increase of 29 cells/mm3 was
observed at the end of treatment with HARVONI for 12 weeks.
14.5 Clinical Trials in Liver Transplant Recipients and/or Subjects with
Decompensated Cirrhosis
SOLAR-1 and SOLAR-2 were two open-label trials that evaluated 12 and 24 weeks of
treatment with HARVONI in combination with ribavirin in HCV treatment-naïve and
previously treated adult subjects with genotype 1 and 4 infection who had undergone
liver transplantation and/or who had decompensated liver disease. The two trials were
identical in study design. Subjects were enrolled in one of the seven groups in the trials
based on liver transplantation status and severity of hepatic impairment (see Table 19).
Subjects with a CPT score greater than 12 were excluded. Within each group, subjects
were randomized in a 1:1 ratio to receive HARVONI + ribavirin for 12 weeks or
HARVONI + ribavirin for 24 weeks. For subjects with decompensated cirrhosis in
SOLAR-1 and SOLAR-2 studies, the starting ribavirin dosage was 600 mg per day
regardless of transplantation status. Ribavirin dose adjustments were performed
according to the ribavirin labeling [see Clinical Studies (14.1)].
Demographics and baseline characteristics were balanced across the treatment groups.
Of the 670 treated subjects, the median age was 59 years (range: 21 to 81); 77% of the
subjects were male; 91% were White; mean body mass index was 28 kg/m2 (range:
18 to 49 kg/m2); 94% and 6% had genotype 1 and 4 HCV infection, respectively; 78% of
the subjects failed a prior HCV therapy.
Table 19 presents the pooled SVR12 rates for SOLAR-1 and SOLAR-2 in subjects with
genotype 1 HCV treated with HARVONI + ribavirin for 12 weeks. The SVR12 rates
observed with 24 weeks of HARVONI + ribavirin were similar to the SVR12 rates
observed with 12 weeks of treatment. Therefore, the results for the HARVONI + ribavirin
24 weeks arm are not presented in Table 19.
Reference ID: 5499805
Table 19
Studies SOLAR-1 and SOLAR-2: SVR12 and Relapse Rates After
12 Weeks of Treatment with HARVONI and Ribavirin in Subjects with
Genotype 1 HCV Who Were Post Liver Transplant and/or Who Had
Decompensated Liver Disease
HARVONI + RBV 12 weeks
(N=307)
SVR12 (N=300)a,b
Relapse (N=288)a,b,c
Pre-transplant
CPT B
87% (45/52)
12% (6/51)
CPT C
88% (35/40)
5% (2/37)
Post-transplant
Metavir score F0-F3
95% (94/99)
3% (3/97)
CPT A
98% (55/56)
0% (0/55)
CPT B
89% (41/46)
2% (1/42)
CPT C
57% (4/7)
33% (2/6)
a.
Five subjects transplanted prior to post-treatment Week 12 with HCV RNA<LLOQ at last measurement prior to
transplant were excluded.
b.
Two subjects were excluded due to failure to meet the inclusion criteria for any of the treatment groups (i.e., did
not have decompensated cirrhosis and had also not received a liver transplant).
c.
Twelve subjects were excluded from relapse analysis because they died (N=11) or withdrew consent (N=1) prior
to reaching the 12-week post-treatment follow-up visit.
There were 7 subjects with fibrosing cholestatic hepatitis in the 12-week treatment arm,
and all subjects achieved SVR12.
In genotype 4 HCV post-transplant subjects without cirrhosis or with compensated
cirrhosis treated with HARVONI + ribavirin for 12 weeks (N=12), the SVR12 rate was
similar to rates reported with genotype 1; no subjects relapsed. Available data in
subjects with genotype 4 HCV who had decompensated cirrhosis (pre- and post-liver
transplantation) were insufficient for dosing recommendations; therefore, these results
are not presented.
14.6 Clinical Trials in Adults with Severe Renal Impairment, Including those
Requiring Dialysis
Trial 0154 was an open-label clinical trial that evaluated 12 weeks of treatment with
HARVONI in 18 treatment-naïve and treatment-experienced (subjects with prior
exposure to an HCV NS5B polymerase inhibitor were excluded) genotype 1 HCV-
infected adults with severe renal impairment not requiring dialysis. At baseline, two
subjects (11%) had cirrhosis and the mean eGFR was 24.9 mL/min (range: 9.0 to 39.6).
The SVR rate was 100% (18/18).
As shown in the table below, Trial 4063 was an open-label three-arm clinical trial that
evaluated 8, 12, and 24 weeks of treatment with HARVONI in a total of 63 adults with
chronic HCV infection and ESRD requiring dialysis. Of the 63 subjects, 10% had
cirrhosis, 24% were treatment-experienced, 95% were on hemodialysis, and 5% were
on peritoneal dialysis; mean duration on dialysis was 12 years (range: 0.2 to 43 years).
The SVR rates for the 8, 12, and 24 week HARVONI treatment groups are shown in
Table 20.
Reference ID: 5499805
Table 20
Trial 4063: SVR12 after 8, 12, and 24 Weeks of Treatment in Adults
with HCV with or without Cirrhosis and with Severe Renal
Impairment Requiring Dialysis
HARVONI
8 Weeks
(N=45)
HARVONI
12 Weeks
(N=12)
HARVONI
24 Weeks
(N=6)
Population
Treatment-naïve,
GT 1 HCV
Non-cirrhotic
Treatment-naïve
and treatment
experienceda GT
1, 5, 6b HCV
Non-cirrhotic
Treatment-
experienced, GT 1
HCV with
compensated
cirrhosis
SVR12
93% (42/45)
100% (12/12)
83% (5/6)
Outcome for Subjects without SVR
On-Treatment Virologic Failure
0/45
0/12
0/6
Relapse
0/44
0/12
0/6
Otherc
7% (3/45)
0/12
17% (1/6)
a.
Subjects with prior exposure to any HCV NS5A inhibitor were excluded.
b.
One subject had an indeterminant HCV GT.
c.
“Other” outcomes includes subjects who did not achieve SVR and did not meet virologic failure criteria. All
subjects who failed without virologic relapse or on-treatment virologic failure died prior to follow-up Week 12.
None of these deaths were assessed as treatment-related.
14.7 Clinical Trial in Pediatric Subjects
The efficacy of HARVONI was evaluated in an open-label trial (Study 1116) in 224 HCV
treatment-naïve (N=186) and treatment-experienced (N=38) pediatric subjects 3 years
of age or older. This study evaluated 12 weeks of treatment with HARVONI once daily
in genotype 1 (N=183) or genotype 4 (N=3) treatment-naive subjects without cirrhosis or
with compensated cirrhosis; genotype 1 treatment-experienced subjects without
cirrhosis (N=37); and evaluated 24 weeks of treatment with HARVONI once daily in one
genotype 1 subject who was both treatment-experienced and cirrhotic.
Subjects 12 Years to <18 Years of Age: HARVONI was evaluated in 100 subjects 12
years to <18 years of age with HCV genotype 1 infection. Demographics and baseline
characteristics were balanced across treatment-naïve and treatment-experienced
subjects (patients had failed an interferon based regimen with or without ribavirin). The
median age was 15 years (range: 12 to 17); 63% of the subjects were female; 91%
were White, 7% were Black, and 2% were Asian; 13% were Hispanic/Latino; mean body
mass index was 23 kg/m2 (range: 13.1 to 36.6 kg/m2); mean weight was 61 kg (range
33 to 126 kg); 55% had baseline HCV RNA levels greater than or equal to
800,000 IU/mL; 81% had genotype 1a HCV infection. One subject (treatment-naïve)
had known compensated cirrhosis. The majority of subjects (84%) had been infected
through vertical transmission.
Reference ID: 5499805
The SVR12 rate was 98% overall (98% [78/80] in treatment-naïve subjects and
100% [20/20] in treatment-experienced subjects). No subject experienced on-treatment
virologic failure or relapse. Two subjects were lost to follow-up.
Subjects 6 Years to <12 Years of Age: HARVONI was evaluated in 90 subjects 6 years
to <12 years of age with HCV genotype 1 or 4 infection. Among these subjects, 72
(80%) were treatment-naïve and 18 (20%) were treatment-experienced. Eighty-nine of
the subjects (87 with genotype 1 HCV infection and 2 with genotype 4 HCV infection)
were treated with HARVONI for 12 weeks, 1 subject with genotype 1 HCV infection was
treated with HARVONI for 24 weeks. The median age was 9 years (range: 6 to 11);
59% of the subjects were male; 79% were White, 8% were Black, and 6% were Asian;
10% were Hispanic/Latino; mean body mass index was 18 kg/m2 (range: 13 to
31kg/m2); mean weight was 33 kg (range 18 to 76 kg); 59% had baseline HCV RNA
levels greater than or equal to 800,000 IU/mL; 86% had genotype 1a HCV infection; 2
subjects (1 treatment-naïve, 1 treatment-experienced) had known compensated
cirrhosis. The majority of subjects (97%) had been infected through vertical
transmission.
The SVR12 rate was 99% (86/87) in subjects with genotype 1 HCV infection, and 100%
(2/2) in subjects with genotype 4 HCV infection. The one genotype 1 subject treated
with HARVONI for 24 weeks also achieved SVR12. The one subject (genotype 1) who
did not achieve SVR12 and relapsed had been treated with HARVONI for 12 weeks.
Subjects 3 Years to <6 Years of Age: HARVONI was evaluated in 34 subjects 3 years to
<6 years of age with HCV genotype 1 (N = 33) or genotype 4 (N = 1) infection. All of the
subjects were treatment-naïve and treated with HARVONI for 12 weeks. The median
age was 5 years (range: 3 to 5); 71% of the subjects were female; 79% were White, 3%
were Black, and 6% were Asian; 18% were Hispanic/Latino; mean body mass index
was 17 kg/m2 (range: 13 to 25 kg/m2); mean weight was 19 kg (range 11 to 34 kg); 56%
had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 82% had
genotype 1a HCV infection; no subjects had known cirrhosis. All subjects (100%) had
been infected through vertical transmission.
The SVR12 rate was 97% (32/33) in subjects with genotype 1 HCV infection, and the
one subject with genotype 4 HCV infection also achieved SVR12. One subject
prematurely discontinued study treatment due to an adverse event.
16
HOW SUPPLIED/STORAGE AND HANDLING
Tablets
HARVONI tablets 90 mg/400 mg are orange, diamond-shaped, film-coated, debossed
with “GSI” on one side and “7985” on the other side of the tablet. Each bottle contains
28 tablets (NDC 61958-1801-1), a silica gel desiccant and polyester coil, and is closed
with a child-resistant closure.
HARVONI tablets, 45 mg/200 mg, are white, capsule-shaped, film-coated, debossed
with “GSI” on one side and “HRV” on the other side of the tablet. Each bottle contains
28 tablets (NDC 61958-1803-1), a silica gel desiccant and polyester coil, and is closed
with a child-resistant closure.
Reference ID: 5499805
• Store below 30 °C (86 °F).
• Dispense only in original container.
• Do not use if seal over bottle opening is broken or missing.
Oral Pellets
HARVONI pellets, 45 mg/200 mg, are orange pellets supplied as unit-dose packets in
cartons. Each carton contains 28 packets (NDC 61958-1804-1).
HARVONI pellets, 33.75 mg/150 mg, are orange pellets supplied as unit-dose packets
in cartons. Each carton contains 28 packets (NDC 61958-1805-1).
• Store below 30 °C (86 °F).
• Do not use if carton tamper-evident seal or packet seal is broken or damaged.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during
or after treatment of HCV infection. Advise patients to tell their healthcare provider if
they have a history of HBV infection [see Warnings and Precautions (5.1)].
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Advise patients to seek medical evaluation immediately for symptoms of bradycardia
such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness,
excessive tiredness, shortness of breath, chest pain, confusion, or memory problems
[see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions
(7.2)].
Drug Interactions
Inform patients that HARVONI may interact with other drugs. Advise patients to report to
their healthcare provider the use of any other prescription or nonprescription medication
or herbal products including St. John’s wort [see Warnings and Precautions (5.2, 5.3)
and Drug Interactions (7)].
Pregnancy
Advise patients to avoid pregnancy during combination treatment with HARVONI and
ribavirin and for 6 months after completion of treatment. Inform patients to notify their
healthcare provider immediately in the event of a pregnancy [see Use in Specific
Populations (8.1)].
Reference ID: 5499805
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus
during treatment or in the event of treatment failure should be taken.
Administration
Advise patients to take HARVONI every day at the regularly scheduled time with or
without food. Inform patients that it is important not to miss or skip doses and to take
HARVONI for the duration that is recommended by the physician.
For HARVONI oral pellets, advise patients or caregivers to read and follow the
Instructions for Use for preparing the correct dose.
Manufactured and distributed by:
Gilead Sciences, Inc.
Foster City, CA 94404
HARVONI, ATRIPLA, COMPLERA, TRUVADA and VIREAD are trademarks of Gilead
Sciences, Inc., or its related companies. All other trademarks referenced herein are the
property of their respective owners.
© 2024 Gilead Sciences, Inc. All rights reserved.
205834-GS-012
Reference ID: 5499805
Patient Information
HARVONI® (har-VOE-nee)
HARVONI® (har-VOE-nee)
(ledipasvir and sofosbuvir)
(ledipasvir and sofosbuvir)
tablets
oral pellets
Important: If you take HARVONI with ribavirin, you should also read the Medication Guide for ribavirin.
What is the most important information I should know about HARVONI?
HARVONI can cause serious side effects, including,
Hepatitis B virus reactivation: Before starting treatment with HARVONI, your healthcare provider will do blood tests
to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could
become active again during or after treatment of hepatitis C virus with HARVONI. Hepatitis B virus becoming active
again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider
will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking HARVONI.
For more information about side effects, see the section “What are the possible side effects of HARVONI?”
What is HARVONI?
HARVONI is a prescription medicine used to treat adults and children 3 years of age and older with chronic (lasting a
long time) hepatitis C virus (HCV):
•
genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
•
genotype 1 infection with advanced cirrhosis (decompensated) in combination with ribavirin
•
genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis who have had a liver transplant, in
combination with ribavirin
It is not known if HARVONI is safe and effective in children with HCV under 3 years of age.
Before taking HARVONI, tell your healthcare provider about all of your medical conditions, including if you:
•
have ever had hepatitis B virus infection
•
have liver problems other than hepatitis C infection
•
have had a liver transplant
•
have kidney problems or you are on dialysis
•
have HIV infection
•
are pregnant or plan to become pregnant. It is not known if HARVONI will harm your unborn baby.
o
Males and females who take HARVONI in combination with ribavirin should also read the ribavirin
Medication Guide for important pregnancy, contraception, and infertility information.
•
are breastfeeding or plan to breastfeed. It is not known if HARVONI passes into your breast milk.
o
Talk to your healthcare provider about the best way to feed your baby during treatment with HARVONI.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. HARVONI and other medicines may affect each other. This can cause
you to have too much or not enough HARVONI or other medicines in your body. This may affect the way HARVONI or
your other medicines work, or may cause side effects. Keep a list of your medicines to show your healthcare
provider and pharmacist.
•
You can ask your healthcare provider or pharmacist for a list of medicines that interact with HARVONI.
Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you
if it is safe to take HARVONI with other medicines.
How should I take HARVONI?
•
Take HARVONI exactly as your healthcare provider tells you to take it. Do not change your dose unless your
healthcare provider tells you to.
•
Do not stop taking HARVONI without first talking with your healthcare provider.
•
Take HARVONI tablets or oral pellets by mouth, with or without food.
•
It is important that you do not miss or skip doses of HARVONI during treatment.
•
For adults the usual dose of HARVONI is one 90/400 mg tablet each day.
•
For children 3 years of age and older your healthcare provider will prescribe the right dose of HARVONI tablets or
oral pellets based on your child’s body weight.
o
Tell your healthcare provider if your child has problems with swallowing tablets.
o
If your healthcare provider prescribes HARVONI oral pellets for your child, see “How should I give
HARVONI oral pellets to my child.”
Reference ID: 5499805
•
Do not miss a dose of HARVONI. Missing a dose lowers the amount of medicine in your blood. Refill your
HARVONI prescription before you run out of medicine.
If you take too much HARVONI, call your healthcare provider or go to the nearest hospital emergency room right
away.
How should I give HARVONI oral pellets to my child?
See the detailed Instructions for Use for information about how to give or take a dose of HARVONI oral
pellets.
•
Administer HARVONI oral pellets exactly as instructed by your healthcare provider.
•
Do not open the packet until ready to use.
•
Hold the HARVONI pellets packet with the cut line on top.
•
Shake the HARVONI pellets packet gently to settle the pellets.
•
Tear or cut the HARVONI packet along the cut line.
•
HARVONI oral pellets can be taken right in the mouth without chewing, or with food.
•
If HARVONI pellets are taken with food, sprinkle the pellets on one or more spoonfuls of non-acidic soft food at or
below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed potato, and ice
cream. Take HARVONI pellets within 30 minutes of gently mixing with food and swallow the entire contents
without chewing to avoid a bitter taste.
•
Do not store any leftover HARVONI mixture (oral pellets mixed with food) for use at a later time. Throw away any
unused portion.
What are the possible side effects of HARVONI?
HARVONI can cause serious side effects, including:
•
Hepatitis B virus reactivation. See “What is the most important information I should know about HARVONI?”
•
Slow heart rate (bradycardia). HARVONI treatment may result in slowing of the heart rate along with other
symptoms when taken with amiodarone (Cordarone®, Nexterone®, Pacerone®), a medicine used to treat certain
heart problems. In some cases bradycardia has led to death or the need for a heart pacemaker when amiodarone
is taken with HARVONI. Get medical help right away if you take amiodarone with HARVONI and get any of the
following symptoms:
•
fainting or near-fainting
•
weakness
•
chest pains
•
dizziness or lightheadedness
•
extreme tiredness
•
confusion
•
not feeling well
•
shortness of breath
•
memory problems
The most common side effects of HARVONI include:
•
tiredness
•
headache
•
weakness
These are not all the possible side effects of HARVONI. For more information, ask your healthcare provider or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store HARVONI?
•
Store HARVONI tablets or pellets below 86°F (30°C).
•
Keep HARVONI tablets in the original container.
•
Do not use HARVONI tablets if the seal over the bottle opening is broken or missing.
•
Do not use HARVONI pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or damaged.
Keep HARVONI and all medicines out of the reach of children.
General information about the safe and effective use of HARVONI
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
HARVONI for a condition for which it was not prescribed. Do not give HARVONI to other people, even if they have the
same symptoms you have. It may harm them.
You can ask your healthcare provider or pharmacist for information about HARVONI that is written for health
professionals.
What are the ingredients in HARVONI?
Active ingredients: ledipasvir and sofosbuvir
Inactive ingredients, Tablets 90/400 mg: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose
monohydrate, magnesium stearate, and microcrystalline cellulose.
The tablet film-coat contains: FD&C yellow #6/sunset yellow FCF aluminum lake, polyethylene glycol, polyvinyl
alcohol, talc, and titanium dioxide.
Inactive ingredients, Tablets 45/200 mg: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose
monohydrate, magnesium stearate, and microcrystalline cellulose.
Reference ID: 5499805
The tablet film-coat contains: polyethylene glycol, polyvinyl alcohol partially hydrolyzed, talc, and titanium dioxide.
Inactive ingredients, Oral Pellets: amino-methacrylate copolymer, colloidal silicon dioxide, copovidone,
croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
Manufactured and distributed by:
Gilead Sciences, Inc., Foster City, CA 94404
For more information, call 1-800-445-3235 or go to www.HARVONI.com.
HARVONI is a trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.
©2024 Gilead Sciences, Inc. All rights reserved.
205834-GS-012
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 03/2020
Reference ID: 5499805
I
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INSTRUCTIONS FOR USE
HARVONI® (har-VOE-nee)
(ledipasvir and sofosbuvir)
pellets, for oral use
Read the Patient Information that comes with HARVONI oral pellets for important information about HARVONI.
This Instructions for Use contains information on how to take HARVONI oral pellets. Be sure you understand and follow
the instructions. If you have any questions, ask your healthcare provider or pharmacist.
Important Information You Need to Know Before Taking HARVONI oral pellets
•
For oral use only (take by mouth with or without food).
•
Do not open the HARVONI oral pellet packet(s) until ready to use.
•
HARVONI oral pellets are orange pellets supplied as single-use packets in cartons. Each carton contains 28
packets.
•
Do not use HARVONI oral pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or
damaged.
Preparing a dose of HARVONI oral pellets to be taken with food:
Before you prepare a dose of HARVONI oral pellets to be taken with food, gather the following supplies:
•
Daily HARVONI oral pellet packet(s), as prescribed by your healthcare provider
•
One or more spoonfuls of non-acidic soft food such as pudding, chocolate syrup, mashed potato, or ice cream
•
Bowl
•
Spoon
•
Scissors (optional)
Step 1: Add one or more spoonfuls of non-acidic soft food to the bowl first.
Step 2: Hold the HARVONI oral pellets packet
Step 3: Shake the packet gently to settle the
with the cut line on top (see Figure A).
pellets to the bottom of the packet (see Figure B).
Figure A
Figure B
Reference ID: 5499805
Step 4: Cut the packet along the cut line with scissors (see Figure C), or fold the packet back at the tear line (see
Figure D) and tear open (see Figure E).
OR
Figure C
Figure D
Figure E
Step 5: Carefully pour the entire contents of the prescribed number of HARVONI oral pellet packet(s) onto the food in
the bowl and gently mix with a spoon (see Figure F). Make sure that no HARVONI oral pellets remain in the packet(s).
Figure F
Step 6: Take the HARVONI oral pellets and food mixture within 30 minutes without chewing to avoid a bitter taste.
Ensure all of the HARVONI oral pellets are taken.
Preparing a dose of HARVONI oral pellets to be taken without food:
Before you prepare a dose of HARVONI oral pellets to be taken without food, gather the following supplies:
•
Daily HARVONI oral pellet packet(s), as prescribed by your healthcare provider
•
Scissors (optional)
•
Water (optional)
Reference ID: 5499805
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Step 1: Hold the HARVONI oral pellets packet
Step 2: Shake the packet gently to settle the
with the cut line on top (see Figure G).
pellets to the bottom of the packet (see Figure H).
Figure G
Figure H
Step 3: Cut the packet along the cut line with scissors (see Figure I), or fold the packet back at the tear line (see
Figure J) and tear open (see Figure K).
OR
Figure I
Figure J
Figure K
Reference ID: 5499805
Step 4: Pour the entire contents of the HARVONI oral pellets packet directly in the mouth and swallow without chewing to
avoid a bitter taste (see Figure L). Water may be taken after swallowing the pellets, if needed. Make sure that no HARVONI
oral pellets remain in the packet. If your healthcare provider prescribed more than one HARVONI oral pellets packet, repeat
Steps 1 through 4.
Figure L
Storing HARVONI oral pellets
•
Store HARVONI pellets below 86°F (30°C).
•
Keep HARVONI oral pellets and all medicines out of the reach of children.
Disposing of HARVONI oral pellets
•
Throw away any unused portion. Do not store and reuse any leftover HARVONI mixture (pellets mixed with food).
For more information, call 1-800-445-3235 or go to www.HARVONI.com.
Manufactured for and distributed by: Gilead Sciences, Inc., Foster City, CA 94404
HARVONI is a trademark of Gilead Sciences, Inc., or its related companies.
© 2024 Gilead Sciences, Inc. All rights reserved.
205834-GS-012
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: March 2020
Reference ID: 5499805
| custom-source | 2025-02-12T15:48:05.442665 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205834s036,212477s006lbl.pdf', 'application_number': 212477, 'submission_type': 'SUPPL ', 'submission_number': 6} |
80,697 | HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IMCIVREE safely and effectively. See full prescribing information for
IMCIVREE
IMCIVREE® (setmelanotide) injection, for subcutaneous use
Initial U.S. Approval: 2020
_________________ RECENT MAJOR CHANGES _________________
Indications and Usage (1)
12/2024
Dosage and Administration (2.4, 2.5)
12/2024
Warnings and Precautions (5.4)
12/2024
__________________ INDICATIONS AND USAGE _________________
IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated to reduce
excess body weight and maintain weight reduction long term by reducing
hunger and food intake and increasing energy expenditure in adults and
pediatric patients 2 years of age and older with syndromic or monogenic
obesity due to:
• Bardet-Biedl syndrome (BBS). (1)
• Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type
1 (PCSK1), or leptin receptor (LEPR) deficiency as determined by an
FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR
genes that are interpreted as pathogenic, likely pathogenic, or of uncertain
significance (VUS). (1)
Limitations of Use:
IMCIVREE is not indicated for the treatment of patients with the following
conditions as IMCIVREE would not be expected to be effective:
• Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC,
PCSK1, or LEPR variants classified as benign or likely benign. (1)
• Other types of obesity not related to BBS or POMC, PCSK1 or LEPR
deficiency, including obesity associated with other genetic syndromes and
general (polygenic) obesity. (1)
_______________ DOSAGE AND ADMINISTRATION ______________
• Select patients for treatment who have a clinical diagnosis of BBS or who
have genetically determined or suspected deficiency of POMC, PCSK1, or
LEPR. (2.1)
• Recommended starting dosage injected subcutaneously for:
o Adults and pediatric patients aged 12 years and older is 2 mg (0.2 mL)
once daily for 2 weeks. (2.2)
o Pediatric patients aged 6 to less than 12 years is 1 mg (0.1 mL) once
daily for 2 weeks. (2.3)
o Pediatric patients aged 2 to less than 6 years is 0.5 mg (0.05 mL) once
daily for 2 weeks. (2.4)
• Recommended maintenance dosage for adults and pediatric patients aged 6
years and older is 3 mg (0.3 mL) injected subcutaneously once daily. (2.2,
2.3)
• Recommended maintenance dose for pediatric patients aged 2 to less than 6
years is determined by body weight. (2.4)
• For recommended dosage in patients with renal impairment, see Full
Prescribing Information. (2.5)
• For titration and administration recommendations, see Full Prescribing
Information. (2.2, 2.3, 2.4, 2.5, 2.6)
_____________ DOSAGE FORMS AND STRENGTHS ______________
Injection: 10 mg/mL solution in a 1 mL multiple-dose vial (3)
___________________ CONTRAINDICATIONS ___________________
Prior serious hypersensitivity to setmelanotide or any of the excipients in
IMCIVREE (4)
_______________ WARNINGS AND PRECAUTIONS _______________
• Disturbance in Sexual Arousal: Spontaneous penile erections in males and
sexual adverse reactions in females have occurred. Inform patients that
these events may occur and instruct patients who have an erection lasting
longer than 4 hours to seek emergency medical attention. (5.1)
• Depression and Suicidal Ideation: Depression and suicidal ideation have
occurred. Monitor patients for new onset or worsening depression or
suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if
patients experience suicidal thoughts or behaviors, or clinically significant
or persistent depression symptoms occur. (5.2)
• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
anaphylaxis) have been reported. If suspected, advise patients to promptly
seek medical attention and discontinue IMCIVREE. (5.3).
• Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and
Development of New Melanocytic Nevi: Generalized increased skin
pigmentation, darkening of pre-existing nevi, and development of new nevi
have occurred. Perform a full body skin examination prior to initiation and
periodically during treatment to monitor pre-existing and new pigmentary
lesions. (5.4)
• Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in
Neonates and Low Birth Weight Infants: IMCIVREE is not approved for
use in neonates or infants. Serious and fatal adverse reactions including
“gasping syndrome” can occur in neonates and low birth weight infants
treated with benzyl alcohol-preserved drugs. (5.5)
___________________ ADVERSE REACTIONS ___________________
Most common adverse reactions (incidence ≥20%) included skin
hyperpigmentation, injection site reactions, nausea, headache, diarrhea,
abdominal pain, vomiting, depression, and spontaneous penile erection. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Rhythm
Pharmaceuticals at 1-833-789-6337 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
______________ USE IN SPECIFIC POPULATIONS _______________
Lactation: Not recommended when breastfeeding. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Patient Selection
2.2
Recommended Dosage in Adults and Pediatric Patients Aged 12
Years and Older
2.3
Recommended Dosage in Pediatric Patients Aged 6 to Less Than
12 Years
2.4
Recommended Dosage in Pediatric Patients Aged 2 to Less Than
6 Years
2.5
Recommended Dosage in Patients with Renal Impairment
2.6
Administration Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Disturbance in Sexual Arousal
5.2
Depression and Suicidal Ideation
5.3
Hypersensitivity Reactions
5.4
Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and
Development of New Melanocytic Nevi
5.5
Risk of Serious Adverse Reactions Due to Benzyl Alcohol
Preservative in Neonates and Low Birth Weight Infants
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 Immunogenicity
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6
Years and Older)
Reference ID: 5500420
14.2 POMC, PCSK1, and LEPR Deficiency (Adults and Pediatric
Patients Aged 6 Years and Older)
14.3 POMC, PCSK1, and LEPR Deficiency and BBS (Pediatric
Patients Aged 2 to Less Than 6 Years)
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5500420
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term
in adults and pediatric patients aged 2 years and older with syndromic or monogenic obesity due
to:
• Bardet-Biedl syndrome (BBS) [see Dosage and Administration (2.1)]
• Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1),
or leptin receptor (LEPR) deficiency as determined by an FDA-approved test
demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as
pathogenic, likely pathogenic, or of uncertain significance (VUS) [see Dosage and
Administration (2.1)].
Limitations of Use:
IMCIVREE is not indicated for the treatment of patients with the following conditions as
IMCIVREE would not be expected to be effective:
• Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or
LEPR variants classified as benign or likely benign
• Other types of obesity not related to BBS or POMC, PCSK1, or LEPR deficiency,
including obesity associated with other genetic syndromes and general (polygenic)
obesity
2
DOSAGE AND ADMINISTRATION
2.1
Patient Selection
BBS
• Select patients for treatment with IMCIVREE who have a clinical diagnosis of BBS [see
Clinical Studies (14)]. Consider genetic confirmation in pediatric patients aged <6 years.
POMC, PCSK1, or LEPR Deficiency
• Select patients for treatment with IMCIVREE who have genetically determined or
suspected deficiency of POMC, PCSK1, or LEPR [see Clinical Studies (14)].
• Treat patients with variants in POMC, PCSK1, or LEPR genes that are interpreted as
pathogenic, likely pathogenic, or of uncertain significance (VUS) in the clinical context
of the patient [see Clinical Studies (14)].
• Information on an FDA-approved test for the detection of variants in the POMC, PCSK1,
or LEPR is available at http://www.fda.gov/CompanionDiagnostics.
Reference ID: 5500420
2.2
Recommended Dosage in Adults and Pediatric Patients Aged
12 Years and Older
• The recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily
for 2 weeks in adults and pediatric patients aged 12 years and older.
• Monitor patients for gastrointestinal (GI) adverse reactions during dosage initiation and
titration [see Adverse Reactions (6.1)].
• If the starting dosage is:
o Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily. If the 1 mg once
daily dosage is tolerated for at least 1 week, increase the dosage to 2 mg (0.2 mL)
once daily.
o Tolerated for 2 weeks, increase the dosage to 3 mg (0.3 mL) once daily. If the
3 mg once daily dosage is not tolerated, decrease the dosage to 2 mg (0.2 mL)
once daily.
• The recommended maintenance dosage is 3 mg (0.3 mL) injected subcutaneously once
daily.
2.3
Recommended Dosage in Pediatric Patients Aged 6 to Less Than
12 Years
• The recommended starting dosage is 1 mg (0.1 mL) injected subcutaneously once daily
for 2 weeks in pediatric patients aged 6 to less than 12 years.
• Monitor patients for GI adverse reactions during dosage initiation and titration [see
Adverse Reactions (6.1)].
• If the starting dosage is:
o Not tolerated, reduce the dosage to 0.5 mg (0.05 mL) once daily. If the 0.5 mg
once daily dosage is tolerated for at least 1 week, increase the dosage to 1 mg
(0.1 mL) once daily.
o Tolerated for 2 weeks, increase the dosage to 2 mg (0.2 mL) once daily. If the
2 mg daily dosage is:
Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily.
Tolerated, increase the dosage to 3 mg (0.3 mL) once daily.
• The recommended maintenance dosage is 3 mg (0.3 mL) injected subcutaneously once
daily.
2.4
Recommended Dosage in Pediatric Patients Aged 2 to Less Than
6 Years
• The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once
daily for 2 weeks in pediatric patients aged 2 to less than 6 years.
• Monitor patients for GI adverse reactions during dosage initiation and titration [see
Adverse Reactions (6.1)].
Reference ID: 5500420
• If the starting dosage is:
o Not tolerated, discontinue the product.
o Tolerated for 2 weeks, increase the dosage based on baseline body weight, as
presented in Table 1.
Table 1:Recommended Maintenance Dosage Based on Baseline Body Weight in Pediatric Patients
Aged 2 to Less Than 6 Years
Patient Weight/Treatment Week
Daily Dose
Volume to be Injected
15 kg to less than 20 kg
Week 1 and onward
0.5 mg once daily
0.05 mL once daily
20 kg to less than 30 kg
Weeks 1-2
0.5 mg once daily
0.05 mL once daily
Week 3 and onward
1 mg once daily
0.1 mL once daily
30 kg to less than 40 kg
Weeks 1-2
0.5 mg once daily
0.05 mL once daily
Weeks 3-4
1 mg once daily
0.1 mL once daily
Week 5 and onward
1.5 mg once daily
0.15 mL once daily
Greater than or equal to 40 kg
Weeks 1-2
0.5 mg once daily
0.05 mL once daily
Weeks 3-4
1 mg once daily
0.1 mL once daily
Weeks 5-6
1.5 mg once daily
0.15 mL once daily
Weeks 7 and onward
2 mg once daily
0.2 mL once daily
2.5
Recommended Dosage in Patients with Renal Impairment
Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older with End Stage
Renal Disease [estimated glomerular filtration (eGFR) less than 15 mL/min/1.73 m2]
IMCIVREE is not recommended for use in patients with end stage renal disease.
Recommended Dosage in Patients with Severe Renal Impairment (eGFR of 15 to
29 mL/min/1.73 m2)
Adults and Pediatric Patients Aged 12 Years and Older
• The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once
daily for 2 weeks in adults and pediatric patients aged 12 years and older with severe
renal impairment.
• Monitor patients for GI adverse reactions during dosage initiation and titration [see
Adverse Reactions (6.1)].
• If the recommended starting dosage is [see Use in Specific Populations (8.6)]:
o Not tolerated, discontinue IMCIVREE.
o Tolerated for 2 weeks, increase the dosage to 1 mg (0.1 mL) once daily. If the
1 mg daily dosage is tolerated for at least 1 week, increase the dosage to 1.5 mg
(0.15 mL) once daily. The recommended maintenance dosage is 1.5 mg (0.15 mL)
injected subcutaneously once daily [see Use in Specific Populations (8.6) and
Clinical Pharmacology (12.3)].
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Pediatric Patients Ages 6 Years to Less Than 12 Years
• The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once
daily for 2 weeks in pediatric patients aged 6 to less than 12 years with severe renal
impairment.
• Monitor patients for GI adverse reactions during dosage initiation and titration [see
Adverse Reactions (6.1)].
• If the recommended starting dosage is [see Use in Specific Populations (8.6)]:
o Not tolerated, discontinue IMCIVREE.
o Tolerated for 2 weeks, increase the dosage to 1 mg (0.1 mL) injected
subcutaneously once daily. The recommended maintenance dosage is 1 mg
(0.1 mL) injected subcutaneously once daily
Pediatric Patients Aged 2 to Less Than 6 Years Weighing at Least 20 kg
• The recommended starting dosage is 0.5 mg (0.05 mL) injected subcutaneously once daily
for 2 weeks in pediatric patients aged 2 to less than 6 years with severe renal impairment
and weight of at least 20 kg.
o The use of IMCIVREE in pediatric patients aged 2 to less than 6 years with
weight less than 20 kg and severe renal impairment is not recommended [see Use
in Specific Populations (8.6) and Clinical Pharmacology (12.3).
• Monitor patients for GI adverse reactions during dosage initiation and titration [see Adverse
Reactions (6.1)].
• If the recommended starting dosage is [see Use in Specific Populations (8.6)]:
o
Not tolerated, discontinue IMCIVREE.
o
Tolerated for 2 weeks, increase the dosage based on baseline body weight, as
presented in Table 2 [see Use in Specific Populations (8.6) and Clinical
Pharmacology (12.3)].
Table 2: Recommended Maintenance Dosage Based on Baseline Body Weight in Pediatric Patients 2
to Less Than 6 Years of Age Weighing at Least 20 kg and with Severe Renal Impairment
Patient Weight/Treatment Week
Daily Dose
Volume to be Injected
20 kg to less than 30 kg
Week 1 and onward
0.5 mg once daily
0.05 mL once daily
30 kg to less than 40 kg
Weeks 1-2
0.5 mg once daily
0.05 mL once daily
Week 3 and onward
1 mg once daily
0.1 mL once daily
Greater than or equal to 40 kg
Weeks 1-2
0.5 mg once daily
0.05 mL once daily
Weeks 3 and onward
1 mg once daily
0.1 mL once daily
• The recommended maintenance dosage is 1 mg (0.1 mL) injected subcutaneously once daily
[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Monitor patients
for adverse reactions [see Adverse Reactions (6.1)].
I
I
I
I
I
I
I
I
I
I
I
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Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older with Mild
(eGFR of 60 to 89 mL/min/1.73 m2) or Moderate (eGFR of 30 to 59 mL/min/1.73 m2) Renal
Impairment
The recommended dosage in patients with mild or moderate renal impairment is the same as in
those with normal kidney function [see Dosage and Administration (2.2, 2.3, 2.4)].
2.6
Administration Instructions
• Prior to initiation of IMCIVREE, train patients or their caregivers on proper injection
technique. Instruct patients to use a 1 mL syringe with a 28-gauge or 29-gauge needle
appropriate for subcutaneous injection.
• Remove IMCIVREE from the refrigerator approximately 15 minutes prior to administration.
Alternatively, warm IMCIVREE prior to administration by rolling the vial gently between
the palms of the hands for 60 seconds.
• Inspect IMCIVREE visually before use. It should appear clear to slightly opalescent,
colorless to slightly yellow. Do not use if particulate matter or discoloration is seen.
• Administer IMCIVREE once daily, at the beginning of the day, without regard to meals.
• Inject IMCIVREE subcutaneously in the abdomen, thigh, or arm, rotating to a different site
each day. Do not administer IMCIVREE intravenously or intramuscularly.
• If a dose is missed, resume the once daily regimen as prescribed with the next scheduled
dose.
3
DOSAGE FORMS AND STRENGTHS
Injection: 10 mg/mL, clear to slightly opalescent, colorless to slightly yellow solution in a 1-mL
multiple-dose vial.
4
CONTRAINDICATIONS
IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to
setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions have
included anaphylaxis [see Warnings and Precautions (5.3)].
5
WARNINGS AND PRECAUTIONS
5.1
Disturbance in Sexual Arousal
Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile
erections in males (24% in patients aged 6 years and older; 8% in patients aged 2 to less than
6 years) and sexual adverse reactions in females (7% in IMCIVREE-treated patients aged 6 years
and older and 0% in placebo-treated patients from an unapproved population) occurred in
clinical studies with IMCIVREE [see Adverse Reactions (6.1)].
Reference ID: 5500420
Inform patients that these events may occur and instruct patients who have an erection lasting
longer than 4 hours to seek emergency medical attention.
5.2
Depression and Suicidal Ideation
Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or
suicidal ideation. Depression (26% in patients aged 6 years and older), suicidal ideation (11% in
patients aged 6 years and older), and depressed mood (8% in patients aged 2 to less than 6 years)
occurred in adults and pediatric patients in IMCIVREE clinical studies [see Adverse Reactions
(6.1)]. Patients with a history of depression or suicidal ideation may be at increased risk for
recurrent episodes while taking IMCIVREE.
Monitor patients for new onset or worsening of depression, suicidal thoughts or behavior, or any
unusual changes in mood or behavior. Consider discontinuing IMCIVREE if patients experience
suicidal thoughts or behaviors or if clinically significant or persistent depression symptoms
occur.
5.3
Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis, have been reported with IMCIVREE.
These reactions generally occurred within minutes to hours after injecting IMCIVREE [see
Adverse Reactions (6.2)]. If hypersensitivity reactions occur, advise patients to promptly seek
medical attention and discontinue use of IMCIVREE. IMCIVREE is contraindicated in patients
with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in
IMCIVREE.
5.4
Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and
Development of New Melanocytic Nevi
Generalized or focal increases in skin pigmentation occurred in the majority of patients (67% in
patients aged 6 years and older; 83% in patients 2 to less than 6 years) treated with IMCIVREE
in clinical trials [see Adverse Reactions (6.1) and Clinical Pharmacology (12.1)]. This effect is
reversible upon discontinuation of the drug.
IMCIVREE may also cause the development of new melanocytic nevi or darkening of pre-
existing nevi due to its pharmacologic effect. Development of new melanocytic nevi and
darkening or increase in size of existing melanocytic nevi occurred in 16% of patients aged
6 years and older and 33% of patients aged 2 to less than 6 years.
Perform a full body skin examination prior to initiation and periodically during treatment with
IMCIVREE to monitor pre-existing and new skin pigmented lesions.
5.5
Risk of Serious Adverse Reactions Due to Benzyl Alcohol
Preservative in Neonates and Low Birth Weight Infants
IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions
including “gasping syndrome” can occur in neonates and low birth weight infants treated with
benzyl alcohol-preserved drugs, including IMCIVREE. The “gasping syndrome” is characterized
by central nervous system depression, metabolic acidosis, and gasping respirations. The
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minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known
(IMCIVREE contains 10 mg of benzyl alcohol per mL) [see Use in Specific Populations (8.4)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Disturbance in Sexual Arousal [see Warnings and Precautions (5.1)]
• Depression and Suicidal Ideation [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New
Melanocytic Nevi [see Warnings and Precautions (5.4)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6 Years and Older)
The safety of IMCIVREE was evaluated in a clinical study, which included a 14-week,
randomized, double-blind, placebo-controlled period followed by a 52-week open-label,
treatment period, in 44 patients aged 6 years and older with obesity and a clinical diagnosis of
BBS (Study 1) [see Clinical Studies (14)]. The study duration was 66 weeks.
During the 14-week placebo-controlled period in Study 1, the most common reported adverse
reactions in IMCIVREE-treated patients when compared to placebo-treated patients were
hyperpigmentation disorders (67% vs 0%, respectively) and vomiting (11% vs 0%, respectively).
Adverse reactions were also evaluated during the 52-week active-treatment period, defined as the
period from randomization to Week 52 in patients initially randomized to IMCIVREE, and from
Week 14 to Week 66 in patients initially randomized to placebo. Table 3 summarizes the adverse
reactions that occurred in 2 or more IMCIVREE-treated patients in Study 1 during the 52-week
active treatment period.
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Table 3: Adverse Reactions Occurring in 2 or More IMCIVREE-Treated Patients Aged 6 Years and
Older with Obesity and a Clinical Diagnosis of BBS During the 52-week Active-
Treatment Period from the Start of IMCIVREE Treatment (Study 1)
Adverse Reaction
IMCIVREE-treated Patients
N = 431
%
Skin hyperpigmentation 2
63
Injection site reactions 3
51
Nausea
26
Spontaneous penile erection 4
25
Vomiting
19
Diarrhea
14
Melanocytic nevus 5
14
Headache
7
Skin striae
7
Aggression
5
Fatigue
5
1 43 patients were treated with at least 1 dose of IMCIVREE; 1 patient initially randomized to placebo withdrew from the study prior to receiving
IMCIVREE and is not included
2 Includes skin hyperpigmentation, hair color changes, melanoderma
3 Includes injection site erythema, pruritis, induration, pain, bruising, edema, reaction, hemorrhage, irritation, mass
4 n = 20 male patients
5 Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic nevus
POMC, PCSK1, and LEPR Deficiency (Adults and Pediatric Patients Aged 6 Years and Older)
The safety of IMCIVREE was evaluated in two 52-week, open-label clinical studies of
27 patients aged 6 years and older with obesity due to POMC, PCSK1, or LEPR deficiency with
POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of
uncertain significance (Study 2 and Study 3) [see Clinical Studies (14)].
Table 4 summarizes the adverse reactions that occurred in the open-label studies during the first
52 weeks of treatment in 3 or more patients treated with IMCIVREE.
Table 4: Adverse Reactions Occurring in 3 or More IMCIVREE-Treated Patients Aged 6 Years and
Older with Obesity due to POMC, PCSK1, or LEPR Deficiency in Open-Label Clinical
Studies of 52-Week Duration (Study 2 and Study 3)
Adverse Reaction
IMCIVREE-treated Patients
N = 27
%
Injection site reaction 1
96
Skin hyperpigmentation 2
78
Nausea
56
Headache
41
Diarrhea
37
Abdominal pain 3
33
Back pain
33
Fatigue
30
Vomiting
30
Depression 4
26
Upper respiratory tract infection
26
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Adverse Reaction
IMCIVREE-treated Patients
N = 27
%
Spontaneous penile erection 5
23
Arthralgia
19
Asthenia
19
Melanocytic nevus 6
19
Dizziness
15
Dry mouth
15
Dry skin
15
Insomnia
15
Vertigo
15
Alopecia
11
Chills
11
Constipation
11
Influenza-like illness
11
Muscle spasm
11
Pain in extremity
11
Rash
11
Suicidal ideation
11
1 Includes injection site erythema, pruritus, edema, pain, induration, bruising, injection site hypersensitivity, hematoma,
nodule, and discoloration
2 Includes skin hyperpigmentation, pigmentation disorders, skin discoloration, gingival discoloration
3 Includes abdominal pain and upper abdominal pain
4 Includes depressed mood
5 n = 13 male patients
6 Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic
nevus
POMC, PCSK1, and LEPR Deficiency and BBS (Pediatric Patients Aged 2 to <6 Years)
The safety of IMCIVREE was evaluated in one 52-week, open-label clinical study of 12 patients
aged 2 to less than 6 years with obesity due to POMC, PCSK1, or LEPR deficiency with POMC,
PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain
significance, or obesity due to BBS (Study 4) [see Clinical Studies (14)]. No patients with
PCSK1 were enrolled in the trial.
Table 5 summarizes the adverse reactions that occurred in the open-label study during 52 weeks
of treatment in 3 or more patients treated with IMCIVREE.
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Table 5: Adverse Reactions Occurring in 3 or More IMCIVREE-Treated Patients Aged 2 to <6
Years with Obesity due to POMC or LEPR Deficiency or BBS in an Open-Label Clinical
Study of 52-Week Duration (Study 4)
Adverse Reaction
IMCIVREE-treated Patients
N = 12
%
Skin hyperpigmentation 1
83
Injection site reactions 2
67
Vomiting
58
Nasopharyngitis
42
Melanocytic nevus3
33
Fall
33
Fever
33
Upper respiratory tract infection
33
Cough
25
Diarrhea
25
1 Includes skin hyperpigmentation, ephelides, nail pigmentation, pigmentation lip, skin discoloration, gingival
hyperpigmentation
2 Includes injection site bruising, pruritus, discoloration, erythema, induration, oedema, pain, urticaria
3 Includes new melanocytic nevus formation, increased melanocytic nevus size, and darkening of pre-existing melanocytic
nevus
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of IMCIVREE.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
• Hypersensitivity, including anaphylaxis
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh
the potential risks to the fetus.
IMCIVREE contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly
metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However,
adverse reactions have occurred in premature neonates and low birth weight infants who
received intravenously administered benzyl alcohol-containing drugs [see Warnings and
Precautions (5.5) and Use in Specific Populations (8.4)].
There are no available data with IMCIVREE in pregnant women to inform a drug-associated risk
for major birth defects and miscarriage, or adverse maternal or fetal outcomes. For the general
US population, weight loss offers no potential benefit to a pregnant woman and may result in
Reference ID: 5500420
fetal harm (see Clinical Considerations). In animal reproduction studies, setmelanotide
subcutaneously administered to pregnant rats from before mating to the end of organogenesis
was not teratogenic at doses 11 times the maximum recommended human dose (MRHD) of
3 mg. Setmelanotide subcutaneously administered to pregnant rabbits during the period of
organogenesis was not teratogenic at clinical doses. Setmelanotide administered subcutaneously
to pregnant rats during organogenesis through lactation did not result in adverse developmental
effects at doses 7 times the MRHD (see Data).
The estimated background risk of birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Maternal obesity increases the risk for congenital malformations, including neural tube defects,
cardiac malformations, oral clefts, and limb reduction defects. In addition, weight loss during
pregnancy may result in fetal harm including increased risk of small for gestational age.
Appropriate weight gain based on pre-pregnancy weight is currently recommended for all
pregnant women, including those who are already overweight or have obesity, due to the
obligatory weight gain that occurs in maternal tissues during pregnancy.
Data
Animal Data
Embryo-fetal development was evaluated in female rats administered setmelanotide
subcutaneously during mating to end of major organogenesis (14 days prior to mating to
gestation day 17) at doses of 0.5, 3, and 5 mg/kg/day, resulting in exposures up to 11 times the
human exposure at MRHD of 3 mg, based on AUC. Dose-related decreases in maternal food
intake and body weight gain were observed during the premating period but not during gestation.
No evidence of embryo-fetal toxicity was observed.
Embryo-fetal development was evaluated in pregnant rabbits subcutaneously administered
setmelanotide during organogenesis (gestation days 7 to 19) at doses of 0.05, 0.1, and
0.2 mg/kg/day, resulting in clinically relevant exposures at the MRHD, based on AUC.
Decreases in maternal food consumption and body weight were observed at all doses. Increases
in embryo-fetal resorptions and post-implantation losses were observed at ≥0.1 mg/kg/day in the
presence of significant maternal toxicity, and fetal body weights were 7% lower than controls at
0.2 mg/kg/day.
Pre- and post-natal development was evaluated in rats subcutaneously administered
setmelanotide during organogenesis and continuing until weaning (gestation day 6 to lactation
day 21) at doses of 0.5, 3.0, and 5.0 mg/kg/day, which resulted in exposures up to 7 times the
human exposure at the MRHD, based on AUC. Pup body weights at birth were 9% lower than
controls at 3.0 and 5.0 mg/kg/day, which was consistent with reduced maternal body weight gain
and food consumption during gestation. No adverse setmelanotide-related effects on pup
survival, growth, maturation, visual function, neurobehavioral performance, or reproductive
performance were observed up to the highest dose.
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8.2
Lactation
Risk Summary
Treatment with IMCIVREE is not recommended for use while breastfeeding.
IMCIVREE from multiple-dose vials contains the preservative benzyl alcohol. Because benzyl
alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed
infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth
weight infants who received intravenously administered benzyl alcohol-containing drugs [see
Warnings and Precautions (5.5) and Use in Specific Populations (8.4)].
There is no information on the presence of setmelanotide or its metabolites in human milk, the
effects on the breastfed infant, or the effects on milk production. However, setmelanotide is
present in the milk of rats (see Data). When a drug is present in rat milk, it is likely that the drug
will be present in human milk.
Data
Dose-related setmelanotide concentrations were observed in milk 2 hours after subcutaneous
injection in the preweaning phase of a pre- and post-natal development study in rats. No
quantifiable setmelanotide concentrations were detected in plasma from nursing pups on post-
natal Day 11.
8.4
Pediatric Use
The safety and effectiveness of IMCIVREE have been established to reduce excess body weight
and maintain weight reduction long term in pediatric patients aged 2 years and older with obesity
due to:
• BBS [see Clinical Studies (14.1)]
• POMC, PCSK1, or LEPR deficiency with variants in POMC, PCSK1, or LEPR genes
that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)
[see Clinical Studies (14.2)]
Use of IMCIVREE for these indications is supported by evidence from one 66-week study,
which included a 14-week, randomized, double-blind, placebo-controlled period followed by a
52-week open-label period, and included 22 pediatric patients with BBS aged 6 to 17 years
(Study 1); from two 1-year, open-label studies that included 9 pediatric patients with POMC,
PCSK1, or LEPR deficiency aged 6 to 17 years (Study 2 and Study 3); and one 1-year, open-
label study that included 12 pediatric patients with POMC or LEPR deficiency or BBS aged 2 to
less than 6 years (Study 4) [see Clinical Studies (14.1, 14.2, 14.3)].
Adverse reactions with IMCIVREE treatment in pediatric patients aged 2 to less than 6 years
were generally similar to those reported in adults and in pediatric patients aged 6 years and older.
Pediatric patients treated with IMCIVREE had greater incidences of vomiting, skin
hyperpigmentation, and new or darkening nevi compared to adults treated with IMCIVREE [see
Adverse Reactions (6.1)]. Perform a full body skin examination prior to initiation and
Reference ID: 5500420
periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmented
lesions. [see Warnings and Precautions (5.4)]
The safety and effectiveness of IMCIVREE have not been established in pediatric patients
younger than 2 years of age.
IMCIVREE is not approved for use in neonates or infants. Serious adverse reactions including
fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight
infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a
preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels
of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were
0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration,
seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal
failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants
may be more likely to develop these reactions because they may be less able to metabolize
benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may
occur is not known (IMCIVREE contains 10 mg of benzyl alcohol) [see Warnings and
Precautions (5.5)].
8.5
Geriatric Use
Clinical studies of IMCIVREE did not include patients aged 65 and over. It is not known
whether geriatric patients would respond differently than younger adult patients.
8.6
Renal Impairment
Patients with severe renal impairment have a higher exposure of setmelanotide relative to
patients with normal kidney function. Reduce the recommended starting and maintenance dosage
of IMCIVREE in adults and pediatric patients 2 years of age and older with severe renal
impairment (eGFR 15-29 mL/min/1.73 m2). The use of IMCIVREE in pediatric patients aged 2
to less than 6 years with weight less than 20 kg and severe renal impairment is not recommended
[see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
The recommended dosage in patients with mild (eGFR of 60-89 mL/min/1.73 m2) or moderate
renal impairment (eGFR of 30-59 mL/min/1.73 m2) is the same as those with normal kidney
function [see Clinical Pharmacology (12.3)].
IMCIVREE is not recommended for use in patients with end stage renal disease (eGFR less than
15 mL/min/1.73 m2).
10
OVERDOSAGE
In the event of an overdose initiate appropriate supportive treatment according to the patient’s
clinical signs and symptoms.
Reference ID: 5500420
11
DESCRIPTION
IMCIVREE contains setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist.
Setmelanotide is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide
α-MSH (alpha-melanocyte stimulating hormone).
The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-
histidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2→8)-disulfide
acetate. Its molecular formula is C49H68N18O9S2 (anhydrous, free-base), and molecular mass is
1117.3 Daltons (anhydrous, free-base).
The chemical structure of setmelanotide acetate is:
IMCIVREE (setmelanotide) injection is a sterile clear to slightly opalescent, colorless to slightly
yellow solution for subcutaneous use. Each 1 mL of IMCIVREE contains 10 mg of
setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of
acetate, and the following inactive ingredients: 10 mg benzyl alcohol, 8 mg
carboxymethylcellulose sodium (average MWt 90,500), 1 mg edetate disodium dihydrate,
100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl- glycero-3-
phosphoethanolamine sodium salt, 11 mg mannitol, 5 mg phenol, and Water for Injection. The
pH of IMCIVREE is 5 to 6.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Setmelanotide is an MC4 receptor agonist with 20-fold less activity at the melanocortin 3 (MC3)
and melanocortin 1 (MC1) receptors. MC4 receptors in the brain are involved in regulation of
hunger, satiety, and energy expenditure. Based on nonclinical evidence, setmelanotide may
re-establish MC4 receptor pathway activity to reduce food intake and promote weight loss
through decreased caloric intake and increased energy expenditure in patients with obesity due to
BBS or POMC, PCSK1, or LEPR deficiency associated with insufficient activation of the MC4
receptor. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to
Reference ID: 5500420
accumulation of melanin and increased skin pigmentation independently of ultraviolet light [see
Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
12.2
Pharmacodynamics
At a dose 2.3 times the maximum recommended dose, IMCIVREE does not prolong the QT
interval to any clinically relevant extent.
Energy Expenditure
Short-term administration of IMCIVREE in 12 otherwise healthy patients with obesity increased
resting energy expenditure and shifted substrate oxidation to fat. The safety and effectiveness of
IMCIVREE have not been established in such patients and IMCIVREE is not approved to treat
such patients [see Indications and Usage (1)].
12.3
Pharmacokinetics
The mean steady state setmelanotide Cmax,ss, AUCtau, and trough concentration for a 3-mg dose
administered subcutaneously once daily was 31 ng/mL, 373 h*ng/mL, and 5 ng/mL, respectively
simulated using individual PK model parameters from 109 adult patients with normal renal
function. Steady-state plasma concentrations of setmelanotide were achieved within 2 days with
daily dosing of 1-3 mg setmelanotide. The accumulation of setmelanotide in the systemic
circulation during once-daily dosing over 12 weeks was approximately 30%. Setmelanotide
AUC and Cmax increased proportionally following multiple-dose subcutaneous administration in
the proposed dose range (1-3 mg).
Absorption
After subcutaneous injection of IMCIVREE, plasma concentrations of setmelanotide reached
maximum concentrations at a median tmax of 8 h after dosing.
Distribution
The mean apparent volume of distribution of setmelanotide after subcutaneous administration of
IMCIVREE 3 mg once daily was estimated to be 75.2 L. Protein binding of setmelanotide is
79.1%.
Elimination
The effective elimination half-life (t½) of setmelanotide was approximately 11 hours. The total
apparent steady state clearance of setmelanotide following subcutaneous administration of
IMCIVREE 3 mg once daily was estimated to be 7.15 L/h in a typical male patient weighing
120 kg (actual body weight) with normal renal function.
Metabolism
Setmelanotide is expected to be metabolized into small peptides by catabolic pathways.
Excretion
Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine
during the 24-hour dosing interval following subcutaneous administration of 3 mg once daily.
Reference ID: 5500420
Specific Populations
No clinically significant differences in the pharmacokinetics of setmelanotide were observed
based on sex or disease. The effect of age 65 years or older, pregnancy, or hepatic impairment on
the pharmacokinetics of setmelanotide is unknown.
Pediatric Patients
IMCIVREE has been evaluated in pediatric patients aged 2 to less than 6 years, 6 to less than 12
years, and aged 12 to 17 years. Simulations were performed using population pharmacokinetic
analysis for pediatric patients aged 2 to less than 6 years, following the maximum recommended
doses in each of the body weight groups - 2 mg, 1.5 mg, 1 mg, and 0.5 mg in patients weighing
≥40 kg, 30 to <40 kg, 20 to <30 kg, and 15 to <20 kg, respectively. The analyses suggest that
AUC and Cmax in pediatric patients aged 2 to less than 6 years are 52% and 75% higher in
patients weighing ≥40 kg, 45% and 63% higher in patients weighing 30 to <40 kg, 24% and 38%
higher in patients weighing 20 to <30 kg, and 17% and 14% lower in patients weighing 15 to
<20 kg as compared to patients greater than or equal to 18 years (3 mg dose). For patients aged 6
to less than 12 years, the setmelanotide AUC and Cmax were 88% and 89% higher compared to
patients greater than or equal to 18 years. For patients aged 12 to 17 years, the setmelanotide
AUC and Cmax were both 26% higher as compared to patients greater than or equal to 18 years
[see Dosage and Administration (2.2, 2.3, 2.4)].
Patients with Renal Impairment
Exposure parameters, AUC0-t and AUC0-inf, were approximately 13%-15%, 34%-35%, and
86%-96% higher for patients with mild, moderate, and severe renal impairment, respectively, as
compared to patients with normal renal function [see Dosage and Administration (2.5)].
Renal impairment did not appear to affect plasma protein binding. The average fraction unbound
(fu) was approximately 0.2 and was independent of renal function.
Drug Interaction Studies
In vitro assessment of drug-drug interactions
Setmelanotide has low potential for pharmacokinetic drug-drug interactions related to
cytochrome P450 (CYP), transporters and plasma protein binding.
In vivo assessment of drug-drug interactions
No clinical studies evaluating the drug-drug interaction potential of setmelanotide have been
conducted.
12.6
Immunogenicity
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
incidence of ADA in the studies described below with the incidence of ADA in other studies,
including those of setmelanotide or of other setmelanotide products.
In patients with BBS or in patients with POMC, PCSK1, or LEPR deficiency , there is
insufficient information to characterize the ADA response to setmelanotide and the effects of
Reference ID: 5500420
ADA on pharmacokinetics, pharmacodynamics, safety, or effectiveness of setmelanotide
products.
During the 1-year treatment period in Study 3 in patients with obesity due to LEPR deficiency
[see Clinical Studies (14.2)], 3/7 (43%) of IMCIVREE-treated patients developed antibodies to
endogenous alpha-melanocyte stimulating hormone (MSH). Of these 3 patients, 2 tested positive
post-IMCIVREE treatment and 1 was positive pre-treatment. Because of the limited sample size,
the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or
effectiveness of setmelanotide products or consequences from these antibodies against
endogenous alpha-MSH could not be determined. None of the IMCIVREE-treated patients with
POMC-deficiency developed antibodies to alpha-MSH.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Setmelanotide was not carcinogenic in Tg.rasH2 mice at doses up to 10 mg/kg/day when given
subcutaneously for 26 weeks.
Setmelanotide was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro
chromosome aberration test in human lymphocyte cultures, or an in vivo bone marrow
micronucleus study in rats.
There were no effects on the fertility of male rats subcutaneously administered up to
3.0 mg/kg/day setmelanotide, which represents 9 times the MRHD of 3 mg, based on AUC. No
effects on the fertility of female rats were observed with subcutaneous administration up to
5 mg/kg/day setmelanotide, which represents 11 times the MRHD of 3 mg, based on AUC.
14
CLINICAL STUDIES
14.1
Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6 Years
and Older)
The safety and efficacy of IMCIVREE for weight reduction in adults and pediatric patients aged
6 years and older with obesity and a clinical diagnosis of Bardet-Biedl syndrome (BBS) were
assessed in a 66-week clinical study, which included a 14-week randomized, double-blind,
placebo-controlled period and a 52-week open-label period (Study 1 [NCT03746522]). The
study enrolled patients aged 6 years and above with obesity and a clinical diagnosis of BBS.
Adult patients had a BMI of ≥30 kg/m2 and pediatric patients had weight ≥97th percentile using
growth chart assessments.
In Study 1, eligible patients entered a 14-week, randomized, double-blind, placebo-controlled
treatment period (Period 1) in which patients received IMCIVREE or placebo, followed by a 52-
week open-label treatment period (Period 2) in which all patients received IMCIVREE. To
maintain the blind during Period 1, dose titration to a fixed dose of 3 mg given subcutaneously
once daily was performed during the first 2 weeks of both Period 1 and Period 2.
Reference ID: 5500420
Efficacy analyses were conducted in 44 patients at the end of Period 1 (Week 14, placebo-
controlled data) and in 31 patients during the active-treatment period, defined as the period from
randomization to Week 52 in patients initially randomized to IMCIVREE, and from Week 14 to
Week 66 in patients initially randomized to placebo. Analyses of the active-treatment period
include patients who had either completed 52 weeks from the start of IMCIVREE treatment or
discontinued the study early at the time of the prespecified data cutoff.
A total of 44 patients with obesity and a clinical diagnosis of BBS were enrolled; 50% were
adults, 32% were aged 12 to <18 years, and 18% were aged 6 to <12 years; 46% were male; 77%
were White, 5% were Black or African American, 2% were Asian, and 16% had an unknown or
not reported race; 2% were Hispanic or Latino ethnicity and 14% had an unknown or not
reported ethnicity; and the mean BMI was 41.5 kg/m2 (range: 24.4-66.1 kg/m2) at baseline.
Effect of IMCIVREE on BMI in Patients with Obesity and a Clinical Diagnosis of BBS
In patients aged ≥6 years with obesity and a clinical diagnosis of BBS in Study 1, the mean
percent change in BMI after 52 weeks of IMCIVREE treatment was -7.9% (Table 6), 61.3% of
patients achieved a ≥5% BMI decrease from baseline, and 38.7% had a ≥10% decrease in BMI
(Table 7).
Table 6: Percent Change from Baseline in BMI after 52 Weeks from the Start of IMCIVREE
Treatment in Patients Aged ≥6 Years with Obesity and a Clinical Diagnosis of BBS
(Study 1)*
Statistic
Result
Baseline BMI (kg/m2)
Mean (SD)
41.8 (9.0)
Median
41.5
Min, Max
24.4, 61.3
BMI after 52 Weeks (kg/m2)
Mean (SD)
38.6 (9.2)
Median
39.1
Min, Max
20.4, 60.9
95% CI
35.2, 41.9
Percent Change from Baseline to 52 Weeks (%)
Mean (SD)
-7.9 (6.7)
Median
-8.8
Min, Max
-25.4, 5.3
95% CI
-10.4, -5.5
Abbreviations: CI = confidence interval; SD = standard deviation
*BBS patients (N=31) who completed 52 weeks from the start of IMCIVREE treatment or discontinued the study early. Five patients who
discontinued study early were defined as 0 percent change.
Reference ID: 5500420
Table 7: Proportion of IMCIVREE-Treated Patients Aged ≥6 Years with Obesity and a Clinical
Diagnosis of BBS Who Achieved at Least 5% and 10% BMI Decrease from Baseline
After 52 Weeks from the Start of IMCIVREE Treatment (Study 1)
Parameter
Statistic
Result
Patients* Achieving at Least 5% BMI Loss at
52 Weeks
%
61.3
95% CI
42.2, 78.2
Patients* Achieving at Least 10% BMI Loss at
52 Weeks
%
38.7
95% CI
21.8, 57.8
Abbreviations: CI = confidence interval; SD = standard deviation
*BBS patients (N=31) who completed 52 weeks from the start of IMCIVREE treatment or discontinued the study early. Five patients who
discontinued study early were defined as not achieving 5% or 10% reduction.
During the 14-week double-blind, placebo-controlled portion of Study 1 (Period 1), there was a
statistically significant difference in BMI reduction between the IMCIVREE-treated group and
the placebo-treated group (Table 8).
Table 8: Percent Change from Baseline in BMI after 14 Weeks of Treatment in Patients Aged ≥6
Years with Obesity and a Clinical Diagnosis of BBS (Study 1)*
Parameter
IMCIVREE
(N = 22)
Placebo
(N = 22)
Baseline BMI (SD)
41.4 (10.0)
41.6 (10.1)
BMI at 14 Weeks (SD)
39.5 (9.9)
41.6 (9.9)
Percent Change from Baseline to 14 Weeks (SD)
-4.6 (4.1)
-0.1 (2.3)
Placebo-Adjusted Difference
-4.5
95% CI
-6.5, -2.5
Abbreviations: CI = confidence interval; SD = standard deviation
*BBS subjects who completed the 14-week double-blind, placebo-controlled period (N=44).
Effect of IMCIVREE on Hunger in Patients with Obesity and a Clinical Diagnosis of BBS
In Study 1, patients 12 years and older who were able to self-report their hunger (n=14), recorded
their daily maximal hunger in a diary, which was then assessed by the Daily Hunger
Questionnaire Item 2. Hunger was scored on an 11-point scale from 0 (“not hungry at all”) to 10
(“hungriest possible”). Weekly means of daily maximal hunger scores after 52 weeks from the
start of IMCIVREE treatment are summarized in Table 9.
Hunger scores decreased in IMCIVREE-treated patients during the 14-week placebo-controlled
period and during the open-label treatment period.
Reference ID: 5500420
Table 9: Daily Hunger Scores – Change from Baseline in IMCIVREE-Treated Patients Aged ≥12
Years with Obesity and a Clinical Diagnosis of BBS After 52 Weeks From the Start of
IMCIVREE Treatment (Study 1)
Timepoint
Statistic
Result
Baseline
N
14
Mean (SD)
6.99 (1.893)
Median
7.29
Min, Max
4.0, 10.0
Week 52
N
14
Mean (SD)
4.87 (2.499)
Median
4.43
Min, Max
2.0, 10.0
Change at Week 52
N
14
Mean (SD)
-2.12 (2.051)
Median
-1.69
Min, Max
-6.7, 0.0
Abbreviations: BBS = Bardet-Biedl syndrome; CI=confidence interval; Max=maximum; Min=minimum; NC=Not calculated; SD=Standard
Deviation.
Note: Baseline is the last assessment prior to initiation of setmelanotide in both studies.
Note: The Daily Hunger Questionnaire is not administered to patients <12 years or to patients with cognitive impairment as assessed by the
Investigator.
Supportive of IMCIVREE’s effect on weight loss, there were general numeric improvements in
blood pressure, lipids, and waist circumference. However, because of the limited number of
patients studied and the lack of a control group, the treatment effects on these parameters could
not be accurately quantified.
14.2
POMC, PCSK1, and LEPR Deficiency (Adults and Pediatric Patients
Aged 6 Years and Older)
The safety and efficacy of IMCIVREE for weight reduction in adults and pediatric patients 6
years of age and older with obesity due to POMC, PCSK1, or LEPR deficiency were assessed in
2 identically designed, 1-year, open-label studies, each with an 8-week, double-blind withdrawal
period.
• Study 2 (NCT02896192) enrolled patients aged 6 years and above with obesity and
genetically confirmed or suspected POMC or PCSK1 deficiency.
• Study 3 (NCT03287960) enrolled patients aged 6 years and above with obesity and
genetically confirmed or suspected LEPR deficiency.
The studies enrolled patients with homozygous or presumed compound heterozygous
pathogenic, likely pathogenic variants, or VUS for either the POMC or PCSK1 genes (Study 2)
or the LEPR gene (Study 3). In both studies, the local genetic testing results were centrally
confirmed using Sanger sequencing. Patients with double heterozygous variants in 2 different
genes were not eligible for treatment with IMCIVREE. In both studies, adult patients had a body
mass index (BMI) of ≥30 kg/m2. Weight in pediatric patients was ≥95th percentile using growth
chart assessments.
IMCIVREE dose titration occurred over a 2- to 12-week period, followed by a 10-week, open-
label treatment period with IMCIVREE. Patients who achieved at least a 5-kilogram weight loss
(or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open-label
Reference ID: 5500420
treatment period continued into a double-blind withdrawal period lasting 8 weeks, including 4
weeks of IMCIVREE followed by 4 weeks of placebo (investigators and patients were blinded to
this sequence). Following the withdrawal sequence, patients re-initiated treatment with
IMCIVREE at their therapeutic dose for up to 32 weeks.
Efficacy analyses were conducted in 21 patients (10 in Study 2 and 11 in Study 3) who had
completed at least 1 year of treatment at the time of a prespecified data cutoff. Six additional
patients enrolled in the studies (4 in Study 2 and 2 in Study 3) who had not yet completed 1 year
of treatment at the time of the cutoff were not included in the efficacy analyses.
Of the 21 patients included in the efficacy analysis in Studies 2 and 3, 62% were adults and 38%
were pediatric patients aged 16 years or younger.
• In Study 2, 50% of patients were female, 70% were White, and the median BMI was
40 kg/m2 (range: 26.6-53.3) at baseline.
• In Study 3, 73% of patients were female, 91% were White, and the median BMI was
46.6 kg/m2 (range: 35.8-64.6) at baseline.
Effect of IMCIVREE on Body Weight in Patients with Obesity due to POMC, PCSK1, or LEPR
Deficiency
In Study 2, 80% of patients with obesity due to POMC or PCSK1 deficiency met the primary
endpoint, achieving a ≥10% weight loss after 1 year of treatment with IMCIVREE.
In Study 3, 46% of patients with obesity due to LEPR deficiency achieved a ≥10% weight loss
after 1 year of treatment with IMCIVREE (Table 10).
Table 10: Body Weight (kg) – Proportion of IMCIVREE-Treated Patients Aged ≥6 Years with
Obesity due to POMC, PCSK1, or LEPR Deficiency Who Achieved at Least 10% Weight
Loss from Baseline at 1 Year in Studies 2 and 3
Parameter
Statistic
Study 2
(POMC or PCSK1)
(N=10)
Study 3
(LEPR)
(N=11)
Patients Achieving at Least 10% Weight
Loss at Year 1
n (%)
8 (80%)
5 (46%)
95% CI1
(44.4%, 97.5%)
(16.8%, 76.6%)
P-value2
<0.0001
0.0002
Abbreviations: CI = confidence interval
Note: The analysis set includes patients who received at least 1 dose of study drug and had at least 1 baseline assessment.
1 From the Clopper-Pearson (exact) method
2 Testing the null hypothesis: Proportion =5%
When treatment with IMCIVREE was withdrawn in the 16 patients who had lost at least 5 kg (or
5% of body weight if baseline body weight was <100 kg) during the 10-week open-label period
in Studies 2 and 3, these patients gained an average of 5.5 kg in Study 2 and 5.0 kg in Study 3
over 4 weeks. Re-initiation of treatment with IMCIVREE resulted in subsequent weight loss (see
Figure 1).
Reference ID: 5500420
Table 11: Percent Change from Baseline in Weight in IMCIVREE-Treated Patients Aged ≥6 Years
with Obesity due to POMC, PCSK1, or LEPR Deficiency at 1 Year in Studies 2 and 3
(Full Analysis Set)
Parameter
Statistic
Study 2
(POMC or PCSK1)
(N=10)
Study 3
(LEPR)
(N=11)
Baseline Body Weight
(kg)
Mean (SD)
118.7 (37.5)
133.3 (26.0)
Median
115.0
132.3
Min, Max
55.9, 186.7
89.4, 170.4
1-Year Body Weight
(kg)
Mean (SD)
89.8 (29.4)
119.2 (27.0)
Median
84.1
120.3
Min, Max
54.5, 150.5
81.7, 149.9
Percent Change from Baseline to 1 Year
(%)
Mean (SD)
-23.1 (12.1)
-9.7 (8.8)
Median
-26.7
-9.8
Min, Max
-35.6, -1.2
-23.3, 0.1
LS Mean1
-23.12
-9.65
95% CI1
(-31.9, -14.4)
(-16.0, -3.3)
P-value2
0.0003
0.0074
Abbreviations: CI = confidence interval; SD = standard deviation
Note: This analysis includes patients who received at least 1 dose of study drug, had at least 1 baseline assessment.
1 ANCOVA model containing baseline body weight as a covariate
2 Testing the null hypothesis: mean percent change=0
Figure 1: Mean Percent Change in Body Weight from Baseline in Patients Aged ≥6 Years with
Obesity due to POMC, PCSK1, or LEPR Deficiency by Visit (Study 2 [N=9] and Study 3
[N=7])
BL=Baseline (day of first dose)
V2 to V3 = variable dose titration period (2 to 12 weeks)
V3 to V6 = 10-week open-label treatment period
V6 to V8 = 8-week placebo withdrawal period (4 weeks active, 4 weeks placebo)
V8 to V12 = 32-week open-label treatment period
FV = Final visit; time point for primary efficacy analysis
Note: This figure includes patients who had lost at least 5 kg (or 5% of body weight if baseline body weight was <100 kg) during the 10-week
open-label period.
Study 2 (POMC or PCSKl)
Study 3 (LEPR)
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Reference ID: 5500420
Effect of IMCIVREE on Hunger in Patients with Obesity due to POMC, PCSK1, or LEPR
Deficiency
In Studies 2 and 3, patients 12 years and older self-reported their daily maximal hunger in a
diary, assessed by the Daily Hunger Questionnaire Item 2. Hunger was scored on an 11-point
numeric rating scale from 0 (“not hungry at all”) to 10 (“hungriest possible”). Weekly means of
daily hunger scores at Baseline and Week 52 are summarized in Table 12.
Table 12: Daily Hunger Scores – Change from Baseline at 1 Year in IMCIVREE-Treated Patients
Aged ≥12 Years with Obesity due to POMC, PCSK1, or LEPR Deficiency in Studies 2
and 3 with Available Hunger Data
Parameter
Statistic
Hunger in 24 Hours
Study 2
(POMC or PCSK1)
(N=8)
Study 3
(LEPR)
(N=8)
Baseline Hunger Score
Median
7.9
7.0
Min, Max
7.0, 9.1
5.0, 8.4
1-Year Hunger Score
Median
5.5
4.4
Min, Max
2.5, 8.0
2.1, 8.0
Change from Baseline to 1 Year
Median
-2.0
-3.4
Min, Max
-6.5, -0.1
-4.7, 1.0
Note: This analysis includes patients aged 12 years and older who received at least 1 dose of study drug and had available data. Three patients in
Study 3 had missing hunger data at Week 52.
Hunger score was captured in a daily diary and was averaged to calculate a weekly score for analysis. Hunger ranged from 0 to 10 on an 11-point
scale where 0 = “not hungry at all” and 10 = “hungriest possible.”
Hunger scores generally worsened during the double-blind, placebo withdrawal period among
those patients who had experienced an improvement from baseline, and scores improved when
IMCIVREE was reinitiated.
Supportive of IMCIVREE’s effect on weight loss, there were general numeric improvements in
blood pressure, lipids, glycemic parameters, and waist circumference. However, because of the
limited number of patients studied and the lack of a control group, the treatment effects on these
parameters could not be accurately quantified.
14.3
POMC, PCSK1, and LEPR Deficiency and BBS (Pediatric Patients
Aged 2 to Less Than 6 Years)
The safety and efficacy of IMCIVREE for weight reduction in pediatric patients aged 2 to less
than 6 years with obesity due to POMC, PCSK1, or LEPR deficiency or BBS were assessed in a
52-week clinical trial [Study 4 (NCT04966741)]. Patients with PCSK1 deficiency were eligible
but none enrolled. POMC and LEPR deficiency were confirmed by genetic testing demonstrating
biallelic variants interpreted as pathogenic, likely pathogenic, or of undetermined significance;
BBS was diagnosed clinically with genetic confirmation. Obesity was defined as baseline BMI
≥97th percentile for age and sex and body weight ≥20 kg.
In Study 4, IMCIVREE dose titration occurred over an 8-week period, followed by a 44-week
open-label treatment period with IMCIVREE.
Twelve (12) patients were enrolled (3 patients with POMC deficiency, 4 patients with LEPR
deficiency, and 5 patients with BBS); 58% were male; 58% were White, 8% were Asian, and
33% had an unknown or not reported race; 8% were Hispanic or Latino ethnicity and 17% had
Reference ID: 5500420
an unknown or not reported ethnicity; and the mean BMI was 29.9 kg/m2 (range: 19-43 kg/m2) at
baseline.
Efficacy analyses were conducted in all 12 patients at the end of treatment.
Effect of IMCIVREE on BMI in Patients Aged 2 to Less Than 6 Years with POMC or LEPR
Deficiency or BBS
In Study 4, 8% of patients discontinued study drug.
The mean percent change in BMI after 52 weeks of IMCIVREE treatment was -33.8%, -13.1%,
and -9.7% in patients with POMC deficiency, LEPR deficiency, and BBS, respectively (Table
13).
Table 13: Percent Change from Baseline in BMI after 52 Weeks of IMCIVREE Treatment in
Patients Aged 2 to Less Than 6 Years with Obesity due to POMC Deficiency, LEPR
Deficiency, or BBS (Study 4)
Statistic
POMC
(N=3)
LEPR
(N=4)
BBS
(N=5)
Baseline BMI (kg/m2)
N
3
4
5
Mean (SD)
27.8 (1.6)
39.3 (4.8)
23.7 (3.5)
Median
28.4
41.2
23.0
Min, Max
26.0, 28.9
32.2, 42.5
19.3, 29.0
BMI at Week 52 (kg/m2)
N
3
4
5
Mean (SD)
18.3 (1.2)
34.0 (5.0)2
21.4 (3.3)
Median
18.0
32.7
22.2
Min, Max
17.3, 19.7
29.5, 41.1
17.9, 25.2
Percent Change from Baseline to 52 Weeks (%)
Mean (SE)
-33.8 (4.7)
-13.1 (5.4)3
-9.7 (4.0)
Median
-37.6
-15.1
-9.0
Min, Max
-39.3, -24.3
-22.1, 0
-21.6, 2.5
95% CI 1
-54.1, -13.4
-30.4, 4.2
-20.7, 1.3
Abbreviations: CI = confidence interval; SD = standard deviation
1 Two-sided 95% CI is calculated with Student’s t-distribution.
2 Using last observation carried forward (LOCF), the mean BMI (SD), median, min, and max at Week 52 are 34.9 (6.8), 32.7 29.5, and 44.9,
respectively. Using observed data only, the mean BMI (SD), median, min, and max at Week 52 are 31.6 (1.9), 32.2, 29.5, and 33.1,
respectively.
3 Week 52 results are based off baseline observation carried forward (BOCF) for 1 patient lost to follow up after Week 8. Results using last
observation carried forward are -10.8 (-34.4, 12.8) and using observed data excluding 1 patient lost to follow up are –17.4 (-37.2, 2.4).
Supportive of IMCIVREE’s effect on weight loss, general numeric improvements in waist
circumference were observed.
16
HOW SUPPLIED/STORAGE AND HANDLING
IMCIVREE injection is supplied as:
• 10 mg/mL, clear to slightly opalescent, colorless to slightly yellow solution in a 1-mL
multiple-dose vial
Reference ID: 5500420
• Package of 1 multiple-dose vial: NDC 72829-010-01
Store unopened IMCIVREE vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original
carton. After removal from the refrigerator, vials may be kept at temperatures ranging from
refrigerated to room temperature (2°C to 25°C [36°F to 77°F]) for up to 30 days with brief
excursions up to 30°C (86°F). After the vial is punctured (opened), discard after 30 days. See
Table 14 for a summary of storage conditions for IMCIVREE. Store vials in the original carton.
Table 14: Recommended Storage for IMCIVREE Vials
Storage Condition
Unopened Vial
Opened Vial
2°C to 8°C (36°F to 46°F)
Until the expiration date
Up to 30 days, OR
Until the expiration date
(whichever is earlier)
2°C to 25°C (36°F to 77°F) with
excursions permitted up to 30°C
(86°F)1
Up to 30 days, OR
Until the expiration date
(whichever is earlier)
Up to 30 days, OR
Until the expiration date
(whichever is earlier)
>30°C (>86°F)
Discard and do not use
Discard and do not use
1 If necessary, IMCIVREE may be stored at room temperature (≤30°C [≤86°F]) and then returned to refrigerated conditions
17
PATIENT COUNSELING INFORMATION
Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information
and Instructions for Use).
Disturbance in Sexual Arousal
Inform patients that sexual adverse reactions, including spontaneous erection, may occur in
patients treated with IMCIVREE. Advise patients to seek emergency medical treatment if an
erection lasts longer than 4 hours [see Warnings and Precautions (5.1)].
Depression and Suicidal Ideation
Inform patients or caregivers that IMCIVREE may cause depression or suicidal ideation. Advise
patients or caregivers to report any new or worsening symptoms of depression, suicidal thoughts
or behaviors, or unusual changes in mood or behavior [see Warnings and Precautions (5.2)].
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions have been reported with use of
IMCIVREE. Advise patients on the symptoms of hypersensitivity reactions and instruct them to
stop taking IMCIVREE and seek medical advice promptly if such symptoms occur [see
Warnings and Precautions (5.3)].
Skin Hyperpigmentation, Darkening of Pre-Existing Nevi, and Development of New
Melanocytic Nevi
Inform patients or caregivers that skin darkening occurs in the majority of patients treated with
IMCIVREE because of its mechanism of action. This change is reversable upon discontinuation
of IMCIVREE. Inform patients and caregivers that the development of new melanocytic nevi
may occur. Inform patients or caregivers that they should have a full body skin examination
before starting and during treatment with IMCIVREE to monitor these changes [see Warnings
and Precautions (5.4)].
Reference ID: 5500420
Pregnancy
Advise patients who may become pregnant to inform their healthcare provider of a known or
suspected pregnancy [see Use in Specific Populations (8.1)].
Lactation
Advise patients that treatment with IMCIVREE is not recommended while breastfeeding [see
Use in Specific Populations (8.2)].
Administration
Instruct patients and caregivers how to prepare and administer the correct dose of IMCIVREE
and assess their ability to inject subcutaneously to ensure the proper administration of
IMCIVREE. Instruct patients to use a 1 mL syringe with a 28- or 29-gauge needle appropriate
for subcutaneous injection [see Dosage and Administration (2.6)].
Manufactured for:
Rhythm Pharmaceuticals, Inc.
222 Berkeley Street, Suite 1200
Boston, MA 02116
© 2024, Rhythm Pharmaceuticals, Inc. All rights reserved.
IMCIVREE is a registered trademark of Rhythm Pharmaceuticals, Inc.
Reference ID: 5500420
PATIENT INFORMATION
IMCIVREE™ [im-SIV-ree]
(setmelanotide)
injection, for subcutaneous use
What is IMCIVREE?
•
IMCIVREE is a prescription medicine used in adults and children 2 years of age and older with obesity due to:
o
Bardet-Biedl syndrome (BBS) to help them lose weight and keep the weight off.
o
The genetic conditions proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or
leptin receptor (LEPR) deficiency, to help them lose weight and keep the weight off.
•
Your healthcare provider should order a genetic test to confirm POMC, PCSK1, or LEPR deficiency before you start
using IMCIVREE.
•
IMCIVREE is not for use in people with the following conditions because it may not work:
o
Obesity due to suspected POMC, PCSK1, or LEPR deficiency not confirmed by genetic testing or with benign or
likely benign genetic testing results.
o
Other types of obesity not related to BBS or POMC, PCSK1, or LEPR deficiency, including obesity associated with
other genetic conditions and general obesity.
It is not known if IMCIVREE is safe and effective in children under 2 years of age.
Do not use IMCIVREE if you have had a serious allergic reaction to setmelanotide or any of the ingredients in IMCIVREE.
Serious allergic reactions, including a severe allergic reaction called anaphylaxis, can happen when you use IMCIVREE.
See the end of this Patient Information leaflet for a complete list of ingredients in IMCIVREE.
Before using IMCIVREE, tell your healthcare provider about all your medical conditions, including if you:
•
have or have had areas of darkened skin, including skin discoloration (hyperpigmentation).
•
have or have had depression, or suicidal thoughts or behavior.
•
have had a prior allergic reaction to setmelanotide or any of the ingredients in IMCIVREE.
•
have kidney problems.
•
are pregnant or planning to become pregnant. Losing weight while pregnant may harm your unborn baby. Your
healthcare provider may stop your treatment with IMCIVREE if you become pregnant. Tell your healthcare provider if
you become pregnant or think you might be pregnant during treatment with IMCIVREE.
•
are breastfeeding or plan to breastfeed. It is not known if IMCIVREE passes into your breastmilk. You should not
breastfeed during treatment with IMCIVREE.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
How should I use IMCIVREE?
•
See the detailed Instructions for Use to learn how to prepare and inject IMCIVREE.
•
IMCIVREE is given as an injection under your skin (subcutaneous) by you or a caregiver.
•
A healthcare provider should show you or your caregiver how to prepare and inject your dose of IMCIVREE before
injecting for the first time. Do not try to inject IMCIVREE unless you have been trained by a healthcare provider.
•
Use IMCIVREE exactly as prescribed by your healthcare provider.
•
IMCIVREE should be injected 1 time each day when you first wake up. IMCIVREE can be given with or without food.
•
If you miss a dose of IMCIVREE, inject your next dose at the regularly scheduled time the next day.
What are the possible side effects of IMCIVREE?
IMCIVREE may cause serious side effects, including:
•
Male and female sexual function problems. IMCIVREE can cause an erection that happens without any sexual
activity in males (spontaneous penile erection) and unwanted sexual reactions (changes in sexual arousal that happen
without any sexual activity) in females. If you have an erection lasting longer than 4 hours, get emergency medical
help right away.
•
Depression and suicidal thoughts or actions. You or a caregiver should call your healthcare provider right away if
you have any new or worsening symptoms of depression, suicidal thoughts or behaviors, or any unusual changes in
mood or behavior.
•
Serious allergic reactions. Stop taking IMCIVREE and get medical help right away if you have any symptoms of a
serious allergic reaction including:
o
swelling of your face, lips, tongue or throat
o
problems breathing or swallowing
o
severe rash or itching
o
fainting or feeling dizzy
o
rapid heartbeat
•
Increased skin pigmentation, darkening of skin lesions (moles or nevi) you already have, and development of
new skin lesions. These changes happen because of how IMCIVREE works in the body and will go away when you
stop using IMCIVREE. You should have a full body skin exam before starting and during treatment with IMCIVREE to
check for skin changes.
•
Benzyl alcohol toxicity. Benzyl alcohol is a preservative in IMCIVREE. Benzyl alcohol can cause serious side effects,
including death, in premature and low-birth weight infants, who have received medicines that contain benzyl alcohol.
IMCIVREE should not be used in premature and low-birth weight infants.
Reference ID: 5500420
The most common side effects of IMCIVREE include:
•
darkening of the skin
•
injection site reactions
•
nausea
•
headache
•
diarrhea
•
stomach pain
•
vomiting
•
depression
•
erection that happens without any sexual activity
in males
These are not all the possible side effects of IMCIVREE.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Rhythm Pharmaceuticals at 1-833-789-6337.
General information about the safe and effective use of IMCIVREE.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
IMCIVREE for a condition for which it was not prescribed. Do not give IMCIVREE to other people, even if they have the
same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information
about IMCIVREE that is written for health professionals.
What are the ingredients in IMCIVREE?
Active ingredient: setmelanotide
Inactive ingredients: benzyl alcohol, carboxymethylcellulose sodium, edetate disodium dihydrate, N-(carbonyl-
methoxypolyethylene glycol 2000)-1, 2-distearoyl- glycero-3-phosphoethanolamine sodium salt, mannitol, phenol, and
water for injection.
Reference ID: 5500420
INSTRUCTIONS FOR USE
IMCIVREE™ [im-SIV-ree]
(setmelanotide)
injection, for subcutaneous use
This Instructions for Use contains information on how to inject IMCIVREE. Read and follow these instructions
before injecting IMCIVREE.
Important Information You Need to Know Before Injecting IMCIVREE
• IMCIVREE is for injection under the skin only (subcutaneous injection). Do not inject IMCIVREE into a
vein or muscle.
• Inject IMCIVREE 1 time each day when you first wake up.
• Take IMCIVREE with or without food.
• IMCIVREE is given by you or a caregiver. A healthcare provider will show you or your caregiver how to inject
your dose of IMCIVREE before you inject for the first time. Ask your healthcare provider or call IMCIVREE
Guidance, Partnership, Support (GPS) at 1-844-YOUR-GPS (1-844-968-7477) if you have questions.
• Store opened vials of IMCIVREE in the refrigerator between 36°F to 46°F (2°C to 8°C). If needed, opened
vials may be removed from the refrigerator and stored at temperatures ranging from refrigerated to room
temperature (36°F to 77°F (2°C to 25°C)). Vials may be returned to the refrigerator. Throw away all
opened vials 30 days after first opening, even if some medicine is still left.
• Unopened vials of IMCIVREE may be stored in the refrigerator between 36°F to 46°F (2°C to 8°C) until the
expiration date. If needed, unopened vials may also be removed from the refrigerator and stored at
temperatures ranging from refrigerated to room temperature (36°F to 77°F (2°C to 25°C)) for up to 30
days. Vials may be returned to the refrigerator. Throw away IMCIVREE if it has been more than 30 days
since the vial was first removed from the refrigerator.
• If necessary, vials may be stored at room temperature below 86°F (30°C) and may be returned to the
refrigerator. Throw away IMCIVREE that has been stored above 86°F (30°C).
• Write the date on the carton when you first open the vial.
Important note:
• Only use the syringes and needles provided to you for use with IMCIVREE.
• Always use a new syringe and needle for each injection to prevent contamination.
• Throw away used syringes and needles in a puncture-resistant, disposable sharps container as soon
as you finish giving the injection. See “Disposing of IMCIVREE” at the end of these instructions.
• Do not reuse or share your needles with other people.
• Do not recap the needle. Recapping the needle can lead to a needle stick injury.
• Keep IMCIVREE, needles, syringes, and all medicines out of the reach of children.
Reference ID: 5500420
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Understanding Your IMCIVREE Dose
Calculate the number of doses of IMCIVREE in each vial:
• Each unopened IMCIVREE vial contains 10 milligrams (mg) of medicine in 1 milliliter (mL) of solution.
• The vial will contain both medicine and air. Most of the vial will be filled with air.
• Your healthcare provider will determine your dose of medicine in milligrams (mg).
• The IMCIVREE vial may be used to give more than 1 dose of medicine (multiple-dose vial).
• Use Figure A to see how many times you may use each vial based on your prescribed dose.
• Do not use more doses from a single vial than listed in Figure A .
Figure A
10 mg/1 mL
multiple-dose
vial
Prescribed dose (mg)
Prescribed dose (mL)
Number of doses per vial
0.5 mg
0.05 mL
20
1 mg
0.1 mL
10
1.5 mg
0.15 mL
6
2 mg
0.2 mL
5
3 mg
0.3 mL
3
Preparing to Inject IMCIVREE
Step
Gather your supplies.
• Gather the supplies you will need for your injection (Figure B).
• Place your supplies on a clean, flat work surface.
Reference ID: 5500420
Figure B
ALCOHOL WIPE
You will need the following supplies:
Plastic cap
Rubber stopper
Plunger
Barrel
Needle
Black rubber
stopper
Protective
needle cap
Vial
1 mL syringe with 28- or
29-gauge (28-29G) needle
Gauze
pad
Sharps
container
2 Alcohol
wipes
Reference ID: 5500420
Step
Check your IMCIVREE vial.
Figure C
Exp date: MM/YY YY
Exp date: MM/YYYY
• Check the expiration (Exp) date on the vial label (Figure C).
• Check the liquid. The liquid should look clear to almost clear and colorless to
slightly yellow. The liquid should be free of particles.
• Do not use if:
◦ The expiration (Exp) date has passed.
◦ The liquid is cloudy.
◦ There are particles floating in the vial.
◦ The plastic cap on a new vial is broken or missing.
Prepare your IMCIVREE vial.
• Allow the vial to reach room temperature.
◦ Remove the vial from the refrigerator 15 minutes before injection.
◦ You can also warm the vial by rolling it gently between the palms of your hands for
60 seconds (Figure D).
• Do not try to warm the vial by using a heat source such as hot water or a microwave.
• Do not shake the vial.
• Wash your hands with soap and warm water.
• If using a new vial, remove the plastic cap (Figure E) and throw away this plastic
cap in the trash. Do not put the plastic cap back on the vial.
Step
Figure D
Figure E
Figure F
• Clean the top of the vial rubber stopper with 1 alcohol wipe (Figure F). Throw
away the alcohol wipe in the trash.
• Do not remove the vial rubber stopper.
Reference ID: 5500420
u
Step
Prepare the syringe.
When measuring your dose, be sure to read the markings starting from the end closest to the black rubber
stopper (Figure G).
Figure G
1 mg dose = 0.1 mL
2 mg dose = 0.2 mL
3 mg dose =0.3 mL
1.5 mg dose = 0.15 mL
0.5 mg dose = 0.05 mL
Reference ID: 5500420
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I
)
Figure H
Figure I
Figure J
• Fill the syringe with air.
◦ Keep the protective needle cap on the syringe.
◦ Pull back on the plunger until the end of the black rubber stopper stops at your dose.
Fill the syringe with air equal to the amount of the medicine to be given (Figure H).
• Remove the protective needle cap from the syringe.
◦ Remove the protective needle cap by pulling it straight off and away from your body.
• Insert the needle.
◦ Place the vial on the clean, flat work surface.
◦ With the vial in the upright position, place the syringe directly over the vial
and insert the needle straight down into the center of the vial rubber stopper
(Figure I).
◦ Push the air from the syringe into the vial.
• Fill the syringe with IMCIVREE.
◦ Keep the needle in the vial and slowly turn the vial upside down.
◦ Make sure to keep the tip of the needle in the medicine (Figure J).
• Slowly pull back on the plunger to fill the syringe with the amount of IMCIVREE
needed for your prescribed dose.
• Be careful not to pull the plunger out of the syringe.
• Do not use more than 1 vial of IMCIVREE to give a single dose. Use a new vial
that has enough medicine for your prescribed dose.
Figure K
small
air
bubbles
large
air
bubbles
• Check for large air bubbles (Figure K).
◦ Keep the needle in the vial and check the syringe for large air bubbles.
What to do if you see large air bubbles:
Large air bubbles can reduce the dose of medicine you receive. To remove large air bubbles:
• Gently tap the side of the syringe with your finger to move the air bubbles to the top of the syringe.
• Move the tip of the needle above the medicine and slowly push the plunger up to push the large air
bubbles back into the vial.
• After the large air bubbles are removed, pull back on the plunger again (more slowly this time) to fill the
syringe with your prescribed dose of medicine.
• Withdraw the needle
Figure L
◦ Return the vial to an upright position and place it on the clean, flat work surface.
◦ While holding the vial with 1 hand and the barrel of the syringe between the
fingertips of your other hand, pull the needle straight out of the vial (Figure L).
◦ Set the syringe down on the clean, flat work surface.
• Make sure the needle does not touch the surface.
• Do not recap the needle
Reference ID: 5500420
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(s)
)
b,A~
l e----~ 1
l
Figure O
Injecting IMCIVREE
Step
Prepare your injection site.
Figure M
2 in
Figure N
• Choose the area where you will give the injection. Choose from the following
recommended injection sites:
◦ belly (abdomen) (Figure M)
◦ front of the middle thighs (Figure N)
◦ back of the upper arm (Figure O)
• Be sure to choose an area on the belly (abdomen) at least 2 inches from the belly
button.
• Do not inject into the belly button, ribs, and hip bones, as well as scars or moles.
• Do not inject in an area that is red, swollen, or irritated
• Clean the injection site with the second alcohol wipe using a circular motion.
• Do not touch, fan, or blow on the cleaned area.
• Allow the skin to dry for about 10 seconds.
Rotate your injection site each day.
You should use a different injection site each time you give an injection, at least 1 inch away from
the area you used for your previous injection. You may want to use a calendar or diary to record your
injection sites.
Step
Place your hands for the injection.
• With 1 hand, pinch about 2 inches of skin at the injection site between your thumb
and index (pointer) finger (Figure P). Pinching the skin is important to help make
sure that you inject the medicine under the skin (into fatty tissue) but not any
deeper (into the muscle).
Figure P
Reference ID: 5500420
Step
Inject and release.
Figure Q
90 degrees
Figure R
(
(7)
__
)
• With your other hand, place the syringe between the thumb and index
(pointer) finger.
• Hold the middle of the syringe (where the markings are printed) at a 90-degree
angle to your body and push the needle straight into the injection site (Figure Q).
Make sure that you push the needle all the way into the skin.
• Do not hold or push on the plunger while inserting the needle.
• Slowly push the plunger down to inject the medicine (Figure R)
• Keep the needle in your skin and count to 5 to make sure that all the medicine
is given.
• Let go of the pinched skin and remove the needle.
• Use the gauze pad to gently apply pressure to the injection site.
• Do not recap the needle.
Tips for giving injections to children
When giving a child an injection, it can help to have the child do other things. Have the child:
• squeeze something soft like a ball or stuffed animal.
• slowly breathe in and out.
• sing a song, count, or name favorite colors or animals.
Storing IMCIVREE
• Store unopened and opened vials in the original carton to protect them from light.
• Store opened vials of IMCIVREE in the refrigerator between 36°F to 46°F (2°C to 8°C). If needed, opened
vials may be removed from the refrigerator and stored at temperatures ranging from refrigerated to room
temperature (36°F to 77°F (2°C to 25°C)). Vials may be returned to the refrigerator. Throw away all opened
vials 30 days after first opening, even if some medicine is still left in the vial.
• Unopened vials of IMCIVREE may be stored in the refrigerator between 36°F to 46°F (2°C to 8°C) until the
expiration date. If needed, unopened vials may also be removed from the refrigerator and stored at
temperatures ranging from refrigerated to room temperature (36°F to 77°F (2°C to 25°C)) for up to 30 days.
Vials may be returned to the refrigerator. Throw away IMCIVREE if it has been more than 30 days since the
vial was first removed from the refrigerator.
• If necessary, vials may be stored at room temperature below 86°F (30°C) and may be returned to
refrigerated conditions. Throw away IMCIVREE that has been stored above 86°F (30°C).
• Write the date on the carton when you first open the vial.
• Keep IMCIVREE, needles, syringes, and all medicines out of the reach of children.
Reference ID: 5500420
Disposing of IMCIVREE
• Alcohol wipes, used gauze pads, and vials can be thrown away in the trash.
Figure S
Throw away (dispose of) used syringes and needles in a puncture-resistant
container, such as an FDA-cleared sharps disposal container immediately after use
(Figure S).
Do not throw away (dispose of) syringes and needles in your household trash.
If you do not have an FDA-cleared sharps disposal container, you may use a
household container that is:
◦ made of a heavy-duty plastic,
◦ can be closed with a tight-fitting, puncture-resistant lid, without sharps being able
to come out,
◦ upright and stable during use,
◦ leak-resistant, and
◦ properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of your sharps disposal
container. There may be state or local laws about how you should throw away
used syringes and needles. For more information about safe sharps disposal and
for specific information about sharps disposal in the state that you live in, go to the
FDA’s website at: http://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash
unless your community guidelines permit this.
• Do not recycle your used sharps disposal container.
Note: Keep your sharps disposal container out of the reach of children and pets.
For more information about IMCIVREE, including how to inject IMCIVREE, go to www.IMCIVREE.com or call
1-844-YOUR-GPS (1-844-968-7477).
IMCIVREE is Manufactured for:
Rhythm Pharmaceuticals, Inc.
222 Berkeley Street, Suite 1200
Boston, MA 02116
Made in France
IMCIVREE is a trademark of Rhythm Pharmaceuticals, Inc.
©2020 Rhythm Pharmaceuticals, Inc.
This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.
Revised [June 2022]
Reference ID: 5500420
| custom-source | 2025-02-12T15:48:05.623688 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213793s007lbl.pdf', 'application_number': 213793, 'submission_type': 'SUPPL ', 'submission_number': 7} |
80,699 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
XIGDUO XR safely and effectively. See full prescribing information for
XIGDUO XR.
XIGDUO® XR (dapagliflozin and metformin hydrochloride
extended-release) tablets, for oral use
Initial U.S. Approval: 2014
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Postmarketing cases of metformin-associated lactic acidosis have
resulted in death, hypothermia, hypotension, and resistant
bradyarrhythmias. Symptoms included malaise, myalgias,
respiratory distress, somnolence, and abdominal pain. Laboratory
abnormalities included elevated blood lactate levels, anion gap
acidosis, increased lactate/pyruvate ratio; and metformin plasma
levels generally >5 mcg/mL. (5.1)
• Risk factors include renal impairment, concomitant use of certain
drugs, age >65 years old, radiological studies with contrast,
surgery and other procedures, hypoxic states, excessive alcohol
intake, and hepatic impairment. Steps to reduce the risk of and
manage metformin-associated lactic acidosis in these high-risk
groups are provided in the Full Prescribing Information. (5.1)
• If lactic acidosis is suspected, discontinue XIGDUO XR and
institute general supportive measures in a hospital setting. Prompt
hemodialysis is recommended. (5.1)
---------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage (1)
12/2024
Dosage and Administration (2.3)
06/2024
--------------------------- INDICATIONS AND USAGE --------------------------
XIGDUO XR is a combination of dapagliflozin, a sodium-glucose
cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a
biguanide, indicated as an adjunct to diet and exercise to improve glycemic
control in adults and pediatric patients aged 10 years and older with type 2
diabetes mellitus. (1)
Dapagliflozin when used as a component of XIGDUO XR, is indicated in
adults with type 2 diabetes mellitus to reduce the risk of:
• Sustained eGFR decline, end-stage kidney disease, cardiovascular death,
and hospitalization for heart failure in patients with chronic kidney
disease at risk of progression. (1)
• Cardiovascular death, hospitalization for heart failure, and urgent heart
failure visit in patients with heart failure. (1)
• Hospitalization for heart failure in patients with type 2 diabetes mellitus
and either established cardiovascular disease or multiple cardiovascular
risk factors. (1)
Limitations of use:
• Not recommended for use to improve glycemic control in patients with
type 1 diabetes mellitus. (1)
• Because of the metformin HCl component, the use of XIGDUO XR is
limited to patients with type 2 diabetes mellitus for all indications. (1)
• Not recommended for the treatment of chronic kidney disease in patients
with polycystic kidney disease or patients requiring or with a recent history
of immunosuppressive therapy for the treatment of kidney disease.
XIGDUO XR is not expected to be effective in these populations. (1)
---------------------- DOSAGE AND ADMINISTRATION ----------------------
• Assess renal function prior to initiating and then as clinically indicated.
(2.1)
• Assess volume status and correct volume depletion before initiating. (2.1)
• Individualize the starting dosage based on the patient’s current treatment.
(2.3)
• Administer orally once daily in the morning with food. (2.2)
• To improve glycemic control, for patients aged 10 years and older not
already taking dapagliflozin, the recommended starting dosage for
dapagliflozin is 5 mg once daily. (2.3)
• For indications in adults related to heart failure and chronic kidney disease
the recommended dosage of dapagliflozin is 10 mg once daily. (2.3)
• Do not exceed a daily dosage of 10 mg dapagliflozin/2,000 mg metformin
HCl extended-release. (2.3)
• See Full Prescribing Information for dosage recommendations in patients
with renal impairment. (2.4)
• XIGDUO XR may need to be discontinued at time of, or prior to, iodinated
contrast imaging procedures. (2.5)
• Withhold XIGDUO XR for at least 3 days, if possible, prior to surgery or
procedures associated with prolonged fasting. (2.6)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
• 2.5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3)
• 5 mg dapagliflozin/500 mg metformin HCl extended-release (3)
• 5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3)
• 10 mg dapagliflozin/500 mg metformin HCl extended-release (3)
• 10 mg dapagliflozin/1,000 mg metformin HCl extended-release (3)
------------------------------ CONTRAINDICATIONS -----------------------------
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) or end-stage
renal disease. (4)
• History of serious hypersensitivity to dapagliflozin, metformin HCl, or any
of the excipients in XIGDUO XR. (4)
• Metabolic acidosis, including diabetic ketoacidosis. (4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Lactic Acidosis: See boxed warning. (5.1)
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other
Ketoacidosis: Consider ketone monitoring in patients at risk for
ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting
blood glucose levels and discontinue XIGDUO XR if ketoacidosis is
suspected. Monitor patients for resolution of ketoacidosis before restarting.
(5.2)
• Volume Depletion: Before initiating XIGDUO XR, assess and correct
volume status in the elderly, patients with renal impairment or low systolic
blood pressure, and in patients on diuretics. Monitor for signs and
symptoms during therapy. (5.3)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of
urinary tract infections and treat promptly, if indicated. (5.4)
• Hypoglycemia: Consider a lower dosage of insulin or an insulin
secretagogue to reduce the risk of hypoglycemia when used concomitantly
with XIGDUO XR. (5.5)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-
threatening cases have occurred in both females and males. Assess patients
presenting with pain or tenderness, erythema, or swelling in the genital or
perineal area, along with fever or malaise. If suspected, institute prompt
treatment. (5.6)
• Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure
hematological parameters annually. (5.7)
• Genital Mycotic Infections: Monitor and treat if indicated. (5.8)
------------------------------ ADVERSE REACTIONS -----------------------------
• Adverse reactions reported in >5% of patients treated with XIGDUO XR
were female genital mycotic infection, nasopharyngitis, urinary tract
infection, diarrhea, and headache. (6.1)
• Adverse reactions reported in >5% of patients treated with metformin
extended-release are: diarrhea and nausea/vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS -----------------------------
• Carbonic anhydrase inhibitors: May increase risk of lactic acidosis.
Consider more frequent monitoring. (7)
• Drugs that reduce metformin clearance: May increase risk of lactic
acidosis. Consider benefits and risks of concomitant use. (7)
• See full prescribing information for additional drug interactions and
information on interference of XIGDUO XR with laboratory tests. (7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Advise females of the potential risk to a fetus, especially
during the second and third trimesters. (8.1)
• Lactation: Not recommended when breastfeeding. (8.2)
• Females and Males of Reproductive Potential: Advise premenopausal
females of the potential for an unintended pregnancy. (8.3)
• Geriatrics: Higher incidence of adverse reactions related to hypotension.
Assess renal function more frequently. (8.5, 8.6)
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• Renal Impairment: Higher incidence of adverse reactions related to volume
depletion. (8.6)
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LACTIC ACIDOSIS
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of XIGDUO XR
2.2 Recommended Administration
2.3 Recommended Dosage
2.4 Recommended Dosage in Patients with Renal Impairment
2.5 Discontinuation for Iodinated Contrast Imaging Procedures
2.6 Temporary Interruption for Surgery
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and
Other Ketoacidosis
5.3 Volume Depletion
5.4 Urosepsis and Pyelonephritis
5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin
Secretagogues
5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
5.7 Vitamin B12 Concentrations
5.8 Genital Mycotic Infections
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus
14.2 Glycemic Control in Pediatric Patients Aged 10 Years and Older with
Type 2 Diabetes Mellitus
14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus
14.4 Chronic Kidney Disease
14.5 Heart Failure
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
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FULL PRESCRIBING INFORMATION
WARNING: LACTIC ACIDOSIS
• Postmarketing cases of metformin-associated lactic acidosis have resulted in death,
hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-
associated lactic acidosis is often subtle, accompanied only by non-specific symptoms
such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
Metformin-associated lactic acidosis was characterized by elevated blood lactate levels
(>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an
increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL
[see Warnings and Precautions (5.1)].
• Risk factors for metformin-associated lactic acidosis include renal impairment,
concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as
topiramate), age 65 years old or greater, having a radiological study with contrast,
surgery and other procedures, hypoxic states (e.g., acute congestive heart failure),
excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metformin-associated lactic acidosis in these
high-risk groups are provided in the full prescribing information [see Dosage and
Administration (2.1 and 2.4), Contraindications (4), Warnings and Precautions (5.1),
Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
• If metformin-associated lactic acidosis is suspected, immediately discontinue XIGDUO
XR and institute general supportive measures in a hospital setting. Prompt
hemodialysis is recommended [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
XIGDUO XR is a combination of dapagliflozin and metformin hydrochloride (HCl) extended-
release, indicated as an adjunct to diet and exercise to improve glycemic control in adults and
pediatric patients aged 10 years and older with type 2 diabetes mellitus.
Dapagliflozin, when used as a component of XIGDUO XR, is indicated in adults with type 2
diabetes mellitus to reduce the risk of:
• Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization
for heart failure in patients with chronic kidney disease at risk of progression.
• Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in
patients with heart failure.
• Hospitalization for heart failure in patients with type 2 diabetes mellitus and either
established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
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Limitations of Use
• XIGDUO XR is not recommended for use to improve glycemic control in patients with type
1 diabetes mellitus [see Warnings and Precautions (5.2)].
• Because of the metformin HCl component, the use of XIGDUO XR is limited to patients
with type 2 diabetes mellitus for all indications.
• XIGDUO XR is not recommended for the treatment of chronic kidney disease in patients
with polycystic kidney disease or patients requiring or with a recent history of
immunosuppressive therapy for kidney disease. XIGDUO XR is not expected to be effective
in these populations.
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of XIGDUO XR
• Assess renal function prior to initiating XIGDUO XR and then as clinically indicated [see
Warnings and Precautions (5.1, 5.3)].
• Assess volume status. In patients with volume depletion, correct this condition before
initiating XIGDUO XR [see Warnings and Precautions (5.3) and Use in Specific
Populations (8.5, 8.6)].
2.2 Recommended Administration
• Take XIGDUO XR orally once daily in the morning with food.
• Swallow XIGDUO XR tablets whole and never crush, cut, or chew.
2.3 Recommended Dosage
• Individualize the starting dosage of XIGDUO XR based upon the patient’s current regimen.
Patients taking an evening dosage of metformin HCl extended-release should skip their last
dose before starting XIGDUO XR.
• To improve glycemic control in adults and pediatric patients aged 10 years and older not
already taking:
∘ Dapagliflozin: the recommended starting dosage of dapagliflozin in XIGDUO XR is
5 mg orally once daily.
∘ Metformin HCl extended-release: the recommended starting dosage of metformin HCl
extended-release in XIGDUO XR is 500 mg orally once daily.
• For XIGDUO XR indications in adults related to heart failure and chronic kidney disease, the
recommended dosage of dapagliflozin in XIGDUO XR is 10 mg orally once daily.
• For all XIGDUO XR indications, the dosage may be adjusted based on effectiveness and
tolerability. The maximum recommended daily dosage of dapagliflozin is 10 mg and
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2,000 mg of metformin HCl extended-release, with gradual dosage escalation to reduce
gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)].
2.4 Recommended Dosage in Patients with Renal Impairment
• The recommended dosage of XIGDUO XR in patients with an estimated glomerular filtration
rate (eGFR) greater than or equal to 45 mL/min/1.73 m2 is the same as the recommended
dosage in patients with normal renal function.
• Initiation of XIGDUO XR is not recommended in patients with an eGFR between 30 and
45 mL/min/1.73 m2. Assess the benefit and risk of continuing therapy if eGFR falls
persistently below this level.
o Dapagliflozin is likely to be ineffective to improve glycemic control in patients
with eGFR less than 45 mL/min/1.73 m2.
o Metformin HCl initiation is not recommended for patients with eGFR less than
45 mL/min/1.73 m2.
• XIGDUO XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 and
end-stage renal disease due to the metformin HCl component [see Contraindications (4),
Warnings and Precautions (5.1, 5.2), and Use in Specific Populations (8.6)].
2.5 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in
patients with an eGFR less than 60 mL/min/1.73 m2, in patients with a history of liver disease,
alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated
contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart XIGDUO XR if renal
function is stable [see Warnings and Precautions (5.1)].
2.6 Temporary Interruption for Surgery
Withhold XIGDUO XR for at least 3 days, if possible, prior to surgery or procedures associated
with prolonged fasting. Resume XIGDUO XR when the patient is clinically stable and has
resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
3 DOSAGE FORMS AND STRENGTHS
XIGDUO XR (dapagliflozin and metformin HCl) extended-release tablets are available as
follows:
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Table 1: Dosage Forms and Strengths for XIGDUO XR
Dapagliflozin
Strength
Metformin
HCl Strength
Color/Shape
Tablet Markings
2.5 mg
1,000 mg
light brown to brown,
biconvex, oval-shaped, and
film-coated tablet
"1074" and "2.5/1000"
debossed on one side and
plain on the reverse side
5 mg
500 mg
orange, biconvex, capsule-
shaped, and film-coated
tablet
"1070" and "5/500"
debossed on one side and
plain on the reverse side
5 mg
1,000 mg
pink to dark pink, biconvex,
oval-shaped, and film-
coated tablet
"1071" and "5/1000"
debossed on one side and
plain on the reverse side
10 mg
500 mg
pink, biconvex, capsule-
shaped, and film-coated
tablet
"1072" and "10/500"
debossed on one side and
plain on the reverse side
10 mg
1,000 mg
yellow to dark yellow,
biconvex, oval-shaped, and
film-coated tablet
"1073" and "10/1000"
debossed on one side and
plain on the reverse side
4 CONTRAINDICATIONS
XIGDUO XR is contraindicated in patients with:
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) or end-stage renal disease [see
Warnings and Precautions (5.1)].
• History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the
excipients in XIGDUO XR. Serious hypersensitivity reactions, including anaphylaxis and
angioedema have been reported with dapagliflozin [see Adverse Reactions (6.1)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1) and
Warnings and Precautions (5.2)].
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
There have been post-marketing cases of metformin-associated lactic acidosis, including fatal
cases. These cases had a subtle onset and were accompanied by non-specific symptoms such as
malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however,
hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
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Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations
(>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased
lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases
liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic
acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be
instituted promptly in a hospital setting, along with immediate discontinuation of XIGDUO XR.
In XIGDUO XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt
hemodialysis is recommended to correct the acidosis and remove accumulated metformin
(metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic
conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms
occur, instruct them to discontinue XIGDUO XR and report these symptoms to their healthcare
provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis,
recommendations to reduce the risk of and manage metformin-associated lactic acidosis are
provided below:
Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily
occurred in patients with significant renal impairment. The risk of metformin accumulation and
metformin-associated lactic acidosis increases with the severity of renal impairment because
metformin is substantially excreted by the kidney. Clinical recommendations based upon the
patient’s renal function include [see Dosage and Administration (2.1, 2.4) and Clinical
Pharmacology (12.3)]:
•
Before initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).
•
XIGDUO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2
[see Contraindications (4)].
•
Obtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at
increased risk for the development of renal impairment (e.g., the elderly), renal function
should be assessed more frequently.
Drug Interactions: The concomitant use of XIGDUO XR with specific drugs may increase the
risk of metformin-associated lactic acidosis: those that impair renal function, result in significant
hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g.,
cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of
patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s
age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac
impairment than younger patients. Assess renal function more frequently in elderly patients [see
Use in Specific Populations (8.5)].
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Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in
metformin-treated patients has led to an acute decrease in renal function and the occurrence of
lactic acidosis. Stop XIGDUO XR at the time of, or prior to, an iodinated contrast imaging
procedure in patients with a history of hepatic impairment, alcoholism, or heart failure; or in
patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours
after the imaging procedure, and restart XIGDUO XR if renal function is stable.
Surgery and Other Procedures: Withholding of food and fluids during surgical or other
procedures may increase the risk for volume depletion, hypotension and renal impairment.
XIGDUO XR should be temporarily discontinued while patients have restricted food and fluid
intake.
Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis
occurred in the setting of acute congestive heart failure (particularly when accompanied by
hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,
sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis
and may also cause prerenal azotemia. When such events occur, discontinue XIGDUO XR.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and
this may increase the risk of metformin-associated lactic acidosis. Warn patients against
excessive alcohol intake while receiving XIGDUO XR.
Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin-
associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher
lactate blood levels. Therefore, avoid use of XIGDUO XR in patients with clinical or laboratory
evidence of hepatic disease.
5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, dapagliflozin, a component of XIGDUO XR,
significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the
background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of
ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2
(SGLT2) inhibitors compared to patients who received placebo. XIGDUO XR is not indicated
for glycemic control in patients with type 1 diabetes mellitus.
Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic
surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal
events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including
dapagliflozin.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include
under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness,
reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include
nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose
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levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less
than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected.
Urinary glucose excretion persists for 3 days after discontinuing XIGDUO XR [see Clinical
Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or
glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2
inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical
situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who
present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is
suspected, discontinue XIGDUO XR, promptly evaluate, and treat ketoacidosis, if confirmed.
Monitor patients for resolution of ketoacidosis before restarting XIGDUO XR.
Withhold XIGDUO XR, if possible, in temporary clinical situations that could predispose
patients to ketoacidosis. Resume XIGDUO XR when the patient is clinically stable and has
resumed oral intake [see Dosage and Administration (2.6)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to
discontinue XIGDUO XR and seek medical attention immediately if signs and symptoms occur.
5.3 Volume Depletion
Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as
symptomatic hypotension or acute transient changes in creatinine. There have been
post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in
patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin.
Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or
patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before
initiating XIGDUO XR in patients with one or more of these characteristics, assess volume
status and renal function. Monitor for signs and symptoms of hypotension and renal function
after initiating therapy.
5.4 Urosepsis and Pyelonephritis
Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization
have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment
with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs
and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions
(6.2)].
5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia.
XIGDUO XR may increase the risk of hypoglycemia when combined with insulin and/or an
insulin secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered
by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin
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secretagogues) or insulin. Inform patients using these concomitant medications of the risk of
hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and
life-threatening necrotizing infection requiring urgent surgical intervention, have been identified
in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors,
including dapagliflozin. Cases have been reported in both females and males. Serious outcomes
have included hospitalization, multiple surgeries, and death.
Patients treated with XIGDUO XR presenting with pain or tenderness, erythema, or swelling in
the genital or perineal area, along with fever or malaise, should be assessed for necrotizing
fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if
necessary, surgical debridement. Discontinue XIGDUO XR, closely monitor blood glucose
levels, and provide appropriate alternative therapy for glycemic control.
5.7 Vitamin B12 Concentrations
In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of
previously normal serum vitamin B12 levels, without clinical manifestations, was observed in
approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption
from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly
reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals
(those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to
developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis
and vitamin B12 at 2- to 3-year intervals in patients on XIGDUO XR and manage any
abnormalities [see Adverse Reactions (6.1)].
5.8 Genital Mycotic Infections
Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital
mycotic infections were more likely to develop genital mycotic infections [see Adverse
Reactions (6.1)]. Monitor and treat appropriately.
6 ADVERSE REACTIONS
The following important adverse reactions are described below and elsewhere in the labeling:
• Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see
Warnings and Precautions (5.2)]
• Volume Depletion [see Warnings and Precautions (5.3)]
• Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
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• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings
and Precautions (5.5)]
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions
(5.6)]
• Vitamin B12 Concentrations [see Warnings and Precautions (5.7)]
• Genital Mycotic Infections [see Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
Clinical Trials with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus
In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and
nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than
in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for
nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients
treated with metformin HCl extended-release.
Clinical Trials with Dapagliflozin in Adults
Dapagliflozin
Dapagliflozin has been evaluated in clinical trials in adult and pediatric patients 10 years of age
and older with type 2 diabetes mellitus, in adult patients with heart failure, and in adult patients
with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the
studied indications. No new adverse reactions were identified in the DAPA-HF, DELIVER and
DAPA-CKD trials.
Pools of Placebo-Controlled Clinical Trials for Glycemic Control in Adults
Pool of 8 Placebo-Controlled Adult Trials for Dapagliflozin and Metformin HCl for Glycemic
Control
Data from a prespecified pool of adult patients from 8 short-term, placebo-controlled trials of
dapagliflozin coadministered with metformin HCl immediate- or extended-release was used to
evaluate safety. This pool included several add-on trials (metformin HCl alone and in
combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin HCl, or insulin and
metformin HCl, 2 initial combination with metformin HCl trials, and 2 trials of patients with
CVD and type 2 diabetes mellitus who received their usual treatment [with metformin HCl as
background therapy]). For trials that included background therapy with and without metformin
HCl, only patients who received metformin HCl were included in the 8-trial placebo-controlled
pool. Across these 8 trials, 983 patients were treated once daily with dapagliflozin 10 mg and
metformin HCl, and 1185 were treated with placebo and metformin HCl. These 8 trials provide a
mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2%
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were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6%
Asian, and 3% Black or African American. At baseline, the population had diabetes for an
average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or
mildly impaired in 90% of patients and moderately impaired in 10% of patients.
The overall incidence of adverse events for the 8-trial, short-term, placebo-controlled pool in
adult patients treated with dapagliflozin 10 mg and metformin HCl was 60.3% compared to
58.2% for the placebo and metformin HCl group. Discontinuation of therapy due to adverse
events in patients who received dapagliflozin 10 mg and metformin HCl was 4% compared to
3.3% for the placebo and metformin HCl group. The most commonly reported events leading to
discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and
metformin HCl were renal impairment (0.7%), increased blood creatinine (0.2%), decreased
renal creatinine clearance (0.2%), and urinary tract infection (0.2%).
Table 2 shows common adverse reactions in adults associated with the use of dapagliflozin and
metformin HCl. These adverse reactions were not present at baseline, occurred more commonly
on dapagliflozin and metformin HCl than on placebo, and occurred in at least 2% of patients
treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.
Table 2: Adverse Reactions in Placebo-Controlled Trials Reported in ≥2% of Adult
Patients Treated with Dapagliflozin and Metformin HCl
Adverse Reaction
% of Patients
Pool of 8 Placebo-Controlled Trials
Placebo
and
Metformin
HCl
N=1185
Dapagliflozin
5 mg and
Metformin
HCl
N=410
Dapagliflozin
10 mg and
Metformin
HCl
N=983
Female genital mycotic infections*
1.5
9.4
9.3
Nasopharyngitis
5.9
6.3
5.2
Urinary tract infections†
3.6
6.1
5.5
Diarrhea
5.6
5.9
4.2
Headache
2.8
5.4
3.3
Male genital mycotic infections‡
0
4.3
3.6
Influenza
2.4
4.1
2.6
Nausea
2.0
3.9
2.6
Back pain
3.2
3.4
2.5
Dizziness
2.2
3.2
1.8
Cough
1.9
3.2
1.4
Constipation
1.6
2.9
1.9
Dyslipidemia
1.4
2.7
1.5
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Table 2: Adverse Reactions in Placebo-Controlled Trials Reported in ≥2% of Adult
Patients Treated with Dapagliflozin and Metformin HCl
Adverse Reaction
% of Patients
Pool of 8 Placebo-Controlled Trials
Placebo
and
Metformin
HCl
N=1185
Dapagliflozin
5 mg and
Metformin
HCl
N=410
Dapagliflozin
10 mg and
Metformin
HCl
N=983
Pharyngitis
1.1
2.7
1.5
Increased urination§
1.4
2.4
2.6
Discomfort with urination
1.1
2.2
1.6
* Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for
females: vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital
infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for
females: Placebo and metformin HCl=534, dapagliflozin 5 mg and metformin HCl=223, dapagliflozin
10 mg and metformin HCl=430).
† Urinary tract infections include the following adverse reactions, listed in order of frequency reported:
urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis.
‡ Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for
males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection, posthitis,
and balanoposthitis. (N for males: Placebo and metformin HCl=651, dapagliflozin 5 mg and metformin
HCl=187, dapagliflozin 10 mg and metformin HCl=553).
§ Increased urination includes the following adverse reactions, listed in order of frequency reported:
pollakiuria, polyuria, and urine output increased.
Pool of 12 Placebo-Controlled Adult Trials for Dapagliflozin 5 and 10 mg for Glycemic Control
The data in Table 3 are derived from 12 glycemic control placebo-controlled trials in adults
ranging from 12 to 24 weeks. In 4 trials dapagliflozin was used as monotherapy, and in 8 trials
dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy
with metformin HCl [see Clinical Studies (14.1)].
These data reflect exposure of 2338 adult patients to dapagliflozin with a mean exposure
duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or
dapagliflozin 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2%
were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were
White, 14% were Asian, and 3% were Black or African American. At baseline, the population
had diabetes for an average of 6 years, had a mean HbA1c of 8.3%, and 21% had established
microvascular complications of diabetes. Baseline renal function was normal or mildly impaired
in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).
Table 3 shows common adverse reactions in adults associated with the use of dapagliflozin.
These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin
than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or
dapagliflozin 10 mg.
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Table 3: Adverse Reactions in Placebo-Controlled Trials of Glycemic Control
Reported in ≥2% of Adults Treated with Dapagliflozin
Adverse Reaction
% of Patients
Pool of 12 Placebo-Controlled Trials
Placebo
N=1393
Dapagliflozin
5 mg
N=1145
Dapagliflozin
10 mg
N=1193
Female genital mycotic infections*
1.5
8.4
6.9
Nasopharyngitis
6.2
6.6
6.3
Urinary tract infections†
3.7
5.7
4.3
Back pain
3.2
3.1
4.2
Increased urination‡
1.7
2.9
3.8
Male genital mycotic infections§
0.3
2.8
2.7
Nausea
2.4
2.8
2.5
Influenza
2.3
2.7
2.3
Dyslipidemia
1.5
2.1
2.5
Constipation
1.5
2.2
1.9
Discomfort with urination
0.7
1.6
2.1
Pain in extremity
1.4
2.0
1.7
* Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for
females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis,
genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval
abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin
10 mg=598).
† Urinary tract infections include the following adverse reactions, listed in order of frequency reported:
urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection,
pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
‡ Increased urination includes the following adverse reactions, listed in order of frequency reported:
pollakiuria, polyuria, and urine output increased.
§ Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for
males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male,
penile infection, balanoposthitis, balanoposthitis infective, genital infection, and posthitis. (N for males:
Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595).
Pool of 13 Placebo-Controlled Adult Trials for Dapagliflozin 10 mg for Glycemic Control
Dapagliflozin 10 mg was also evaluated in a larger glycemic control placebo-controlled trial pool
in adult patients. This pool combined 13 placebo-controlled trials, including 3 monotherapy
trials, 9 add-on to background antidiabetic therapy trials, and an initial combination with
metformin HCl trial. Across these 13 trials, 2360 patients were treated once daily with
dapagliflozin 10 mg for a mean duration of exposure of 22 weeks. The mean age of the
population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the
Reference ID: 5500979
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population were male; 84% were White, 9% were Asian, and 3% were Black or African
American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c
of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or
mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR
82 mL/min/1.73 m2).
Other Adverse Reactions with Dapagliflozin in Adults with Type 2 Diabetes Mellitus
Volume Depletion
Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume.
Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia,
orthostatic hypotension, or hypotension) for the 12-trial and 13-trial, short-term, placebo-
controlled pools and for the DECLARE trial are shown in Table 4 [see Warnings and
Precautions (5.3)].
Table 4: Adverse Reactions Related to Volume Depletion* in Adult Clinical Trials with
Dapagliflozin
Pool of 12 Placebo-Controlled
Trials
Pool of 13 Placebo-
Controlled Trials
DECLARE Trial
Placebo
Dapagliflozin
5 mg
Dapagliflozin
10 mg
Placebo
Dapagliflozin
10 mg
Placebo
Dapagliflozin
10 mg
Overall
population
N (%)
N=1393
5
(0.4%)
N=1145
7
(0.6%)
N=1193
9
(0.8%)
N=2295
17
(0.7%)
N=2360
27
(1.1%)
N=856
9
207
(2.4%)
N=8574
213
(2.5%)
Patient Subgroup n (%)
Patients on
loop
diuretics
n=55
1
(1.8%)
n=40
0
n=31
3
(9.7%)
n=267
4
(1.5%)
n=236
6
(2.5%)
n=934
57
(6.1%)
n=866
57
(6.6%)
Patients
with
moderate
renal
impairment
with eGFR
30 and
<60 mL/mi
n/1.73 m2
n=107
2
(1.9%)
n=107
1
(0.9%)
n=89
1
(1.1%)
n=268
4
(1.5%)
n=265
5
(1.9%)
n=658
30
(4.6%)
n=604
35
(5.8%)
Patients
65 years
of age
n=276
1
(0.4%)
n=216
1
(0.5%)
n=204
3
(1.5%)
n=711
6
(0.8%)
n=665
11
(1.7%)
n=395
0
121
(3.1%)
n=3948
117
(3.0%)
* Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.
Hypoglycemia
The frequency of hypoglycemia in adult patients by trial [see Clinical Studies (14.1)] is shown in
Table 5. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or
insulin [see Warnings and Precautions (5.5)].
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Table 5: Incidence of Severe Hypoglycemia* and Hypoglycemia with Glucose
< 54 mg/dL† in Controlled Glycemic Control Clinical Trials in Adults
Placebo
Dapagliflozin
5 mg
Dapagliflozin
10 mg
Add-on to Metformin HCl (24 weeks)
N=137
N=137
N=135
Severe [n (%)]
0
0
0
Glucose < 54 mg/dL [n (%)]
0
0
0
Add-on to DPP4 inhibitor (with or
without Metformin HCl) (24 weeks)
N=226
–
N=225
Severe [n (%)]
0
–
1 (0.4)
Glucose < 54 mg/dL [n (%)]
1 (0.4)
–
1 (0.4)
Add-on to Insulin with or without
other OADs‡ (24 weeks)
N=197
N=212
N=196
Severe [n (%)]
1 (0.5)
2 (0.9)
2 (1.0)
Glucose < 54 mg/dL [n (%)]
43 (21.8)
55 (25.9)
45 (23.0)
* Severe episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or
behavior, requiring external (third party) assistance, and with prompt recovery after intervention
regardless of glucose level.
† Episodes of hypoglycemia with glucose < 54 mg/dL (3 mmol/L) were defined as reported episodes of
hypoglycemia meeting the glucose criteria that did not also qualify as a severe episode.
‡ OAD = oral antidiabetic therapy.
In the DECLARE trial [see Clinical Studies (14.3)], severe events of hypoglycemia were
reported in 58 (0.7%) out of 8574 adult patients treated with dapagliflozin 10 mg and 83 (1.0%)
out of 8569 adult patients treated with placebo.
Genital Mycotic Infections
In the glycemic control trials in adults, genital mycotic infections were more frequent with
dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo,
5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-trial placebo-controlled
pool. Discontinuation from trial due to genital infection occurred in 0% of placebo-treated
patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently
reported in females than in males (see Table 3). The most frequently reported genital mycotic
infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a
history of genital mycotic infections were more likely to have a genital mycotic infection during
the trial than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0%
on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively). In the DECLARE trial
[see Clinical Studies (14.3)], serious genital mycotic infections were reported in <0.1% of
patients treated with dapagliflozin 10 mg and <0.1% of patients treated with placebo. Genital
mycotic infections that caused trial drug discontinuation were reported in 0.9% of patients
treated with dapagliflozin 10 mg and <0.1% of patients treated with placebo.
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Hypersensitivity Reactions
Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with
dapagliflozin treatment. In glycemic control trials in adults, serious anaphylactic reactions and
severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated
patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur,
discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms
resolve.
Ketoacidosis
In the DECLARE trial [see Clinical Studies (14.3)], events of diabetic ketoacidosis (DKA) were
reported in 27 out of 8574 adult patients in the dapagliflozin-treated group and in 12 out of
8569 adult patients in the placebo group. The events were evenly distributed over the trial period.
Laboratory Tests in Adults with Type 2 Diabetes Mellitus treated with Dapagliflozin or
Metformin HCl
Dapagliflozin
Increases in Serum Creatinine and Decreases in eGFR
Initiation of SGLT2 inhibitors, including dapagliflozin, causes a small increase in serum
creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur
within two weeks of starting therapy and then stabilize regardless of baseline kidney function.
Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of
acute kidney injury [see Warnings and Precautions (5.3)]. In two trials that included adult
patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR
reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role
in the renal function changes observed with dapagliflozin.
Increase in Hematocrit
In the pool of 13 placebo-controlled trials of glycemic control, increases from baseline in mean
hematocrit values were observed in dapagliflozin-treated adult patients starting at Week 1 and
continuing up to Week 16, when the maximum mean difference from baseline was observed. At
Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and
2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in
0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients.
Increase in Low-Density Lipoprotein Cholesterol
In the pool of 13 placebo-controlled trials of glycemic control, changes from baseline in mean
lipid values were reported in dapagliflozin-treated adult patients compared to placebo-treated
patients. Mean percent changes from baseline at Week 24 were 0.0% versus 2.5% for total
cholesterol, and -1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg
groups, respectively. In the DECLARE trial [see Clinical Studies (14.3)], mean changes from
baseline after 4 years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL
Reference ID: 5500979
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versus -4.4 mg/dL for LDL cholesterol, in dapagliflozin 10 mg-treated and the placebo groups,
respectively.
Decrease in Serum Bicarbonate
In a trial of concomitant therapy of dapagliflozin 10 mg with exenatide extended-release (on a
background of metformin HCl) in adults, four patients (1.7%) on concomitant therapy had a
serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the
dapagliflozin and exenatide extended-release treatment groups [see Warning and Precautions
(5.2)].
Metformin HCl
Vitamin B12 Concentrations
In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously
normal serum vitamin B12 levels was observed in approximately 7% of patients.
Clinical Trials in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus
Dapagliflozin
The dapagliflozin safety profile observed in the 26-week placebo-controlled clinical trial with a
26-week extension in 157 pediatric patients aged 10 years and older with type 2 diabetes mellitus
was similar to that observed in adults [see Clinical Studies (14.2)].
Metformin HCl
In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2
diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.
6.2 Postmarketing Experience
Additional adverse reactions have been identified during post-approval use of XIGDUO XR,
dapagliflozin or metformin HCl. Because these reactions are reported voluntarily from a
population of uncertain size, it is generally not possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Dapagliflozin
Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and
pyelonephritis
Metabolism and Nutrition Disorders: Ketoacidosis
Renal and Urinary Disorders: Acute kidney injury
Skin and Subcutaneous Tissue Disorders: Rash
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Metformin HCl
Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury
7 DRUG INTERACTIONS
Table 6: Clinically Relevant Interactions with XIGDUO XR
Carbonic Anhydrase Inhibitors
Clinical
Impact
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide,
acetazolamide or dichlorphenamide) frequently causes a decrease in serum
bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
Concomitant use of these drugs with XIGDUO XR may increase the risk for
lactic acidosis.
Intervention
Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical
Impact
Concomitant use of drugs that interfere with common renal tubular transport
systems involved in the renal elimination of metformin (e.g., organic cationic
transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors, such as
ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic
exposure to metformin and may increase the risk for lactic acidosis [see
Clinical Pharmacology (12.3)].
Intervention
Consider the benefits and risks of concomitant use.
Alcohol
Clinical
Impact
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention
Warn patients against excessive alcohol intake while receiving XIGDUO XR.
Insulin or Insulin Secretagogues
Clinical
Impact
The risk of hypoglycemia may be increased when XIGDUO XR is used
concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see
Warnings and Precautions (5.5)].
Intervention
Concomitant use may require lower doses of insulin or the insulin secretagogue
to reduce the risk of hypoglycemia.
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Drugs Affecting Glycemic Control
Clinical
Impact
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic
control. These medications include thiazides and other diuretics,
corticosteroids, phenothiazines, thyroid products, estrogens, oral
contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid.
Intervention
When such drugs are administered to a patient receiving XIGDUO XR, observe
the patient closely for loss of blood glucose control. When such drugs are
withdrawn from a patient receiving XIGDUO XR, observe the patient closely
for hypoglycemia.
Lithium
Clinical
Impact
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum
lithium concentrations.
Intervention
Monitor serum lithium concentration more frequently during XIGDUO XR
initiation and dosage changes.
Positive Urine Glucose Test
Clinical
Impact
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive
urine glucose tests.
Intervention
Monitoring glycemic control with urine glucose tests is not recommended in
patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic
control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical
Impact
Measurements of 1,5-AG are unreliable in assessing glycemic control in
patients taking SGLT2 inhibitors.
Intervention
Monitoring glycemic control with 1,5-AG assay is not recommended. Use
alternative methods to monitor glycemic control.
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on animal data showing adverse renal effects, XIGDUO XR is not recommended during
the second and third trimesters of pregnancy.
Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to
determine drug-associated risk for major birth defects or miscarriage. Published studies with
metformin use during pregnancy have not reported a clear association with metformin and major
birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated
with poorly controlled diabetes in pregnancy (see Clinical Considerations).
In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were
observed in rats when dapagliflozin was administered during a period of renal development
corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the
lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data).
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational
diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in
women with HbA1c greater than 10%. The estimated background risk of miscarriage for the
indicated population is unknown. In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to
20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryofetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,
preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly
controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia
related morbidity.
Data
Human Data
Published data from post-marketing studies have not reported a clear association with metformin
and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was
used during pregnancy. However, these studies cannot definitely establish the absence of any
metformin-associated risk because of methodological limitations, including small sample size
and inconsistent comparator groups.
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Animal Data
Dapagliflozin
Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses
of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic
and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the
10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in
juvenile animals did not fully reverse within a 1-month recovery period.
In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats
from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were
indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal
pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day
(maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the
human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body
weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC).
No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg
clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of
renal development in rats that corresponds to the late second and third trimester of human
development.
In embryofetal development studies in rats and rabbits, dapagliflozin was administered
throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats,
dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times
the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural
abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than
150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were
associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses
up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).
Metformin HCl
Metformin HCl did not cause adverse developmental effects when administered to pregnant
Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This
represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface
area (mg/m2) for rats and rabbits, respectively. Determination of fetal concentrations
demonstrated a partial placental barrier to metformin.
8.2 Lactation
Risk Summary
There is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk,
the effects on the breastfed infant, or the effects on milk production.
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Limited published studies report that metformin is present in human milk (see Data). However,
there is insufficient information on the effects of metformin on the breastfed infant and no
available information on the effects of metformin on milk production. Dapagliflozin is present in
the milk of lactating rats (see Data). However, due to species specific differences in lactation
physiology, the clinical relevance of these data is not clear. Since human kidney maturation
occurs in utero and during the first 2 years of life when lactational exposure may occur, there
may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in breastfed infants, advise women that use
of XIGDUO XR is not recommended while breastfeeding.
Data
Dapagliflozin
Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin
and its metabolites are transferred into milk at a concentration that is approximately 50% of that
in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing
kidney (renal pelvic and tubular dilatations) during maturation.
Metformin HCl
Published clinical lactation studies report that metformin is present in human milk which resulted
in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a
milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to
definitely establish the risk of use of metformin during lactation because of small sample size
and limited adverse event data collected in infants.
8.3 Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with
metformin may result in ovulation in some anovulatory women.
8.4 Pediatric Use
The safety and effectiveness of XIGDUO XR as an adjunct to diet and exercise to improve
glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged
10 years and older.
Use of XIGDUO XR for this indication is supported by a 26-week placebo-controlled trial of
dapagliflozin with a 26-week extension in 157 pediatric patients aged 10 to 17 years with type 2
diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes
mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)]. The safety profile
observed in the placebo-controlled trial of dapagliflozin in pediatric patients with type 2 diabetes
mellitus was similar to that observed in adults [see Adverse Reactions (6.1)].
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The use of XIGDUO XR for this indication is also supported by evidence from adequate and
well-controlled trials of metformin HCl immediate-release tablets in adults with additional data
from a controlled clinical trial using metformin HCl immediate-release tablets in pediatric
patients 10 to 16 years old with type 2 diabetes mellitus, and pharmacokinetic data with
metformin HCl extended-release tablets in adults [see Clinical Pharmacology (12.3) and
Clinical Studies (14.1, 14.2)]. In the clinical trial with pediatric patients receiving metformin
HCl immediate-release tablets, adverse reactions with metformin HCl immediate-release tablets
were similar to those described in adults [see Adverse Reactions (6.1)].
The safety and effectiveness of XIGDUO XR for glycemic control in patients with type 2
diabetes mellitus have not been established in pediatric patients less than 10 years of age.
The safety and effectiveness of XIGDUO XR have not been established in pediatric patients to
reduce the risk of [see Indications and Usage (1)]:
• sustained eGFR decline, end-stage kidney disease, cardiovascular death, and
hospitalization for heart failure in patients with chronic kidney disease at risk of
progression.
• cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in
patients with heart failure.
• hospitalization for heart failure in patients with type 2 diabetes mellitus and either
established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
8.5 Geriatric Use
XIGDUO XR
No XIGDUO XR dosage change is recommended based on age. More frequent assessment of
renal function is recommended in elderly patients.
Dapagliflozin
A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207
(3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical trials
assessing the efficacy of dapagliflozin in improving glycemic control. After controlling for level
of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years
and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin
for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.3)
and Adverse Reactions (6.1)].
In the DAPA-HF, DELIVER and DAPA-CKD trials, safety and efficacy were similar for
patients aged 65 years and younger and those older than 65 in both the overall population and in
the patients with type 2 diabetes mellitus. In the DAPA-HF trial, 2714 (57%) out of 4744
patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out
of 2139 patients with HFrEF and type 2 diabetes mellitus, 1211 (57%) were older than 65 years.
In the DELIVER trial, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were
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older than 65 years. Out of 2806 patients with LVEF >40% and type 2 diabetes mellitus, 2072
(74%) were older than 65 years. In the DAPA-CKD trial, 1818 (42%) out of 4304 patients with
chronic kidney disease were older than 65 years. Out of 2906 patients with chronic kidney
disease and type 2 diabetes mellitus, 1399 (48%) were older than 65 years.
Metformin HCl
Controlled clinical trials of metformin did not include sufficient numbers of elderly patients to
determine whether they respond differently than younger patients. In general, dosage selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal
function more frequently in elderly patients [see Warnings and Precautions (5.1)].
8.6 Renal Impairment
Initiation of XIGDUO XR is not recommended in patients with an eGFR below
45 mL/min/1.73 m2 and is contraindicated in patients with severe renal impairment (eGFR less
than 30 mL/min/1.73 m2) or end-stage renal disease [see Dosage and Administration (2.4),
Contraindications (4) and Warnings and Precautions (5.1, 5.3)].
Dapagliflozin
Dapagliflozin 10 mg was evaluated in 4304 adult patients with chronic kidney disease (eGFR 25
to 75 mL/min/1.73 m2) in the DAPA-CKD trial. Dapagliflozin 10 mg was also evaluated in
1926 adult patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF trial. The safety
profile of dapagliflozin across eGFR subgroups was consistent with the known safety profile
[see Adverse Reactions (6.1) and Clinical Studies (14.4 and 14.5)].
Dapagliflozin 10 mg was evaluated in two glycemic control trials that included adult patients
with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2, and an eGFR
of 30 to less than 60 mL/min/1.73 m2) [see Clinical Studies (14.1)]. Patients with diabetes and
renal impairment using dapagliflozin 10 mg are more likely to experience hypotension and may
be at higher risk for acute kidney injury secondary to volume depletion. In the trial of adult
patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving dapagliflozin
experienced bone fractures compared to none receiving placebo. Use of dapagliflozin 10 mg for
glycemic control in patients without established CV disease or CV risk factors is not
recommended when eGFR is less than 45 mL/min/1.73 m2 [see Dosage and Administration
(2.4)].
Metformin HCl
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and
lactic acidosis increases with the degree of renal impairment. XIGDUO XR is contraindicated in
severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below
30 mL/min/1.73 m2 [see Dosage and Administration (2.4), Contraindications (4), Warnings and
Precautions (5.1), and Clinical Pharmacology (12.3)].
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8.7 Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of
lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment [see
Warnings and Precautions (5.1)].
10 OVERDOSAGE
Dapagliflozin
In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a
medical toxicologist for additional overdosage management recommendations. The removal of
dapagliflozin by hemodialysis has not been studied.
Metformin HCl
Overdose of metformin HCl has occurred, including ingestion of amounts >50 grams. Lactic
acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings
and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under
good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of
accumulated drug from patients in whom metformin overdosage is suspected.
11 DESCRIPTION
XIGDUO XR tablets contain: dapagliflozin, a SGLT2 inhibitor, and metformin HCl, a
biguanide.
Dapagliflozin
Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-
ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1).
The empirical formula is C21H25ClO6•C3H8O2•H2O and the formula weight is 502.98. The
structural formula is:
Metformin HCl
Metformin HCl (N,N-dimethylimidodicarbonimidic diamide HCl) is a white to off-white
crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of
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165.63. Metformin HCl is freely soluble in water, slightly soluble in alcohol, and is practically
insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1%
aqueous solution of metformin HCl is 6.68. The structural formula is:
XIGDUO XR
XIGDUO XR is available for oral administration as tablets containing the equivalent of 2.5 mg
dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to
779.86 mg metformin base (XIGDUO XR 2.5 mg/1,000 mg), 5 mg dapagliflozin as
dapagliflozin propanediol and 500 mg metformin HCl which is equivalent to 389.9 mg
metformin base (XIGDUO XR 5 mg/500 mg), the equivalent of 5 mg dapagliflozin as
dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg
metformin base (XIGDUO XR 5 mg/1,000 mg), the equivalent of 10 mg dapagliflozin as
dapagliflozin propanediol and 500 mg metformin HCl which is equivalent to 389.9 mg
metformin base (XIGDUO XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as
dapagliflozin propanediol and 1,000 mg metformin HCl which is equivalent to 779.86 mg
metformin base (XIGDUO XR 10 mg/1,000 mg).
Each film-coated tablet of XIGDUO XR contains the following inactive ingredients: anhydrous
lactose, carboxymethylcellulose sodium, crospovidone, hypromellose, magnesium stearate,
microcrystalline cellulose, and silicon dioxide.
The film coatings contain the following inactive ingredients: polyethylene glycol, polyvinyl
alcohol, talc, and titanium dioxide. Additionally, the film coating for the XIGDUO XR
5 mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF aluminum lake. The film
coating for the XIGDUO XR 2.5 mg/1,000 mg, 5 mg/1,000 mg, 10 mg/500 mg, and
10 mg/1,000 mg tablets contains iron oxides.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dapagliflozin
Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible
for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is
an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered
glucose, and thereby promotes urinary glucose excretion.
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Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal
tubule. This may influence several physiological functions including, but not restricted to,
lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and
decreased intraglomerular pressure which is believed to be mediated by increased
tubuloglomerular feedback.
Metformin HCl
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type
2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases
hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin
sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy,
insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin
response may decrease.
12.2 Pharmacodynamics
General
Dapagliflozin
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in
patients with type 2 diabetes mellitus following the administration of dapagliflozin (see
Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for
12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. A near
maximum glucose excretion was observed at the dapagliflozin daily dosage of 20 mg. This
urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see
Adverse Reactions (6.1)]. After discontinuation of dapagliflozin, on average, the elevation in
urinary glucose excretion approaches baseline by about 3 days for the 10 mg dosage.
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Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary
Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2
Diabetes Mellitus (T2DM) (Semi-Log Plot)
Cardiac Electrophysiology
Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily
doses up to 150 mg (15-times the recommended maximum dose) in a study of healthy subjects.
In addition, no clinically meaningful effect on QTc interval was observed following single doses
of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy
subjects.
12.3 Pharmacokinetics
XIGDUO XR
The administration of XIGDUO XR in healthy subjects after a standard meal compared to the
fasted state resulted in the same extent of exposure for both dapagliflozin and metformin
extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and
a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is
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not considered to be clinically meaningful. Food has no relevant effect on the pharmacokinetics
of metformin when administered as XIGDUO XR combination tablets.
Absorption
Dapagliflozin
Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is
usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose
proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute
oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.
Administration of dapagliflozin with a high-fat meal decreases its Cmax by up to 50% and
prolongs Tmax by approximately 1 hour but does not alter AUC as compared with the fasted state.
These changes are not considered to be clinically meaningful and dapagliflozin can be
administered with or without food.
Metformin HCl
Following a single oral dose of metformin HCl extended-release, Cmax is achieved with a median
value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measured by
AUC) from the metformin HCl extended-release tablet increased by approximately 50% when
given with food. There was no effect of food on Cmax and Tmax of metformin. Metformin HCl
extended-release tablets and metformin HCl immediate-release tablets have a similar extent of
absorption (as measured by AUC), while peak plasma levels of metformin extended-release
tablets are approximately 20% lower than those of metformin immediate-release tablets at the
same dose.
Distribution
Dapagliflozin
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with
renal or hepatic impairment.
Metformin HCl
Distribution studies with extended-release metformin have not been conducted; however, the
apparent volume of distribution (V/F) of metformin following single oral doses of immediate-
release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma
proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin
partitions into erythrocytes.
Metabolism
Dapagliflozin
The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism
is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to
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yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-
glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-
related component in human plasma.
Metformin HCl
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted
unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been
identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Elimination
Dapagliflozin
Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following
a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine
and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces,
approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life
(t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin
10 mg.
Metformin HCl
Renal clearance is approximately 3.5-times greater than creatinine clearance, which indicates
that tubular secretion is the major route of metformin elimination. Following oral administration,
approximately 90% of the absorbed drug is eliminated via the renal route within the first
24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the
elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a
compartment of distribution.
Specific Populations
Geriatric Patients
Dapagliflozin
Based on a population pharmacokinetic analysis, age does not have a clinically meaningful effect
on systemic exposures of dapagliflozin.
Metformin HCl
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects
suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax
is increased, compared to healthy young subjects. From these data, it appears that the change in
metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
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Pediatric Patients
Dapagliflozin
The pharmacokinetics and pharmacodynamics (glucosuria) of dapagliflozin in pediatric patients
aged 10 to 17 years with type 2 diabetes mellitus were similar to those observed in adult patients
with same renal function.
Metformin HCl
After administration of a single oral metformin 500 mg tablet with food, geometric mean
metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16
years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with
normal renal function.
Male and Female Patients
Dapagliflozin
Based on a population pharmacokinetic analysis, gender does not have a clinically meaningful
effect on systemic exposures of dapagliflozin.
Metformin HCl
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and
patients with type 2 diabetes mellitus when analyzed according to gender (males=19,
females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the
antihyperglycemic effect of metformin was comparable in males and females.
Racial or Ethnic Groups
Dapagliflozin
Based on a population pharmacokinetic analysis, race (White, Black or African American, or
Asian) does not have a clinically meaningful effect on systemic exposures of dapagliflozin.
Metformin HCl
No studies of metformin pharmacokinetic parameters according to race have been performed. In
controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the
antihyperglycemic effect was comparable in Whites (n=249), Black or African Americans
(n=51), and Hispanic or Latino Ethnicity (n=24).
Patients with Renal Impairment
Dapagliflozin
At steady-state (20 mg once daily dapagliflozin for 7 days), adult patients with type 2 diabetes
mellitus with mild, moderate, or severe renal impairment (as determined by eGFR) had
geometric mean systemic exposures of dapagliflozin that were 45%, 100% and 200% higher,
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respectively, as compared to patients with type 2 diabetes mellitus with normal renal function.
Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal
impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The
steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild,
moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in
patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on
dapagliflozin exposure is not known [see Dosage and Administration (2.4), Warnings and
Precautions (5.3), Use in Specific Populations (8.6) and Clinical Studies (14)].
Metformin HCl
In patients with decreased renal function, the plasma and blood half-life of metformin is
prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and
Precautions (5.1)].
Patients with Hepatic Impairment
Dapagliflozin
In adult patients with mild and moderate hepatic impairment (Child-Pugh classes A and B),
mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared
to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin.
These differences were not considered to be clinically meaningful. In adult patients with severe
hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40%
and 67% higher, respectively, as compared to healthy matched controls.
Metformin HCl
No pharmacokinetic studies of metformin have been conducted in patients with hepatic
impairment [see Warnings and Precautions (5.1)].
Body Weight
Dapagliflozin
Based on a population pharmacokinetic analysis, body weight does not have a clinically
meaningful effect on systemic exposures of dapagliflozin.
Drug Interactions
Specific pharmacokinetic drug interaction studies with XIGDUO XR have not been performed,
although such studies have been conducted with the individual dapagliflozin and metformin
components.
In Vitro Assessment of Drug Interactions
Dapagliflozin
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2,
2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate
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of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate
for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not
meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is
unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp,
OCT2, OAT1, or OAT3 substrates.
Effects of Other Drugs on Metformin
Table 7 shows the effect of coadministered drugs on the pharmacokinetics of metformin in
adults.
Table 7: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure
Coadministered Drug
(Dose Regimen)*
Metformin
(Dose Regimen)*
Metformin
Change† in AUC‡
Change† in
Cmax
No dosing adjustments required for the following:
Glyburide (5 mg)
850 mg
↓9%§
↓7%§
Furosemide (40 mg)
850 mg
↑15%§
↑22%§
Nifedipine (10 mg)
850 mg
↑9%
↑20%
Propranolol (40 mg)
850 mg
↓10%
↓6%
Ibuprofen (400 mg)
850 mg
↑5%§
↑7%§
Drugs eliminated by renal tubular secretion may increase the accumulation of
metformin [see Drug Interactions (7)].
Cimetidine (400 mg)
850 mg
↑40%
↑60%
* All metformin and coadministered drugs were given as single doses.
† Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure
increase and decrease, respectively.
‡ AUC = AUC(INF).
§ Ratio of arithmetic means.
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Effects of Metformin on Other Drugs
Table 8 shows the effect of metformin on the pharmacokinetics of coadministered drugs in
adults.
Table 8: Effect of Metformin on Coadministered Drug Systemic Exposure
Coadministered Drug
(Dose Regimen)*
Metformin
(Dose Regimen)*
Coadministered Drug
Change† in AUC‡
Change† in
Cmax
No dosing adjustments required for the following:
Glyburide (5 mg)
850 mg
↓22%§
↓37%§
Furosemide (40 mg)
850 mg
↓12%§
↓31%§
Nifedipine (10 mg)
850 mg
↑10%¶
↑8%
Propranolol (40 mg)
850 mg
↑1%¶
↑2%
Ibuprofen (400 mg)
850 mg
↓3%#
↑1%#
Cimetidine (400 mg)
850 mg
↓5%¶
↑1%
* All metformin and coadministered drugs were given as single doses.
† Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure
increase and decrease, respectively.
‡ AUC = AUC(INF) unless otherwise noted.
§ Ratio of arithmetic means, p-value of difference <0.05.
¶ AUC(0-24 hr) reported.
# Ratio of arithmetic means.
Effects of Other Drugs on Dapagliflozin
Table 9 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in
adults. No dose adjustments are recommended for dapagliflozin.
Table 9: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure
Coadministered Drug
(Dose Regimen)*
Dapagliflozin
(Dose
Regimen)*
Dapagliflozin
Change† in
AUC‡
Change† in Cmax
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1,000 mg)
20 mg
↓1%
↓7%
Pioglitazone (45 mg)
50 mg
0%
↑9%
Sitagliptin (100 mg)
20 mg
↑8%
↓4%
Glimepiride (4 mg)
20 mg
↓1%
↑1%
Voglibose (0.2 mg three times
daily)
10 mg
↑1%
↑4%
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Other Medications
Hydrochlorothiazide (25 mg)
50 mg
↑7%
↓1%
Bumetanide (1 mg)
10 mg once daily
for 7 days
↑5%
↑8%
Valsartan (320 mg)
20 mg
↑2%
↓12%
Simvastatin (40 mg)
20 mg
↓1%
↓2%
Anti-infective Agent
Rifampin (600 mg once daily
for 6 days)
10 mg
↓22%
↓7%
Nonsteroidal Anti-inflammatory Agent
Mefenamic Acid (loading dose
of 500 mg followed by 14 doses
of 250 mg every 6 hours)
10 mg
↑51%
↑13%
* Single dose unless otherwise noted.
† Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure
increase and decrease, respectively.
‡ AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.
Effects of Dapagliflozin on Other Drugs
Table 10 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin
did not meaningfully affect the pharmacokinetics of the coadministered drugs.
Table 10: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs
Coadministered Drug
(Dose Regimen)*
Dapagliflozin
(Dose Regimen)*
Coadministered Drug
Change† in
AUC‡
Change† in Cmax
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1,000 mg)
20 mg
0%
↓5%
Pioglitazone (45 mg)
50 mg
0%
↓7%
Sitagliptin (100 mg)
20 mg
↑1%
↓11%
Glimepiride (4 mg)
20 mg
↑13%
↑4%
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Other Medications
Hydrochlorothiazide (25
mg)
50 mg
↓1%
↓5%
Bumetanide (1 mg)
10 mg once daily
for 7 days
↑13%
↑13%
Valsartan (320 mg)
20 mg
↑5%
↓6%
Simvastatin (40 mg)
20 mg
↑19%
↓6%
Digoxin (0.25 mg)
20 mg loading
dose then 10 mg
once daily for 7
days
0%
↓1%
Warfarin (25 mg)
S-warfarin
R-warfarin
20 mg loading
dose then 10 mg
once daily for 7
days
↑3%
↑6%
↑7%
↑8%
* Single dose unless otherwise noted.
† Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure
increase and decrease, respectively.
‡ AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
XIGDUO XR
No animal studies have been conducted with XIGDUO XR to evaluate carcinogenesis,
mutagenesis, or impairment of fertility. The following data are based on the findings in the
studies with dapagliflozin and metformin individually.
Dapagliflozin
Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year
carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2,
10 and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both
males and females. The highest doses evaluated in mice were approximately 72-times (males)
and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the
highest dose was approximately 131-times (males) and 186-times (females) the clinical dose of
10 mg per day, based on AUC exposure.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in
vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or
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equal to 100 µg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies
evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the
clinical dose.
There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that
dapagliflozin does not represent a genotoxic risk to humans.
Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male
or female rats at exposure multiples less than or equal to 1708-times and 998-times the
maximum recommended human dose in males and females, respectively.
Metformin HCl
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks)
and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1,500 mg/kg/day,
respectively. These doses are both approximately 4-times the maximum recommended human
dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with
metformin was found in either male or female mice. Similarly, there was no tumorigenic
potential observed with metformin in male rats. There was, however, an increased incidence of
benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests:
Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal
aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also
negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high
as 600 mg/kg/day, which is approximately 3-times the maximum recommended human dose
based on body surface area comparisons.
14 CLINICAL STUDIES
14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus
The effectiveness of XIGDUO XR has been established in clinical trials of the coadministration
of oral dapagliflozin and metformin HCl extended-release tablets in treatment-naive adult
patients inadequately controlled on diet and exercise alone. The coadministration of
dapagliflozin and metformin HCl immediate-release or extended-release tablets has been studied
in adult patients with type 2 diabetes mellitus inadequately controlled on metformin HCl and
compared with a sulfonylurea (glipizide) in combination with metformin HCl. Treatment with
dapagliflozin plus metformin HCl at all doses produced statistically significant improvements in
HbA1c and fasting plasma glucose (FPG) compared to placebo in combination with metformin
HCl (initial or add-on therapy). HbA1c reductions were seen across subgroups including gender,
age, race, duration of disease, and baseline body mass index (BMI).
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Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release
A total of 1236 treatment-naive adult patients with inadequately controlled type 2 diabetes
mellitus (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled trials of 24-week duration
to evaluate initial therapy with dapagliflozin 5 mg (NCT00643851) or 10 mg (NCT00859898) in
combination with metformin extended-release formulation.
In one trial, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period
received: dapagliflozin 10 mg plus metformin HCl extended-release (up to 2,000 mg/day),
dapagliflozin 10 mg plus placebo, or metformin HCl extended-release (up to 2,000 mg/day) plus
placebo. Metformin HCl extended-release dosage was up-titrated weekly in 500 mg increments,
as tolerated, with a median dosage achieved of 2,000 mg.
The combination treatment of dapagliflozin 10 mg plus metformin HCl extended-release
provided statistically significant improvements in HbA1c and FPG compared with either of the
monotherapy treatments and statistically significant reduction in body weight compared with
metformin HCl extended-release alone (see Table 11 and Figure 2). Dapagliflozin 10 mg as
monotherapy also provided statistically significant improvements in FPG and statistically
significant reduction in body weight compared with metformin HCl alone and was non-inferior
to metformin HCl extended-release monotherapy in lowering HbA1c.
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Table 11: Results at Week 24 (LOCF*) in an Active-Controlled Trial of Dapagliflozin
Initial Combination Therapy with Metformin HCl Extended-Release in Adults with
Type 2 Diabetes Mellitus
Efficacy Parameter
Dapagliflozin
10 mg
+
Metformin
HCl extended-
release
Dapagliflozin
10 mg
Metformin
HCl
extended-
release
N=211†
N=219†
N=208†
HbA1c (%)
Baseline (mean)
9.1
9.0
9.0
Change from baseline (adjusted mean‡)
−2.0
−1.5
−1.4
Difference from dapagliflozin (adjusted
mean‡)
(95% CI)
−0.5§
(−0.7, −0.3)
Difference from metformin HCl
extended-release (adjusted mean‡)
(95% CI)
−0.5§
(−0.8, −0.3)
0.0¶
(−0.2, 0.2)
Percent of patients achieving
HbA1c <7% adjusted for baseline
46.6%
31.7%
35.2%
FPG (mg/dL)
Baseline (mean)
189.6
197.5
189.9
Change from baseline (adjusted mean‡)
−60.4
−46.4
−34.8
Difference from dapagliflozin (adjusted
mean‡)
(95% CI)
−13.9§
(−20.9, −7.0)
Difference from metformin HCl
extended-release (adjusted mean‡)
(95% CI)
−25.5§
(−32.6, −18.5)
−11.6#
(−18.6, −4.6)
Body Weight (kg)
Baseline (mean)
88.6
88.5
87.2
Change from baseline (adjusted mean‡)
−3.3
−2.7
−1.4
Difference from metformin HCl
extended-release (adjusted mean‡)
(95% CI)
−2.0§
(−2.6, −1.3)
−1.4§
(−2.0, −0.7)
* LOCF: last observation (prior to rescue for rescued patients) carried forward.
† All randomized patients who took at least one dose of double-blind trial medication during the short-term
double-blind period.
‡ Least squares mean adjusted for baseline value.
§ p-value <0.0001.
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¶ Non-inferior versus metformin HCl extended-release.
# p-value <0.05.
Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week
Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin HCl
Extended-Release in Adults with Type 2 Diabetes Mellitus
In the second trial (NCT00643851), 603 patients were randomized to 1 of 3 treatment arms
following a 1-week lead-in period: dapagliflozin 5 mg plus metformin HCl extended-release (up
to 2,000 mg/day), dapagliflozin 5 mg plus placebo, or metformin HCl extended-release (up to
2,000 mg/day) plus placebo. Metformin HCl extended-release dosage was up-titrated weekly in
500 mg increments, as tolerated, with a median dosage achieved of 2,000 mg.
The combination treatment of dapagliflozin 5 mg plus metformin HCl extended-release provided
statistically significant improvements in HbA1c and FPG compared with either of the
monotherapy treatments and statistically significant reduction in body weight compared with
metformin HCl extended-release alone (see Table 12).
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Table 12: Results at Week 24 (LOCF*) in an Active-Controlled Trial of Dapagliflozin
Initial Combination Therapy with Metformin HCl Extended-Release in Adults with
Type 2 Diabetes Mellitus
Efficacy Parameter
Dapagliflozin
5 mg
+
Metformin
HCl extended-
release
Dapagliflozin
5 mg
Metformin
HCl
extended-
release
N=194†
N=203†
N=201†
HbA1c (%)
Baseline (mean)
9.2
9.1
9.1
Change from baseline (adjusted mean‡)
−2.1
−1.2
−1.4
Difference from dapagliflozin (adjusted
mean‡)
(95% CI)
−0.9§
(−1.1, −0.6)
Difference from metformin HCl
extended-release (adjusted mean‡)
(95% CI)
−0.7§
(−0.9, −0.5)
Percent of patients achieving HbA1c
<7%
adjusted for baseline
52.4%¶
22.5%
34.6%
FPG (mg/dL)
Baseline (mean)
193.4
190.8
196.7
Change from baseline (adjusted mean‡)
−61.0
−42.0
−33.6
Difference from dapagliflozin (adjusted
mean‡)
(95% CI)
−19.1§
(−26.7, −11.4)
Difference from metformin HCl
extended-release (adjusted mean‡)
(95% CI)
−27.5§
(−35.1, −19.8)
Body Weight (kg)
Baseline (mean)
84.2
86.2
85.8
Change from baseline (adjusted mean‡)
−2.7
−2.6
−1.3
Difference from metformin HCl
extended-release (adjusted mean‡)
(95% CI)
−1.4§
(−2.0, −0.7)
* LOCF: last observation (prior to rescue for rescued patients) carried forward.
† All randomized patients who took at least one dose of double-blind trial medication during the short-term
double-blind period.
‡ Least squares mean adjusted for baseline value.
§ p-value <0.0001.
¶ p-value <0.05.
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Dapagliflozin Add-On to Metformin HCl Immediate-Release
A total of 546 adult patients with type 2 diabetes mellitus with inadequate glycemic control
(HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled trial to evaluate
dapagliflozin in combination with metformin HCl (NCT00528879). Patients on metformin HCl
at a dosage of at least 1,500 mg/day were randomized after completing a 2-week, single-blind,
placebo lead-in period. Following the lead-in period, eligible patients were randomized to
dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dosage of
metformin HCl.
As add-on treatment to metformin HCl, dapagliflozin 10 mg provided statistically significant
improvements in HbA1c and FPG, and statistically significant reduction in body weight
compared with placebo at Week 24 (see Table 13 and Figure 3). Statistically significant (p<0.05
for both dosages) mean changes from baseline in systolic blood pressure relative to placebo plus
metformin were −4.5 mmHg and −5.3 mmHg with dapagliflozin 5 mg and 10 mg plus metformin
HCl, respectively.
Table 13: Results of a 24-Week (LOCF*) Placebo-Controlled Trial of Dapagliflozin in
Add-On Combination with Metformin HCl Immediate-Release in Adults with Type 2
Diabetes Mellitus
Efficacy Parameter
Dapagliflozin
10 mg
+
Metformin HCl
immediate-
release
N=135†
Dapagliflozin
5 mg
+
Metformin HCl
immediate-
release
N=137†
Placebo
+
Metformin
HCl
immediate-
release
N=137†
HbA1c (%)
Baseline (mean)
7.9
8.2
8.1
Change from baseline (adjusted
mean‡)
−0.8
−0.7
−0.3
Difference from placebo (adjusted
mean‡)
(95% CI)
−0.5§
(−0.7, −0.3)
−0.4§
(−0.6, −0.2)
Percent of patients achieving
HbA1c <7%
adjusted for baseline
40.6%¶
37.5%¶
25.9%
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FPG (mg/dL)
Baseline (mean)
156.0
169.2
165.6
Change from baseline at Week 24
(adjusted mean‡)
−23.5
−21.5
−6.0
Difference from placebo (adjusted
mean‡)
(95% CI)
−17.5§
(−25.0, −10.0)
−15.5§
(−22.9, −8.1)
Change from baseline at Week 1
(adjusted mean‡)
−16.5§
(N=115)
−12.0§
(N=121)
1.2
(N=126)
Body Weight (kg)
Baseline (mean)
86.3
84.7
87.7
Change from baseline (adjusted
mean‡)
−2.9
−3.0
−0.9
Difference from placebo (adjusted
mean‡)
(95% CI)
−2.0§
(−2.6, −1.3)
−2.2§
(−2.8, −1.5)
* LOCF: last observation (prior to rescue for rescued patients) carried forward.
† All randomized patients who took at least one dose of double-blind trial medication during the short-term
double-blind period.
‡ Least squares mean adjusted for baseline value.
§ p-value <0.0001 versus placebo + metformin HCl.
¶ p-value <0.05 versus placebo + metformin HCl.
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Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week
Placebo-Controlled Trial of Dapagliflozin in Combination with Metformin HCl Immediate-
Release in Adults with Type 2 Diabetes Mellitus
Active Glipizide-Controlled Trial of Dapagliflozin as Add-On to Metformin HCl Immediate-
Release in Adults with Type 2 Diabetes Mellitus
A total of 816 adult patients with type 2 diabetes mellitus with inadequate glycemic control
(HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, non-inferiority
trial to evaluate dapagliflozin as add-on therapy to metformin HCl (NCT00660907). Patients on
metformin HCl at a dosage of at least 1,500 mg/day were randomized following a 2-week
placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-
titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the
highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients.
Thereafter, dosages were kept constant, except for down-titration to prevent hypoglycemia.
At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to
the maximum trial dosage (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin
treatment led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF),
compared with glipizide, thus demonstrating non-inferiority (see Table 14). Dapagliflozin
treatment led to a statistically significant mean reduction in body weight from baseline at
Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group.
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Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative
to glipizide plus metformin was -5.0 mmHg with dapagliflozin plus metformin.
Table 14: Results at Week 52 (LOCF*) in an Active-Controlled Trial Comparing
Dapagliflozin to Glipizide as Add-On to Metformin in Adults with Type 2 Diabetes
Mellitus
Efficacy Parameter
Dapagliflozin
+
Metformin HCl
immediate-release
N=400†
Glipizide
+
Metformin HCl
immediate-release
N=401†
HbA1c (%)
Baseline (mean)
7.7
7.7
Change from baseline (adjusted mean‡)
−0.5
−0.5
Difference from glipizide + metformin HCl
immediate-release (adjusted mean‡)
(95% CI)
0.0§
(−0.1, 0.1)
Body Weight (kg)
Baseline (mean)
88.4
87.6
Change from baseline (adjusted mean‡)
−3.2
1.4
Difference from glipizide + metformin HCl
immediate-release (adjusted mean‡)
(95% CI)
−4.7¶
(−5.1, −4.2)
* LOCF: last observation carried forward.
† Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement.
‡ Least squares mean adjusted for baseline value.
§ Noninferior to glipizide + metformin HCl.
¶ p-value <0.0001.
Use in Adults with Type 2 Diabetes Mellitus and Moderate Renal Impairment
Dapagliflozin was assessed in two placebo-controlled trials of adult patients with type 2 diabetes
mellitus and moderate renal impairment.
Patients with type 2 diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m2
inadequately controlled on current diabetes therapy participated in a 24-week, double-blind,
placebo-controlled clinical trial (NCT02413398). Patients were randomized to either
dapagliflozin 10 mg or placebo, administered orally once daily. At Week 24, dapagliflozin
provided statistically significant reductions in HbA1c compared with placebo (Table 15).
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Table 15: Results at Week 24 of Placebo-Controlled Trial for Dapagliflozin in Adults
with Type 2 Diabetes Mellitus and Renal Impairment (eGFR 45 to less than
60 mL/min/1.73 m2)
Dapagliflozin 10 mg
Placebo
Number of patients:
N=160
N=161
HbA1c (%)
Baseline (mean)
8.3
8.0
Change from baseline (adjusted mean*)
-0.4
-0.1
Difference from placebo (adjusted mean*)
(95% CI)
-0.3†
(-0.5, - 0.1)
* Least squares mean adjusted for baseline value; at Week 24, HbA1c was missing for 5.6% and 6.8% of
individuals treated with dapagliflozin and placebo, respectively. Retrieved dropouts, i.e., observed HbA1c at
Week 24 from subjects who discontinued treatment, were used to impute missing values in HbA1c.
† p-value =0.008 versus placebo.
14.2 Glycemic Control in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes
Mellitus
Glycemic Control Trial of Dapagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2
Diabetes Mellitus
In a pediatric trial (NCT03199053), patients aged 10 to 17 years with inadequately controlled
type 2 diabetes mellitus (HbA1c ≥6.5% and ≤10.5%) were randomized to dapagliflozin
(81 patients) or placebo (76 patients) as add-on to metformin HCl, insulin or a combination of
metformin HCl and insulin. In this 26-week, placebo-controlled, double-blind randomized
clinical trial with a 26-week safety extension, patients received 5 mg of dapagliflozin or placebo
following a lead-in period. At Week 14, patients with HbA1c values <7% remained on 5 mg
while patients with HbA1c values ≥7% were randomized to either continue on 5 mg or up-titrate
to 10 mg.
At baseline, 88% of dapagliflozin-treated patients and 89% of placebo-treated patients were on
metformin HCl with or without insulin as background medication. The mean HbA1c at baseline
was 8.2% in dapagliflozin-treated patients and 8.0% in placebo-treated patients, and the mean
duration of type 2 diabetes mellitus was 2.3 years in dapagliflozin-treated patients and 2.5 years
in placebo-treated patients. The mean age was 14.4 years in dapagliflozin-treated patients and
14.7 years in placebo-treated patients, and approximately 61% of dapagliflozin-treated patients
and 58% of placebo-treated patients were female. In dapagliflozin-treated patients,
approximately 52% were White, 22% were Asian, 9% were Black or African American, and
56% were of Hispanic or Latino ethnicity. In placebo-treated patients, approximately 42% were
White, 32% were Asian, 4% were Black or African American, and 45% were of Hispanic or
Latino ethnicity. The mean BMI was 29.7 kg/m2 in dapagliflozin-treated patients and 28.5 kg/m2
in placebo-treated patients, and mean BMI Z-score was 1.7 in dapagliflozin-treated patients and
1.5 in placebo-treated patients. The mean eGFR at baseline was 115 mL/min/1.73 m2 in
dapagliflozin-treated patients and 113 mL/min/1.73 m2 in placebo-treated patients.
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At Week 26, treatment with dapagliflozin provided statistically significant improvements in
HbA1c compared with placebo (Table 16). This effect was consistent across subgroups including
race, ethnicity, sex, age group (≥10 to <15 years of age and ≥15 to <18 years of age), background
antidiabetic treatment, and baseline BMI.
The treatment benefit with dapagliflozin was consistent in the subgroup of patients with
metformin HCl with or without insulin as background therapy [adjusted mean change in HbA1c
relative to placebo from baseline to Week 26 was -1.0% (95% CI -1.6, -0.4)].
Table 16: Results at Week 26 in a Placebo-Controlled Trial of Dapagliflozin as Add-On
to Metformin HCl and/or Insulin in Pediatric Patients Aged 10 Years and Older with
Type 2 Diabetes Mellitus
Efficacy Parameter
Dapagliflozin
5 mg and 10 mg
Placebo
Intent-to-Treat Population (N)*
81
76
HbA1c† (%)
Baseline (mean)
8.2
8.0
Change from baseline (adjusted mean‡)
-0.6
0.4
Difference from placebo (adjusted mean‡)
(95% CI)
-1.0§
(-1.6, -0.5)
FPG† (mg/dL)
Baseline (mean)
162.2
152.0
Change from baseline (adjusted mean‡)
-10.3
9.2
Difference from placebo (adjusted mean‡)
(95% CI)
-19.5¶
(-36.4, -2.6)
Percent of Subjects Achieving a HbA1c
Level <7%
34.6%
25.0%
CI=confidence interval
* All randomized patients who received at least one dose of double-blind trial medication during the treatment
period. Includes data regardless of rescue or premature treatment discontinuation.
† Multiple imputations using placebo washout approach for missing efficacy endpoint. Imputed for HbA1c
(dapagliflozin N=6 (7.4%), placebo N=6 (7.9%)), for FPG (dapagliflozin N=6 (7.4%), placebo N=8
(10.5%)).
‡ Least squares mean adjusted for baseline value, treatment, age, gender and baseline diabetic medication.
§ p-value versus placebo <0.001. p-value is two-sided.
¶ p-value versus placebo <0.05. p-value is two-sided.
Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to
16 Years with Type 2 Diabetes Mellitus
A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years
with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with
metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean
duration of treatment 11 weeks). The results are displayed in Table 17.
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Table 17: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl
vs. Placebo in Pediatric Patientsa with Type 2 Diabetes Mellitus
Metformin HCl
Placebo
p-value
FPG
Baseline
Change at Final Visit
(n=37)
162.4
-42.9
(n=36)
192.3
21.4
<0.001
a Pediatric patients mean age 13.8 years (range 10-16 years)
Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release
and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3
lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively.
14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus
Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an
international, multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted
to determine the effect of dapagliflozin 10 mg relative to placebo on cardiovascular (CV)
outcomes when added to current background therapy. All patients had type 2 diabetes mellitus
and either established CV disease or two or more additional CV risk factors (age ≥55 years in
men or ≥60 years in women and one or more of dyslipidemia, hypertension, or current tobacco
use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion
of investigators, to ensure participants were treated according to the standard care for these
diseases.
Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did
not have established CV disease. A total of 8582 patients were randomized to dapagliflozin
10 mg, 8578 to placebo, and patients were followed for a median of 4.2 years.
Approximately 80% of the trial population was White, 4% Black or African American, and 13%
Asian. The mean age was 64 years, and approximately 63% were male.
Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than
5 years. Mean eGFR was 85.2 mL/min/1.73 m2. At baseline, 23.5% of patients had
microalbuminuria (UACR ≥30 to ≤300 mg/g) and 6.8% had macroalbuminuria (UACR
>300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m2. At baseline, 10% of
patients had a history of heart failure.
Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the
patients were being treated with metformin HCl, 40.9% with insulin, 42.7% with a sulfonylurea,
16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 receptor agonist.
Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or
angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with
acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0%
with thiazide diuretics, and 10.5% with loop diuretics.
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A Cox proportional hazards model was used to test for non-inferiority against the pre-specified
risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction
(MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority
on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death,
and 2) MACE.
The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per
100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The
estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with
a 95% CI of (0.84, 1.03). The upper bound of this confidence interval, 1.03, excluded the pre-
specified non-inferiority margin of 1.3.
Dapagliflozin 10 mg was superior to placebo in reducing the incidence of the primary composite
endpoint of hospitalization for heart failure or CV death [HR 0.83 (95% CI 0.73, 0.95)].
The treatment effect was due to a significant reduction in the risk of hospitalization for heart
failure in subjects randomized to dapagliflozin 10 mg [HR 0.73 (95% CI 0.61, 0.88)], with no
change in the risk of CV death (Table 18 and Figures 4 and 5).
Table 18: Treatment Effects for the Primary Endpoints* and their Components* in the
DECLARE Trial
Patients with events n(%)
Efficacy Variable
(time to first occurrence)
Dapagliflozin
10 mg
N=8582
Placebo
N=8578
Hazard Ratio
(95% CI)
Primary Endpoints
Composite of Hospitalization for
Heart Failure, CV Death†
417 (4.9)
496 (5.8)
0.83 (0.73, 0.95)
Composite Endpoint of CV
Death, MI, Ischemic Stroke
756 (8.8)
803 (9.4)
0.93 (0.84, 1.03)
Components of the composite
endpoints‡
Hospitalization for Heart Failure
212 (2.5)
286 (3.3)
0.73 (0.61, 0.88)
CV Death
245 (2.9)
249 (2.9)
0.98 (0.82, 1.17)
Myocardial Infarction
393 (4.6)
441 (5.1)
0.89 (0.77, 1.01)
Ischemic Stroke
235 (2.7)
231 (2.7)
1.01 (0.84, 1.21)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, eGFR=estimated
glomerular filtration rate, ESRD=End-stage renal disease
* Full analysis set.
† p-value =0.005 versus placebo.
‡ Total number of events presented for each component of the composite endpoints.
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Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the
DECLARE Trial
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Figure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE
Trial
14.4 Chronic Kidney Disease
The Trial to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular
Mortality in Patients with Chronic Kidney Disease (DAPA-CKD, NCT03036150) was an
international, multicenter, randomized, double-blind, placebo-controlled trial in adult patients
with chronic kidney disease (CKD) (eGFR between 25 and 75 mL/min/1.73 m2) and albuminuria
[urine albumin creatinine ratio (UACR) between 200 and 5000 mg/g] who were receiving
standard of care background therapy, including a maximally tolerated, labeled daily dosage of an
angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The
trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney
disease, lupus nephritis, or ANCA-associated vasculitis and patients requiring cytotoxic,
immunosuppressive, or immunomodulatory therapies in the preceding 6 months.
The primary objective was to determine whether dapagliflozin 10 mg reduces the incidence of
the composite endpoint of ≥50% sustained decline in eGFR, progression to end-stage kidney
disease (ESKD) (defined as sustained eGFR<15 mL/min/1.73 m2, initiation of chronic dialysis
treatment or renal transplant), CV or renal death.
A total of 4304 patients were randomized equally to dapagliflozin 10 mg or placebo and were
followed for a median of 28.5 months. The trial included patients with type 2 diabetes mellitus
(n=2906) and patients without diabetes (n=1398). The mean age of the trial population was
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62 years and 67% were male. The population was 53% White, 4% Black or African American,
and 34% Asian; 25% were of Hispanic or Latino ethnicity. At baseline, mean eGFR was
43 mL/min/1.73 m2, 44% of patients had an eGFR 30 mL/min/1.73m2 to less than
45 mL/min/1.73m2, and 15% of patients had an eGFR less than 30 mL/min/1.73m2. Median
UACR was 950 mg/g. The most common etiologies of CKD were diabetic nephropathy (58%),
ischemic/hypertensive nephropathy (16%), and IgA nephropathy (6%). At baseline, 97% of
patients were treated with ACEi or ARB. Approximately 44% were taking antiplatelet agents,
and 65% were on a statin.
Out of 2906 (68%) patients who had type 2 diabetes mellitus at randomization, 1455 patients
received dapagliflozin 10 mg and 1451 received placebo. At baseline of the patients with type 2
diabetes mellitus, 43% were being treated with metformin HCl (631 patients on dapagliflozin
10 mg and 613 on placebo) and 55% were treated with insulin.
The mean age of the type 2 diabetes mellitus trial population was 64 years, 67% were male, 53%
White, 5% Black or African American and 32% Asian, 27% were of Hispanic or Latino
ethnicity. In these patients, mean eGFR was 44 mL/min/1.73 m2, 43% of patients had an eGFR
30 mL/min/1.73 m2 to below 45 mL/min/1.73 m2, and 14% of patients had an eGFR below
30 mL/min/1.73 m2. Median UACR was 1017 mg/g. The most common etiologies of CKD in
this group were diabetic nephropathy (86%) and ischemic/hypertensive nephropathy (7%).
Dapagliflozin 10 mg reduced the incidence of the primary composite endpoint of ≥50%
sustained decline in eGFR, progression to ESKD, CV or renal death in overall population [HR
0.61 (95% CI 0.51,0.72); p<0.0001]. The dapagliflozin 10 mg and placebo event curves separate
by Month 4 and continue to diverge over the trial period. The treatment effect reflected a
reduction in ≥50% sustained decline in eGFR, progression to ESKD, and CV death. There were
few renal deaths during the trial (Table 19 and Figure 6).
The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the
primary composite endpoint in patients with type 2 diabetes mellitus [HR 0.64 (95% CI 0.52,
0.79)] and in patients with type 2 diabetes mellitus and metformin HCl as background therapy
[HR 0.74 (95% CI 0.53, 1.03)].
The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the
composite endpoint of CV death or hospitalization for heart failure and all-cause mortality in
patients with type 2 diabetes mellitus [HR 0.70 (95% CI 0.53, 0.92) and HR 0.74 (95% CI 0.56,
0.98), respectively] and in patients with type 2 diabetes mellitus and metformin HCl as
background therapy [HR 0.59 (95% CI 0.38, 0.91) and HR 0.71 (95% CI 0.46, 1.10)].
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Table 19: Treatment Effect for the Primary Composite Endpoint, its Components, and
Secondary Composite Endpoints in DAPA-CKD Trial
Patients with events (event
rate)
Efficacy Variable
(time to first occurrence)
Dapagliflozin
10 mg
N=2152
Placebo
N=2152
Hazard ratio
(95% CI)
p-value
Composite of ≥50% sustained
eGFR decline, ESKD, CV or
renal death
197 (4.6)
312 (7.5)
0.61
(0.51, 0.72)
<0.0001
Components of the primary composite endpoint
≥50% Sustained eGFR Decline
112 (2.6)
201 (4.8)
0.53
(0.42, 0.67)
ESKD*
109 (2.5)
161 (3.8)
0.64
(0.50, 0.82)
CV Death
65 (1.4)
80 (1.7)
0.81
(0.58, 1.12)
Renal Death
2 (<0.1)
6 (0.1)
≥50% sustained eGFR decline,
ESKD or renal death
142 (3.3)
243 (5.8)
0.56
(0.45, 0.68)
<0.0001
CV death or Hospitalization for
Heart Failure
100 (2.2)
138 (3.0)
0.71
(0.55, 0.92)
0.0089
Hospitalization for Heart Failure
37 (0.8)
71 (1.6)
0.51
(0.34, 0.76)
All-Cause Mortality
101 (2.2)
146 (3.1)
0.69
(0.53, 0.88)
0.0035
N=Number of patients, CI=Confidence interval, CV=Cardiovascular.
* ESKD is defined as sustained eGFR<15 mL/min/1.73 m2, initiation of chronic dialysis treatment, or transplant.
NOTE: Time to first event was analyzed in a Cox proportional hazards model. Event rates are presented as the
number of subjects with event per 100 patient years of follow-up.
There were too few events of renal death to compute a reliable hazard ratio.
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Figure 6: Time to First Occurrence of the Primary Composite Endpoint, ≥50% Sustained
Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Trial)
DAPA-CKD enrolled a population with relatively advanced CKD at high risk of progression.
Exploratory analyses of a randomized, double-blind, placebo-controlled trial conducted to
determine the effect of dapagliflozin 10 mg on CV outcomes (the DECLARE trial) support the
conclusion that dapagliflozin 10 mg is also likely to be effective in patients with less advanced
CKD.
14.5 Heart Failure
The efficacy and safety of dapagliflozin 10 mg were assessed independently in two Phase 3 trials
in patients with heart failure.
Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF,
NCT03036124) was an international, multicenter, randomized, double-blind, placebo-controlled
trial in adult patients with heart failure [New York Heart Association (NYHA) functional class
II-IV] with reduced ejection fraction [left ventricular ejection fraction (LVEF) 40% or less] to
determine whether dapagliflozin reduces the risk of cardiovascular death and hospitalization for
heart failure. Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to
placebo and were followed for a median of 18 months. The trial included patients with type 2
diabetes mellitus (n=2139) and patients without diabetes (n=2605).
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Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction
Heart Failure (DELIVER, NCT03619213) was an international, multicenter, randomized,
double-blind, placebo-controlled trial in patients aged ≥40 years with heart failure (NYHA class
II-IV) with LVEF >40% and evidence of structural heart disease to determine whether
dapagliflozin reduces the risk of cardiovascular death, hospitalization for heart failure or urgent
heart failure visits. Of 6263 patients, 3131 were randomized to dapagliflozin 10 mg and 3132 to
placebo and were followed for a median of 28 months. The trial included 654 (10%) heart failure
patients who were randomized during hospitalization for heart failure or within 30 days of
discharge. The trial included patients with type 2 diabetes mellitus (n=2806) and patients without
diabetes (n=3457).
In DAPA-HF, at baseline, 94% of patients were treated with ACEi, ARB or angiotensin
receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker,
71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an
implantable device (with defibrillator function). History of type 2 diabetes mellitus was present
in 42%, and an additional 3% had type 2 diabetes mellitus based on a HbA1c ≥6.5% at both
enrollment and randomization, totaling to 1075 patients in the dapagliflozin group and 1064 in
the placebo group. At baseline of the patients with type 2 diabetes mellitus, 48% were treated
with metformin HCl (505 patients on dapagliflozin 10 mg and 515 on placebo) and 25% were
treated with insulin.
In DAPA-HF, the mean age of the type 2 diabetes mellitus population was 67 years, 78% were
male, 70% White, 6% Black or African American and 23% Asian. At baseline, 64% patients
were classified as NYHA class II, 35% class III and 1% class IV, median LVEF was 32%.
Patients were on standard of care therapy; 93% of type 2 diabetes mellitus patients were treated
with ACEi, ARB, or ARNI (11%), 97% with beta-blocker, 71% with MRA, 95% with diuretic
and 27% had an implantable device (with defibrillator function). In these patients, mean eGFR
was 63 mL/min/1.73 m2.
In DELIVER, at baseline, 77% of patients were treated with ACEi, ARB or ARNI, 83% with
beta-blocker, 43% with MRA and 98% with diuretic. History of type 2 diabetes mellitus was
present in 45% of the patients. At baseline of the patients with type 2 diabetes mellitus, 58%
were treated with metformin HCl (809 patients on dapagliflozin 10 mg and 832 on placebo) and
30% were treated with insulin.
In DELIVER, the mean age of the type 2 diabetes mellitus population was 71 years, 58% were
male, 73% White, 3% Black or African American and 18% Asian. At baseline, 74% patients
were classified as NYHA class II, 26% class III and 0.4% class IV, 35% of the patients had
LVEF ≤49%, 36% had LVEF 50-59% and 29% had LVEF ≥60%. In the type 2 diabetes mellitus
population, 80% were treated with ACEi, ARB or ARNI, 84% with beta-blocker, 40% with
MRA, and 98% with diuretic. In these patients, mean eGFR was 59 mL/min/1.73 m2.
In both trials, dapagliflozin reduced the incidence of the primary composite endpoint of CV
death, hospitalization for heart failure or urgent heart failure visit in the overall population (see
Table 20). All three components of the primary composite endpoint individually contributed to
the treatment effect. In both trials, the dapagliflozin and placebo event curves separated early and
continued to diverge over the trial period (see Figure 7).
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Table 20: Treatment Effect for the Primary Composite Endpoint* and its Components* in
the DAPA-HF and DELIVER Trials (Overall Population)
DAPA-HF Trial
DELIVER Trial
Patients with events
(event rate)
Hazard
ratio
(95%
CI)
p-
value†
Patients with events
(event rate)
Hazard
ratio
(95%
CI)
p-
value†
Efficacy
Variable
(Time to first
occurrence)
Dapa-
gliflozin
10 mg
N=2373
Placebo
N=2371
Dapa-
gliflozin
10 mg
N=3131
Placebo
N=3132
Composite of
Hospitalization
for Heart
Failure, CV
Death‡ or
Urgent Heart
Failure Visit
386
(11.6)
502
(15.6)
0.74
(0.65,
0.85)
<0.0001
512
(7.8)
610
(9.6)
0.82
(0.73,
0.92)
0.0008
Components of the composite endpoints
CV Death‡
227
(6.5)
273
(7.9)
0.82
(0.69,
0.98)
231
(3.3)
261
(3.8)
0.88
(0.74,
1.05)
Hospitalization
for Heart
Failure or
Urgent Heart
Failure Visit
237
(7.1)
326
(10.1)
0.70
(0.59,
0.83)
368
(5.6)
455
(7.2)
0.79
(0.69,
0.91)
Hospitalization
for Heart
Failure
231
(6.9)
318
(9.8)
0.70
(0.59,
0.83)
329
(5.0)
418
(6.5)
0.77
(0.67,
0.89)
Urgent Heart
Failure Visit
10
(0.3)
23
(0.7)
0.43
(0.20,
0.90)
60
(0.9)
78
(1.1)
0.76
(0.55,
1.07)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular.
* Full analysis set.
† Two-sided p-values.
‡ In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In
DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.
NOTE: Time to first event was analyzed in a Cox proportional hazards model. The number of first events for the
single components are the actual number of first events for each component and does not add up to the number of
events in the composite endpoint. Event rates are presented as the number of subjects with event per 100 patient
years of follow-up.
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Figure 7: Time to the First Occurrence of the Composite of Cardiovascular Death*,
Hospitalization for Heart Failure or Urgent Heart Failure Visit
A) DAPA-HF Trial
B) DELIVER Trial
NOTE: An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g., in an Emergency
Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).
* In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In
DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.
† Patients at risk is the number of patients at risk at the beginning of the period.
HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.
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The treatment effect of dapagliflozin on the composite endpoint of cardiovascular death,
hospitalization for heart failure or urgent heart failure was consistent across the LVEF range as
evaluated in DAPA-HF and DELIVER trials (Figure 8).
Figure 8: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and
Heart Failure Events) by LVEF (DAPA-HF and DELIVER Trials)
* 1 patient in DAPA-HF trial had LVEF >40. 4 patients in DELIVER trial had LVEF ≤40.
In DAPA-HF trial, the 5% and 95% percentiles of LVEF were 20 and 40 respectively. In DELIVER trial, the 5%
and 95% percentiles of LVEF were 42 and 70, respectively.
In DAPA-HF, the treatment benefit of dapagliflozin 10 mg in reducing the incidence of the
primary composite endpoint was consistent in patients with type 2 diabetes mellitus [HR 0.75
(95% CI 0.63, 0.90)], and in patients with type 2 diabetes mellitus and metformin HCl as
background therapy [HR 0.67 (95% CI 0.51, 0.88)].
In DELIVER, the treatment benefit of dapagliflozin 10 mg in reducing the incidence of the
primary composite endpoint was consistent in patients with type 2 diabetes mellitus [HR 0.83
(95% CI 0.70, 0.97)].
In DELIVER, the hazard ratio of treatment benefit of dapagliflozin 10 mg in reducing the
incidence of the primary composite endpoint in patients with type 2 diabetes mellitus and
metformin HCl as background therapy was 0.90 (95% CI 0.72, 1.12).
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
XIGDUO® XR (dapagliflozin and metformin HCl extended-release) tablets have markings on
one side, are plain on the reverse side, and are available in the strengths and packages listed in
Table 21.
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Table 21: XIGDUO XR Tablet Presentations
Tablet
Strength
Film-Coated
Tablet
Color/Shape
Tablet
Markings
Pack Size
NDC Code
2.5 mg/
1,000 mg
Light brown to
brown, biconvex,
oval-shaped
"1074" and "2.5/1000"
debossed on one side
and plain on the reverse
side
Bottle of 60
0310-6225-60
5 mg/
500 mg
orange, biconvex,
capsule-shaped
"1070" and "5/500"
debossed on one side
and plain on the reverse
side
Bottle of 30
0310-6250-30
5 mg/
1,000 mg
pink to dark pink,
biconvex, oval-
shaped
"1071" and "5/1000"
debossed on one side
and plain on the reverse
side
Bottle of 60
0310-6260-60
10 mg/
500 mg
pink, biconvex,
capsule-shaped
"1072" and "10/500"
debossed on one side
and plain on the reverse
side
Bottle of 30
0310-6270-30
10 mg/
1,000 mg
yellow to dark
yellow, biconvex,
oval-shaped
"1073" and "10/1000"
debossed on one side
and plain on the reverse
side
Bottle of 30
0310-6280-30
Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and
86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Lactic Acidosis
Inform patients of the risks of lactic acidosis due to the metformin component and its symptoms
and conditions that predispose to its development [see Warnings and Precautions (5.1)]. Advise
patients to discontinue XIGDUO XR immediately and to promptly notify their healthcare
provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow
or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other non-
specific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin
treatment and may occur during initiation of XIGDUO XR therapy; however, inform patients to
consult their physician if they develop unexplained symptoms. Although gastrointestinal
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symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of
symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious
disease.
Counsel patients against excessive alcohol intake while receiving XIGDUO XR [see Warnings
and Precautions (5.1)].
Inform patients about the importance of regular testing of renal function and hematological
parameters when receiving treatment with XIGDUO XR [see Contraindications (4) and
Warnings and Precautions (5.1)].
Instruct patients to inform their healthcare provider that they are taking XIGDUO XR prior to
any surgical or radiological procedure, as temporary discontinuation of XIGDUO XR may be
required until renal function has been confirmed to be normal [see Warnings and Precautions
(5.1)].
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Inform patients that XIGDUO XR can cause potentially fatal ketoacidosis and that type 2
diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are
risk factors.
Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin
doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse)
and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and
labored breathing). Inform patients that blood glucose may be normal even in the presence of
ketoacidosis.
Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur,
instruct patients to discontinue XIGDUO XR and seek medical attention immediately [see
Warnings and Precautions (5.2)].
Volume Depletion
Inform patients that symptomatic hypotension may occur with XIGDUO XR and advise them to
contact their healthcare provider if they experience such symptoms [see Warnings and
Precautions (5.3)]. Inform patients that dehydration may increase the risk for hypotension, and
to have adequate fluid intake.
Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them
with information on the symptoms of urinary tract infections. Advise them to seek medical
advice promptly if such symptoms occur [see Warnings and Precautions (5.4)].
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Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues
Inform patients that the incidence of hypoglycemia may increase when XIGDUO XR is added to
an insulin secretagogue (e.g., sulfonylurea) and/or insulin. Educate patients on the signs and
symptoms of hypoglycemia [see Warnings and Precautions (5.5)].
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred
with dapagliflozin, a component of XIGDUO XR. Counsel patients to promptly seek medical
attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from
the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and
Precautions (5.6)].
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with
information on the signs and symptoms of vaginal yeast infections. Advise them of treatment
options and when to seek medical advice [see Warnings and Precautions (5.8)].
Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)
Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may
occur, especially in patients with prior history. Provide them with information on the signs and
symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis).
Advise them of treatment options and when to seek medical advice [see Warnings and
Precautions (5.8)].
Hypersensitivity Reactions
Inform patients that serious hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and
angioedema) have been reported with the components of XIGDUO XR. Advise patients to
immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to
take no more of the drug until they have consulted prescribing physicians.
Pregnancy
Advise pregnant patients of the potential risk to a fetus with treatment with XIGDUO XR.
Instruct patients to immediately inform their healthcare provider if pregnant or planning to
become pregnant [see Use in Specific Populations (8.1)].
Lactation
Advise patients that use of XIGDUO XR is not recommended while breastfeeding [see Use in
Specific Populations (8.2)].
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Females and Males of Reproductive Potential
Inform female patients that treatment with metformin may result in an unintended pregnancy in
some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific
Populations (8.3)].
Administration
Instruct patients that XIGDUO XR must be swallowed whole and not crushed or chewed, and
that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may
resemble the original tablet.
Laboratory Tests
Due to the mechanism of action of dapagliflozin, patients taking XIGDUO XR will test positive
for glucose in their urine.
Missed Dose
If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time
for the next dose, in which case patients should skip the missed dose and take the medicine at the
next regularly scheduled time. Advise patients not to take two doses of XIGDUO XR at the same
time.
FARXIGA® is a registered trademark of the AstraZeneca group of companies.
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
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MEDICATION GUIDE
XIGDUO® XR [ZIG-DO-OH X-R]
(dapagliflozin and metformin hydrochloride)
extended-release tablets, for oral use
What is the most important information I should know about XIGDUO XR?
XIGDUO XR can cause serious side effects, including:
•
Lactic Acidosis. Metformin, one of the medicines in XIGDUO XR, can cause a rare but serious condition called
lactic acidosis (a build-up of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and
must be treated in the hospital.
Stop taking XIGDUO XR and call your healthcare provider right away if you have any of the following
symptoms, which could be signs of lactic acidosis:
o
you feel cold in your hands or feet
o
you feel dizzy or lightheaded
o
you have a slow or irregular heartbeat
o
you feel very weak or tired
o
you have unusual (not normal) muscle pain
o
you have trouble breathing
o
you feel unusual sleepiness or sleep longer than usual
o
you have stomach pains, nausea or vomiting
Most people who have had lactic acidosis with metformin have other things that, combined with the metformin use, led
to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance
for getting lactic acidosis with XIGDUO XR if you:
o
have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.
o
have liver problems.
o
drink alcohol very often or drink a lot of alcohol in the short-term ("binge" drinking).
o
get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting,
or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink
enough fluids.
o
have surgery.
o
have new or worsening symptoms of congestive heart failure such as shortness of breath or increased fluid
or swelling of the legs.
o
have a heart attack, severe infection, or stroke.
o
are 65 years of age or older.
The best way to keep from having a problem with lactic acidosis from metformin is to tell your healthcare provider if you
have any of the problems in the list above. Your healthcare provider may decide to stop your XIGDUO XR for a while if
you have any of these things.
•
Diabetic Ketoacidosis (increased ketones in your blood or urine) in people with type 1 diabetes and
other ketoacidosis. XIGDUO XR can cause ketoacidosis that can be life-threatening and may lead to death.
Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a
high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk
of getting ketoacidosis. Ketoacidosis can also happen in people who are sick, cannot eat or drink as usual, skip
meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of
insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume
depletion), or who have surgery or a procedure that requires not having food for a long time (prolonged fasting).
Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask
you to periodically check ketones in your urine or blood.
Stop taking XIGDUO XR and call your healthcare provider or get medical help right away if you get any of
the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250
mg/dL.
o
nausea
o
tiredness
o
vomiting
o
stomach area (abdominal) pain
o
trouble breathing
o
ketones in your urine or blood
XIGDUO XR can have other serious side effects. See “What are the possible side effects of XIGDUO XR?”
What is XIGDUO XR?
•
XIGDUO XR is a prescription medicine that contains 2 medicines called dapagliflozin (FARXIGA) and metformin
HCl.
•
XIGDUO XR can be used along with diet and exercise to improve blood sugar (glucose) in adults and children
who are 10 years of age and older with type 2 diabetes.
•
One of the medicines in XIGDUO XR, dapagliflozin (FARXIGA), can also be used in adults with type 2 diabetes
who have:
o
chronic kidney disease and dapagliflozin is needed to reduce the risk of further worsening of your kidney
disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization for
heart failure.
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o
heart failure (when the heart cannot pump enough blood to the rest of your body) and dapagliflozin is
needed to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure
visit.
o
known cardiovascular disease or multiple cardiovascular risk factors and dapagliflozin is needed to reduce
the risk of hospitalization for heart failure.
•
XIGDUO XR is not for use to improve blood sugar (glucose) control in people with type 1 diabetes.
•
XIGDUO XR is only for use in people with type 2 diabetes mellitus, because it contains the prescription medicine
metformin HCl.
•
XIGDUO XR is not for use for treatment of chronic kidney disease in people with certain genetic forms of polycystic
kidney disease, or who are taking or have recently received immunosuppressive therapy to treat kidney disease. If
you have these conditions, XIGDUO XR is not expected to work for treatment of chronic kidney disease.
•
It is not known if XIGDUO XR is safe and effective to lower blood sugar (glucose) in children younger than 10 years
of age with type 2 diabetes mellitus.
•
It is not known if XIGDUO XR is safe and effective for treatment of heart failure or chronic kidney disease in
children younger than 18 years of age.
Who should not take XIGDUO XR?
Do not take XIGDUO XR if you:
•
have severe kidney problems.
•
are allergic to dapagliflozin, metformin HCl, or any of the ingredients in XIGDUO XR. See the end of this Medication
Guide for a complete list of ingredients in XIGDUO XR. Symptoms of a serious allergic reaction to XIGDUO XR
may include:
o
rash
o
raised red patches on your skin (hives)
o
swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.
If you have any of these symptoms, stop taking XIGDUO XR and contact your healthcare provider or go to the
nearest hospital emergency room right away.
•
have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).
What should I tell my healthcare provider before taking XIGDUO XR?
Before you take XIGDUO XR, tell your healthcare provider if you:
•
have type 1 diabetes or have had diabetic ketoacidosis.
•
have a decrease in your insulin dose.
•
have a serious infection.
•
have a history of infection of the vagina or penis.
•
have kidney problems.
•
have liver problems.
•
have a history of urinary tract infections or problems with urination.
•
are on a low sodium (salt) diet. Your healthcare provider may ask you to change your diet.
•
have heart problems, including congestive heart failure.
•
are 65 years of age or older.
•
are going to have surgery or a procedure that requires not having food for a long time (prolonged fasting). Your
healthcare provider may stop XIGDUO XR before you have surgery. Talk to your healthcare provider if you are
having surgery about when to stop taking XIGDUO XR and when to start it again.
•
are eating less, or there is a change in your diet.
•
are dehydrated.
•
have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.
•
drink alcohol very often or drink a lot of alcohol in the short-term (“binge” drinking).
•
are going to get an injection of dye or contrast agents for an x-ray procedure. XIGDUO XR may need to be stopped
for a short time. Talk to your healthcare provider about when you should stop XIGDUO XR and when you should
start XIGDUO XR again. See “What is the most important information I should know about XIGDUO XR?”
•
have low levels of vitamin B12 in your blood.
•
are pregnant or plan to become pregnant. XIGDUO XR may harm your unborn baby. If you are pregnant or plan to
become pregnant, talk to your healthcare provider about the best way to control your blood sugar.
•
are breastfeeding or plan to breastfeed. It is not known if XIGDUO XR passes into your breast milk. Talk with your
healthcare provider about the best way to feed your baby if you are taking XIGDUO XR. You should not breastfeed
if you take XIGDUO XR.
•
are a person who has not gone through menopause (premenopausal) who does not have periods regularly or at all.
XIGDUO XR can cause the release of an egg from an ovary in a person (ovulation). This can increase your chance
of getting pregnant. Tell your healthcare provider right away if you become pregnant while taking XIGDUO XR.
Reference ID: 5500979
3
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
XIGDUO XR may affect the way other medicines work and other medicines may affect the way XIGDUO XR works.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get
a new medicine.
How should I take XIGDUO XR?
•
Take XIGDUO XR exactly as your healthcare provider tells you to take it.
•
Your healthcare provider will tell you how much XIGDUO XR to take and when to take it. Your healthcare provider
may change your dose if needed.
•
Take XIGDUO XR by mouth 1 time each day with meals to lower your chance of an upset stomach. Talk to your
healthcare provider about the best time of day for you.
•
Swallow XIGDUO XR whole. Do not crush, cut, or chew XIGDUO XR.
•
You may sometimes pass a soft mass in your stools (bowel movement) that looks like XIGDUO XR tablets.
•
If you miss a dose of XIGDUO XR, take it as soon as you remember. If it is almost time for your next dose, skip the
missed dose and take the medicine at the next regularly scheduled time. Do not take 2 doses of XIGDUO XR at the
same time. Talk with your healthcare provider if you have questions about a missed dose.
•
If you take too much XIGDUO XR, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the
nearest hospital emergency room right away.
•
When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or
surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you
have any of these conditions and follow your healthcare provider’s instructions.
•
Your healthcare provider may tell you to stop taking XIGDUO XR at least 3 days before any surgery or procedure
that requires not having food or water for a long time (prolonged fasting).
•
Your healthcare provider may tell you to take XIGDUO XR along with other diabetes medicines. Low blood sugar
can happen more often when XIGDUO XR is taken with certain other diabetes medicines. See “What are the
possible side effects of XIGUDO XR?”.
•
XIGDUO XR will cause your urine to test positive for glucose.
•
Your healthcare provider may do certain blood tests before you start XIGDUO XR and during treatment as needed.
Your healthcare provider may change your dose of XIGDUO XR based on the results of your blood tests.
What should I avoid while taking XIGDUO XR?
•
Avoid drinking alcohol very often or drinking a lot of alcohol in a short period of time (“binge” drinking). It can
increase your chances of getting serious side effects.
What are the possible side effects of XIGDUO XR?
XIGDUO XR may cause serious side effects including:
See “What is the most important information I should know about XIGDUO XR?”.
•
Dehydration. XIGDUO XR can cause some people to become dehydrated (the loss of body water and salt).
Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic
hypotension). There have been reports of sudden kidney injury in people with type 2 diabetes mellitus who are
taking dapagliflozin, a medicine in XIGDUO XR.
You may be at a higher risk of dehydration if you:
o
take medicines to lower your blood pressure, including water pills (diuretics)
o
are on a low salt diet
o
have kidney problems
o
are 65 years of age or older
Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should
drink on a daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink,
for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or
being in the sun too long.
•
Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in
people who are taking dapagliflozin, one of the medicines in XIGDUO XR. Tell your healthcare provider if you have
any signs or symptoms of a urinary tract infection, such as a burning feeling when passing urine, a need to urinate
often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine.
Sometimes people also may have a fever, back pain, nausea or vomiting.
•
Low blood sugar (hypoglycemia). If you take XIGDUO XR with another medicine that can cause low blood sugar,
such as sulfonylureas or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea
medicine or insulin may need to be lowered while you take XIGDUO XR. Signs and symptoms of low blood sugar
may include:
o
headache
o
drowsiness
o
weakness
o
confusion
o
dizziness
o
sweating
Reference ID: 5500979
4
o
hunger
o
fast heartbeat
o
irritability
o
shaking or feeling jittery
•
A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis)
in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has
happened in women and men who take dapagliflozin, one of the medicines in XIGDUO XR. Necrotizing fasciitis of
the perineum may lead to hospitalization, may require multiple surgeries and may lead to death. Seek medical
attention right away if you have a fever or you are feeling very weak, tired or uncomfortable (malaise) and
you develop any of the following symptoms in the area between and around the anus and genitals:
o
pain or tenderness
o
swelling
o
redness of skin (erythema)
•
Serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking XIGDUO XR and
call your healthcare provider right away or go to the nearest hospital emergency room. See “Who should not take
XIGDUO XR?”. Your healthcare provider may give you a medicine for your allergic reaction and prescribe a
different medicine for your diabetes.
•
Low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a decrease in the
amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare
provider may do blood tests to check your vitamin B12 levels.
•
Vaginal yeast infection. Women who take XIGDUO XR may get vaginal yeast infections. Symptoms of a vaginal
yeast infection include:
o
vaginal odor
o
white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)
o
vaginal itching
•
Yeast infection of the penis (balanitis). Men who take XIGDUO XR may get a yeast infection of the skin around
the penis. Men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin
around the tip of the penis. Other symptoms of a yeast infection of the penis include:
o
redness, itching, or swelling of the penis
o
foul smelling discharge from the penis
o
rash of the penis
o
pain in the skin around the penis
Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis.
Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare
provider right away if you use an over-the-counter antifungal medicine and your symptoms do not go away.
The most common side effects of XIGDUO XR include:
o
vaginal yeast infections
o
stuffy or runny nose and sore throat
o
diarrhea
o
urinary tract infection
o
headache
Tell your healthcare provider or pharmacist if you have any side effect that bothers you or does not go away.
These are not all of the possible side effects of XIGDUO XR. For more information, ask your healthcare provider or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store XIGDUO XR?
Store XIGDUO XR at room temperature between 68°F and 77°F (20°C and 25°C).
Keep XIGDUO XR and all medicines out of the reach of children.
General information about the safe and effective use of XIGDUO XR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
XIGDUO XR for a condition for which it is not prescribed. Do not give XIGDUO XR to other people, even if they have
the same symptoms you have. It may harm them.
This Medication Guide summarizes the most important information about XIGDUO XR. If you would like more
information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about
XIGDUO XR that is written for health professionals.
For more information, go to www.xigduoxr.com or call 1-800-236-9933
What are the ingredients in XIGDUO XR?
Active ingredients: dapagliflozin and metformin hydrochloride
Inactive ingredients: anhydrous lactose, carboxymethylcellulose sodium, crospovidone, hypromellose, magnesium
stearate, microcrystalline cellulose, and silicon dioxide.
The film coatings contain the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium
dioxide. Additionally, the film coating for the XIGDUO XR 5 mg/500 mg tablets contains FD&C Yellow No. 6/Sunset
Yellow FCF aluminum lake and the film coating for the XIGDUO XR 2.5 mg/1000 mg, 5 mg/1000 mg, 10 mg/500 mg,
and 10 mg/1000 mg tablets contains iron oxides.
Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850
Reference ID: 5500979
5
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
Reference ID: 5500979
| custom-source | 2025-02-12T15:48:06.277228 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205649s023lbl.pdf', 'application_number': 205649, 'submission_type': 'SUPPL ', 'submission_number': 23} |
80,701 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
REVATIO safely and effectively. See full prescribing information for
REVATIO.
REVATIO (sildenafil) tablets, for oral use
REVATIO (sildenafil) for oral suspension
REVATIO (sildenafil) injection, for intravenous use
Initial U.S. Approval: 1998
--------------------------- INDICATIONS AND USAGE ---------------------------
Adults
REVATIO is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the
treatment of pulmonary arterial hypertension (PAH) (World Health
Organization [WHO] Group I) in adults to improve exercise ability and delay
clinical worsening. (1)
Pediatric Patients (1 to 17 years old)
REVATIO is indicated in pediatric patients 1 to 17 years old for the treatment
of pulmonary arterial hypertension (PAH) (WHO Group I) to improve
exercise ability and, in pediatric patients too young to perform standard
exercise testing, pulmonary hemodynamics thought to underlie improvements
in exercise (1, 14)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Adults: 20 mg orally three times a day. Dose may be increased based on
symptoms and tolerability. (2.1)
•
Pediatric patients (2.2)
o
≤ 20 kg: 10 mg three times a day
o
20 kg to 45 kg: 20 mg three times a day
o
> 45 kg: 20 mg three times a day. Dose may be increased based on
symptoms and tolerability.
•
Injection (Adults): 10 mg three times a day administered as an
intravenous bolus injection. (2.1)
--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
•
Tablets: 20 mg (3)
•
For oral suspension: 10 mg/mL (when reconstituted) (3)
•
Injection: 10 mg/12.5 mL (0.8 mg/mL) in a single-dose vial (3)
----------------------------- CONTRAINDICATIONS ------------------------------
•
Use with organic nitrates or riociguat. (4)
•
History of hypersensitivity reaction to sildenafil or any component of the
tablet, injection, or oral suspension. (4)
----------------------- WARNINGS AND PRECAUTIONS -----------------------
•
Vasodilation effects may be more common in patients with hypotension
or on antihypertensive therapy. (5.1)
•
Use in pulmonary veno-occlusive disease (PVOD) may cause
pulmonary edema and is not recommended. (5.2)
•
Hearing or visual impairment: Seek medical attention if sudden decrease
or loss of vision or hearing occurs. (5.4, 5.5)
•
Pulmonary hypertension (PH) secondary to sickle cell disease:
REVATIO may cause serious vaso-occlusive crises. (5.8)
------------------------------ ADVERSE REACTIONS ------------------------------
Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain and
diarrhea. (6.1, 6.2)
Children: Priapism. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-
877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS ------------------------------
•
Use with strong CYP3A inhibitors: Not recommended. (7, 12.3)
•
Concomitant PDE-5 inhibitors: Avoid use with Viagra® or other PDE-5
inhibitors. (5.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage in Adults
2.2
Recommended Dosage in Pediatric Patients
2.3
Reconstitution of the Powder for Oral Suspension
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypotension
5.2
Worsening Pulmonary Vascular Occlusive Disease
5.3
Epistaxis
5.4
Visual Loss
5.5
Hearing Loss
5.6
Combination with Other PDE-5 Inhibitors
5.7
Priapism
5.8
Vaso-occlusive Crisis in Patients with Pulmonary
Hypertension Secondary to Sickle Cell Disease
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Patients with Hepatic Impairment
8.7
Patients with Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Adults
REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health
Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening
[see Clinical Studies (14)].
Pediatric Patients (1 to 17 Years Old)
REVATIO is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary
arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients
too young to perform standardized exercise testing, pulmonary hemodynamics thought to
underlie improvements in exercise [see Clinical Studies (14)].
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage in Adults
Oral Dosage
The recommended dosage of REVATIO is 20 mg three times a day. Dose may be titrated to a
maximum of 80 mg three times a day, if required, based on symptoms and tolerability [see
Clinical Studies (14)].
Although dose-response improvement in exercise ability was not observed in short-term studies
in adults with PAH, the delay in clinical worsening with long-term use of sildenafil in Study
A1481324 supports dosing up to a maximum of 80 mg three times a day [see Clinical Studies
(14)].
Intravenous Dosage
The recommended dose is 10 mg administered as an intravenous bolus injection three times a
day. The dose of REVATIO injection does not need to be adjusted for body weight.
A 10-mg dose of REVATIO injection is predicted to provide pharmacological effect of sildenafil
and its N-desmethyl metabolite equivalent to that of a 20-mg oral dose.
2.2
Recommended Dosage in Pediatric Patients
Oral Dosage
The recommended dosage in patients ≤ 20 kg is 10 mg three times a day.
3
For pediatric patients 20 kg to 45 kg, the recommended dosage is 20 mg three times a day.
For pediatric patients 45 kg and greater, the recommended dosage is 20 mg three times a day. A
maximum dose in pediatric patients has not been identified. Based on the experience in adults,
dose may be titrated to a maximum of 40 mg three times a day for pediatric patients > 45 kg, if
required, based on symptoms and tolerability [see Clinical Studies (14)].
2.3
Reconstitution of the Powder for Oral Suspension
Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by
30 mL). Refer to the detailed instructions below.
1. Tap the bottle to loosen the powder.
2. Add 60 mL of water to the bottle.
3. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds.
4. Add another 30 mL of water to the bottle.
5. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds.
6. Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the
bottle.
7. Write the expiration date of the reconstituted oral suspension on the bottle label (the
expiration date of the reconstituted oral suspension is 60 days from the date of
reconstitution).
Incompatibilities
Do not mix with any other medication or additional flavoring agent.
3
DOSAGE FORMS AND STRENGTHS
REVATIO Tablets
White to off-white, film-coated, round tablets engraved with “RVT 20” on one side and “VLE”
on the other side. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil.
REVATIO for Oral Suspension
White to slight pink powder containing 1.57 g of sildenafil citrate (equivalent to 1.12 g
sildenafil) in a bottle for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of
water, the total volume of the oral suspension is 112 mL. A 2 mL oral dosing syringe (with 1 mL
and 2 mL dose markings) and a press-in bottle adaptor are also provided.
REVATIO Injection
Single-dose vial containing 10 mg/12.5 mL (0.8 mg/mL) of sildenafil.
4
4
CONTRAINDICATIONS
REVATIO is contraindicated in patients with:
•
Concomitant use of organic nitrates in any form, either regularly or intermittently, because of
the greater risk of hypotension [see Warnings and Precautions (5.1)].
•
Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5)
inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.
•
Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral
suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and
anaphylactoid reaction, has been reported in association with the use of sildenafil.
5
WARNINGS AND PRECAUTIONS
5.1
Hypotension
REVATIO has vasodilatory properties, resulting in mild and transient decreases in blood
pressure. Before prescribing REVATIO, carefully consider whether patients with certain
underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on
antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid
depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood
pressure when co-administering blood pressure lowering drugs with REVATIO.
5.2
Worsening Pulmonary Vascular Occlusive Disease
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with
pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of
REVATIO to patients with veno-occlusive disease, administration of REVATIO to such patients
is not recommended. Should signs of pulmonary edema occur when REVATIO is administered,
consider the possibility of associated PVOD.
5.3
Epistaxis
The incidence of epistaxis was 13% in patients taking REVATIO with PAH secondary to CTD.
This effect was not seen in idiopathic PAH (REVATIO 3%, placebo 2%) patients. The incidence
of epistaxis was also higher in REVATIO-treated patients with a concomitant oral vitamin K
antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).
The safety of REVATIO is unknown in patients with bleeding disorders or active peptic
ulceration.
5.4
Visual Loss
5
When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy
(NAION), a cause of decreased vision including permanent loss of vision, has been reported post
marketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most
patients had underlying anatomic or vascular risk factors for developing NAION, including low
cup to disc ratio (“crowded disc”).
Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one
or both eyes while taking REVATIO.
There are no controlled clinical data on the safety or efficacy of REVATIO in patients with
retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases.
Therefore, use of REVATIO in patients with retinitis pigmentosa is not recommended.
5.5
Hearing Loss
Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and
dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including
REVATIO. In some of the cases, medical conditions and other factors were reported that may
have played a role. In many cases, medical follow-up information was limited. It is not possible
to determine whether these reported events are related directly to the use of REVATIO, to the
patient’s underlying risk factors for hearing loss, a combination of these factors, or to other
factors.
Advise patients to seek prompt medical attention in the event of sudden decrease or loss of
hearing while taking PDE-5 inhibitors, including REVATIO.
5.6
Combination with Other PDE-5 Inhibitors
Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of REVATIO
with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking
REVATIO not to take VIAGRA or other PDE-5 inhibitors.
5.7
Priapism
Use REVATIO with caution in patients with anatomical deformation of the penis (e.g.,
angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which
may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In
the event of an erection that persists longer than 4 hours, the patient should seek immediate
medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated
immediately, penile tissue damage and permanent loss of potency could result.
5.8
Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle
Cell Disease
In a small, prematurely terminated study of patients with pulmonary hypertension (PH)
secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more
6
commonly reported by patients who received REVATIO than by those randomized to placebo.
The effectiveness and safety of REVATIO in the treatment of PH secondary to sickle cell disease
has not been established.
6
ADVERSE REACTIONS
The following serious adverse events are discussed elsewhere in the labeling:
•
Hypotension [see Warnings and Precautions (5.1)]
•
Vision Loss [see Warnings and Precautions (5.4)]
•
Hearing Loss [see Warnings and Precautions (5.5)]
•
Priapism [see Warnings and Precautions (5.7)]
•
Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell
Disease [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
In a 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in
277 REVATIO-treated adults with PAH (WHO Group I) [see Clinical Studies (14)] the adverse
reactions that were reported by at least 10% of REVATIO-treated patients in any dosing group,
and were more frequent in REVATIO-treated patients than in placebo-treated patients are shown
in Table 1. Adverse reactions were generally transient and mild to moderate in nature. The
overall frequency of discontinuation in REVATIO-treated patients was 3% (20 mg and 40 mg
three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation
for placebo was 3%.
Table 1. Most Common Adverse Reactions in Patients Treated with REVATIO 20 mg, 40
mg, 80 mg and Placebo Three Times Per Day in SUPER-1 (More Frequent in
REVATIO-Treated Patients than Placebo-Treated Patients)
REVATIO
20 mg
(n = 69)
REVATIO
40 mg
(n = 67)
REVATIO
80 mg
(n = 71)
Placebo
(n = 70)
Headache
46%
42%
49%
39%
Flushing
10%
9%
16%
4%
Pain in Limb
7%
15%
9%
6%
Myalgia
7%
6%
14%
4%
Back Pain
13%
13%
9%
11%
Dyspepsia
13%
8%
13%
7%
Diarrhea
9%
12%
10%
6%
In a placebo-controlled fixed dose titration study (PACES-1) of REVATIO (starting with
recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an
adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified
7
except for edema, which occurred in 25% of subjects in the combined REVATIO + epoprostenol
group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)].
In a study to assess the effects of multiple doses of REVATIO on mortality in adults with PAH
(StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths
(all related to underlying disease/disease under study), serious adverse events, and severe adverse
events than the 20 mg and 80 mg TID groups [see Clinical Studies (14)]. Overall, the safety data
for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety
profile of sildenafil in previous adult PAH studies.
Pediatric Patients
REVATIO was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week,
double-blind placebo-controlled study (STARTS-1); 220 patients continued in a long-term
extension study (STARTS-2). Erection increased was observed in 9% of patients treated with
sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see
Use in Specific Populations (8.4)].
REVATIO Injection
Adverse events with REVATIO injection were similar to those seen with oral tablets.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of sildenafil
(marketed for both PAH and erectile dysfunction). Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Cardiovascular Events
In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious
cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden
cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack,
hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have
been reported in temporal association with the use of the drug. Most, but not all, of these patients
had preexisting cardiovascular risk factors. Many of these events were reported to occur during
or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil
without sexual activity. Others were reported to have occurred hours to days after use concurrent
with sexual activity. It is not possible to determine whether these events are related directly to
sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a
combination of these or other factors.
Nervous System
Seizure, seizure recurrence
8
Ophthalmologic
NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)].
7
DRUG INTERACTIONS
Nitrates
Concomitant use of REVATIO with nitrates in any form is contraindicated [see
Contraindications (4)].
Strong CYP3A Inhibitors
Concomitant use of REVATIO with strong CYP3A inhibitors is not recommended [see Clinical
Pharmacology (12.3)].
Moderate-to-Strong CYP3A Inducers
Concomitant use of REVATIO with moderate-to-strong CYP3A inducers (such as bosentan)
decreases the sildenafil exposure. Dose up-titration of REVATIO may be needed when initiating
treatment with moderate-to-strong CYP3A inducers. Reduce the dose of REVATIO to 20 mg
three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see
Clinical Pharmacology (12.3) and Clinical Studies (14)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Limited published data from randomized controlled trials, case-controlled trials, and case series
do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse
maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the
mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations).
Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal
toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD)
of 20 mg three times a day in rats and rabbits, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
9
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure,
stroke, preterm delivery, and maternal and fetal death.
Data
Animal Data
No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or
rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2
basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times
a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30
mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis).
8.2
Lactation
Risk Summary
Limited published data from a case report describe the presence of sildenafil and its active
metabolite in human milk. There is insufficient information about the effects of sildenafil on the
breastfed infant and no information on the effects of sildenafil on milk production. Limited
clinical data during lactation preclude a clear determination of the risk of REVATIO to an infant
during lactation.
8.4
Pediatric Use
The safety and efficacy of REVATIO have been established in pediatric patients 1 to 17 years
old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too
young to perform standard exercising testing, pulmonary hemodynamics thought to underlie
improvements in exercise. Use of REVATIO for this indication is supported by evidence from
adequate and well-controlled studies in adults with additional PK and safety data in pediatric
patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety
and effectiveness of REVATIO have not been established in pediatric patients younger than 1
year of age.
During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies
(14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100
(22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death
were related to the progression of PAH. This safety observation in pediatrics was not confirmed
in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the
beneficial effects on clinical worsening and death observed in adults with increasing doses
(Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal
association for the observed dose-related effect on mortality in pediatric patients is unlikely, and
therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40
mg three times a day.
10
8.5
Geriatric Use
Clinical studies of REVATIO did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger patients. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
drug therapy [see Clinical Pharmacology (12.3)].
8.6
Patients with Hepatic Impairment
No dose adjustment for mild to moderate impairment is required. Severe impairment has not
been studied [see Clinical Pharmacology (12.3)].
8.7
Patients with Renal Impairment
No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical
Pharmacology (12.3)].
10
OVERDOSAGE
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to
those seen at lower doses but rates and severities were increased.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis
is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is
not eliminated in the urine.
11
DESCRIPTION
REVATIO, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective
inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-
5). Sildenafil is also marketed as VIAGRA® for erectile dysfunction.
Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-
pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has
the following structural formula:
11
Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in
water and a molecular weight of 666.7.
REVATIO (sildenafil) Tablets: REVATIO is formulated as white to off-white, film-coated, round
tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of
sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following
inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium
dioxide, and triacetin.
REVATIO (sildenafil) Injection: REVATIO is supplied as a clear, colorless, sterile, ready to use
solution in a single-dose vial containing 10 mg/12.5 mL of sildenafil. Each mL of solution
contains 1.124 mg sildenafil citrate (equivalent to 0.8 mg sildenafil), 50.5 mg dextrose, and
water for injection.
REVATIO (sildenafil) for Oral Suspension: REVATIO is supplied as white to slight pink powder
containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle
intended for reconstitution. Following reconstitution with 90 mL water, the total volume of the
oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive
ingredients include citric acid anhydrous, colloidal silicon dioxide anhydrous, grape flavor,
sodium benzoate, sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide, and xanthan
gum. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 1 mL and
2 mL dose markings) are provided.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary
vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore,
increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In
patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser
degree, vasodilatation in the systemic circulation.
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on
PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for
PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11).
12
The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is
involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5
compared to PDE6, an enzyme found in the retina and involved in the phototransduction
pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to
color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)].
In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also
found in other tissues including vascular and visceral smooth muscle and in platelets. The
inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-
aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous
dilatation in vivo.
12.2
Pharmacodynamics
Effects of REVATIO on Hemodynamic Measures
Adults
Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary
arterial pressure (mPAP) compared to those on placebo in a study with no background
vasodilators [see SUPER-1 in Clinical Studies (14)]. Data on other hemodynamic measures for
the REVATIO 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The
relationship between these effects and improvements in 6-minute walk distance is unknown.
Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95%
CI)] for the REVATIO 20 mg Three Times a Day and Placebo Group
Placebo
(n = 65)*
REVATIO 20 mg
(n = 65)*
mPAP (mmHg)
0.6 (-0.8, 2.0)
-2.1 (-4.3, 0.0)
PVR (dyn×s/cm5)
49 (-54, 153)
-122 (-217, -27)
SVR (dyn×s/cm5)
-78 (-197, 41)
-167 (-307, -26)
RAP (mmHg)
0.3 (-0.9, 1.5)
-0.8 (-1.9, 0.3)
CO (L/min)
-0.1 (-0.4, 0.2)
0.4 (0.1, 0.7)
HR (beats/min)
-1.3 (-4.1, 1.4)
-3.7 (-5.9, -1.4)
mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR =
systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart
rate.
*The number of patients per treatment group varied slightly for each parameter due to missing
assessments.
Pediatric Patients
Patients on REVATIO medium and high dose groups achieved dose related improvements in
pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP)
compared to those on placebo [see STARTS-1 in Clinical Studies (14)]. Improvements were
observed with cardiac index in all three REVATIO dose groups over placebo. Data on other
13
hemodynamic measures for the REVATIO low, medium and high dose groups compared to
placebo is displayed in Table 3.
Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group
Parameter
[Estimate (95% CI)]
Low Dose
Medium Dose
High Dose
PVRI (%)
-2% (-20%, 20%)
n = 37
-18% (-32%, -2%)
n = 51
-27% (-39%, -14%)
n = 68
mPAP (mmHg)
1.6 (-4.5, 7.6)
n = 39
-3.5 (-8.9, 1.9)
n = 55
-7.3 (-12.4, -2.1)
n = 71
CI (%)
10% (-4%, 26%)
n = 37
4% (-7%, 18%)
n = 51
15% (3%, 29%)
n = 69
SVRI (%)
-9% (-22%, 7%)
n = 37
-5% (-17%, 10%)
n = 50
-16% (-26%, -4%)
n = 68
RAP (mmHg)
-0.17 (-1.91, 1.57)
n = 39
-0.19 (-1.73, 1.36)
n = 55
-1.14 (-2.61, 0.33)
n = 71
HR (%)
3% (-5%, 12%)
n = 39
2% (-5%, 9%)
n = 55
-2% (-9%, 5%)
n = 71
Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial
pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI =
systemic vascular resistance index.
Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and
HR, respectively.
Effects of REVATIO on Blood Pressure
Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in
supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5
mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing
and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with
25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or
plasma levels within this dosage range. Larger effects were recorded among patients receiving
concomitant nitrates [see Contraindications (4)].
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant
effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients
with PAH, no clinically relevant effects on ECG were reported.
After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean
change from baseline in supine systolic and supine diastolic blood pressures was a decrease of
9.0 mmHg and 8.4 mmHg, respectively.
After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension,
the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4
and 9.1 mmHg, respectively.
14
After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions
than above in systolic and diastolic blood pressures were observed (a decrease in both of 2
mmHg).
Effects of REVATIO on Vision
At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color
discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak
effects near the time of peak plasma levels. This finding is consistent with the inhibition of
PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at
doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or
pupillometry.
12.3
Pharmacokinetics
Absorption and Distribution
REVATIO is rapidly absorbed after oral administration, with a mean absolute bioavailability of
41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120
minutes (median 60 minutes) of oral dosing in the fasted state. When REVATIO is taken with a
high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a
mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil
is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl
metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent
of total drug concentrations.
Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension
when administered as a 20 mg single oral dose of sildenafil (as citrate).
Metabolism and Excretion
Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9
(CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results
from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a
phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5
approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this
metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for
about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the
metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-
lives of about 4 hours.
After either oral or intravenous administration, sildenafil is excreted as metabolites
predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser
extent in the urine (approximately 13% of the administered oral dose).
15
REVATIO Injection: The pharmacokinetic profile of REVATIO has been characterized following
intravenous administration. A 10 mg dose of REVATIO Injection is predicted to provide a
pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg
oral dose.
Population Pharmacokinetics
Age, gender, race, and renal and hepatic function were included as factors assessed in the
population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH.
The dataset available for the population pharmacokinetic evaluation contained a wide range of
demographic data and laboratory parameters associated with hepatic and renal function. None of
these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.
In patients with PAH, the average steady-state concentrations were 20 to 50% higher when
compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to
healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability
of sildenafil in patients with PAH compared to healthy volunteers.
Pediatric Patients
Body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma
concentration half-life values were estimated to range from 2.9 to 4.4 hours for a range of 10 to
70 kg of body weight. Tmax was estimated at approximately 1 hour.
Geriatric Patients
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in
approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-
desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to
45 years). Due to age-differences in plasma protein binding, the corresponding increase in the
AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%,
respectively.
Renal Impairment
In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal
impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In
volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was
reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched
volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values
were significantly increased 200% and 79%, respectively, in patients with severe renal
impairment compared to patients with normal renal function.
Hepatic Impairment
16
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil
clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-
matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-
Pugh class C) have not been studied.
Drug Interaction Studies
In vitro Studies
Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor
route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce
sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and
3A (IC50 greater than150 µM).
Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of
these CYP enzymes at clinically relevant concentrations.
In vivo Studies
The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the
exposure to other drugs are shown in Figure 1 and Figure 2, respectively.
Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics
17
Figure 2. Effects of Sildenafil on Other Drugs
18
CYP3A Inhibitors and Beta Blockers
Population pharmacokinetic analysis of data from patients in clinical trials indicated an
approximately 30% reduction in sildenafil clearance when it was co-administered with
mild/moderate CYP3A inhibitors and an approximately 34% reduction in sildenafil clearance
when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a
day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three
times a day. This concentration range covers the same increased sildenafil exposure observed in
specifically-designed drug interaction studies with CYP3A inhibitors (except for potent
inhibitors such as ketoconazole, itraconazole, and ritonavir).
REVATIO Injection: Predictions based on a pharmacokinetic model suggest that drug-drug
interactions with CYP3A inhibitors will be less than those observed after oral sildenafil
administration.
CYP3A4 Inducers Including Bosentan
19
Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases
in plasma levels of sildenafil.
Population pharmacokinetic analysis of data from patients in clinical trials indicated
approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A
inducers.
Epoprostenol
The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered
with epoprostenol was 28%, resulting in about 22% lower mean average steady state
concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of
epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol
pharmacokinetics is not known.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of
which are metabolized by CYP2C9.
Alcohol
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with
mean maximum blood alcohol levels of 0.08%.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a
dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite
33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20
mg three times a day. Sildenafil was not carcinogenic when administered to male and female
mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10
mg/kg/day, a dose equivalent to the RHD on a mg/m2 basis.
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect
mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect
clastogenicity.
There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a
dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite
of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20
mg three times a day.
14
CLINICAL STUDIES
20
SUPER-1 (NCT00644605) - REVATIO Monotherapy [20 mg, 40 mg, and 80 mg Three Times a
Day]
A randomized, double-blind, placebo-controlled study of REVATIO (SUPER-1) was conducted
in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥ 25 mmHg at rest with
a pulmonary capillary wedge pressure < 15 mmHg). Patients were predominantly WHO
Functional Classes II-III. Allowed background therapy included a combination of anticoagulants,
digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues,
endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who
had failed to respond to bosentan were also excluded. Patients with left ventricular ejection
fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
Patients were randomized to receive placebo (n = 70) or REVATIO 20 mg (n = 69), 40 mg (n =
67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary
pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following
surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of
25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-
minute walk distance between 100 and 450 meters (mean 343).
The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after
the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance
of 45-50 meters were observed with all doses of REVATIO. These increases were significantly
different from placebo, but the REVATIO dose groups were not different from each other (see
Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a
day. The improvement in walk distance was apparent after 4 weeks of treatment and was
maintained at Week 8 and Week 12.
Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12
in SUPER-1: Mean (95% Confidence Interval)
21
Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6-
Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional
class, gender, age, and hemodynamic parameters.
Figure 4. Placebo-Corrected Change from Baseline in 6-Minute Walk Distance (meters) at
Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval)
Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary
hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index;
TID = three times daily.
SUPER-2 (NCT00159887) Long-Term Treatment of PAH
In a long-term follow-up of patients who were treated with sildenafil (n = 277), K-M estimates of
survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively. These uncontrolled
observations do not allow comparison with a group not given sildenafil and cannot be used to
determine the long term-effect of sildenafil on mortality.
PACES-1 (NCT00159861) - REVATIO Co-Administered with Epoprostenol
A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients
with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean
22
pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary
wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization
within 21 days before randomization, and a baseline 6-minute walk test distance greater than or
equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were
randomized to placebo or REVATIO (in a fixed titration starting from 20 mg to 40 mg and then
80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.
At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I
(1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and
79% were Caucasian.
There was a statistically significant greater increase from baseline in 6-minute walk distance at
Week 16 (primary endpoint) for the REVATIO group compared with the placebo group. The
mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the
REVATIO group compared with 4 meters for the placebo group giving an adjusted treatment
difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).
Patients on REVATIO achieved a statistically significant reduction in mPAP compared to those
on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of
REVATIO (95% CI: -5.7, -2.1) (p = 0.00003).
Time to clinical worsening of PAH was defined as the time from randomization to the first
occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan
therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the
number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a
stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to
experience a clinical worsening event than REVATIO-treated patients and that REVATIO-treated
patients experienced a significant delay in time to clinical worsening versus placebo-treated
patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5.
Table 4. Clinical Worsening Events in PACES-1
Placebo
(N = 131)
REVATIO
(N = 134)
Number of patients with clinical
worsening first event
23
8
First Event
All Events
First Event
All Events
Death, n
3
4
0
0
Lung transplantation, n
1
1
0
0
Hospitalization due to PAH, n
9
11
8
8
Clinical deterioration resulting in:
Change of Epoprostenol Dose, n
Initiation of Bosentan, n
9
1
16
1
0
0
2
0
Proportion worsened
95% Confidence Interval
0.187
(0.12-0.26)
0.062
(0.02-0.10)
Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1
23
Improvements in WHO Functional Class for PAH were also demonstrated in patients on
REVATIO compared to placebo. More than twice as many REVATIO-treated patients (36%) as
placebo-treated patients (14%) showed an improvement in at least one functional New York
Heart Association (NYHA) class for PAH.
Study A1481243 (NCT00323297) - REVATIO Added to Bosentan Therapy – Lack of Effect on
Exercise Capacity
A randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH
who were on bosentan therapy for a minimum of 3 months. The PAH patients included those
with primary PAH and PAH associated with CTD. Patients were randomized to placebo or
sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day).
The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk
distance (6MWD). The results indicate that there is no significant difference in mean change
from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.
STARTS-1 (NCT00159913) - Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, with
Pulmonary Arterial Hypertension
A total of 234 patients with PAH aged 1 to 17 years were treated in a randomized, double-blind,
multi-center, placebo-controlled parallel group, dose-ranging study. Patients (38% male and 62%
female) had body weight ³ 8 kg and had idiopathic pulmonary arterial hypertension (33%), or
PAH associated with congenital heart disease (systemic-to-pulmonary shunt 37%, surgical repair
30%). In this trial, 27% of patients were < 7 years old. Patients were WHO Functional Class I
(32%), II (51%), III (15%), or IV (0.4%).
Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues
and endothelin receptor antagonists were not permitted in the study, and neither were arginine
supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors.
24
The primary objective of the study was to assess the effect of REVATIO on percent change from
baseline in PVO2, normalized to body weight, from baseline to week 16 as measured by the
Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the
test, n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment,
WHO Functional Class, change in background treatment, and quality of life measurements (n =
234).
Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or
placebo. Actual doses administered were dependent on body weight (see Table 5).
Table 5. Treatment Allocation by Dose and Body Weight in Pediatric Study
Placebo
Low Dose
Medium Dose
High Dose
Body Weight (kg)
N
Dose
N
Dose
N
Dose
N
³ 8-20
18
na
10 mg
15
20 mg
35
> 20-45
32
10 mg
31
20 mg
30
40 mg
31
> 45
10
10 mg
11
40 mg
10
80 mg
11
The proportion of patients receiving supportive medicinal products at baseline (anticoagulants,
digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined
sildenafil treatment group (48%) and the placebo treatment group (42%).
The primary endpoint was a percentage change in VO2peak from baseline to week 16 assessed by
CPET. Mean baseline peak volume of oxygen consumed (VO2) values were similar across the
sildenafil treatment groups (17 to 18 mL/kg/min), and slightly higher for the placebo treatment
group (20 mL/kg/min). See Figure 6.
A total of 45% of patients were evaluable for CPET, which comprised those children ≥ 7 years
old and developmentally able to perform the test. Children < 7 years were evaluable only for the
secondary endpoints.
Mean increases in VO2peak percentage change from baseline at Week 16, were observed with all 3
sildenafil doses (range of 6% to 13%, Figure 6), with little change with placebo (0.5%).
Figure 6. Percentage Change from Baseline in VO2Peak: Mean (95% Confidence Intervals)
25
The estimated difference between the combined sildenafil doses and placebo was 8% (95% CI: -
0.2 to 16). The results of the main analysis (combined dose groups versus placebo) were not
statistically significant (p = 0.056).
The estimated difference between the sildenafil medium dose group and placebo was 11 ± 5%
(95% CI: 2 to 21).
Impact on Hemodynamic Parameters
Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI
reductions compared to placebo were seen with the sildenafil medium and high dose groups
(18% [95% CI: -32% to -2%] and 27% [95% CI: -39% to -14%], respectively) but not the low
dose group (2% (95% CI: -20%, 20%). The sildenafil medium and high dose groups displayed
mPAP changes from baseline compared to placebo, of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3
mmHg (95% CI: -12.4, -2.1), respectively; while the low dose group showed little difference
from placebo (difference of 1.6 mmHg [95% CI: -4.5, 7.6]). Improvements were observed with
cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low,
medium, and high dose groups, respectively [see Clinical Pharmacology (12.2)].
STARTS-2 (NCT00159874) - Long-Term Survival with Oral Sildenafil Monotherapy in
Treatment-Naïve Pediatric Pulmonary Arterial Hypertension
Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients
entered the long-term extension study. Patients who had been in the placebo group in the short-
term study were randomly reassigned to sildenafil treatment; patients weighing ≤ 20 kg entered
the medium or high dose groups (1:2), while patients weighing > 20 kg entered the low, medium,
or high dose groups (1:1:1). Of the total 229 patients who received sildenafil, there were 55, 74,
and 100 patients in the low, medium, and high dose groups, respectively. Across the short-term
and long-term studies, the overall duration of treatment from start of double-blind for individual
patients ranged from 3 to 3,129 days. By sildenafil treatment group, median duration of sildenafil
26
treatment was 1,696 days (excluding the 5 patients who received placebo in double-blind and
were not treated in the long-term extension study).
Peak VO2 was assessed 1 year after the start of the placebo-controlled study. Of sildenafil-treated
patients developmentally able to perform the CPET 59/114 patients (52%) had not shown any
deterioration in PVO2 from start of sildenafil. Similarly, 191 of 229 patients (83%) who had
received sildenafil had either maintained or improved their WHO Functional Class at 1 year
assessment.
Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94%,
93%, and 85% in the low, medium, and high dose groups, respectively; for patients ≤ 20 kg in
weight at baseline, the survival estimates were 94% and 93% for patients in the medium and high
dose groups, respectively [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)].
Study A1481324 (NCT02060487) - Study to Assess the Effects of REVATIO on Mortality in
Adults with PAH
A study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was
conducted following the observation of a higher risk of mortality in pediatric patients taking a
high dose of REVATIO TID, based on body weight, compared to those taking a lower dose of
REVATIO in the long-term extension of the pediatric clinical trial.
The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients
were randomly assigned 1:1:1 to one of three treatment groups (5, 20, and 80 mg TID). Most
patients were PAH treatment naïve (83%). For most patients the etiology of PAH was idiopathic
(72%). The most common WHO Functional Class was Class III (58% of patients). Treatment
groups were well balanced with respect to baseline demographics of strata history of PAH
treatment and etiology of PAH, as well as the WHO Functional Class categories.
The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for
mortality, with success defined by ruling out twice the mortality at 80 mg.
The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a
composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease
progression. An additional secondary endpoint was 6MWD at Months 6 and 12.
Overall Survival
At the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy
objective of this protocol was met and therefore the study was stopped. Based on the primary
efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID
arm was met using a 2-sided significance level of 0.003 for the interim analysis. Primary
comparison of the 80 mg TID group to the 5 mg TID group yielded the HR (99.7% CI) = 0.51
(0.22, 1.21); i.e., non-inferiority was established.
27
Table 6. Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model
– Intent To Treat Population
Sildenafil 5 mg
N = 129
Sildenafil 20 mg
N = 128
Sildenafil 80 mg
N = 128
Patient-years of follow-up
329.8
340.5
356.7
Number of deaths (%)
34 (26)
25 (20)
19 (15)
On treatment deathsa (%)
22 (17)
13 (10)
15 (12)
Off treatment deaths (%)
12 (9)
12 (9)
4 (3)
Hazard ratio relative to sildenafil
5 mg
Hazard ratio estimateb
0.68
0.51
99.7% CI
0.31, 1.49
0.22, 1.21
Hazard ratio relative to sildenafil
20 mg
Hazard ratio estimate
0.74
99.7% CI
0.30, 1.84
a.
On treatment deaths: Any death within 7 days of last dose was regarded as “On
treatment”, thus might include deaths occurred after discontinuation from study treatment.
b.
Hazard ratio estimates from the proportional Hazards model, stratified by actual previous
PAH treatment and etiology of PAH.
Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80-
mg TID dose groups, respectively.
Clinical Worsening
Sildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR
(99.7% CI) = 0.44 (0.22, 0.89).
Table 7. Hazard Ratios for Time to First Event of Clinical Worsening – Intent To Treat
Population
Sildenafil 5 mg
N = 129
Sildenafil 20 mg
N = 128
Sildenafil 80 mg
N = 128
Patient-years of follow-up
249.6
276.4
306.5
Number of patients with clinical
worsening
52
36
28
First Event of clinical
worseninga n (%)
Disease progressionb
8 (6)
2 (2)
6 (5)
Hospitalization for PAHc
28 (22)
23 (18)
11 (9)
Deathd
16 (12)
11 (9)
11 (9)
Hazard ratio relative to sildenafil
5 mg
Hazard ratio estimatee
0.63
0.44
99.7% CI
0.33, 1.21
0.22, 0.89
p-value
0.035
< 0.001
28
Hazard ratio relative to sildenafil
20 mg
Hazard ratio estimatee
0.72
99.7% CI
0.34, 1.52
p-value
0.195
Note: Sildenafil 5 mg is not an approved dosage.
Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary
arterial hypertension.
a. Clinical worsening events were defined as reduction from baseline in the 6MWD test by at
least 15% and worsening functional class from baseline, both confirmed by a second
test/evaluation within 2 weeks.
b. Count of cases of disease progression as the first event of clinical worsening.
c. Count of non-elective hospital stays for worsening PAH as the first event of clinical
worsening.
d. Count of deaths as the first event of clinical worsening.
e. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous
PAH treatment and etiology of PAH. P-value from the Wald test.
6MWD at Months 6 and 12
At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 to 352 m. At
Month 6, the median change from baseline was highest for sildenafil 80 mg TID with 28 m
compared to 18 m and 19 m for sildenafil 5 mg TID and sildenafil 20 mg TID groups,
respectively. The same was seen at Month 12, the median change from baseline for sildenafil 80
mg TID group was 33 m compared to 17 m for sildenafil 5 mg TID and 31 m in sildenafil 20 mg
TID groups.
Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose
were consistent with the established safety profile of sildenafil in previous adult PAH studies
[see Adverse Reactions (6.1)].
16
HOW SUPPLIED/STORAGE AND HANDLING
REVATIO tablets are supplied as white to off-white, film-coated, round tablets containing
sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:
REVATIO Tablets
Package Configuration
Strength
NDC
Engraving on Tablet
Bottle of 90 Tablets
20 mg
58151-402-77
“RVT 20” on one
side and “VLE” on
the other side
Recommended Storage for REVATIO Tablets: Store at controlled room temperature 20°C to
25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature].
29
REVATIO injection is supplied as a clear, colorless, sterile, ready to use solution containing 10
mg sildenafil/12.5 mL (0.8 mg/mL) presented in a single-dose glass vial.
REVATIO Injection
Package Configuration
Strength
NDC
Vial individually packaged in
a carton
10 mg/12.5 mL (0.8 mg/mL)
58151-395-31
Recommended Storage for REVATIO Injection: Store at controlled room temperature 20°C to
25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled
Room Temperature]. Discard unused portion.
REVATIO powder for oral suspension is supplied in amber glass bottles. Each bottle contains
white to slight pink powder containing 1.57 g of sildenafil citrate (equivalent to 1.12 g
sildenafil). Following reconstitution, the total volume of the oral suspension is 112 mL (10 mg
sildenafil/mL). A 2 mL oral dosing syringe (with 1 mL and 2 mL dose markings) and a press-in
bottle adaptor are also provided.
REVATIO Powder for Oral Suspension
Package Configuration
Strength
NDC
Powder for oral suspension -
bottle
10 mg/mL (when
reconstituted)
58151-385-35
Recommended Storage for REVATIO for Oral Suspension: Store below 30°C (86°F) in the
original package in order to protect from moisture.
Recommended Storage for Reconstituted Oral Suspension: Store below 30°C (86°F) or in
refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. The shelf-life of the reconstituted oral
suspension is 60 days. Any remaining oral suspension should be discarded 60 days after
reconstitution.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
•
Inform patients of contraindication of REVATIO with regular and/or intermittent use of
organic nitrates.
•
Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise
patients taking REVATIO not to take VIAGRA or other PDE-5 inhibitors.
•
Advise patients to seek immediate medical attention for a sudden loss of vision in one or both
eyes while taking REVATIO. Such an event may be a sign of NAION.
30
•
Advise patients to seek prompt medical attention in the event of sudden decrease or loss of
hearing while taking REVATIO. These events may be accompanied by tinnitus and dizziness.
Distributed by:
Viatris Specialty LLC
Morgantown, WV 26505 U.S.A.
© 2024 Viatris Inc.
REVATIO is a registered trademark of Viatris Specialty LLC, a Viatris Company.
UPJ:RVTTOSI:R2
PATIENT INFORMATION
REVATIO® (re-VAH-tee-oh)
(sildenafil)
tablets
REVATIO® (re-VAH-tee-oh)
(sildenafil)
oral suspension
What is the most important information I should know about REVATIO?
Never take REVATIO with any nitrate or guanylate cyclase stimulator medicines.
•
Your blood pressure could drop quickly to an unsafe level.
Nitrates include:
•
Medicines that treat chest pain (angina)
•
Nitroglycerin in any form including tablets, patches, sprays, and ointments
•
Isosorbide mononitrate or dinitrate
•
Street drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite)
Guanylate cyclase stimulators include:
•
Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary
hypertension.
Ask your healthcare provider or pharmacist if you are not sure if you or your child are taking a nitrate or a guanylate
cyclase stimulator medicine.
See “What are the possible side effects of REVATIO?” for more information about side effects.
What is REVATIO?
REVATIO is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood
pressure in the arteries of your lungs. REVATIO may be used in:
•
adults to improve your ability to exercise and help slow down the worsening of your physical condition.
•
children 1 to 17 years old to improve their ability to exercise, and in children too young to do certain exercise and
lung testing.
It is not known if REVATIO is safe and effective in children younger than 1 year of age.
Do not take REVATIO if you or your child:
•
take medicines called nitrates.
•
take riociguat, a guanylate cyclase stimulator medicine.
•
are allergic to sildenafil or any of the ingredients in REVATIO. See the end of this leaflet for a complete list of
ingredients in REVATIO.
Before taking REVATIO, tell your healthcare provider about all of your medical conditions, including if you or
your child:
•
have low blood pressure
•
have heart problems
•
have pulmonary veno-occlusive disease (PVOD)
•
have bleeding problems or a stomach (peptic) ulcer. It is not known if REVATIO is safe in people with bleeding
problems or who have a stomach ulcer.
•
have an eye problem called retinitis pigmentosa
•
have ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior
ischemic optic neuropathy (NAION)
•
have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing
•
have a deformed penis shape or Peyronie’s disease
•
have any blood cell problems such as sickle cell anemia
•
are pregnant or plan to become pregnant. It is not known if REVATIO will harm your unborn baby.
•
are breastfeeding or plan to breastfeed. REVATIO passes into your breast milk. It is not known if it can harm your
baby. Talk with your healthcare provider about the best way to feed your baby during treatment with REVATIO.
Tell your healthcare provider about all of the medicines you or your child take, including prescription and over-
the-counter medicines, vitamins, and herbal supplements. REVATIO and certain other medicines may affect each other
and can cause side effects.
Especially tell your healthcare provider if you or your child take:
•
nitrates or guanylate cyclase stimulators. See “What is the most important information I should know about
REVATIO?”
•
medicines to treat high blood pressure
•
medicines for erectile dysfunction (impotence). REVATIO contains sildenafil, which is the same medicine found in
another medicine called VIAGRA®. VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA
or other PDE-5 inhibitors during treatment with REVATIO.
Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
Know the medicines you or your child take. Keep a list of your or your child’s medicines and show it to your healthcare
provider and pharmacist when you get a new medicine.
How should I take REVATIO?
•
Take or give REVATIO exactly as your healthcare provider tells you.
•
Your healthcare provider may change your or your child’s dose of REVATIO as needed. Do not change your dose
or stop taking REVATIO without talking to your healthcare provider.
•
REVATIO may be prescribed to you as REVATIO tablets or REVATIO oral suspension.
•
Take your prescribed dose of REVATIO tablets or oral suspension 3 times a day.
•
See the detailed Instructions for Use that comes with REVATIO oral suspension for information on how to
take or give REVATIO oral suspension. REVATIO oral suspension will be mixed for you by your pharmacist. Do
not mix REVATIO oral suspension with other medicine or flavoring.
•
If you or your child take too much REVATIO, call your healthcare provider or go to the nearest hospital emergency
room right away.
What are the possible side effects of REVATIO?
REVATIO may cause serious side effects, including:
•
See “What is the most important information I should know about REVATIO?”
•
Decreased blood pressure. REVATIO may cause low blood pressure that last for a short time. If you take
medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during
treatment with REVATIO.
•
Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior
ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your
healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of
vision in one or both eyes during treatment with REVATIO, contact your healthcare provider right away.
•
Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden
decrease or loss of hearing during treatment with REVATIO, contact your healthcare provider right away.
•
In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain,
that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful
erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis,
including the inability to have erections.
The most common side effects of REVATIO in adults include:
•
nosebleeds
•
headache
•
upset stomach
•
getting red or hot in the face (flushing)
•
arm or leg pain
•
muscle aches and pain
•
back pain
•
diarrhea
The most common side effect of REVATIO in children is an erection that lasts for more than 4 hours (priapism).
These are not all the possible side effects of REVATIO.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store REVATIO?
•
Store REVATIO tablets at room temperature between 68°F to 77°F (20°C to 25°C).
•
Store mixed (reconstituted) REVATIO oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F
(2°C to 8°C).
•
Do not freeze mixed REVATIO oral suspension.
•
Throw away (discard) any remaining REVATIO oral suspension 60 days after mixed by the pharmacist. See the
“Discard after” date written on the bottle label.
Keep REVATIO and all medicines out of the reach of children.
General information about the safe and effective use of REVATIO.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
REVATIO for a condition for which it was not prescribed. Do not give REVATIO to other people, even if they have the
same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information
about REVATIO that is written for health professionals.
What are the ingredients in REVATIO?
Active ingredients: sildenafil citrate
Inactive ingredients:
REVATIO tablets: anhydrous dibasic calcium phosphate, croscarmellose sodium, hypromellose, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin
REVATIO oral suspension: citric acid anhydrous, colloidal silicon dioxide anhydrous, grape flavor, sodium benzoate,
sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide, and xanthan gum
Distributed by:
Viatris Specialty LLC
Morgantown, WV 26505 U.S.A.
© 2024 Viatris Inc.
REVATIO is a registered trademark of Viatris Specialty LLC, a Viatris Company.
UPJ:PL:RVTTOSI:R1
For more information call Viatris at 1-877-446-3679 (1-877-4-INFO-RX).
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: Month 2024
TABLE OF CONTENTS
Instructions for Use ...............................................................................................................................................2
Important information:.........................................................................................................................................2
Supplies you will need to take or give a dose of REVATIO oral suspension (See Figure A): .........................2
How should I store REVATIO? ............................................................................................................................6
Instructions for Use
REVATIO® (re-VAH-tee-oh)
(sildenafil)
oral suspension
Read this Instructions for Use before you start taking REVATIO oral suspension or giving REVATIO oral suspension to
your child and each time you get a refill. There may be new information. This information does not take the place of talking
to your healthcare provider about your or your child’s medical condition or treatment.
Important information:
•
Ask your healthcare provider or pharmacist to show you how to measure and take or give your child’s prescribed dose
of REVATIO oral suspension.
•
Your pharmacist will mix (reconstitute) REVATIO oral suspension before it is given to you. Do not take or give
REVATIO oral suspension and contact your pharmacist if the medicine in the bottle is still a powder.
•
Always use the oral dosing syringe that comes with REVATIO oral suspension. If your carton does not come with an
oral dosing syringe, contact your pharmacist.
•
Do not take or give REVATIO oral suspension if the bottle adaptor is not in the bottle. If the bottle adaptor is not in the
bottle, contact your pharmacist.
•
REVATIO oral suspension should not be mixed with any other medicine or flavoring.
Supplies you will need to take or give a dose of REVATIO oral suspension (See Figure A):
•
1 bottle of REVATIO oral suspension with pre-inserted bottle adaptor
•
1 oral dosing syringe (provided in the carton)
Step 1. Shake the bottle of REVATIO oral suspension for 10 seconds before each use. (See Figure B)
Step 2.
Remove the cap. Open the bottle by pushing down on the cap and twisting it in the direction of the
arrow (counter-clockwise). (See Figure C)
Step 3.
Fully push down (depress) the plunger of the oral dosing syringe. Then insert the tip of the oral dosing
syringe into the bottle adaptor while holding the bottle upright, on a flat surface. (See Figure D)
Step 4.
Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back the
plunger of the oral dosing syringe until the bottom of the plunger is even with the mL marking on the
syringe for your or your child’s prescribed dose. (See Figure E)
If your or your child’s dose of REVATIO oral suspension is more than 2 mL (20 mg), you will need to
divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about
how to prepare the divided dose.
If you see air bubbles in the oral dosing syringe, slowly push the plunger all the way up so that
REVATIO oral suspension flows back into the bottle and repeat Step 4.
Step 5.
Turn the bottle back upright with the oral dosing syringe still in place. Place the bottle on a flat
surface. Remove the oral dosing syringe from the bottle adaptor by pulling straight up on the barrel of
the oral dosing syringe. (See Figure F) Do not press on the plunger of the oral dosing syringe at
this time.
Step 6.
Put the tip of the oral dosing syringe into your or your child’s mouth and point it towards the inside of
the cheek. Slowly push the plunger of the oral dosing syringe all the way down to give the entire
dose. Do not squirt the medicine out quickly. (See Figure G)
If you are giving REVATIO oral suspension to a child, make sure they are in an upright position before
giving the medicine.
Step 7.
Replace the cap on the bottle, leaving the bottle adaptor in place. Turn the cap in the direction of the
arrow (clockwise) to close the bottle. (See Figure H)
Gurpreet
Gill Sangha
Digitally signed by Gurpreet Gill Sangha
Date: 12/16/2024 12:45:38PM
GUID: 5135f2ad000117842392c50c36c7f28a
| custom-source | 2025-02-12T15:48:06.357653 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021845Orig1s028lbl.pdf', 'application_number': 21845, 'submission_type': 'SUPPL ', 'submission_number': 28} |
80,729 |
infusion over 30−90 minutes every three weeks to complete a total of
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
KANJINTI safely and effectively. See full prescribing information for
KANJINTI.
KANJINTI® (trastuzumab-anns) for injection, for intravenous use
Initial U.S. Approval: 2019
KANJINTI (trastuzumab-anns) is biosimilar* to HERCEPTIN®
(trastuzumab).
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS,
EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
See full prescribing information for complete boxed warning
Cardiomyopathy: Trastuzumab products can result in subclinical and
clinical cardiac failure manifesting as CHF, and decreased LVEF, with
greatest risk when administered concurrently with anthracyclines.
Evaluate cardiac function prior to and during treatment. Discontinue
KANJINTI for cardiomyopathy. (2.5, 5.1)
Infusion Reactions, Pulmonary Toxicity: Discontinue KANJINTI for
anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory
distress syndrome. (5.2, 5.4)
Embryo-Fetal Toxicity: Exposure to trastuzumab products during
pregnancy can result in oligohydramnios, in some cases complicated by
pulmonary hypoplasia and neonatal death. Advise patients of these risks
and the need for effective contraception. (5.3, 8.1, 8.3)
--------------------------RECENT MAJOR CHANGES---------------------------
Dosage and Administration, Evaluation and Testing Before Initiating
KANJINTI (2.1)
12/2024
------------------------INDICATIONS AND USAGE------------------------------
KANJINTI is a HER2/neu receptor antagonist indicated in adults for:
•
the treatment of HER2-overexpressing breast cancer. (1.1, 1.2)
•
the treatment of HER2-overexpressing metastatic gastric or
gastroesophageal junction adenocarcinoma. (1.3)
Select patients for therapy based on an FDA-approved companion diagnostic
for a trastuzumab product (1, 2.2).
---------------------DOSAGE AND ADMINISTRATION------------------------
For intravenous (IV) infusion only. Do not administer as an IV push or
bolus. KANJINTI has different dosage and administration instructions
than subcutaneous trastuzumab products. (2.3)
Do not substitute KANJINTI (trastuzumab-anns) for or with ado-trastuzumab
emtansine or fam-trastuzumab deruxtecan. (2.3)
Perform HER2 testing using FDA-approved tests by laboratories with
demonstrated proficiency. (1, 2.2)
Adjuvant Treatment of HER2-Overexpressing Breast Cancer (2.2)
Administer at either:
•
Initial dose of 4 mg/kg over 90 minutes IV infusion, then 2 mg/kg over
30 minutes IV infusion weekly for 12 weeks (with paclitaxel or
docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after
the last weekly dose of KANJINTI, administer 6 mg/kg as an IV
52 weeks of therapy, or
•
Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over
30–90 minutes IV infusion every three weeks for 52 weeks.
Metastatic HER2-Overexpressing Breast Cancer (2.3)
•
Initial dose of 4 mg/kg as a 90 minutes IV infusion followed by
subsequent weekly doses of 2 mg/kg as 30 minutes IV infusions.
Metastatic HER2-Overexpressing Gastric Cancer (2.3)
•
Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by
6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.
-----------------------DOSAGE FORMS AND STRENGTHS-------------------
•
For Injection: 150 mg lyophilized powder in a single-dose vial for
reconstitution
•
For Injection: 420 mg lyophilized powder in a multiple-dose vial for
reconstitution
---------------------------------CONTRAINDICATIONS---------------------------
•
None. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
•
Exacerbation of Chemotherapy-Induced Neutropenia. (5.5, 6.1)
------------------------------------ADVERSE REACTIONS-------------------------
Adjuvant Breast Cancer
•
Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea,
and chills. (6.1)
Metastatic Breast Cancer
•
Most common adverse reactions (≥ 10%) are fever, chills, headache,
infection, congestive heart failure, insomnia, cough, and rash. (6.1)
Metastatic Gastric Cancer
•
Most common adverse reactions (≥ 10%) are neutropenia, diarrhea,
fatigue, anemia, stomatitis, weight loss, upper respiratory tract
infections, fever, thrombocytopenia, mucosal inflammation,
nasopharyngitis, and dysgeusia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen
Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
-------------------------USE IN SPECIFIC POPULATIONS---------------------
Females and Males of Reproductive Potential: Verify the pregnancy status of
females prior to initiation of KANJINTI (8.3).
See 17 for PATIENT COUNSELING INFORMATION.
*Biosimilar means that the biological product is approved based on data
demonstrating that it is highly similar to an FDA-approved biological product,
known as a reference product, and that there are no clinically meaningful
differences between the biosimilar product and the reference product.
Biosimilarity of KANJINTI has been demonstrated for the condition(s) of use
(e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and
route(s) of administration described in its Full Prescribing Information.
Revised: 12/2024
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Reference ID: 5499161
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS,
EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
1
INDICATIONS AND USAGE
1.1 Adjuvant Breast Cancer
1.2 Metastatic Breast Cancer
1.3 Metastatic Gastric Cancer
2
DOSAGE AND ADMINISTRATION
2.1 Evaluation and Testing Before Initiating KANJINTI
2.2 Patient Selection
2.3 Recommended Dosage
2.4 Important Dosing Considerations
2.5 Dosage Modifications for Adverse Reactions
2.6 Preparation Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Cardiomyopathy
5.2 Infusion Reactions
5.3 Embryo-Fetal Toxicity
5.4 Pulmonary Toxicity
5.5 Exacerbation of Chemotherapy-Induced Neutropenia
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 Immunogenicity
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Adjuvant Breast Cancer
14.2 Metastatic Breast Cancer
14.3 Metastatic Gastric Cancer
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed.
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Reference ID: 5499161
FULL PRESCRIBING INFORMATION
WARNING: CARDIOMYOPATHY, INFUSION REACTIONS,
EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY
Cardiomyopathy
Administration of trastuzumab products can result in sub-clinical and
clinical cardiac failure. The incidence and severity was highest in patients
receiving trastuzumab with anthracycline-containing chemotherapy regimens.
Evaluate left ventricular function in all patients prior to and during
treatment with KANJINTI. Discontinue KANJINTI treatment in patients
receiving adjuvant therapy and withhold KANJINTI in patients with
metastatic disease for clinically significant decrease in left ventricular
function [see Dosage and Administration (2.5) and Warnings and Precautions
(5.1)].
Infusion Reactions; Pulmonary Toxicity
Administration of trastuzumab products can result in serious and fatal
infusion reactions and pulmonary toxicity. Symptoms usually occur during or
within 24 hours of administration of trastuzumab products. Interrupt
KANJINTI infusion for dyspnea or clinically significant hypotension. Monitor
patients until symptoms completely resolve. Discontinue KANJINTI for
anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress
syndrome [see Warnings and Precautions (5.2, 5.4)].
Embryo-Fetal Toxicity
Exposure to trastuzumab products during pregnancy can result in
oligohydramnios and oligohydramnios sequence manifesting as pulmonary
hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these
risks and the need for effective contraception [see Warnings and Precautions
(5.3) and Use in Specific Populations (8.1, 8.3)].
1
INDICATIONS AND USAGE
1.1
Adjuvant Breast Cancer
KANJINTI is indicated in adults for adjuvant treatment of HER2-overexpressing
node positive or node negative (ER/PR negative or with one high risk feature [see
Clinical Studies (14.1)]) breast cancer
•
as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either
paclitaxel or docetaxel
•
as part of a treatment regimen with docetaxel and carboplatin
•
as a single agent following multi-modality anthracycline-based therapy.
Select patients for therapy based on an FDA-approved companion diagnostic for a
trastuzumab product [see Dosage and Administration (2.2)].
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1.2
Metastatic Breast Cancer
KANJINTI is indicated in adults:
•
In combination with paclitaxel for first-line treatment of HER2-overexpressing
metastatic breast cancer
•
As a single agent for treatment of HER2-overexpressing breast cancer in patients who
have received one or more chemotherapy regimens for metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for a
trastuzumab product [see Dosage and Administration (2.2)]
1.3
Metastatic Gastric Cancer
KANJINTI is indicated in adults, in combination with cisplatin and capecitabine or
5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or
gastroesophageal junction adenocarcinoma who have not received prior treatment for
metastatic disease.
Select patients for therapy based on an FDA-approved companion diagnostic for a
trastuzumab product [see Dosage and Administration (2.2)].
2
DOSAGE AND ADMINISTRATION
2.1
Evaluation and Testing Before Initiating KANJINTI
Assess left ventricular ejection fraction (LVEF) prior to initiation of KANJINTI and at regular
intervals during treatment [see Boxed Warning, Dosage and Administration (2.5), Warnings
and Precautions (5.1)].
Verify the pregnancy status of females of reproductive potential prior to the initiation of
KANJINTI [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].
2.2
Patient Selection
Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor
specimens [see Indications and Usage (1) and Clinical Studies (14)]. Assessment of HER2
protein overexpression and HER2 gene amplification should be performed using
FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated
proficiency. Information on the FDA-approved tests for the detection of HER2 protein
overexpression and HER2 gene amplification is available at:
http://www.fda.gov/CompanionDiagnostics.
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic
gastric cancer should be performed using FDA-approved tests specifically for gastric cancers
due to differences in gastric vs. breast histopathology, including incomplete membrane
staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize
specified reagents, deviation from specific assay instructions, and failure to include
appropriate controls for assay validation, can lead to unreliable results.
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Reference ID: 5499161
2.3
Recommended Dosage
•
KANJINTI is for intravenous infusion only. Do not administer as an intravenous
push or bolus.
•
KANJINTI has different dosage and administration instructions than
subcutaneous trastuzumab products.
•
Do not mix KANJINTI with other drugs.
•
Do not substitute KANJINTI (trastuzumab-anns) for or with ado-trastuzumab
emtansine or fam-trastuzumab deruxtecan.
Adjuvant Treatment of Breast Cancer:
Administer according to one of the following doses and schedules for a total of
52 weeks of KANJINTI therapy:
During and following paclitaxel, docetaxel, or docetaxel and carboplatin:
•
Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an
intravenous infusion over 30 minutes weekly during chemotherapy for the first
12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin).
•
One week following the last weekly dose of KANJINTI, administer KANJINTI at
6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.
As a single agent within three weeks following completion of multi-modality,
anthracycline-based chemotherapy regimens:
•
Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes.
•
Subsequent doses at 6 mg/kg as an intravenous infusion over 30-90 minutes every three
weeks.
•
Extending adjuvant treatment beyond one year is not recommended [see Adverse
Reactions (6.1)].
Metastatic Breast Cancer:
•
Administer KANJINTI, alone or in combination with paclitaxel, at an initial dose of
4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses
of 2 mg/kg as 30-minute intravenous infusions until disease progression.
Metastatic Gastric Cancer:
•
Administer KANJINTI at an initial dose of 8 mg/kg as a 90-minute intravenous infusion
followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30-90 minutes
every three weeks until disease progression.
2.4
Important Dosing Considerations
Missed Dose
If the patient has missed a dose of KANJINTI by one week or less, then the usual
maintenance dose (weekly schedule: 2 mg/kg; once every three weeks schedule: 6 mg/kg)
should be administered as soon as possible. Do not wait until the next planned cycle.
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Reference ID: 5499161
Subsequent KANJINTI maintenance doses should be administered 7 days or 21 days later
according to the weekly or once every three week schedules, respectively.
If the patient has missed a dose of KANJINTI by more than one week, a re-loading dose of
KANJINTI should be administered over approximately 90 minutes (weekly schedule:
4 mg/kg; once every three week schedule: 8 mg/kg) as soon as possible. Subsequent
KANJINTI maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg)
should be administered 7 days or 21 days later according to the weekly or once every three
week schedules, respectively.
2.5
Dosage Modifications for Adverse Reactions
Infusion Reactions
[see Boxed Warning, Warnings and Precautions (5.2)]
•
Decrease the rate of infusion for mild or moderate infusion reactions
•
Interrupt the infusion in patients with dyspnea or clinically significant hypotension
•
Discontinue KANJINTI for severe or life-threatening infusion reactions.
Cardiomyopathy
[see Boxed Warning, Warnings and Precautions (5.1)]
Assess left ventricular ejection fraction (LVEF) prior to initiation of KANJINTI and at regular
intervals during treatment. Withhold KANJINTI dosing for at least 4 weeks for either of the
following:
•
≥ 16% absolute decrease in LVEF from pre-treatment values
•
LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from
pre-treatment values.
KANJINTI may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the
absolute decrease from baseline is ≤ 15%.
Permanently discontinue KANJINTI for a persistent (> 8 weeks) LVEF decline or for
suspension of KANJINTI dosing on more than 3 occasions for cardiomyopathy.
2.6
Preparation Instructions
To prevent medication errors, it is important to check the vial labels to ensure that the drug
being prepared and administered is KANJINTI (trastuzumab-anns) and not ado-trastuzumab
emtansine or fam-trastuzumab deruxtecan.
420 mg Multiple-dose vial
Reconstitution
Reconstitute each 420 mg vial of KANJINTI with 20 mL of Bacteriostatic Water for
Injection (BWFI), USP, containing 0.9% to 1.1% benzyl alcohol as a preservative to yield a
multiple-dose solution containing 21 mg/mL trastuzumab-anns that delivers 20 mL
(420 mg trastuzumab-anns). In patients with known hypersensitivity to benzyl alcohol,
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Reference ID: 5499161
reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield
a one-time use solution.
Use appropriate aseptic technique when performing the following reconstitution steps:
•
Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the
lyophilized powder of KANJINTI, which has a cake-like appearance. The stream of
diluent should be directed into the cake. The reconstituted vial yields a solution for
multiple-dose use, containing 21 mg/mL trastuzumab-anns.
•
Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
•
Slight foaming of the product may be present upon reconstitution. Allow the vial to
stand undisturbed for approximately 5 minutes.
•
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit. Inspect
visually for particulates and discoloration. The solution should be free of visible
particulates, clear to slightly opalescent and colorless to pale yellow.
•
Store reconstituted KANJINTI in the refrigerator at 2°C to 8°C (36°F to 46°F); discard
unused KANJINTI after 28 days. If KANJINTI is reconstituted with SWFI without
preservative, use immediately and discard any unused portion. Do not freeze.
Dilution
•
Determine the dose (mg) of KANJINTI [see Dosage and Administration (2.3)].
Calculate the volume of the 21 mg/mL reconstituted KANJINTI solution needed,
withdraw this amount from the vial using a sterile needle and syringe and add it to an
infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
DO NOT USE DEXTROSE (5%) SOLUTION.
•
Gently invert the bag to mix the solution.
•
The solution of KANJINTI for infusion diluted in polyvinylchloride or polyethylene
bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C
(36°F to 46°F) for no more than 24 hours prior to use. This storage time is additional to
the time allowed for the reconstituted vials. Do not freeze.
150 mg Single-dose vial
Reconstitution
Reconstitute each 150 mg vial of KANJINTI with 7.4 mL of Sterile Water for Injection
(SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab-anns
that delivers 7.15 mL (150 mg trastuzumab-anns).
Use appropriate aseptic technique when performing the following reconstitution steps:
•
Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial
containing the lyophilized powder of KANJINTI, which has a cake-like appearance.
The stream of diluent should be directed into the cake. The reconstituted vial yields a
solution containing 21 mg/mL trastuzumab-anns.
•
Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
•
Slight foaming of the product may be present upon reconstitution. Allow the vial to
stand undisturbed for approximately 5 minutes.
•
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit. Inspect
7 of 41
Reference ID: 5499161
visually for particulates and discoloration. The solution should be free of visible
particulates, clear to slightly opalescent and colorless to pale yellow.
•
Use the KANJINTI solution immediately following reconstitution with SWFI, as it
contains no preservatives and is intended for one-time use only. If not used
immediately, store the reconstituted KANJINTI solution for up to 24 hours at 2°C to
8°C (36°F to 46°F); discard any unused KANJINTI after 24 hours. Do not freeze.
Dilution
•
Determine the dose (mg) of KANJINTI [see Dosage and Administration (2.3)].
•
Calculate the volume of the 21 mg/mL reconstituted KANJINTI solution needed.
•
Withdraw this amount from the vial using a sterile needle and syringe and add it to an
infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT
USE DEXTROSE 5% SOLUTION.
•
Gently invert the bag to mix the solution.
•
The solution of KANJINTI for infusion diluted in polyvinylchloride or polyethylene
bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C
(36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This
storage time is additional to the time allowed for the reconstituted vials. Do not freeze.
3
DOSAGE FORMS AND STRENGTHS
•
For injection: 150 mg of KANJINTI as a white to pale yellow lyophilized powder in a
single-dose vial.
•
For injection: 420 mg of KANJINTI as a white to pale yellow lyophilized powder in a
multiple-dose vial.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Cardiomyopathy
Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias,
hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed
Warning: Cardiomyopathy]. Trastuzumab products can also cause asymptomatic decline in
left ventricular ejection fraction (LVEF).
There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among
patients receiving trastuzumab products as a single agent or in combination therapy compared
with those not receiving trastuzumab products. The highest absolute incidence occurs when a
trastuzumab product is administered with an anthracycline.
Withhold KANJINTI for ≥ 16% absolute decrease in LVEF from pre-treatment values or an
LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from
pretreatment values [see Dosage and Administration (2.5)]. The safety of continuation or
8 of 41
Reference ID: 5499161
resumption of trastuzumab products in patients with trastuzumab product-induced left
ventricular cardiac dysfunction has not been studied.
Patients who receive anthracycline after stopping trastuzumab products may also be at
increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology
(12.3)].
Cardiac Monitoring
Conduct thorough cardiac assessment, including history, physical examination, and
determination of LVEF by echocardiogram or MUGA scan. The following schedule is
recommended:
•
Baseline LVEF measurement immediately prior to initiation of KANJINTI
•
LVEF measurements every 3 months during and upon completion of KANJINTI
•
Repeat LVEF measurement at 4-week intervals if KANJINTI is withheld for significant
left ventricular cardiac dysfunction [see Dosage and Administration (2.5)]
•
LVEF measurements every 6 months for at least 2 years following completion of
KANJINTI as a component of adjuvant therapy.
In NSABP B31, 15% (158/1031) of patients discontinued trastuzumab due to clinical
evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up
duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and
trastuzumab) arm. In HERA (one-year trastuzumab treatment), the number of patients who
discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up
was 2.6% (44/1678). In BCIRG006, a total of 2.9% (31/1056) of patients in the TCH
(docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and
1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm
(1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued
trastuzumab due to cardiac toxicity.
Among 64 patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who
developed congestive heart failure, one patient died of cardiomyopathy, one patient died
suddenly without documented etiology and 33 patients were receiving cardiac medication at
last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF
(defined as ≥ 50%) and no symptoms on continuing medical management at the time of last
follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of
continuation or resumption of trastuzumab products in patients with trastuzumab
product-induced left ventricular cardiac dysfunction has not been studied.
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Table 1. Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies
Incidence of Congestive Heart Failure % (n)
Trastuzumab
Control
Study
Regimen
NSABP B31
ACb → Paclitaxel + Trastuzumab
3.2% (64/2000)c
1.3% (21/1655)
& NCCTG
N9831a
HERAd
Chemotherapy → Trastuzumab
2% (30/1678)
0.3% (5/1708)
BCIRG006
ACb→Docetaxel + Trastuzumab
2% (20/1068)
0.3% (3/1050)
BCIRG006
Docetaxel + Carboplatin + Trastuzumab
0.4% (4/1056)
0.3% (3/1050)
a Median follow-up duration for NSABP B31 & NCCTG N9831 combined was 8.3 years in the AC→paclitaxel +
trastuzumab arm.
b Anthracycline (doxorubicin) and cyclophosphamide.
c Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology.
d Includes NYHA II-IV and cardiac death at 12.6 months median duration of follow-up in the one-year
trastuzumab arm.
In HERA (one-year trastuzumab treatment), at a median follow-up duration of 8 years, the
incidence of severe CHF (NYHA III & IV) was 0.8%, and the rate of mild symptomatic and
asymptomatic left ventricular dysfunction was 4.6%.
Table 2. Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies
Incidence
NYHA I-IV
NYHA III-IV
Study
Event
Trastuzumab
Control
Trastuzumab
Control
H0648g
Cardiac Dysfunction
28%
7%
19%
3%
(AC)b
H0648g
Cardiac Dysfunction
11%
1%
4%
1%
(paclitaxel)
H0649g
c
Cardiac Dysfunction
7%
N/A
5%
N/A
a Congestive heart failure or significant asymptomatic decrease in LVEF.
b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
c Includes 1 patient with fatal cardiomyopathy.
In BCIRG006, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in
the trastuzumab-containing regimens (AC-TH: 0.3% (3/1068) and TCH: 0.2% (2/1056)) as
compared to none in AC-T.
5.2
Infusion Reactions
Infusion reactions consist of a symptom complex characterized by fever and chills, and on
occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness,
dyspnea, hypotension, rash, and asthenia [see Adverse Reactions (6.1)].
In post-marketing reports, serious and fatal infusion reactions have been reported. Severe
reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe
hypotension, were usually reported during or immediately following the initial infusion.
However, the onset and clinical course were variable, including progressive worsening, initial
improvement followed by clinical deterioration, or delayed post-infusion events with rapid
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Reference ID: 5499161
clinical deterioration. For fatal events, death occurred within hours to days following a serious
infusion reaction.
Interrupt KANJINTI infusion in all patients experiencing dyspnea, clinically significant
hypotension, and intervention of medical therapy administered (which may include
epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should
be evaluated and carefully monitored until complete resolution of signs and symptoms.
Permanent discontinuation should be strongly considered in all patients with severe infusion
reactions.
There are no data regarding the most appropriate method of identification of patients who
may safely be retreated with trastuzumab products after experiencing a severe infusion
reaction. Prior to resumption of trastuzumab infusion, the majority of patients who
experienced a severe infusion reaction were pre-medicated with antihistamines and/or
corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent
severe infusion reactions despite pre-medications.
5.3
Embryo-Fetal Toxicity
Trastuzumab products can cause fetal harm when administered to a pregnant woman. In
post-marketing reports, use of trastuzumab during pregnancy resulted in cases of
oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia,
skeletal abnormalities, and neonatal death.
Verify the pregnancy status of females of reproductive potential prior to the initiation of
KANJINTI. Advise pregnant women and females of reproductive potential that exposure to
KANJINTI during pregnancy or within 7 months prior to conception can result in fetal harm.
Advise females of reproductive potential to use effective contraception during treatment and
for 7 months following the last dose of KANJINTI [see Use in Specific Populations (8.1, 8.3)
and Clinical Pharmacology (12.3)].
5.4
Pulmonary Toxicity
Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary
toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions,
non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory
distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion
reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung
disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear
to have more severe toxicity.
5.5
Exacerbation of Chemotherapy-Induced Neutropenia
In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3–4
neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in
combination with myelosuppressive chemotherapy as compared to those who received
chemotherapy alone. The incidence of septic death was similar among patients who received
trastuzumab and those who did not [see Adverse Reactions (6.1)].
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6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
•
Cardiomyopathy [see Warnings and Precautions (5.1)]
•
Infusion Reactions [see Warnings and Precautions (5.2)]
•
Embryo-Fetal Toxicity [see Warnings and Precautions (5.3)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.4)]
•
Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions
(5.5)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
The most common adverse reactions in patients receiving trastuzumab products in the
adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions,
diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia,
and myalgia. Adverse reactions requiring interruption or discontinuation of trastuzumab
product treatment include CHF, significant decline in left ventricular cardiac function, severe
infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.5)].
In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were
increased (≥ 5% difference) in the trastuzumab arm as compared to the chemotherapy alone
arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory
tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and
dysgeusia.
The most common adverse reactions which resulted in discontinuation of treatment on the
trastuzumab-containing arm in the absence of disease progression were infection, diarrhea,
and febrile neutropenia.
Adjuvant Breast Cancer
The information below reflects exposure to one-year trastuzumab therapy across three
randomized, open-label studies, NSABP B31, NCCTG N9831, and HERA, with (n = 3678) or
without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer.
HERA
Table 3 reflects exposure to trastuzumab in 1678 patients in HERA; the median treatment
duration was 51 weeks and median number of infusions was 18 [see Clinical Studies (14.1)].
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Table 3. Adverse Reactions (≥ 1%) in HERA (All Grades)a
Adverse Reactions
Trastuzumab
(n = 1678)
%
Observation
(n = 1708)
%
Nervous System
Headache
Paresthesia
Musculoskeletal
Arthralgia
Back Pain
Myalgia
Bone Pain
Muscle Spasm
Infections
Nasopharyngitis
Urinary tract infection
Gastrointestinal
Diarrhea
Nausea
Vomiting
Constipation
Dyspepsia
Upper abdominal pain
General
Pyrexia
Peripheral edema
Chills
Asthenia
Influenza-like illness
Respiratory Thoracic Mediastinal
Cough
Influenza
Dyspnea
URI
Rhinitis
Pharyngolaryngeal pain
Sinusitis
Epistaxis
Cardiac
Hypertension
Dizziness
Ejection fraction decreased
Palpitations
Cardiac arrhythmiasb
Cardiac failure (congestive)
10
2
8
5
4
3
3
8
3
7
6
3.5
2
2
2
6
5
5
4.5
2
5
4
3
3
2
2
2
2
4
4
3.5
3
3
2
3
0.6
6
3
1
2
0.2
3
0.8
1
1
0.6
1
0.5
1
0.4
2
0
2
0.2
2
0.5
2
1
0.4
0.5
0.3
0.06
2
2
0.6
0.7
1
0.3
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Adverse Reactions
Trastuzumab
(n = 1678)
%
Observation
(n = 1708)
%
Skin & Subcutaneous Tissue
Rash
Nail disorders
Pruritus
4
2
2
0.6
0
0.6
a The incidence of Grade 3 or higher adverse reactions was < 1% in both arms for each listed
term.
b Higher level grouping term.
Clinically relevant adverse reactions in < 1% of patients who received trastuzumab in HERA
included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial
pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%),
autoimmune thyroiditis (0.3%), and sudden death (0.06%).
Adjuvant Treatment of Breast Cancer with Trastuzumab Beyond One Year
Extending adjuvant treatment beyond one year is not recommended [see Dosage and
Administration (2.3)]. In HERA, a comparison of trastuzumab administered once every
3 weeks for two years versus one year was performed. The rate of asymptomatic cardiac
dysfunction was increased in the 2-year trastuzumab compared to the 1-year trastuzumab
treatment arm (8.1% versus 4.6%, respectively). More patients experienced at least one
adverse reaction of Grade 3 or higher in the 2-year trastuzumab treatment arm (20.4%)
compared with the one-year trastuzumab treatment arm (16.3%).
NSABP B31 and NCCTG N9831
The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of
whom 2000 received trastuzumab; the median treatment duration was 51 weeks [see Clinical
Studies (14.1)].
In NSABP B31, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade
2–5 dyspnea were collected during and for up to 3 months following protocol-specified
treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence
of at least 2% greater among patients receiving trastuzumab plus chemotherapy as compared
to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24% vs. 12.8%), hot flashes
(17.1% vs. 15%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation
(10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache
(6.2% vs. 3.8%), pain (5.5% vs. 3%), edema (4.7% vs. 2.7%) and insomnia (4.3% vs. 1.5%).
The majority of these events were Grade 2 in severity.
In NCCTG N9831, data collection was limited to the following investigator-attributed
treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade
3-5 non-hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes
(myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5
cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The
following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least
2% greater among patients receiving trastuzumab plus chemotherapy as compared to
chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs.6.8%), dyspnea
(2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in
severity.
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BCIRG006
Safety data from BCIRG006 reflect exposure to trastuzumab as part of an adjuvant treatment
regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068;
TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and
TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH
arm, including weekly infusions during the chemotherapy phase and once every three week
dosing in the monotherapy period [see Clinical Studies (14.1)]. In BCIRG006, the toxicity
profile was similar to that reported in NSABP B31, NCCTG N9831, and HERA with the
exception of a lower incidence of CHF in the TCH arm.
Metastatic Breast Cancer Studies
The safety of trastuzumab was evaluated in one randomized, open-label study (H0648g) of
chemotherapy with (n = 235) or without (n = 234) intravenous trastuzumab in patients with
metastatic breast cancer and in one single-arm study (H0649g) in patients with metastatic
breast cancer (n = 222) [see Clinical Studies (14.1)]. Patients received 4 mg/kg initial dose of
trastuzumab followed by 2 mg/kg weekly. In H0648g, 58% of patients received trastuzumab
for ≥ 6 months and 9% received trastuzumab ≥ 12 months, respectively. In H0649g, 31% of
patients received trastuzumab for ≥ 6 months and 16% received trastuzumab for ≥ 12 months,
respectively.
Table 4 shows the adverse reactions (≥ 5%) in patients from H0648g and H0649g.
Table 4. Adverse Reactions (≥ 5%) in the Trastuzumab Arms in H0648g and H0649g
Trastuzum Trastuzumab
Paclitaxel
Trastuzumab
ACb
aba
+
n = 95
+
n = 135
n = 352
Paclitaxel
%
ACb
%
%
n = 91
n = 143
%
%
General
Pain
47
61
62
57
42
Asthenia
42
62
57
54
55
Fever
36
49
23
56
34
Chills
32
41
4
35
11
Headache
26
36
28
44
31
Abdominal pain
22
34
22
23
18
Back pain
22
34
30
27
15
Infection
20
47
27
47
31
Flu syndrome
10
12
5
12
6
Accidental injury
6
13
3
9
4
Allergic reaction
3
8
2
4
2
Gastrointestinal
Nausea
33
51
9
76
77
Diarrhea
25
45
29
45
26
Vomiting
23
37
28
53
49
Anorexia
14
24
16
31
26
Nausea and vomiting
8
14
11
18
9
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Trastuzum Trastuzumab
Paclitaxel
Trastuzumab
ACb
aba
+
n = 95
+
n = 135
n = 352
Paclitaxel
%
ACb
%
%
n = 91
n = 143
%
%
Respiratory
Cough increased
26
41
22
43
29
Dyspnea
22
27
26
42
25
Rhinitis
14
22
5
22
16
Pharyngitis
12
22
14
30
18
Sinusitis
9
21
7
13
6
Skin
Rash
18
38
18
27
17
Herpes simplex
2
12
3
7
9
Acne
2
11
3
3
< 1
Nervous
Insomnia
14
25
13
29
15
Dizziness
13
22
24
24
18
Paresthesia
9
48
39
17
11
Depression
6
12
13
20
12
Peripheral neuritis
2
23
16
2
2
Neuropathy
1
13
5
4
4
Metabolic
Peripheral edema
10
22
20
20
17
Edema
8
10
8
11
5
Cardiovascular
Congestive heart failure
7
11
1
28
7
Tachycardia
5
12
4
10
5
Musculoskeletal
Bone pain
7
24
18
7
7
Arthralgia
6
37
21
8
9
Urogenital
Urinary tract infection
5
18
14
13
7
Blood and Lymphatic
Anemia
4
14
9
36
26
Leukopenia
3
24
17
52
34
a Data for trastuzumab single agent were from 4 studies, including 213 patients from H0649g.
b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
Metastatic Gastric Cancer
The safety of trastuzumab was evaluated in patients with previously untreated metastatic
gastric or gastroesophageal junction adenocarcinoma in an open-label, multicenter trial
(ToGA) [see Clinical Studies (14.3)]. Patients were randomized (1:1) to receive trastuzumab
in combination with cisplatin and a fluoropyrimidine (FC+H) (n = 294) or chemotherapy
alone (FC) (n = 290). Patients in the trastuzumab plus chemotherapy arm received
trastuzumab 8 mg/kg administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg
every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and
the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day
on Days 1-14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1
through 5. Chemotherapy was administered for six 21-day cycles. Median duration of
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Reference ID: 5499161
trastuzumab treatment was 21 weeks and the median number of trastuzumab infusions
administered was eight.
Table 5. Adverse Reactions (All Grades ≥ 5% or Grade 3-4 ≥ 1% between Arms) in
ToGA
Trastuzumab + FC
(N = 294)
%
FC
(N = 290) %
Adverse Reactions
All Grades
Grades 3-4
All Grades
Grades 3-4
Investigations
Neutropenia
Hypokalemia
Anemia
Thrombocytopenia
78
28
28
16
34
10
12
5
73
24
21
11
29
6
10
3
Blood and Lymphatic System Disorders
Febrile Neutropenia
−−
5
−−
3
Gastrointestinal Disorders
Diarrhea
Stomatitis
Dysphagia
37
24
6
9
1
2
28
15
3
4
2
< 1
General
Fatigue
Fever
Mucosal Inflammation
Chills
35
18
13
8
4
1
2
< 1
28
12
6
0
2
0
1
0
Metabolism and Nutrition Disorders
Weight Decrease
23
2
14
2
Infections and Infestations
Upper Respiratory Tract Infections
Nasopharyngitis
19
13
0
0
10
6
0
0
Renal and Urinary Disorders
Renal Failure and Impairment
18
3
15
2
Nervous System Disorders
Dysgeusia
10
0
5
0
The following subsections provide additional detail regarding adverse reactions observed in
clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or
post-marketing experience.
Cardiomyopathy
Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant
treatment of breast cancer. In HERA, the median duration of follow-up was12.6 months (12.4
months in the observation arm; 12.6 months in the 1-year trastuzumab arm); and in NSABP
B31 and NCCTG N9831, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm.
Following initiation of trastuzumab therapy, the incidence of new-onset dose-limiting
myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as
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Reference ID: 5499161
compared to those receiving paclitaxel alone in NSABP B31 and NCCTG N9831, and in
patients receiving one-year trastuzumab monotherapy compared to observation in HERA (see
Table 6, Figures 1 and 2). The incidence of new-onset cardiac dysfunction, as measured by
LVEF, remained similar when compared to the analysis performed at a median follow-up of
2.0 years in the AC-TH arm. This analysis showed evidence of reversibility of left ventricular
dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group
being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery.
Table 6a. Myocardial Dysfunction (by LVEF) in NSABP B31, NCCTG N9831, HERA
and BCIRG006
LVEF < 50%
and Decrease from Baseline
LVEF Decrease
LVEF
≥ 10%
≥ 16%
< 20% and
Study and Arm
< 50%
decrease
decrease
≥ 10%
≥ 20%
NSABP B31 & NCCTG N9831b,c
AC→TH
23.1%
18.5%
11.2%
37.9%
8.9%
(n = 1856)
(428)
(344)
(208)
(703)
(166)
AC→T
11.7%
7.0%
3.0%
22.1%
3.4%
(n = 1170)
(137)
(82)
(35)
(259)
(40)
HERAd
Trastuzumab
8.6%
7.0%
3.8%
22.4%
3.5%
(n = 1678)
(144)
(118)
(64)
(376)
(59)
Observation
2.7%
2.0%
1.2%
11.9%
1.2%
(n = 1708)
(46)
(35)
(20)
(204)
(21)
BCIRG006e
TCH
8.5%
5.9%
3.3%
34.5%
6.3%
(n = 1056)
(90)
(62)
(35)
(364)
(67)
AC→TH
17%
13.3%
9.8%
44.3%
13.2%
(n = 1068)
(182)
(142)
(105)
(473)
(141)
AC→T
9.5%
6.6%
3.3%
34%
5.5%
(n = 1050)
(100)
(69)
(35)
(357)
(58)
a For NSABP B31, NCCTG N9831 and HERA, events are counted from the beginning of trastuzumab treatment. For
BCIRG006, events are counted from the date of randomization.
b NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or
paclitaxel plus trastuzumab (AC→TH).
c Median duration of follow-up for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→TH arm.
d Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
e BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus
trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
18 of 41
Reference ID: 5499161
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
1959
1316
0
0.50
0.45
0.40
0.35
Cl)
0.30
<->
C:
Cl)
'C
0.25
·u
.s
Cl)
0.20
>
'I;;
0.15
'5
E
0.10
:::,
u
0.05
0.00
-
~
~
#
~-----;
~~_,--~-------~
;_,.,~
.~
1670
1156
1678
1708
951
764
0
2
1142
1154
6
Number at Risk
492
481
257
256
3
4
5
6
Time from Initiation of Paclitaxel/Trastuzumab (Years)
AC->T
873
831
12
AC->T+H
Number at Risk
538
498
18
263
245
Time from Randomization (Months)
221
159
7
24
139
AC->T+H
93
ft£•>T
8
Trastuzumab 1-Year
Observation Only
-
-
-
Observation Only
Trastuzumab 1-Year
Figure 1. NSABP B31 and NCCTG N9831: Cumulative Incidence of Time to First LVEF
Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a
Competing Risk Event
Time 0 is initiation of paclitaxel or trastuzumab + paclitaxel therapy.
Figure 2. HERA: Cumulative Incidence of Time to First LVEF Decline of ≥ 10
Percentage Points from Baseline and to Below 50% with Death as a Competing Risk
Event
Time 0 is the date of randomization.
19 of 41
Reference ID: 5499161
0.50
0.45
0.40
Q)
0.35
(.)
C:
Q)
0.30
-0
·c:;
..!:
0.25
Q)
>
~ 0.20
:5
E
:,
(..)
0.15
0.10
0.05
0.00
~
0
Number at risk
AC->T
1050
AC·>TH
1066
TCH
1056
-
AC-> T {doxorubicin and cyclophosphamide -> docetaxel)
AC-> TH {doxorubicin and cyclophosphamide -> docetaxel + Trastuzumab)
TCH (docetaxel + carboplatin + Trastuzumab)
#------------------------------
-----------
♦---
,_, .... #
•
-
•
-
•
-
•
-
••
---
6
947
975
975
12
836
639
877
18
Time (Months)
523
474
535
24
359
315
350
36
259
246
271
Figure 3. BCIRG006: Cumulative Incidence of Time to First LVEF Decline of ≥ 10
Percentage Points from Baseline and to Below 50% with Death as a Competing Risk
Event
Time 0 is the date of randomization.
The incidence of congestive heart failure among patients in the metastatic breast cancer trials
was classified for severity using the New York Heart Association classification system (I-IV,
where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast
cancer trials, the probability of cardiac dysfunction was highest in patients who received
trastuzumab concurrently with anthracyclines.
In ToGA, 5% of patients in the trastuzumab plus chemotherapy arm compared to 1.1% of
patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute
decrease in LVEF from pre-treatment values.
Infusion Reactions
During the first infusion with trastuzumab, the symptoms most commonly reported were
chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were
treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in
the rate of trastuzumab infusion); permanent discontinuation of trastuzumab for infusion
reactions was required in < 1% of patients. Other signs and/or symptoms may include nausea,
vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea,
hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21%
and 35% of patients, and were severe in 1.4% and 9% of patients, on second or subsequent
trastuzumab infusions administered as monotherapy or in combination with chemotherapy,
respectively. In the post-marketing setting, severe infusion reactions, including
hypersensitivity, anaphylaxis, and angioedema have been reported.
Anemia
In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21%
[H0648g]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [NSABP B31]), and of
anemia requiring transfusions (0.1% vs. 0 patients [NCCTG N9831]) were increased in
20 of 41
Reference ID: 5499161
patients receiving trastuzumab and chemotherapy compared with those receiving
chemotherapy alone. Following the administration of trastuzumab as a single agent (H0649g),
the incidence of NCI-CTC Grade 3 anemia was < 1%. In ToGA (metastatic gastric cancer),
on the trastuzumab-containing arm as compared to the chemotherapy alone arm, the overall
incidence of anemia was 28% compared to 21% and of NCI-CTC Grade 3/4 anemia was
12.2% compared to 10.3%.
Neutropenia
In randomized controlled clinical trials in the adjuvant setting, the incidence of selected
NCI-CTC Grade 4–5 neutropenia (1.7% vs. 0.8% [NCCTG N9831]) and of selected
Grade 2-5 neutropenia (6.4% vs. 4.3% [NSABP B31]) were increased in patients receiving
trastuzumab and chemotherapy compared with those receiving chemotherapy alone. In a
randomized, controlled trial in patients with metastatic breast cancer, the incidences of
NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%)
were also increased in patients randomized to trastuzumab in combination with
myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic
gastric cancer) on the trastuzumab-containing arm as compared to the chemotherapy alone
arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile
neutropenia 5.1% compared to 2.8%.
Infection
The overall incidences of infection (46% vs. 30% [H0648g]), of selected NCI-CTC Grade 2–5
infection/febrile neutropenia (24.3% vs. 13.4% [NSABP B31]) and of selected Grade 3–5
infection/febrile neutropenia (2.9% vs. 1.4%) [NCCTG N9831]) were higher in patients
receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone.
The most common site of infections in the adjuvant setting involved the upper respiratory
tract, skin, and urinary tract.
In BCIRG006, the overall incidence of infection was higher with the addition of trastuzumab
to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of
NCI-CTC Grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across
the three arms.
In a randomized, controlled trial in treatment of metastatic breast cancer, the reported
incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving trastuzumab
in combination with myelosuppressive chemotherapy as compared to chemotherapy alone.
Pulmonary Toxicity
Adjuvant Breast Cancer
Among women receiving adjuvant therapy for breast cancer, the incidence of selected
NCI-CTC Grade 2-5 pulmonary toxicity (14.3% vs. 5.4% [NSABP B31]) and of selected
NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea
(3.4% vs. 0.9% [NCCTG N9831]) was higher in patients receiving trastuzumab and
chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity
was dyspnea (NCI-CTC Grade 2–5: 11.8% vs. 4.6% [NSABP B31]; NCI-CTC Grade 2–5:
2.4% vs. 0.2% [NCCTG N9831]).
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Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab
compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred
in 3 patients receiving trastuzumab, one as a component of multi-organ system failure, as
compared to 1 patient receiving chemotherapy alone.
In HERA, there were 4 cases of interstitial pneumonitis in the one-year trastuzumab treatment
arm compared to none in the observation arm at a median follow-up duration of 12.6 months.
Metastatic Breast Cancer
Among women receiving trastuzumab for treatment of metastatic breast cancer, the incidence
of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the
post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary
events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions,
non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed
description, [see Warnings and Precautions (5.4)].
Thrombosis/Embolism
In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was
higher in patients receiving trastuzumab and chemotherapy compared to chemotherapy alone
in three studies (2.6% vs. 1.5% [NSABP B31], 2.5% and 3.7% vs. 2.2% [BCIRG006] and
2.1% vs. 0% [H0648g]).
Diarrhea
Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC
Grade 2–5 diarrhea (6.7% vs. 5.4% [NSABP B31]) and of NCI-CTC Grade 3–5 diarrhea
(2.2% vs. 0% [NCCTG N9831]), and of Grade 1–4 diarrhea (7% vs. 1% [HERA; one-year
trastuzumab treatment at 12.6 months median duration of follow-up]) were higher in patients
receiving trastuzumab as compared to controls. In BCIRG006, the incidence of Grade 3–4
diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher
[51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving trastuzumab. Of patients
receiving trastuzumab as a single agent for the treatment of metastatic breast cancer,
25% experienced diarrhea. An increased incidence of diarrhea was observed in patients
receiving trastuzumab in combination with chemotherapy for treatment of metastatic breast
cancer.
Renal Toxicity
In ToGA (metastatic gastric cancer) on the trastuzumab-containing arm as compared to the
chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%.
Severe (Grade 3/4) renal failure was 2.7% on the trastuzumab-containing arm compared to
1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure
was 2% on the trastuzumab-containing arm and 0.3% on the chemotherapy only arm.
In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of
glomerulopathy have been reported. The time to onset ranged from 4 months to
approximately 18 months from initiation of trastuzumab therapy. Pathologic findings included
membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis.
Complications included volume overload and congestive heart failure.
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6.2
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of trastuzumab
products. Because these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal relationship
to drug exposure.
•
Infusion reaction [see Warnings and Precautions (5.2)]
•
Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia,
skeletal abnormalities, and neonatal death [see Warnings and Precautions (5.3)]
•
Glomerulopathy [see Adverse Reactions (6.1)]
•
Immune thrombocytopenia
•
Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients
treated with trastuzumab products. Patients with significant tumor burden (e.g. bulky
metastases) may be at a higher risk. Patients could present with hyperuricemia,
hyperphosphatemia, and acute renal failure which may represent possible TLS.
Providers should consider additional monitoring and/or treatment as clinically indicated.
7
DRUG INTERACTIONS
Anthracyclines
Patients who receive anthracycline after stopping trastuzumab products may be at increased
risk of cardiac dysfunction because of trastuzumab products estimated long washout period
[see Clinical Pharmacology (12.3)]. If possible, avoid anthracycline-based therapy for up to
7 months after stopping trastuzumab products. If anthracyclines are used, closely monitor the
patient's cardiac function.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Trastuzumab products can cause fetal harm when administered to a pregnant woman. In
post-marketing reports and published literature, use of trastuzumab products during pregnancy
resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as
pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Data]. Apprise the
patient of the potential risks to a fetus. There are clinical considerations if a trastuzumab
product is used in a pregnant woman or if a patient becomes pregnant within 7 months
following the last dose of a trastuzumab product [see Clinical Considerations].
The background risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
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Clinical Considerations
Fetal/Neonatal Adverse Reactions
Monitor women who received KANJINTI during pregnancy or within 7 months prior to
conception for oligohydramnios. If oligohydramnios occurs, perform fetal/neonatal testing
that is appropriate for gestational age and consistent with community standards of care.
Data
Human Data
In post-marketing reports and published literature, use of trastuzumab products during
pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence. Fetal
manifestations included pulmonary hypoplasia, skeletal abnormalities and neonatal death.
These case reports described oligohydramnios in pregnant women who received trastuzumab
either alone or in combination with chemotherapy. In most reported cases, amniotic fluid
index increased after trastuzumab was stopped. In reported cases where trastuzumab therapy
was resumed after amniotic index improved, oligohydramnios recurred.
Animal Data
In studies where trastuzumab was administered to pregnant Cynomolgus monkeys during the
period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the
recommended weekly human dose of 2 mg/kg), trastuzumab crossed the placental barrier
during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of
gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were
approximately 33% and 25%, respectively, of those present in the maternal serum but were
not associated with adverse developmental effects.
8.2
Lactation
Risk Summary
There is no information regarding the presence of trastuzumab products in human milk, the
effects on the breastfed infant, or the effects on milk production. Published data suggest
human IgG is present in human milk but does not enter the neonatal and infant circulation in
substantial amounts.
Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated
with neonatal toxicity [see Data]. Consider the developmental and health benefits of
breastfeeding along with the mother's clinical need for KANJINTI treatment and any potential
adverse effects on the breastfed child from KANJINTI or from the underlying maternal
condition. This consideration should also take into account the trastuzumab product wash out
period of 7 months [see Clinical Pharmacology (12.3)].
Data
In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of
maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum
(through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the
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recommended weekly human dose of 2 mg/kg of trastuzumab products). Infant monkeys with
detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or
development from birth to 1 month of age.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to the initiation of
KANJINTI.
Contraception
Females
Trastuzumab products can cause embryo-fetal harm when administered during pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with
KANJINTI and for 7 months following the last dose of KANJINTI [see Use in Specific
Populations (8.1) and Clinical Pharmacology (12.3)].
8.4
Pediatric Use
The safety and effectiveness of KANJINTI in pediatric patients have not been established.
8.5
Geriatric Use
Trastuzumab has been administered to 386 patients who were 65 years of age or over (253 in
the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of
cardiac dysfunction was increased in geriatric patients as compared to younger patients in
both those receiving treatment for metastatic disease in H0648g and H0649g, or adjuvant
therapy in NSABP B31 and NCCTG N9831. Limitations in data collection and differences in
study design of the 4 studies of trastuzumab in adjuvant treatment of breast cancer preclude a
determination of whether the toxicity profile of trastuzumab in older patients is different from
younger patients. The reported clinical experience is not adequate to determine whether the
efficacy improvements (ORR, TTP, OS, DFS) of trastuzumab treatment in older patients is
different from that observed in patients < 65 years of age for metastatic disease and adjuvant
treatment.
In ToGA (metastatic gastric cancer), of the 294 patients treated with trastuzumab, 108 (37%)
were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in
safety or effectiveness were observed.
11
DESCRIPTION
Trastuzumab-anns is a humanized IgG1 kappa monoclonal antibody that selectively binds
with high affinity to the extracellular domain of the human epidermal growth factor receptor 2
protein, HER2.
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Trastuzumab-anns is produced by recombinant DNA technology in a mammalian cell
(Chinese Hamster Ovary) culture containing the antibiotic geneticin. Geneticin is not
detectable in the final product.
KANJINTI (trastuzumab-anns) for injection is a sterile, white to pale yellow,
preservative-free lyophilized powder with a cake-like appearance, for intravenous
administration.
Each multiple-dose vial of KANJINTI delivers 420 mg trastuzumab-anns, 381.8 mg
α,α-trehalose dihydrate, 9.5 mg L-histidine HCl monohydrate, 6.1 mg L-histidine, and 1.7 mg
polysorbate 20. Reconstitution with 20 mL of the appropriate diluent (BWFI or SWFI) yields
a solution containing 21 mg/mL trastuzumab-anns that delivers 20 mL (420 mg
trastuzumab-anns), at a pH of approximately 6. If KANJINTI is reconstituted with SWFI
without preservative, the reconstituted solution is considered single-dose.
Each single-dose vial of KANJINTI delivers 150 mg trastuzumab-anns, 136.2 mg
α,α-trehalose dihydrate, 3.4 mg L-histidine HCl monohydrate, 2.2 mg L-histidine, and 0.6 mg
polysorbate 20. Reconstitution with 7.4 mL of Sterile Water for Injection (SWFI) yields a
solution containing 21 mg/mL trastuzumab-anns that delivers 7.15 mL (150 mg
trastuzumab-anns), at a pH of approximately 6.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of
185 kDa, which is structurally related to the epidermal growth factor receptor. Trastuzumab
products have been shown, in both in vitro assays and in animals, to inhibit the proliferation
of human tumor cells that overexpress HER2.
Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC).
In vitro, trastuzumab product-mediated ADCC has been shown to be preferentially exerted on
HER2-overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
12.2
Pharmacodynamics
Trastuzumab product exposure-response relationships and the time course of
pharmacodynamic responses are not fully characterized.
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval
duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no
clinically relevant effect on the QTc interval duration and there was no apparent relationship
between serum trastuzumab concentrations and change in QTcF interval duration in patients
with HER2 positive solid tumors.
12.3
Pharmacokinetics
The pharmacokinetics of trastuzumab was evaluated in a pooled population pharmacokinetic
(PK) model analysis of 1582 subjects with primarily breast cancer and metastatic gastric
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cancer (MGC) receiving intravenous trastuzumab. Total trastuzumab clearance increases with
decreasing concentrations due to parallel linear and non-linear elimination pathways.
Although the average trastuzumab exposure was higher following the first cycle in breast
cancer patients receiving the once every three week schedule compared to the weekly
schedule of trastuzumab, the average steady-state exposure was essentially the same at both
dosages. The average trastuzumab exposure following the first cycle and at steady-state as
well as the time to steady-state was higher in breast cancer patients compared to MGC
patients at the same dosage; however, the reason for this exposure difference is unknown.
Additional predicted trastuzumab exposure and PK parameters following the first trastuzumab
cycle and at steady-state exposure are described in Tables 7 and 8, respectively.
Population PK based simulations indicate that following discontinuation of trastuzumab,
concentrations in at least 95% of breast cancer and MGC patients will decrease to
approximately 3% of the population predicted steady-state trough serum concentration
(approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in
Specific Populations (8.1, 8.3)].
Table 7. Population Predicted Cycle 1 PK Exposures (Median with 5th - 95th Percentiles)
in Breast Cancer and MGC Patients
Schedule
Primary tumor
type
N
Cmin
(µg/mL)
Cmax (µg/mL)
AUC0 - 21days
(µg.day/mL)
8 mg/kg +
Breast cancer
1195
29.4
(5.8 - 59.5)
178
(117 - 291)
1373
(736 - 2245)
6 mg/kg q3w
MGC
274
23.1
(6.1 - 50.3)
132
(84.2 - 225)
1109
(588 - 1938)
4 mg/kg +
2 mg/kg qw
Breast cancer
1195
37.7
(12.3 - 70.9)
88.3
(58 - 144)
1066
(586 - 1754)
Table 8. Population Predicted Steady-State PK Exposures (Median with 5th - 95th
Percentiles) in Breast Cancer and MGC Patients
Schedule
Primary
tumor type
N
Cmin,ssa
(µg/mL)
b
Cmax,ss
(µg/mL)
AUCss, 0-21
days
(µg.day/mL)
Time to
steady- state
(week)
Total CL
range at
steady-state
(L/day)
8 mg/kg +
6 mg/kg
q3w
Breast
cancer
1195
47.4
(5 - 115)
179
(107 - 309)
1794
(673 - 3618)
12
0.173 - 0.283
MGC
274
32.9
(6.1 - 88.9)
131
(72.5 - 251)
1338
(557 - 2875)
9
0.189 - 0.337
4 mg/kg +
2 mg/kg
qw
Breast
cancer
1195
66.1
(14.9 - 142)
109
(51.0 - 209)
1765
(647 - 3578)
12
0.201 - 0.244
a Steady-state trough serum concentration of trastuzumab.
b Maximum steady-state serum concentration of trastuzumab.
Specific Populations: Based on a population pharmacokinetic analysis, no clinically
significant differences were observed in the pharmacokinetics of trastuzumab based on age
(< 65 (n = 1294); ≥ 65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal
impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr
30 to 60 mL/min) (n = 133). The pharmacokinetics of trastuzumab products in patients with
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severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic
impairment is unknown.
Drug Interaction Studies:
There have been no formal drug interaction studies performed with trastuzumab products in
humans. Clinically significant interactions between trastuzumab and concomitant medications
used in clinical trials have not been observed.
Paclitaxel and doxorubicin: Concentrations of paclitaxel and doxorubicin and their major
metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively)
were not altered in the presence of trastuzumab when used as combination therapy in clinical
trials. Trastuzumab concentrations were not altered as part of this combination therapy.
Docetaxel and carboplatin: When trastuzumab was administered in combination with
docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the
plasma concentrations of trastuzumab were altered.
Cisplatin and capecitabine: In a drug interaction substudy conducted in patients in ToGA, the
pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when
administered in combination with trastuzumab.
12.6
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
incidence of anti-drug antibodies in the studies described below with the incidence of
anti-drug antibodies in other studies, including those of trastuzumab or of other trastuzumab
products.
Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to
trastuzumab was detected in one patient using an enzyme linked immunosorbent assay
(ELISA). This patient did not experience an allergic reaction. Samples for assessment of
HAHA were not collected in studies of adjuvant breast cancer.
The clinical relevance of the development of anti-trastuzumab antibodies after treatment with
trastuzumab is not known.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Trastuzumab products have not been tested for carcinogenic potential.
No evidence of mutagenic activity was observed when trastuzumab was tested in the standard
Ames bacterial and human peripheral blood lymphocyte mutagenicity assays, at
concentrations of up to 5000 µg/mL. In an in vivo micronucleus assay, no evidence of
chromosomal damage to mouse bone marrow cells was observed following bolus intravenous
doses of up to 118 mg/kg of trastuzumab.
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A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the
weekly recommended human dose of 2 mg/kg of trastuzumab and has revealed no evidence of
impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.
14
CLINICAL STUDIES
14.1
Adjuvant Breast Cancer
The safety and efficacy of trastuzumab in women receiving adjuvant chemotherapy for
HER2-overexpressing breast cancer were evaluated in an integrated analysis of two
randomized, open-label, clinical trials (NSABP B31 and NCCTG N9831) with a total of 4063
women at the protocol-specified final overall survival analysis, a third randomized,
open-label, clinical trial (HERA) with a total of 3386 women at definitive Disease-Free
Survival analysis for one-year trastuzumab treatment versus observation, and a fourth
randomized, open-label clinical trial with a total of 3222 patients (BCIRG006).
NSABP B31 and NCCTG N9831
In NSABP B31 and NCCTG N9831, breast tumor specimens were required to show HER2
overexpression (3+ by IHC) or gene amplification (by FISH). HER2 testing was verified by a
central laboratory prior to randomization (NCCTG N9831) or was required to be performed at
a reference laboratory (NSABP B31). Patients with a history of active cardiac disease based
on symptoms, abnormal electrocardiographic, radiologic, or left ventricular ejection fraction
findings or uncontrolled hypertension (diastolic > 100 mm Hg or systolic > 200 mm Hg) were
not eligible.
Patients were randomized (1:1) to receive doxorubicin and cyclophosphamide followed by
paclitaxel (AC→paclitaxel) alone or paclitaxel plus trastuzumab (AC→paclitaxel +
trastuzumab). In both trials, patients received four 21-day cycles of doxorubicin 60 mg/m2 and
cyclophosphamide 600 mg/m2.
Paclitaxel was administered either weekly (80 mg/m2) or every 3 weeks (175 mg/m2) for a
total of 12 weeks in NSABP B31; paclitaxel was administered only by the weekly schedule in
NCCTG N9831. Trastuzumab was administered at 4 mg/kg on the day of initiation of
paclitaxel and then at a dose of 2 mg/kg weekly for a total of 52 weeks. Trastuzumab
treatment was permanently discontinued in patients who developed congestive heart failure,
or persistent/recurrent LVEF decline [see Dosage and Administration (2.5)]. Radiation
therapy, if administered, was initiated after the completion of chemotherapy. Patients with
ER+ and/or PR+ tumors received hormonal therapy. The major efficacy outcome measure of
the combined efficacy analysis was Disease-Free Survival (DFS), defined as the time from
randomization to recurrence, occurrence of contralateral breast cancer, other second primary
cancer, or death. An additional efficacy outcome measure was overall survival (OS).
A total of 3752 patients were included in the joint efficacy analysis of DFS following a
median follow-up of 2.0 years in the AC→paclitaxel + trastuzumab arm. The pre-planned
final OS analysis from the joint analysis included 4063 patients and was performed when
707 deaths had occurred after a median follow-up of 8.3 years in the AC→paclitaxel +
trastuzumab arm. The data from both arms in NSABP B31 and two of the three study arms in
NCCTG N9831 were pooled for efficacy analyses.
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The patients included in the DFS analysis had a median age of 49 years (range: 22–80 years;
6% > 65 years), 84% were white, 7% black, 4% Hispanic, and 4% Asian/Pacific Islander.
Disease characteristics included 90% infiltrating ductal histology, 38% T1, 91% nodal
involvement, 27% intermediate and 66% high grade pathology, and 53% ER+ and/or PR+
tumors.
HERA
In HERA, breast tumor specimens were required to show HER2 overexpression (3+ by IHC)
or gene amplification (by FISH) as determined at a central laboratory. Patients with
node-negative disease were required to have ≥ T1c primary tumor. Patients with a history of
congestive heart failure or LVEF < 55%, uncontrolled arrhythmias, angina requiring
medication, clinically significant valvular heart disease, evidence of transmural infarction on
ECG, poorly controlled hypertension (systolic > 180 mm Hg or diastolic > 100 mm Hg) were
not eligible.
Patients were randomized (1:1:1) upon completion of definitive surgery, and at least four
cycles of chemotherapy to receive no additional treatment, or one year of trastuzumab
treatment or two years of trastuzumab treatment. Patients undergoing a lumpectomy had also
completed standard radiotherapy. Patients with ER+ and/or PgR+ disease received systemic
adjuvant hormonal therapy at investigator discretion. Trastuzumab was administered with an
initial dose of 8 mg/kg followed by subsequent doses of 6 mg/kg once every three weeks. The
major efficacy outcome measure was Disease-Free Survival (DFS), defined as in NSABP B31
and NCCTG N9831.
HERA was designed to compare one and two years of once every three week trastuzumab
treatment versus observation in patients with HER2 positive EBC following surgery,
established chemotherapy and radiotherapy (if applicable). A protocol specified interim
efficacy analysis comparing one-year trastuzumab treatment to observation was performed at
a median follow-up duration of 12.6 months in the trastuzumab arm.
Among the 3386 patients randomized to the observation (n = 1693) and trastuzumab one-year
(n = 1693) treatment arms, the median age was 49 years (range: 21–80), 83% were White, and
13% were Asian. Disease characteristics: 94% infiltrating ductal carcinoma, 50% ER+ and/or
PgR+, 57% node positive, 32% node negative, and in 11% of patients, nodal status was not
assessable due to prior neo-adjuvant chemotherapy. Ninety-six percent (1055/1098) of
patients with node-negative disease had high risk features: among the 1098 patients with
node-negative disease, 49% (543) were ER− and PgR−, and 47% (512) were ER and/or PgR
+ and had at least one of the following high risk features: pathological tumor size greater than
2 cm, Grade 2–3, or age < 35 years. Prior to randomization, 94% of patients had received
anthracycline-based chemotherapy regimens.
After the DFS results comparing observation to one-year trastuzumab treatment were
disclosed, a prospectively planned analysis that included comparison of one year versus two
years of trastuzumab treatment at a median follow-up duration of 8 years was performed.
Based on this analysis, extending trastuzumab treatment for a duration of two years did not
show additional benefit over treatment for one year [Hazard Ratios of two-years trastuzumab
versus one-year trastuzumab treatment in the intent to treat (ITT) population for Disease-Free
Survival (DFS) = 0.99 (95% CI: 0.87, 1.13), p-value = 0.90 and Overall Survival (OS) = 0.98
(0.83, 1.15); p-value = 0.78].
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BCIRG006
In BCIRG006, breast tumor specimens were required to show HER2 gene amplification
(FISH+ only) as determined at a central laboratory. Patients were required to have either
node-positive disease, or node-negative disease with at least one of the following high-risk
features: ER/PR-negative, tumor size > 2 cm, age < 35 years, or histologic and/or nuclear
Grade 2 or 3. Patients with a history of CHF, myocardial infarction, Grade 3 or 4 cardiac
arrhythmia, angina requiring medication, clinically significant valvular heart disease, poorly
controlled hypertension (diastolic > 100 mm Hg), any T4 or N2 or known N3 or M1 breast
cancer were not eligible.
Patients were randomized (1:1:1) to receive doxorubicin and cyclophosphamide followed by
docetaxel (AC-T), doxorubicin and cyclophosphamide followed by docetaxel plus
trastuzumab (AC-TH), or docetaxel and carboplatin plus trastuzumab (TCH). In both the
AC-T and AC-TH arms, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 were
administered every 3 weeks for four cycles; docetaxel 100 mg/m2 was administered every
3 weeks for four cycles. In the TCH arm, docetaxel 75 mg/m2 and carboplatin (at a target
AUC of 6 mg/mL/min as a 30- to 60-minute infusion) were administered every 3 weeks for
six cycles. Trastuzumab was administered weekly (initial dose of 4 mg/kg followed by
weekly dose of 2 mg/kg) concurrently with either T or TC, and then every 3 weeks (6 mg/kg)
as monotherapy for a total of 52 weeks. Radiation therapy, if administered, was initiated after
completion of chemotherapy. Patients with ER+ and/or PR+ tumors received hormonal
therapy. Disease-Free Survival (DFS) was the major efficacy outcome measure.
Among 3222 patients, the median age was 49 (range: 22 to 74 years; 6% ≥ 65 years). Disease
characteristics included 54% ER+ and/or PR+ and 71% node positive. Prior to randomization,
all patients underwent primary surgery for breast cancer.
The results for DFS for the integrated analysis of NSABP B31 and NCCTG N9831, HERA,
and BCIRG006 and OS results for the integrated analysis of NSABP B31 and NCCTG
N9831, and HERA are presented in Table 9. For NSABP B31 and NCCTG N9831, the
duration of DFS following a median follow-up of 2.0 years in the AC→TH arm is presented
in Figure 4, and the duration of OS after a median follow-up of 8.3 years in the AC→TH arm
is presented in Figure 5. The duration of DFS for BCIRG006 is presented in Figure 6. For
NSABP B31 and NCCTG N9831, the OS hazard ratio was 0.64 (95% CI: 0.55, 0.74). At 8.3
years of median follow-up [AC→TH], the survival rate was estimated to be 86.9% in the
AC→TH arm and 79.4% in the AC→T arm. The final OS analysis results from NSABP B31
and NCCTG N9831 indicate that OS benefit by age, hormone receptor status, number of
positive lymph nodes, tumor size and grade, and surgery/radiation therapy was consistent with
the treatment effect in the overall population. In patients ≤ 50 years of age (n = 2197), the OS
hazard ratio was 0.65 (95% CI: 0.52, 0.81) and in patients > 50 years of age (n = 1866), the
OS hazard ratio was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone
receptor-positive disease (ER-positive and/or PR-positive) (n = 2223), the hazard ratio for OS
was 0.63 (95% CI: 0.51, 0.78). In the subgroup of patients with hormone receptor-negative
disease (ER-negative and PR-negative) (n = 1830), the hazard ratio for OS was 0.64 (95% CI:
0.52, 0.80). In the subgroup of patients with tumor size ≤ 2 cm (n = 1604), the hazard ratio for
OS was 0.52 (95% CI: 0.39, 0.71). In the subgroup of patients with tumor size > 2 cm
(n = 2448), the hazard ratio for OS was 0.67 (95% CI: 0.56, 0.80).
31 of 41
Reference ID: 5499161
Table 9. Efficacy Results from Adjuvant Treatment of Breast Cancer
(NSABP B31 and NCCTG N9831, HERA, and BCIRG006)
DFS
events
DFS Hazard
ratio
(95% CI)
p-value
Deaths
(OS events)
OS Hazard ratio
p-value
NSABP B31 and NCCTG N9831a
AC→TH
(n = 1872)b
(n = 2031)c
133b
0.48b,d
(0.39, 0.59)
p ˂ 0.0001e
289c
0.64c,d
(0.55, 0.74)
p ˂ 0.0001e
AC→T
(n = 1880)b
(n = 2032)c
261b
418c
HERAf
Chemo→Trastuzumab
(n = 1693)
127
0.54
(0.44, 0.67)
p ˂ 0.0001g
31
0.75
p = NSh
Chemo→ Observation
(n = 1693)
219
40
BCIRG006i
TCH
(n = 1075)
134
0.67
(0.54 – 0.84)
p = 0.0006e,j
56
AC→TH
(n = 1074)
121
0.60
(0.48 – 0.76)
p < 0.0001e,i
49
AC→T
(n = 1073)
180
80
CI = confidence interval.
a NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or
paclitaxel plus trastuzumab (AC→TH).
b Efficacy evaluable population, for the primary DFS analysis, following a median follow-up of 2.0 years in the AC→TH
arm.
c Efficacy evaluable population, for the final OS analysis, following 707 deaths (8.3 years of median follow-up in the
AC→TH arm).
d Hazard ratio estimated by Cox regression stratified by clinical trial, intended paclitaxel schedule, number of positive nodes,
and hormone receptor status.
e stratified log-rank test.
f At definitive DFS analysis with median duration of follow-up of 12.6 months in the one-year trastuzumab treatment arm.
g log-rank test.
h NS = non-significant.
i BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab
(AC→TH); docetaxel and carboplatin plus trastuzumab (TCH).
j A two-sided alpha level of 0.025 for each comparison.
32 of 41
Reference ID: 5499161
1.0
0.8
a,
~
u...
~
0.6
a,
,1i
C:
.Q
-e
0 a. £
0.4
0.2
0.0
0.0
Number at risk
AC->T
1880
AC->T +H
1872
1.0
0.8
~
~
0.6
6
'E
0 a.
0.4
e
c..
0.2
0.0
I
0
Number at risk
AC->T
2032
AC->T + H
2031
-...... __ - -~---~-----------------------·-----•• 1
••••
I
-
AC-> TH (doxorubicin + cyctophosphamide -> paclitaxel + Trastuzumab)
AC-> T (doxorubicin and cyclophosphamide -> paclitaxel)
0.5
1490
1529
1.0
1.5
2.0
Disease-Free Survival (years)
1159
1240
926
997
=---... ~ ----------
689
764
----------
--- AC-> T (doxorubicln + cyclophosphamlde -> paclltaxeQ
-
- -
• AC ->T + H (doxorubicin and cyclopnosphamide ·> pac1ItaxeI +Trastuzumab)
I
I
I
I
I
I
I
2
3
4
5
6
7
Overall Survival (years)
1961
1883
1806
1732
1643
1538
1377
1992
1957
1897
1843
1787
1714
1533
2.5
534
575
3.0
375
426
------------
I
I
I
8
9
10
979
630
399
1127
787
485
-
3.5
195
239
----
I
11
151
159
Figure 4. Duration of Disease-Free Survival in Patients with Adjuvant Treatment of
Breast Cancer (NSABP B31 and NCCTG N9831)
Figure 5. Overall Survival in Patients with Adjuvant Treatment of Breast Cancer
(NSABP B31 and NCCTG N9831)
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Reference ID: 5499161
1.0
~---..... ._
~
.......... . _. ___ - ··-
--
..... - ... i: •.-..i:-..... ...... __ -...
0.8
0.6
0.4
0.2
----AC->T+H (doxorubicin and cyclophosphamide-> docetaxel +Trastuzumab)
- -TCH (docetaxel + carboplatin + Trastuzumab)
-
AC-> T (doxorubicin and cyclophosphamide -> docetaxel)
0.0
0
2
3
Number at risk
Disease-Free Survival (years)
AC->T
1073
971
802
417
AC->TH
1074
1023
885
457
TCH
1075
1018
877
447
AC=doxorublcln and cydophosphamide; T=docetaxel; TCH=docetaxel, platinum sail. and Trastuzumab; TH=docetaxel and Trastuzumab.
Kaplan-Meier estimates are shown.
4
103
126
126
L-
;
!
5
Figure 6. Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer
(BCIRG006)
Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification
were conducted for patients in NCCTG N9831 and HERA, where central laboratory testing
data were available. The results are shown in Table 10. The number of events in NCCTG
N9831 was small with the exception of the IHC 3+/FISH+ subgroup, which constituted 81%
of those with data. Definitive conclusions cannot be drawn regarding efficacy within other
subgroups due to the small number of events. The number of events in HERA was adequate
to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and the FISH +/IHC
unknown subgroups.
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Table 10. DFS in NCCTG N9831 and HERA for Patients with HER2 Overexpression or
Amplification
HER2 Assay Resultb
NCCTG N9831
Number
Hazard
of
Ratio DFS
Patients
(95% CI)
HERAa
Number
Hazard
of
Ratio DFS
Patients
(95% CI)
IHC 3+
FISH (+)
FISH (−)
FISH Unknown
1170
0.42
(0.27, 0.64)
51
0.71
(0.04, 11.79)
51
0.69
(0.09, 5.14)
91
0.56
(0.13, 2.50)
8
−
2258
0.53
(0.41, 0.69)
IHC < 3+ / FISH (+)
174
1.01
(0.18, 5.65)
299c
0.53
(0.20, 1.42)
IHC unknown / FISH (+)
−
−
724
0.59
(0.38, 0.93)
a Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.
b IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) as performed at a
central laboratory.
c All cases in this category in HERA were IHC 2+.
14.2
Metastatic Breast Cancer
The safety and efficacy of trastuzumab in treatment of women with metastatic breast cancer
were studied in a randomized, controlled clinical trial in combination with chemotherapy
(H0648g, n = 469 patients) and an open-label single agent clinical trial (H0649g, n = 222
patients). Both trials studied patients with metastatic breast cancer whose tumors overexpress
the HER2 protein. Patients were eligible if they had 2 or 3 levels of overexpression (based on
a 0 to 3 scale) by immunohistochemical assessment of tumor tissue performed by a central
testing lab.
Previously Untreated Metastatic Breast Cancer (H0648g)
H0648g was a multicenter, randomized, open-label clinical trial conducted in 469 women
with metastatic breast cancer who had not been previously treated with chemotherapy for
metastatic disease. Tumor specimens were tested by IHC (Clinical Trial Assay, CTA) and
scored as 0, 1+, 2+, or 3+, with 3+ indicating the strongest positivity. Only patients with 2+ or
3+ positive tumors were eligible (about 33% of those screened). Patients were randomized to
receive chemotherapy alone or in combination with trastuzumab given intravenously as a
4 mg/kg loading dose followed by weekly doses of trastuzumab at 2 mg/kg. For those who
had received prior anthracycline therapy in the adjuvant setting, chemotherapy consisted of
paclitaxel (175 mg/m2 over 3 hours every 21 days for at least six cycles); for all other patients,
chemotherapy consisted of anthracycline plus cyclophosphamide (AC: doxorubicin 60 mg/m2
or epirubicin 75 mg/m2 plus 600 mg/m2 cyclophosphamide every 21 days for six cycles).
Sixty-five percent of patients randomized to receive chemotherapy alone in this study
received trastuzumab at the time of disease progression as part of a separate extension study.
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Based upon the determination by an independent Response Evaluation Committee the patients
randomized to trastuzumab and chemotherapy experienced a significantly longer median time
to disease progression (TTP), a higher overall response rate (ORR), and a longer median
duration of response (DoR) as compared with patients randomized to chemotherapy alone.
Patients randomized to trastuzumab and chemotherapy also had a longer median overall
survival (OS) (see Table 11). These treatment effects were observed both in patients who
received trastuzumab plus paclitaxel and in those who received trastuzumab plus AC;
however, the magnitude of the effects was greater in the paclitaxel subgroup.
Table 11. H0648g: Efficacy Results in First-Line Treatment for Metastatic Breast
Cancer
Combined Results
Paclitaxel Subgroup
ACa Subgroup
Trastuzumab +
All
All
Chemotherapy
Chemotherapy
(n = 234)
(n = 235)
Trastuzumab
+
Paclitaxel
Paclitaxel
(n = 96)
(n = 92)
Trastuzumab
ACa
+
(n =
ACa
138)
(n = 143)
Time to Disease Progression (TTP)
Median
7.2
4.5
(months)b,c
95% CI
7, 8
4, 5
p-valued
˂ 0.0001
6.7
2.5
5, 10
2, 4
˂ 0.0001
7.6
5.7
7, 9
5, 7
0.002
Overall Response Rate (ORR)b
Events (n)
45
29
95% CI
39, 51
23, 35
p-valuee
˂ 0.001
38
15
28, 48
8, 22
˂ 0.001
50
38
42, 58
30, 46
0.10
Duration of Response (DoR)
Median
8.3
5.8
(months)b,c
25%, 75%
6, 15
4, 8
Quartile
Overall Survival (OS)
Median
25.1
20.3
(months)c
95% CI
22, 30
17, 24
p-valued
0.05
8.3
4.3
5, 11
4, 7
22.1
18.4
17, 29
13, 24
0.17
8.4
6.4
6, 15
4, 8
26.8
21.4
23, 33
18, 27
0.16
a AC = Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.
b Assessed by an independent Response Evaluation Committee.
c Kaplan-Meier Estimate.
d log-rank test.
e Χ2-test.
Data from H0648g suggest that the beneficial treatment effects were largely limited to
patients with the highest level of HER2 protein overexpression (3+) (see Table 12).
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Table 12. Treatment Effects in H0648g as a Function of HER2 Overexpression or
Amplification
HER2 Assay
Result
Number of
Patients
(N)
Relative Riska for Time
to Disease Progression
(95% CI)
Relative Riska for Mortality
(95% CI)
CTA 2+ or 3+
FISH (+)b
FISH (−)b
CTA 2+
FISH (+)
FISH (−)
CTA 3+
FISH (+)
FISH (−)
469
325
126
120
32
83
349
293
43
0.49 (0.40, 0.61)
0.44 (0.34, 0.57)
0.62 (0.42, 0.94)
0.76 (0.50, 1.15)
0.54 (0.21, 1.35)
0.77 (0.48, 1.25)
0.42 (0.33, 0.54)
0.42 (0.32, 0.55)
0.43 (0.20, 0.94)
0.80 (0.64, 1.00)
0.70 (0.53, 0.91)
1.06 (0.70, 1.63)
1.26 (0.82, 1.94)
1.31 (0.53, 3.27)
1.11 (0.68, 1.82)
0.70 (0.51, 0.90)
0.67 (0.51, 0.89)
0.88 (0.39, 1.98)
a The relative risk represents the risk of progression or death in the trastuzumab plus chemotherapy arm
versus the chemotherapy arm.
b FISH testing results were available for 451 of the 469 patients enrolled on study.
Previously Treated Metastatic Breast Cancer (H0649g)
Trastuzumab was studied as a single agent in a multicenter, open-label, single-arm clinical
trial (H0649g) in patients with HER2-overexpressing metastatic breast cancer who had
relapsed following one or two prior chemotherapy regimens for metastatic disease. Of
222 patients enrolled, 66% had received prior adjuvant chemotherapy, 68% had received two
prior chemotherapy regimens for metastatic disease, and 25% had received prior
myeloablative treatment with hematopoietic rescue. Patients were treated with a loading dose
of 4 mg/kg IV followed by weekly doses of trastuzumab at 2 mg/kg IV.
The ORR (complete response + partial response), as determined by an independent Response
Evaluation Committee, was 14%, with a 2% complete response rate and a 12% partial
response rate. Complete responses were observed only in patients with disease limited to skin
and lymph nodes. The overall response rate in patients whose tumors tested as CTA 3+ was
18% while in those that tested as CTA 2+, it was 6%.
14.3
Metastatic Gastric Cancer
The safety and efficacy of trastuzumab in combination with cisplatin and a fluoropyrimidine
(capecitabine or 5-fluorouracil) were studied in patients previously untreated for metastatic
gastric or gastroesophageal junction adenocarcinoma (ToGA). In this open-label, multi-center
trial, 594 patients were randomized 1:1 to trastuzumab in combination with cisplatin and a
fluoropyrimidine (FC+H) or chemotherapy alone (FC). Randomization was stratified by
extent of disease (metastatic vs. locally advanced), primary site (gastric vs. gastroesophageal
junction), tumor measurability (yes vs. no), ECOG performance status (0,1 vs. 2), and
fluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene
37 of 41
Reference ID: 5499161
amplified (FISH+) or HER2-overexpressing (IHC 3+). Patients were also required to have
adequate cardiac function (e.g. LVEF > 50%).
On the trastuzumab-containing arm, trastuzumab was administered as an IV infusion at an
initial dose of 8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both
study arms cisplatin was administered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles
as a 2 hour IV infusion. On both study arms capecitabine was administered at 1000 mg/m2
dose orally twice daily (total daily dose 2000 mg/m2) for 14 days of each 21 day cycle for
6 cycles. Alternatively, continuous intravenous infusion (CIV) 5-fluorouracil was
administered at a dose of 800 mg/m2/day from Day 1 through Day 5 every three weeks for
6 cycles.
The median age of the study population was 60 years (range: 21-83); 76% were male; 53%
were Asian, 38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS
of 0 or 1; 82% had primary gastric cancer and 18% had primary gastroesophageal
adenocarcinoma. Of these patients, 23% had undergone prior gastrectomy, 7% had received
prior neoadjuvant and/or adjuvant therapy, and 2% had received prior radiotherapy.
The main outcome measure of ToGA was overall survival (OS), analyzed by the unstratified
log-rank test. The final OS analysis based on 351 deaths was statistically significant (nominal
significance level of 0.0193). An updated OS analysis was conducted at one year after the
final analysis. The efficacy results of both the final and the updated analyses are summarized
in Table 13 and Figure 7.
Table 13. Overall Survival in ToGA (ITT Population)
FCa + Trastuzumab
FCa Arm
Arm
N = 296
N = 298
Overall Survival (interim analysis)
N (%)
Median (months)
95% CI
Hazard Ratio
95% CI
p-valueb
167 (56.0%)
184 (62.2%)
13.5
11.0
(11.7, 15.7)
(9.4, 12.5)
0.73
(0.60, 0.91)
0.0038
Overall Survival (updated)
N (%)
Median (months)
95% CI
Hazard Ratio
95% CI
221 (74.2%)
227 (76.7%)
13.1
11.7
(11.9, 15.1)
(10.3, 13.0)
0.80
(0.67, 0.97)
a FC = capecitabine vs. 5-fluorouracil
b Two sided p-value comparing with the nominal significance level of 0.0193.
38 of 41
Reference ID: 5499161
1.0
0.8
:5
:S 0.6
~
e
CL.
1
-~
0.4
::I
Cl)
0.2
0.0
I + Censored I
I 111
11 I-+
•
1
296
207
130
60
34
14
3
2
0
!
2~=29~a.........,_~23=2.........,_~1=5~a ___
a~6........., __
4=a __ ~2~4 __ ~1~1 __ ~ 5 ___ =0-~~
I
I
0
10
20
30
40
50
Duration of Survival (months)
I -- 1: Fluoropyrimidine + Cisplatin -
-
- 2: Fluoropyrimidine + Cisplatin + Trastuzumab I
Figure 7. Updated Overall Survival in Patients with Metastatic Gastric Cancer (ToGA)
An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and
protein overexpression (IHC) testing is summarized in Table 14.
39 of 41
Reference ID: 5499161
Table 14. Exploratory Analyses by HER2 Status Using Updated Overall Survival
Results
FC
(N = 296)a
FC + H
(N = 298)b
FISH+ / IHC 0, 1+ subgroup (N = 133)
No. Deaths / n (%)
Median OS Duration (mos.)
95% CI (mos.)
Hazard ratio (95% CI)
57/71 (80%)
8.8
(6.4, 11.7)
56/62 (90%)
8.3
(6.2, 10.7)
1.33 (0.92, 1.92)
FISH+ / IHC2+ subgroup (N = 160)
No. Deaths / n (%)
Median OS Duration (mos.)
95% CI (mos.)
65/80 (81%)
10.8
(6.8, 12.8)
64/80 (80%)
12.3
(9.5, 15.7)
Hazard ratio (95% CI)
0.78 (0.55, 1.10)
FISH+ or FISH- / IHC 3+c subgroup (N = 294)
No. Deaths / n (%)
Median OS Duration (mos.)
95% CI (mos.)
Hazard ratio (95% CI)
104/143 (73%)
13.2
(11.5, 15.2)
96/151 (64%)
18.0
(15.5, 21.2)
0.66 (0.50, 0.87)
a Two patients on the FC arm who were FISH+ but IHC status unknown were excluded from the exploratory subgroup analyses.
b Five patients on the trastuzumab-containing arm who were FISH+, but IHC status unknown were excluded from the
exploratory subgroup analyses.
c Includes 6 patients on chemotherapy arm, 10 patients on trastuzumab arm with FISH-, IHC 3+ and 8 patients on chemotherapy
arm, 8 patients on trastuzumab arm with FISH status unknown, IHC 3+.
16
HOW SUPPLIED/STORAGE AND HANDLING
420 mg Multiple-dose vial (NDC 55513-132-01)
• KANJINTI (trastuzumab-anns) for injection 420 mg/vial is supplied in a multiple-dose
vial as a preservative-free, white to pale yellow lyophilized sterile powder, under vacuum.
Each carton contains one multiple-dose vial of KANJINTI.
420 mg Multiple-dose vial (kit) (NDC 55513-164-01)
• KANJINTI (trastuzumab-anns) for injection 420 mg/vial is supplied in a multiple-dose
vial as a preservative-free, white to pale yellow lyophilized sterile powder, under vacuum.
Each carton contains one multiple-dose vial of KANJINTI and one vial (20 mL) of
Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a
preservative.
150 mg Single-dose vial (NDC 55513-141-01).
• KANJINTI (trastuzumab-anns) for injection 150 mg/vial is supplied in a single-dose vial
as a preservative-free, white to pale yellow lyophilized sterile powder, under vacuum.
Each carton contains one single-dose vial of KANJINTI.
40 of 41
Reference ID: 5499161
Store KANJINTI vials in the original carton to protect from light in the refrigerator at 2°C to
8°C (36°F to 46°F) until time of reconstitution.
17
PATIENT COUNSELING INFORMATION
Cardiomyopathy
•
Advise patients to contact a healthcare professional immediately for any of the
following: new onset or worsening shortness of breath, cough, swelling of the
ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in
24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy].
Embryo-Fetal Toxicity
•
Advise pregnant women and females of reproductive potential that KANJINTI exposure
during pregnancy or within 7 months prior to conception can result in fetal harm.
Advise female patients to contact their healthcare provider with a known or suspected
pregnancy [see Use in Specific Populations (8.1)].
•
Advise females of reproductive potential to use effective contraception during treatment
and for 7 months following the last dose of KANJINTI [see Use in Specific
Populations (8.3)].
KANJINTI® (trastuzumab-anns)
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
U.S. License No. 1080
Marketed by Amgen Inc.
AMGEN and KANJINTI® (trastuzumab-anns) are trademarks owned or licensed by Amgen
Inc., its subsidiaries, or affiliates.
© 2019, 2022, 2024 Amgen Inc. All rights reserved.
1xxxxxx
vxx
41 of 41
Reference ID: 5499161
| custom-source | 2025-02-12T15:48:07.026633 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761073s010lbl.pdf', 'application_number': 761073, 'submission_type': 'SUPPL ', 'submission_number': 10} |
80,731 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IMBRUVICA safely and effectively. See full prescribing information for
IMBRUVICA.
IMBRUVICA® (ibrutinib) capsules, for oral use
IMBRUVICA® (ibrutinib) tablets, for oral use
IMBRUVICA® (ibrutinib) oral suspension
Initial U.S. Approval: 2013
----------------------------RECENT MAJOR CHANGES--------------------------
Warnings and Precautions, Hepatotoxicity,
Including Drug-Induced Liver Injury (5.7)
5/2024
----------------------------INDICATIONS AND USAGE---------------------------
IMBRUVICA is a kinase inhibitor indicated for the treatment of:
•
Adult patients with chronic lymphocytic leukemia (CLL)/Small
lymphocytic lymphoma (SLL) (1.1).
•
Adult patients with chronic lymphocytic leukemia (CLL)/Small
lymphocytic lymphoma (SLL) with 17p deletion (1.2).
•
Adult patients with Waldenström’s macroglobulinemia (WM) (1.3).
•
Adult and pediatric patients age 1 year and older with chronic graft versus
host disease (cGVHD) after failure of one or more lines of systemic
therapy (1.4).
-----------------------DOSAGE AND ADMINISTRATION-----------------------
•
CLL/SLL and WM: 420 mg taken orally once daily (2.1).
•
cGVHD:
o Patients 12 years and older: 420 mg taken orally once daily (2.1).
o Patients 1 to less than 12 years of age: 240 mg/m2 taken orally once
daily (up to a dose of 420 mg) (2.1).
Tablets or capsules should be taken orally with a glass of water. Do not open,
break, or chew the capsules. Do not cut, crush, or chew the tablets. See full
prescribing information for oral suspension administration instructions (2.1).
----------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsules: 70 mg and 140 mg (3)
Tablets: 140 mg, 280 mg, and 420 mg (3)
Oral suspension: 70 mg/mL (3)
------------------------------CONTRAINDICATIONS------------------------------
None (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
• Hemorrhage: Monitor for bleeding and manage (5.1).
• Infections: Monitor patients for fever and infections, evaluate promptly,
and treat (5.2).
• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Monitor for
symptoms of arrhythmias and cardiac failure and manage (5.3).
• Hypertension: Monitor blood pressure and treat (5.4).
• Cytopenias: Check complete blood counts monthly (5.5).
• Second Primary Malignancies: Other malignancies have occurred in
patients, including skin cancers, and other carcinomas (5.6).
• Hepatotoxicity, Including Drug-Induced Liver Injury: Monitor hepatic
function throughout treatment (5.7).
• Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.
Monitor and treat for TLS (5.8).
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use effective
contraception (5.9, 8.1, 8.3).
------------------------------ADVERSE REACTIONS-------------------------------
• The most common (≥30%) adverse reactions in patients with B-cell
malignancies are thrombocytopenia, diarrhea, fatigue, musculoskeletal
pain, neutropenia, rash, anemia, bruising, and nausea (6).
• The most common (≥20%) adverse reactions in adult or pediatric patients
with cGVHD are fatigue, anemia, bruising, diarrhea, thrombocytopenia,
musculoskeletal pain, pyrexia, muscle spasms, stomatitis, hemorrhage,
nausea, abdominal pain, pneumonia, and headache (6).
To report SUSPECTED ADVERSE REACTIONS, contact
Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS------------------------------
• CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1).
• CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
(7.2).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
• Lactation: Advise not to breastfeed (8.2).
• Hepatic Impairment: Avoid use of IMBRUVICA in patients with severe
hepatic impairment. In patients with mild or moderate impairment, reduce
IMBRUVICA dose (2.4, 8.6).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma
1.2
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma with 17p deletion
1.3
Waldenström’s Macroglobulinemia
1.4
Chronic Graft versus Host Disease
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2
Dosage Modifications for Adverse Reactions
2.3
Dosage Modifications for Use with CYP3A Inhibitors
2.4
Dosage Modifications for Use in Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hemorrhage
5.2
Infections
5.3
Cardiac Arrhythmias, Cardiac Failure, and Sudden
Death
5.4
Hypertension
5.5
Cytopenias
5.6
Second Primary Malignancies
5.7
Hepatotoxicity, Including Drug-Induced Liver Injury
5.8
Tumor Lysis Syndrome
5.9
Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Effect of CYP3A Inhibitors on Ibrutinib
7.2
Effect of CYP3A Inducers on Ibrutinib
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Plasmapheresis
10 OVERDOSAGE
11
DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Chronic Lymphocytic Leukemia / Small Lymphocytic
Lymphoma
14.2
Waldenström’s Macroglobulinemia
14.3
Chronic Graft versus Host Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5500397
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL).
1.2
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
1.3
Waldenström’s Macroglobulinemia
IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
macroglobulinemia (WM).
1.4
Chronic Graft versus Host Disease
IMBRUVICA is indicated for the treatment of adult and pediatric patients age 1 year and older
with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic
therapy.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s
Macroglobulinemia
The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily
until disease progression or unacceptable toxicity.
For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with
rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).
For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider
administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
Chronic Graft versus Host Disease
The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is
420 mg orally once daily, and for patients 1 to less than 12 years of age with cGVHD is 240
mg/m2 orally once daily (up to a dose of 420 mg), until cGVHD progression, recurrence of an
underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for
the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical
assessment of the individual patient.
Reference ID: 5500397
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Table 1: Recommended dosage based on body surface area (BSA) for patients 1 to less than
12 years of age using either IMBRUVICA capsules/tablets or oral suspension
Recommended dose to achieve 240 mg/m2
BSA* (m2)
Range
Dose (mg) of IMBRUVICA
Capsules/Tablets to Administer
Volume (mL) of IMBRUVICA Oral
Suspension (70 mg/mL) to Administer
> 0.3 to 0.4
-
1.2 mL
> 0.4 to 0.5
-
1.5 mL
> 0.5 to 0.6
-
1.9 mL
> 0.6 to 0.7
-
2.2 mL
> 0.7 to 0.8
210 mg
2.6 mL
> 0.8 to 0.9
210 mg
2.9 mL
> 0.9 to 1
210 mg
3.3 mL
> 1 to 1.1
280 mg
3.6 mL
> 1.1 to 1.2
280 mg
4 mL
> 1.2 to 1.3
280 mg
4.3 mL
> 1.3 to 1.4
350 mg
4.6 mL
> 1.4 to 1.5
350 mg
5 mL
> 1.5 to 1.6
350 mg
5.3 mL
> 1.6
420 mg
6 mL
*BSA = body surface area.
Administration
Administer IMBRUVICA at approximately the same time each day.
Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the
capsules. Do not cut, crush, or chew the tablets.
Follow Instructions for Use for further administration details of IMBRUVICA oral suspension.
If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
on the same day with a return to the normal schedule the following day. Do not take extra doses
of IMBRUVICA to make up for the missed dose.
2.2
Dosage Modifications for Adverse Reactions
For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Once the adverse
reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage
modifications (see Table 2).
Reference ID: 5500397
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Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reactiona,b
Occurrence
Dose Modification for
CLL/SLL, WM, and
Patients 12 Years or older
with cGVHD After
Recovery
Starting Dose = 420 mg
Dose Modification for
Patients 1 Year to less than
12 Years with cGVHD
After Recovery
Starting Dose = 240 mg/m2
Grade 2 cardiac failure
First
Restart at 280 mg dailyc
Restart at 160 mg/m2 dailyc
Second
Restart at 140 mg dailyc
Restart at 80 mg/m2 dailyc
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 cardiac arrhythmias
First
Restart at 280 mg dailyc
Restart at 160 mg/m2 dailyc
Second
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 or 4 cardiac failure
Grade 4 cardiac arrhythmias
First
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Other Grade 3 or 4 non-
hematological toxicitiesd
Grade 3 or 4 neutropenia
with infection or fever
Grade 4 hematological
toxicities
First
Restart at 280 mg daily
Restart at 160 mg/m2 dailyc
Second
Restart at 140 mg daily
Restart at 80 mg/m2 dailyc
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
a [see Warnings and Precautions (5)].
b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.
c Evaluate the benefit-risk before resuming treatment.
d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.
Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA
capsules/tablets or oral suspension
Recommended dose to achieve 160 mg/m2
Recommended dose to achieve 80 mg/m2
BSA* (m2)
Range
Dose (mg) of
IMBRUVICA
Capsules/Tablets to
Administer
Volume (mL) of
IMBRUVICA Oral
Suspension (70
mg/mL) to
Administer
Dose (mg) of
IMBRUVICA
Capsules/Tablets to
Administer
Volume (mL) of
IMBRUVICA Oral
Suspension (70
mg/mL) to
Administer
> 0.3 to 0.4
-
0.8 mL
-
0.4 mL
> 0.4 to 0.5
-
1 mL
-
0.5 mL
> 0.5 to 0.6
-
1.3 mL
-
0.6 mL
> 0.6 to 0.7
-
1.5 mL
-
0.7 mL
Reference ID: 5500397
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*BSA = body surface area.
2.3
Dosage Modifications for Use with CYP3A Inhibitors
Recommended dosage modifications are described below [see Drug Interactions (7.1)]:
Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors
Patient Population
Coadministered Drug
Recommended IMBRUVICA Dosage
B-cell Malignancies
•
Moderate CYP3A inhibitor
280 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Voriconazole 200 mg twice daily
•
Posaconazole suspension 100 mg
once daily, 100 mg twice daily, or
200 mg twice daily
140 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Posaconazole suspension 200 mg
three times daily or 400 mg twice
daily
•
Posaconazole intravenously 300 mg
once daily
•
Posaconazole delayed-release tablets
300 mg once daily
70 mg once daily
Interrupt dose as recommended [see
Dosage and Administration (2.2)].
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
Patients 12 years
and older with
cGVHD
• Moderate CYP3A inhibitor
420 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
> 0.7 to 0.8
140 mg
1.7 mL
70 mg
0.9 mL
> 0.8 to 0.9
140 mg
1.9 mL
70 mg
1 mL
> 0.9 to 1
140 mg
2.2 mL
70 mg
1.1 mL
> 1 to 1.1
140 mg
2.4 mL
70 mg
1.2 mL
> 1.1 to 1.2
210 mg
2.6 mL
-
1.3 mL
> 1.2 to 1.3
210 mg
2.9 mL
-
1.4 mL
> 1.3 to 1.4
210 mg
3.1 mL
-
1.5 mL
> 1.4 to 1.5
210 mg
3.3 mL
140 mg
1.7 mL
> 1.5 to 1.6
280 mg
3.5 mL
140 mg
1.8 mL
> 1.6
280 mg
4 mL
140 mg
2 mL
Reference ID: 5500397
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Patient Population
Coadministered Drug
Recommended IMBRUVICA Dosage
•
Voriconazole 200 mg twice daily
•
Posaconazole suspension 100 mg
once daily, 100 mg twice daily, or
200 mg twice daily
280 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Posaconazole suspension 200 mg
three times daily or 400 mg twice
daily
•
Posaconazole intravenously 300 mg
once daily
•
Posaconazole delayed-release tablets
300 mg once daily
140 mg once daily
Interrupt dose as recommended [see
Dosage and Administration (2.2)].
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
Patients 1 year to
less than 12 years of
age with cGVHD
•
Moderate CYP3A inhibitors
240 mg/m2 once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Voriconazole for suspension 9 mg/kg
(maximum dose: 350 mg) twice daily
160 mg/m2 once daily
•
Posaconazole at any dosage
80 mg/m2 once daily
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage
and Administration (2.1), Drug Interactions (7.1)].
2.4
Dosage Modifications for Use in Hepatic Impairment
Adult Patients with B-cell Malignancies
The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-
Pugh class A).
The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-
Pugh class B).
Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C)
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Reference ID: 5500397
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Patients with cGVHD
The recommended dosage is 140 mg daily for patients 12 years of age and older with total
bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to
Gilbert’s syndrome).
The recommended dosage is 80 mg/m2 daily for patients 1 to less than 12 years of age with total
bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of
non-hepatic origin or due to Gilbert’s syndrome) [see Use in Specific Populations (8.6), Clinical
Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Capsules:
Each 70 mg capsule is a yellow, opaque capsule marked with “ibr 70 mg” in black ink.
Each 140 mg capsule is a white, opaque capsule marked with “ibr 140 mg” in black ink.
Tablets:
Each 140 mg tablet is a yellow green to green round tablet debossed with “ibr” on one side and
“140” on the other side.
Each 280 mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on the
other side.
Each 420 mg tablet is a yellow green to green oblong tablet debossed with “ibr” on one side and
“420” on the other side.
Oral Suspension:
70 mg/mL, white to off-white suspension.
4
CONTRAINDICATIONS
None
5
WARNINGS AND PRECAUTIONS
5.1
Hemorrhage
Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage
(≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage
[including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural
hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who
received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and
petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients
who received IMBRUVICA, respectively [see Adverse Reactions (6.1)].
The mechanism for the bleeding events is not well understood.
Reference ID: 5500397
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Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the
risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received
IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The
addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to
4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased
this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy
when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-
surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
5.2
Infections
Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with
IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-
cell malignancies who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1,
6.2)]. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii
pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis
according to standard of care in patients who are at increased risk for opportunistic infections.
Monitor and evaluate patients for fever and infections and treat appropriately.
5.3
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death
Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA.
Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received
IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved
monotherapy or combination regimens. These adverse reactions occurred in patients with and
without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities
may be at greater risk of these events.
Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial
fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was
reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in
patients who received IMBRUVICA in unapproved monotherapy or combination regimens.
These events have occurred particularly in patients with cardiac risk factors including
hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients
with acute infections [see Adverse Reactions (6.1)].
Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias
and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for
patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest
pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and
cardiac failure appropriately, follow dose modification guidelines [see Dosage and
Administration (2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.
Reference ID: 5500397
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5.4
Hypertension
Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received
IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients [see
Adverse Reactions (6.1)]. Based on data from a subset of these patients (N=1,124), the median
time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years
of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98
months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or
greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9%
(year 4-5); the overall incidence for the 5-year period was 11%.
Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive
medication throughout treatment with IMBRUVICA as appropriate, and follow dosage
modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration
(2.2)].
5.5
Cytopenias
In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3
or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3
or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions (6.1)].
Monitor complete blood counts monthly.
5.6
Second Primary Malignancies
Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the
1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials [see
Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma
skin cancer (6%).
5.7
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced
liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors,
including IMBRUVICA.
Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA.
For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for
liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected,
withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA.
5.8
Tumor Lysis Syndrome
Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse
Reactions (6.2)]. Assess the baseline risk (e.g., high tumor burden) and take appropriate
precautions. Monitor patients closely and treat as appropriate.
Reference ID: 5500397
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5.9
Embryo-Fetal Toxicity
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of
organogenesis caused embryo-fetal toxicity including malformations at exposures that were
3-20 times higher than those reported in patients with hematologic malignancies. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.
[see Use in Specific Populations (8.1)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Hemorrhage [see Warnings and Precautions (5.1)]
• Infections [see Warnings and Precautions (5.2)]
• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions
(5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Cytopenias [see Warnings and Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
• Hepatotoxicity, including DILI [see Warnings and Precautions (5.7)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely variable conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
another drug and may not reflect the rates observed in practice.
Unless otherwise specified, the pooled safety population described in the WARNINGS AND
PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered
as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally
once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with
other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In
this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and
68% were exposed for greater than one year. The most common adverse reactions (≥ 30%) were
thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising,
and nausea.
Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received
IMBRUVICA in unapproved monotherapy or combination regimens.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The data described below reflect exposure to IMBRUVICA in one single-arm, open-label
clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE,
Reference ID: 5500397
11
RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total,
including n=1,133 patients exposed to IMBRUVICA). In general, patients with creatinine
clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless
of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or
ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients
with previously treated CLL/SLL. RESONATE included 386 randomized patients with
previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab.
RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65
years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574
randomized patients with previously treated CLL or SLL who received IMBRUVICA in
combination with BR or placebo in combination with BR. iLLUMINATE included 228
randomized patients with treatment naïve CLL/SLL who were 65 years or older or with
coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or
chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously
untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination
with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR).
The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%)
were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia,
bruising, and nausea.
Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment
due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia,
arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in
approximately 9% of patients.
Study 1102
Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent
IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of
≥ 10% with a median duration of treatment of 15.6 months are presented in Table 5 and Table 6.
Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
CLL/SLL (N=51) in Study 1102
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
Constipation
Nausea
Stomatitis
Vomiting
Abdominal pain
Dyspepsia
59
22
20
20
18
14
12
4
2
2
0
2
0
0
Skin and subcutaneous
Bruising
51
2
Reference ID: 5500397
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†One patient death due to histiocytic sarcoma.
Table 6: Treatment-Emergent* Hematologic Laboratory Abnormalities
in Patients with CLL/SLL (N=51) in Study 1102
Percent of Patients (N=51)
All Grades (%)
Grade 3 or 4 (%)
Platelets decreased
69
12
Neutrophils decreased
53
26
Hemoglobin decreased
43
0
* Based on laboratory measurements per IWCLL criteria and adverse reactions.
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.
tissue disorders
Rash
Petechiae
25
16
0
0
Infections and infestations
Upper respiratory tract infection
Sinusitis
Skin infection
Pneumonia
Urinary tract infection
47
22
16
12
12
2
6
6
10
2
General disorders and
administration site
conditions
Fatigue
Pyrexia
Peripheral edema
Asthenia
Chills
33
24
22
14
12
6
2
0
6
0
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain
Arthralgia
Muscle spasms
25
24
18
6
0
2
Respiratory, thoracic and
mediastinal disorders
Cough
Oropharyngeal pain
Dyspnea
22
14
12
0
0
0
Nervous system disorders
Dizziness
Headache
20
18
0
2
Vascular disorders
Hypertension
16
8
Metabolism and nutrition
disorders
Decreased appetite
16
2
Neoplasms benign,
malignant, unspecified
Second malignancies
10
2†
Reference ID: 5500397
13
RESONATE
Adverse reactions and laboratory abnormalities described below in Table 7 and Table 8 reflect
exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.
Table 7: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
Arm in Patients with CLL/SLL in RESONATE
Body System
Adverse Reaction
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
48
4
18
2
Nausea
26
2
18
0
Stomatitis*
17
1
6
1
Constipation
15
0
9
0
Vomiting
14
0
6
1
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
28
2
18
1
Arthralgia
17
1
7
0
Muscle spasms
13
0
8
0
Skin and subcutaneous tissue
disorders
Rash*
24
3
13
0
Petechiae
14
0
1
0
Bruising*
12
0
1
0
General disorders and
administration site conditions
Pyrexia
24
2
15
2†
Respiratory, thoracic and
mediastinal disorders
Cough
19
0
23
1
Dyspnea
12
2
10
1
Infections and infestations
Upper respiratory tract
infection
16
1
11
2†
Pneumonia*
15
12†
13
10†
Sinusitis*
11
1
6
0
Urinary tract infection
10
4
5
1
Reference ID: 5500397
14
Body System
Adverse Reaction
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Nervous system disorders
Headache
14
1
6
0
Dizziness
11
0
5
0
Injury, poisoning and
procedural complications
Contusion
11
0
3
0
Eye disorders
Vision blurred
10
0
3
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a
fatal outcome in the ofatumumab arm.
Table 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients
with CLL/SLL in RESONATE
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Neutrophils decreased
51
23
57
26
Platelets decreased
52
5
45
10
Hemoglobin decreased
36
0
21
0
Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia
(8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.
RESONATE-2
Adverse reactions and laboratory abnormalities described below in Table 9 and Table 10 reflect
exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to
chlorambucil was 7.1 months in RESONATE-2.
Table 9: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
Arm in Patients with CLL/SLL in RESONATE-2
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
42
4
17
0
Nausea
22
1
39
1
Reference ID: 5500397
15
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Constipation
16
1
16
0
Stomatitis*
14
1
4
1
Vomiting
13
0
20
1
Abdominal pain
13
3
11
1
Dyspepsia
11
0
2
0
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
36
4
20
0
Arthralgia
16
1
7
1
Muscle spasms
11
0
5
0
General disorders and
administration site conditions
Fatigue
30
1
38
5
Peripheral edema
19
1
9
0
Pyrexia
17
0
14
2
Respiratory, thoracic and
mediastinal disorders
Cough
22
0
15
0
Dyspnea
10
1
10
0
Skin and subcutaneous tissue
disorders
Rash*
21
4
12
2
Bruising*
19
0
7
0
Eye disorders
Dry eye
17
0
5
0
Lacrimation increased
13
0
6
0
Vision blurred
13
0
8
0
Visual acuity reduced
11
0
2
0
Infections and infestations
Upper respiratory tract
infection
17
2
17
2
Skin infection*
15
2
3
1
Pneumonia*
14
8
7
4
Urinary tract infections
10
1
8
1
Vascular disorders
Hypertension*
14
4
1
0
Nervous system disorders
Headache
12
1
10
2
Dizziness
11
0
12
1
Reference ID: 5500397
16
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Investigations
Weight decreased
10
0
12
0
Subjects with multiple events for a given ADR term are counted once only for each ADR term.
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with
CLL/SLL in RESONATE-2
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Neutrophils Decreased
55
28
67
31
Platelets Decreased
47
7
58
14
Hemoglobin Decreased
36
0
39
2
Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm vs 3% in the chlorambucil arm) and neutropenia
(11% in the IMBRUVICA arm vs 12% in the chlorambucil arm) occurred in patients.
HELIOS
Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + BR with a
median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in
HELIOS in patients with previously treated CLL/SLL.
Reference ID: 5500397
17
Table 11: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the
IMBRUVICA Arm in Patients with CLL/SLL in HELIOS
Body System
Adverse Reaction
IMBRUVICA + BR
(N=287)
Placebo + BR
(N=287)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Blood and lymphatic
system disorders
Neutropenia*
66
61
60
56†
Thrombocytopenia*
34
16
26
16
Gastrointestinal disorders
Diarrhea
36
2
23
1
Abdominal pain
12
1
8
<1
Skin and subcutaneous
tissue disorders
Rash*
32
4
25
1
Bruising *
20
<1
8
<1
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
29
2
20
0
Muscle spasms
12
<1
5
0
General disorders and
administration site
conditions
Pyrexia
25
4
22
2
Vascular disorders
Hemorrhage*
19
2†
9
1
Hypertension*
11
5
5
2
Infections and infestations
Bronchitis
13
2
10
3
Skin infection*
10
3
6
2
Metabolism and nutrition
disorders
Hyperuricemia
10
2
6
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
<1 used for frequency above 0 and below 0.5%.
† Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in
the placebo + BR arm.
Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and
2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was
3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR.
Reference ID: 5500397
18
iLLUMINATE
Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA +
obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil +
obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously
untreated CLL/SLL.
Table 12: Adverse Reactions Reported in ≥ 10% of Patients
in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATE
Body System
Adverse Reaction
IMBRUVICA +
Obinutuzumab
(N=113)
Chlorambucil +
Obinutuzumab
(N=115)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Blood and lymphatic system
disorders
Neutropenia*
48
39
64
48
Thrombocytopenia*
36
19
28
11
Anemia
17
4
25
8
Skin and subcutaneous tissue
disorders
Rash*
36
3
11
0
Bruising*
32
3
3
0
Gastrointestinal disorders
Diarrhea
34
3
10
0
Constipation
16
0
12
1
Nausea
12
0
30
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
33
1
23
3
Arthralgia
22
1
10
0
Muscle spasms
13
0
6
0
Respiratory, thoracic and
mediastinal disorders
Cough
27
1
12
0
Injury, poisoning and
procedural complications
Infusion related reaction
25
2
58
8
Vascular disorders
Hemorrhage*
25
1
9
0
Hypertension*
17
4
4
3
Reference ID: 5500397
19
Body System
Adverse Reaction
IMBRUVICA +
Obinutuzumab
(N=113)
Chlorambucil +
Obinutuzumab
(N=115)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
General disorders and
administration site conditions
Pyrexia
19
2
26
1
Fatigue
18
0
17
2
Peripheral edema
12
0
7
0
Infections and infestations
Pneumonia*
16
9
9
4†
Upper respiratory tract
infection
14
1
6
0
Skin infection*
13
1
3
0
Urinary tract infection
12
3
7
1
Nasopharyngitis
12
0
3
0
Conjunctivitis
11
0
2
0
Metabolism and nutrition
disorders
Hyperuricemia
13
1
0
0
Cardiac disorders
Atrial fibrillation
12
5
0
0
Psychiatric disorders
Insomnia
12
0
4
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
† Includes one event with a fatal outcome.
E1912
Adverse reactions described below in Table 13 reflect exposure to IMBRUVICA + rituximab
with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in
E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.
Reference ID: 5500397
20
Table 13: Adverse Reactions Reported in ≥ 15% of Patients
in the IMBRUVICA Arm in Patients with CLL/SLL in E1912
Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
General disorders and
administration site conditions
Fatigue
80
2
78
3
Peripheral edema
28
1
17
0
Pyrexia
27
1
27
1
Pain
23
2
8
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
61
5
35
2
Arthralgia
41
5
10
1
Gastrointestinal disorders
Diarrhea
53
4
27
1
Nausea
40
1
64
1
Stomatitis*
22
1
8
1
Abdominal pain*
19
2
10
1
Vomiting
18
2
28
0
Constipation
17
0
32
0
Skin and subcutaneous tissue
disorders
Rash*
49
4
29
5
Bruising*
36
1
4
1
Vascular disorders
Hypertension*
42
19
22
6
Hemorrhage*
31
2
8
1
Nervous system disorders
Headache
40
1
27
1
Dizziness
21
1
13
1
Peripheral neuropathy*
19
1
13
1
Respiratory, thoracic and
mediastinal disorders
Cough
32
0
25
0
Dyspnea
22
2
21
1
Reference ID: 5500397
21
Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Infections and infestations
Upper respiratory tract
infection
29
1
19
2
Skin infection*
16
1
3
1
Metabolism and nutrition
disorders
Hyperuricemia
19
1
4
0
Decreased appetite
15
0
20
1
Psychiatric disorders
Insomnia
16
1
19
1
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
Table 14: Select Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from
Baseline in Patients Receiving IMBRUVICA (E1912)
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Hematology abnormalities
Neutrophils decreased
Platelets decreased
Hemoglobin decreased
53
43
26
30
7
0
70
69
51
44
25
2
Chemistry abnormalities
Creatinine increased
Bilirubin increased
AST increased
38
30
25
1
2
3
17
15
23
1
0
<1
Based on laboratory measurements per IWCLL criteria.
Waldenström’s Macroglobulinemia
The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials
(Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial
(INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA. Study 1118
included 63 patients with previously treated WM who received single agent IMBRUVICA.
INNOVATE included 150 patients with treatment naïve or previously treated WM who received
IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm
Reference ID: 5500397
22
included 31 patients with previously treated WM who received IMBRUVICA after failure of
prior rituximab-containing therapy.
The most common adverse reactions in Studies 1118 and INNOVATE (≥ 20%) were
neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and
nausea.
Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE
discontinued treatment due to adverse reactions. The most common adverse reaction leading to
discontinuation was atrial fibrillation. Adverse reactions leading to dose reduction occurred in
14% of patients.
Study 1118 and INNOVATE Monotherapy Arm
Adverse reactions and laboratory abnormalities described below in Table 15 and Table 16 reflect
exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 and 33 months
in the INNOVATE Monotherapy Arm.
Table 15: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM
in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
Nausea
Stomatitis*
Constipation
Gastroesophageal reflux disease
38
21
15
12
12
2
0
0
1
0
Skin and subcutaneous tissue
disorders
Bruising*
Rash*
28
21
1
1
Vascular disorders
Hemorrhage*
Hypertension*
28
14
0
4
General disorders and
administrative site conditions
Fatigue
Pyrexia
18
12
2
2
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
Muscle spasms
21
19
0
0
Infections and infestations
Upper respiratory tract infection
Skin infection*
Sinusitis*
Pneumonia*
19
18
16
13
0
3
0
5
Nervous system disorders
Headache
Dizziness
14
13
0
0
Respiratory, thoracic and
mediastinal disorders
Cough
13
0
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Reference ID: 5500397
23
Table 16: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Percent of Patients (N=94)
All Grades (%)
Grade 3 or 4 (%)
Platelets Decreased
38
11
Neutrophils Decreased
43
16
Hemoglobin Decreased
21
6
Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients.
INNOVATE
Adverse reactions described below in Table 17 reflect exposure to IMBRUVICA + R with a
median duration of 25.8 months and exposure to placebo + R with a median duration of
15.5 months in patients with treatment naïve or previously treated WM in INNOVATE.
Table 17: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the
IMBRUVICA Arm in Patients with WM in INNOVATE
Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades
(%)
Grade 3 or
Higher
(%)
All Grades
(%)
Grade 3 or
Higher
(%)
Skin and subcutaneous tissue
disorders
Bruising*
37
1
5
0
Rash*
24
1
11
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
35
4
21
3
Arthralgia
24
3
11
1
Muscle spasms
17
0
12
1
Vascular disorders
Hemorrhage*
32
3
17
4†
Hypertension*
20
13
5
4
Gastrointestinal disorders
Diarrhea
28
0
15
1
Nausea
21
0
12
0
Dyspepsia
16
0
1
0
Constipation
13
1
11
1
Infections and infestations
Pneumonia*
19
13
5
3
Reference ID: 5500397
24
Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades
(%)
Grade 3 or
Higher
(%)
All Grades
(%)
Grade 3 or
Higher
(%)
Skin infection*
17
3
3
0
Urinary tract infection
13
0
0
0
Bronchitis
12
3
7
0
Influenza
12
0
7
1
Viral upper respiratory tract
infection
11
0
7
0
General disorders and
administration site conditions
Peripheral edema
17
0
12
1
Respiratory, thoracic, and
mediastinal disorders
Cough
17
0
11
0
Blood and lymphatic system
disorders
Neutropenia*
16
12
11
4
Cardiac disorders
Atrial fibrillation
15
12
3
1
Nervous system disorders
Dizziness
11
0
7
0
Psychiatric disorders
Insomnia
11
0
4
0
Metabolism and nutrition
disorders
Hypokalemia
11
0
1
1
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes one event with a fatal outcome.
Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR.
Chronic Graft versus Host Disease
Study 1129
The data described below reflect exposure to IMBRUVICA in an open-label clinical trial
(Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid
therapy and required additional therapy [see Clinical Studies (14.3)].
Reference ID: 5500397
25
The most common adverse reactions in Study 1129 (≥ 20%) were fatigue, bruising, diarrhea,
thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia.
Atrial fibrillation occurred in one patient (2%) which was Grade 3.
Twenty-four percent of patients receiving IMBRUVICA in Study 1129 discontinued treatment
due to adverse reactions. The most common adverse reactions leading to discontinuation were
fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.
Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect
exposure to IMBRUVICA with a median duration of 4.4 months in Study 1129.
Table 18: Non-Hematologic Adverse Reactions in ≥ 10% of Adult Patients with cGVHD in
Study 1129 (N=42)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher
(%)
General disorders and
administration site
conditions
Fatigue
Pyrexia
Edema peripheral
57
17
12
12
5
0
Skin and subcutaneous tissue
disorders
Bruising*
Rash*
40
12
0
0
Gastrointestinal disorders
Diarrhea
Stomatitis*
Nausea
Constipation
36
29
26
12
10
2
0
0
Musculoskeletal and
connective tissue disorders
Muscle spasms
Musculoskeletal pain*
29
14
2
5
Vascular disorders
Hemorrhage*
26
0
Infections and infestations
Pneumonia*
Upper respiratory tract infection
Sepsis*
21
19
10
14†
0
10
Nervous system disorders
Headache
17
5
Injury, poisoning and
procedural complications
Fall
17
0
Respiratory, thoracic and
mediastinal disorders
Cough
Dyspnea
14
12
0
2
Metabolism and nutrition
disorders
Hypokalemia
12
7
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes 2 events with a fatal outcome.
Reference ID: 5500397
26
Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities
in Adult Patients with cGVHD in Study 1129 (N=42)
Percent of Patients (N=42)
All Grades (%)
Grade 3 or 4 (%)
Platelets decreased
33
0
Neutrophils decreased
10
10
Hemoglobin decreased
24
2
Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.
iMAGINE
The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric
and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or
more lines of systemic therapy. Patients age 12 years and older were treated with IMBRUVICA
420 mg orally once daily, and patients age 1 year to less than 12 years were treated with
IMBRUVICA 240 mg/m2 orally once daily [see Clinical Studies (14.3)]. The median duration of
exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months).
Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious
adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis.
Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis
and acute respiratory distress syndrome (ARDS).
Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of
patients. Adverse reactions which resulted in permanent discontinuation in at least two patients
included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in
19% of patients. Adverse reactions which required dose reduction in at least two patients
included stomatitis.
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia,
musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis,
thrombocytopenia, and headache.
Table 20 summarizes the adverse reactions in iMAGINE.
Table 20: Adverse Reactions (≥ 10%) in Patients with Previously Treated cGVHD Who
Received IMBRUVICA in iMAGINE
Body System
Adverse Reaction
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
General disorders and administration site conditions
Pyrexia
30
11
Reference ID: 5500397
27
Body System
Adverse Reaction
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*
30
2
Osteonecrosis
11
9
Gastrointestinal disorders
Diarrhea
28
2
Abdominal pain*
23
4
Stomatitis*
23
9
Vomiting
19
2
Nausea
19
4
Infections and infestations
Pneumonia*
23
13
Skin infection*
17
4
Sepsis*
11
9†
Nervous system disorders
Headache
21
2
Skin and subcutaneous tissue disorders
Rash*
19
2
Pruritus
13
0
Petechiae
13
0
Respiratory, thoracic and mediastinal disorders
Cough
19
2
Vascular disorders
Hemorrhage*
17
0
Hypertension*
11
4
Blood and lymphatic system disorders
Hypokalemia
15
6
Hypogammaglobulinemia*
11
0
Cardiac Disorders
Sinus tachycardia
11
0
Investigations
Alanine aminotransferase increased
11
2
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes 1 fatal outcome.
Table 21 summarizes the laboratory abnormalities in iMAGINE.
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Table 21: Select Hematologic Laboratory Abnormalities (≥ 10%) That Worsened from
Baseline in Patients with Previously Treated cGVHD Who Received
IMBRUVICA in iMAGINE
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
Hemoglobin decreased
49
13
Platelets decreased
21
4
Neutrophils decreased
13
6
Treatment-emergent Grade 4 neutropenia occurred in 3% of patients.
Additional Important Adverse Reactions
Cardiovascular Events
Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA
(n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with
IMBRUVICA and 5.3 months for 958 patients in the control arm). The incidence of ventricular
tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation,
ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade
3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in
the control arm. The incidence of atrial fibrillation and atrial flutter of any grade was 8.4%
versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with
IMBRUVICA compared to patients in the control arm. In addition, the incidence of cardiac
failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater was 1.2% versus 0.3% in
patients treated with IMBRUVICA compared to patients in the control arm.
The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke,
cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3
or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in
the control arm, respectively.
Diarrhea
In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for
1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm),
diarrhea of any grade occurred at a rate of 43% of patients treated with IMBRUVICA compared
to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of
IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%)
of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.
Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0
to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414)
versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients
compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus
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89% had complete resolution, and 15% versus 11% had not reported resolution at time of
analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median
time from onset to resolution in IMBRUVICA-treated subjects was 7 days (range, 1 to 655)
versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days
(range, 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the control
arm, respectively.
Visual Disturbance
In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for
1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm),
blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with
IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control
arm (5% Grade 1 and < 1% Grade 2 and 3).
Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0
to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-treated patients compared to the
control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had
complete resolution and 40% versus 29% had not reported resolution at the time of analysis in
IMBRUVICA-treated patients compared to the control arm, respectively. The median time from
onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in
IMBRUVICA-treated subjects compared to the control arm, respectively.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of IMBRUVICA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
• Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic
cirrhosis, drug-induced liver injury
• Respiratory disorders: interstitial lung disease
• Metabolic and nutrition disorders: tumor lysis syndrome
• Immune system disorders: anaphylactic shock, angioedema, urticaria
• Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis,
panniculitis, neutrophilic dermatoses, cutaneous vasculitis
• Infections: hepatitis B reactivation
• Nervous system disorders: peripheral neuropathy
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7
DRUG INTERACTIONS
7.1
Effect of CYP3A Inhibitors on Ibrutinib
The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase
ibrutinib plasma concentrations [see Clinical Pharmacology (12.3)]. Increased ibrutinib
concentrations may increase the risk of drug-related toxicity.
Dose modifications of IMBRUVICA are recommended when used concomitantly with
posaconazole, voriconazole and moderate CYP3A inhibitors [see Dosage and Administration
(2.3)].
Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these
inhibitors will be used short-term (such as anti-infectives for seven days or less) [see Dosage and
Administration (2.3)].
Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or
moderate inhibitors of CYP3A.
7.2
Effect of CYP3A Inducers on Ibrutinib
The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib
concentrations. Avoid coadministration with strong CYP3A inducers [see Clinical Pharmacology
(12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
IMBRUVICA can cause fetal harm based on findings from animal studies. There are no
available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major
birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to
pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the
clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities
(see Data). Advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of
10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral
malformations (heart and major vessels) and increased resorptions and post-implantation loss.
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The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with
CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or
greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is
approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at
doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated
with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated
with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is
approximately 2.8 times the exposure in patients with CLL/SLL or WM administered a dose of
420 mg daily.
8.2
Lactation
Risk Summary
There is no information regarding the presence of ibrutinib or its metabolites in human milk, the
effects on the breastfed child, or the effects on milk production. Because of the potential for
serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment
with IMBRUVICA and for 1 week after the last dose.
8.3
Females and Males of Reproductive Potential
IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with
IMBRUVICA and for 1 month after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during
treatment with IMBRUVICA and for 1 month following the last dose.
8.4
Pediatric Use
Chronic GVHD
The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD
after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older.
Use of IMBRUVICA for this indication is supported by evidence from iMAGINE, a study which
included pediatric patients age 1 year and older with previously treated cGVHD, including
patients in the following age groups: one patient 1 year to less than 2 years of age, 20 patients 2
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years to less than 12 years of age, and 19 patients 12 years to less than 17 years of age.
Additional supportive efficacy data was provided from Study 1129 in adults [see Adverse
Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].
The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that
in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based
on body-surface area (BSA) [see Dosage and Administration (2.1)].
The safety and effectiveness of IMBRUVICA have not been established for this indication in
pediatric patients less than 1 year of age.
Mature B-cell Non-Hodgkin Lymphoma
The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were
assessed but have not been established based on an open-label, randomized study
(NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years,
with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for
futility. In the randomized population, major hemorrhage and discontinuation of
chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus
chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.
CLL/SLL, CLL/SLL with 17p deletion, WM
The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in
CLL/SLL, CLL/SLL with 17p deletion, or WM.
8.5
Geriatric Use
Of 992 patients in clinical studies of IMBRUVICA for B-cell malignancies or cGVHD, 62%
were ≥ 65 years of age, while 22% were ≥ 75 years of age [see Clinical Studies (14.1, 14.2,
14.3)]. No overall differences in effectiveness were observed between younger and older
patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension,
and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA
[see Adverse Reactions (6.1)].
8.6
Hepatic Impairment
Adult Patients with B-cell Malignancies
Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C). The
safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic
impairment by Child-Pugh criteria.
Reduce the recommended dose when administering IMBRUVICA to patients with mild or
moderate hepatic impairment (Child-Pugh class A and B). Monitor patients more frequently for
adverse reactions of IMBRUVICA [see Dosage and Administration (2.4), Clinical
Pharmacology (12.3)].
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Patients with cGVHD
Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x ULN (unless of non-
hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering
IMBRUVICA to patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin
or due to Gilbert’s syndrome) [see Dosage and Administration (2.4)].
8.7
Plasmapheresis
Management of hyperviscosity in WM patients may include plasmapheresis before and during
treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
10 OVERDOSAGE
There is no specific experience in the management of ibrutinib overdose in patients. One healthy
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of
1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide
appropriate supportive treatment.
11 DESCRIPTION
Ibrutinib is a kinase inhibitor. It is a white to off-white solid with the empirical formula
C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide,
soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-
[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-
propen-1-one and has the following structure:
IMBRUVICA (ibrutinib) is available as immediate-release oral capsules, immediate-release oral
tablets, and immediate-release oral suspension.
IMBRUVICA (ibrutinib) capsules for oral use are available in the following dosage strengths: 70
mg and 140 mg. Each capsule contains ibrutinib (active ingredient) and the following inactive
ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium
lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg
capsule only), and black ink.
N
N
N
N
NH2
(R)
O
N
O
-0
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IMBRUVICA (ibrutinib) tablets for oral use are available in the following dosage strengths: 140
mg, 280 mg, and 420 mg. Each tablet contains ibrutinib (active ingredient) and the following
inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film
coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets),
polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets), talc, titanium dioxide,
and yellow iron oxide (140 mg and 420 mg tablets).
IMBRUVICA (ibrutinib) oral suspension contains 70 mg/mL ibrutinib (active ingredient) and
the following inactive ingredients: benzyl alcohol, citric acid monohydrate, disodium hydrogen
phosphate, hypromellose, microcrystalline cellulose and carboxymethylcellulose sodium,
purified water and sucralose.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a
covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK
enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and
cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results
in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical
studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as
cell migration and substrate adhesion in vitro.
12.2
Pharmacodynamics
In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in
peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of
≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).
In adult patients with cGVHD, 93% occupancy of the BTK active site in peripheral blood
mononuclear cells was observed at the ibrutinib recommended dose. The mean BTK occupancy
in pediatric patients ranged from 95.1% to 99.6%.
In vitro Platelet Aggregation
Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at
4.6 µM (2026 ng/mL), 0.8 µM (352 ng/mL), and 3 µM (1321 ng/mL) in blood samples from
healthy donors, donors taking warfarin, and donors with severe renal dysfunction,
respectively. Ibrutinib did not show meaningful inhibition of platelet aggregation for ADP,
arachidonic acid, ristocetin, and TRAP-6.
Cardiac Electrophysiology
At a single dose 4 times the maximum recommended dose (1680 mg), IMBRUVICA did not
prolong the QT interval to any clinically relevant extent.
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12.3
Pharmacokinetics
Ibrutinib exposure increases with doses up to 840 mg (2 times the maximum approved
recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC
(% coefficient of variation) observed in patients at 420 mg with CLL/SLL is
708 (71%) ng×h/mL, with WM is 707 (72%) ng×h/mL, and in adult patients with previously
treated cGVHD is 1159 (50%) ng×h/mL. Steady-state concentrations of ibrutinib without
CYP3A inhibitors were achieved with an accumulation ratio of 1 to 1.6 after 1 week of multiple
daily doses of 420 mg.
Absorption
Absolute bioavailability of ibrutinib in fasted condition was 2.9% (90% CI: 2.1, 3.9) in healthy
subjects. Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 2 hours.
Effect of Food
The administration of IMBRUVICA with a high-fat and high-calorie meal (800 calories to
1,000 calories with approximately 50% of total caloric content of the meal from fat) increased
ibrutinib Cmax by 2- to 4-fold and AUC by approximately 2-fold, compared with administration
of ibrutinib after overnight fasting.
In vitro studies suggest that ibrutinib is not a substrate of p-glycoprotein (P-gp) or breast cancer
resistance protein (BCRP).
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no
concentration dependence in the range of 50 ng/mL to 1000 ng/mL. The volume of distribution
(Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was
approximately 10,000 L.
Elimination
Intravenous clearance was 62 L/h in fasted conditions and 76 L/h in fed conditions. In line with
the high first-pass effect, the apparent oral clearance is 2000 L/h in fasted conditions and
1000 L/h in fed conditions. The half-life of ibrutinib is 4 hours to 6 hours.
Metabolism
Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites
primarily by cytochrome P450 (CYP) 3A and to a minor extent by CYP2D6. The active
metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK
approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent
ratio for PCI-45227 at steady-state is 1 to 2.8.
Excretion
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral
administration of radiolabeled ibrutinib, 90% of radioactivity was excreted within 168 hours,
Reference ID: 5500397
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with 80% excreted in the feces and less than 10% eliminated in urine. Unchanged ibrutinib
accounted for 1% of the radiolabeled excreted dose in feces and none in urine, with the
remainder of the excreted dose being metabolites.
Specific Populations
Age and Sex
Age and sex have no clinically meaningful effect on ibrutinib pharmacokinetics.
Patients with Renal Impairment
Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by
Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. No data is available in
patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.
Patients with Hepatic Impairment
The AUC of ibrutinib increased 2.7-fold in subjects with mild hepatic impairment (Child-Pugh
class A), 8.2-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and
9.8-fold in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with
normal liver function. The Cmax of ibrutinib increased 5.2-fold in mild hepatic impairment,
8.8-fold in moderate hepatic impairment and 7-fold in severe hepatic impairment relative to
subjects with normal liver function [see Use in Specific Populations (8.6)].
Pediatric Patients
In pediatric patients with cGVHD treated with ibrutinib at 240 mg/m2 once daily (patients age
≥ 1 to < 12 years) or 420 mg once daily (patients age ≥ 12 years), the geometric mean (%CV)
steady state AUC and Cmax in patients age ≥ 1 to < 12 years is 467 (102%) ng×h/mL and 65.7
(96%) ng/mL, respectively, and in patients age ≥ 12 to < 17 years is 966 (78%) ng×h/mL and
149 (79%) ng/mL, respectively.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole
(strong CYP3A inhibitor) increased the Cmax of ibrutinib by 29-fold and AUC by 24-fold. The
coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady
state Cmax of ibrutinib by 6.7-fold and AUC by 5.7-fold. Simulations under fed conditions
suggest that posaconazole (strong CYP3A inhibitor) may increase the AUC of ibrutinib 3-fold to
10-fold.
The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased
steady state Cmax of ibrutinib by 3.4-fold and AUC by 3-fold.
Effect of CYP3A Inducers on Ibrutinib: The coadministration of rifampin (strong CYP3A
inducer) decreased the Cmax of ibrutinib by more than 13-fold and AUC by more than 10-fold.
Reference ID: 5500397
37
Simulations suggest that efavirenz (moderate CYP3A inducer) may decrease the AUC of
ibrutinib by 3-fold.
In Vitro Studies
Effect of Ibrutinib on CYP Substrates: In vitro studies suggest that ibrutinib and PCI-45227 are
unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib
and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses.
Effect of Ibrutinib on Substrates of Transporters: In vitro studies suggest that ibrutinib may
inhibit BCRP and P-gp transport at clinical doses. The coadministration of oral P-gp or BCRP
substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ibrutinib was not carcinogenic in a 6-month rasH2 mouse study at oral doses up to
2000 mg/kg/day resulting in exposures approximately 32 (males) to 52 (females) times higher
than the exposure in humans at a dose of 420 mg daily [see Warnings and Precautions (5.6)].
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during
pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female
rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats
continued until end of study. No effects on fertility or reproductive capacities were observed in
male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose
[HED] 16 mg/kg).
14 CLINICAL STUDIES
14.1
Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma
The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one
uncontrolled trial and five randomized, controlled trials.
Study 1102
Study 1102 (NCT01105247), an open-label, multi-center trial, was conducted in 48 previously
treated CLL patients. IMBRUVICA was administered orally at 420 mg once daily until disease
progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version
of the International Workshop on CLL Criteria by an Independent Review Committee.
The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At
baseline, 46% of subjects had at least one tumor ≥ 5 cm.
Reference ID: 5500397
38
The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients
achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR
was not reached.
RESONATE
The RESONATE study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA
versus ofatumumab (NCT01578707), was conducted in patients with previously treated CLL or
SLL. Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until
disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg,
followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4
additional doses. Fifty-seven patients randomized to ofatumumab crossed over following
progression to receive IMBRUVICA.
The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were White. All
patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with
CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median
number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at
least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.
Efficacy results for RESONATE are shown in Table 22 and the Kaplan-Meier curves for PFS,
assessed by an IRC according to IWCLL criteria, and OS are shown in Figure 1 and Figure 2,
respectively.
Table 22: Efficacy Results in Patients with CLL/SLL in RESONATE
Endpoint
IMBRUVICA
N=195
Ofatumumab
N=196
Progression-Free Survivalb
Number of events (%)
35 (17.9)
111 (56.6)
Disease progression
26
93
Death events
9
18
Median (95% CI), months
NE
8.1 (7.2, 8.3)
HR (95% CI)
0.22 (0.15, 0.32)
Overall Survivala
Number of deaths (%)
16 (8.2)
33 (16.8)
HR (95% CI)
0.43 (0.24, 0.79)
Overall Response Rateb
42.6%
4.1%
a Median OS not evaluable for either arm.
b IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
100 -~
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I
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80
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70
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IMBRUVICA
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60
I I
~ -
~~
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t
40
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30
20
I I
10
p<0.0001
ofatumumab
0
M .rt Risk
0
3
6
9
12
15
(Month)
IMBRUVICA: 195
183
116
38
7
0
Ofatumumab: 196
161
83
15
1
0
100Jw..i __
90
80
- -.
..__ w1unwu ,.,,,,,,w,urn1
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... -
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.1 ofatumumab
70
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50
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40
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20
10
p<0.05
0
0
3
6
9
12
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18
(Month)
Nat Risk
IMBRUVICA: 195
191
184
11 S
32
s
0
Ofatumumab: 196
183
164
88
21
3
0
39
Figure 1: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in RESONATE
Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with
CLL/SLL in RESONATE
Reference ID: 5500397
40
63-Month Follow-Up
With an overall follow-up of 63 months, the median investigator-assessed PFS per IWCLL
criteria was 44.1 months [95% CI (38.5, 56.9)] in the IMBRUVICA arm and 8.1 months
[95% CI (7.8, 8.3)] in the ofatumumab arm. Overall response rate as assessed by investigators
was 87.2% in the IMBRUVICA arm versus 22.4% in the ofatumumab arm.
CLL/SLL with 17p deletion (del 17p CLL/SLL) in RESONATE
RESONATE included 127 patients with del 17p CLL/SLL. The median age was 67 years (range,
30 to 84 years), 62% were male, and 88% were White. All patients had a baseline ECOG
performance status of 0 or 1. PFS and ORR were assessed by an IRC. Efficacy results for del 17p
CLL/SLL are shown in Table 23.
Table 23: Efficacy Results in Patients with del 17p CLL/SLL in RESONATE
Endpoint
IMBRUVICA
N=63
Ofatumumab
N=64
Progression-Free Survivala
Number of events (%)
16 (25.4)
38 (59.4)
Disease progression
12
31
Death events
4
7
Median (95% CI), months
NE
5.8 (5.3, 7.9)
HR (95% CI)
0.25 (0.14, 0.45)
Overall Response Ratea
47.6%
4.7%
a IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NE = not evaluable.
63-Month Follow-Up
With an overall follow-up of 63 months, the median investigator-assessed PFS in patients with
del 17p per IWCLL criteria was 40.6 months [95% CI (25.4, 44.6)] in the IMBRUVICA arm and
6.2 months [95% CI (4.6, 8.1)] in the ofatumumab arm. Overall response rate as assessed by
investigators in patients with del 17p was 88.9% in the IMBRUVICA arm versus 18.8% in the
ofatumumab arm.
RESONATE-2
The RESONATE-2 study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA
versus chlorambucil (NCT01722487), was conducted in patients with treatment naïve CLL or
SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either
IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil
at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12
cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were White.
Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an
Reference ID: 5500397
41
ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with
SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating
CLL therapy include: progressive marrow failure demonstrated by anemia and/or
thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or
symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).
With a median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and
21 (15.8%) in IMBRUVICA and chlorambucil treatment arms, respectively]. With 41% of
patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT
patient population resulted in a statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and
2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)]
in the IMBRUVICA and chlorambucil arms, respectively.
Efficacy results for RESONATE-2 are shown in Table 24 and the Kaplan-Meier curve for PFS,
assessed by an IRC according to IWCLL criteria is shown in Figure 3.
Table 24: Efficacy Results in Patients with CLL/SLL in RESONATE-2
Endpoint
IMBRUVICA
N=136
Chlorambucil
N=133
Progression-Free Survivala
Number of events (%)
15 (11.0)
64 (48.1)
Disease progression
12
57
Death events
3
7
Median (95% CI), months
NE
18.9 (14.1, 22.0)
HRb (95% CI)
0.16 (0.09, 0.28)
Overall Response Ratea (CR + PR)
82.4%
35.3%
P-value
<0.0001
a IRC evaluated; five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved
complete response.
b HR = hazard ratio; NE = not evaluable.
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3
6
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12
15
18
21
24
27 (Month)
Nat Risk
IMBRUVICA:
136
133
130
126
122
98
66
21
2
0
chlorambucil: 133
121
95
85
74
49
34
10
0
0
42
Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in RESONATE-2
55-Month Follow-Up
With an overall follow-up of 55 months, the median PFS was not reached in the IMBRUVICA
arm.
HELIOS
The HELIOS study, a randomized, double-blind, placebo-controlled phase 3 study of
IMBRUVICA in combination with bendamustine and rituximab (BR) (NCT01611090), was
conducted in patients with previously treated CLL or SLL. Patients (n = 578) were randomized
1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease
progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day
cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2
and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles, and all patients had a CLcr ≥ 40
mL/min at baseline. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day
1, and 500 mg/m2 Cycles 2 through 6, Day 1.
The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments).
At baseline, 56% of patients had at least one tumor > 5 cm and 26% presented with del11q.
Efficacy results for HELIOS are shown in Table 25 and the Kaplan-Meier curves for PFS are
shown in Figure 4.
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80
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IMBRUVICA + BR
Placebo+ BR
p<0.0001
0
289
289
0
4
8
12
264
247
200
259
234
117
IMBRUVICA + BR
I
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20
24
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127
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59
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3
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Placebo+ BR
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28
32
36
0
0
0
0
0
0
43
Table 25: Efficacy Results in Patients with CLL/SLL in HELIOS
Endpoint
IMBRUVICA + BR
N=289
Placebo + BR
N=289
Progression-Free Survivala
Number of events (%)
56 (19.4)
183 (63.3)
Median (95% CI), months
NE
13.3 (11.3, 13.9)
HR (95% CI)
0.20 (0.15, 0.28)
Overall Response Ratea
82.7%
67.8%
a IRC evaluated; twenty-four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm
achieved complete response.
BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in HELIOS
iLLUMINATE
The iLLUMINATE study, a randomized, multi-center, phase 3 study of IMBRUVICA in
combination with obinutuzumab versus chlorambucil in combination with obinutuzumab
(NCT02264574), was conducted in patients with treatment naïve CLL or SLL. Patients were 65
Reference ID: 5500397
44
years of age or older or < 65 years of age with coexisting medical conditions, reduced renal
function as measured by creatinine clearance < 70 mL/min, or presence of del 17p/TP53
mutation. Patients (n = 229) were randomized 1:1 to receive either IMBRUVICA 420 mg daily
until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on
Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1,000 mg of
obinutuzumab on Days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5
subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided
between Day 1 (100 mg) and Day 2 (900 mg).
The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were White. All
patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). The trial enrolled
214 patients with CLL and 15 patients with SLL. At baseline, 65% of patients presented with
CLL/SLL with high risk factors (del 17p/TP53 mutation [18%], del 11q [15%], or unmutated
immunoglobulin heavy-chain variable region (unmutated IGHV) [54%]). The most common
reasons for initiating CLL therapy included: lymphadenopathy (38%), night sweats (34%),
progressive marrow failure (31%), fatigue (29%), splenomegaly (25%), and progressive
lymphocytosis (21%).
With a median follow-up time on study of 31 months, efficacy results for iLLUMINATE
assessed by an IRC according to IWCLL criteria are shown in Table 26, and the Kaplan-Meier
curve for PFS is shown in Figure 5.
Table 26: Efficacy Results in Patients with CLL/SLL in iLLUMINATE
Endpoint
IMBRUVICA +
Obinutuzumab
N=113
Chlorambucil +
Obinutuzumab
N=116
Progression-Free Survivala
Number of events (%)
24 (21)
74 (64)
Disease progression
11
64
Death events
13
10
Median (95% CI), months
NE
19.0 (15.1, 22.1)
HR (95% CI)
0.23 (0.15, 0.37)
P-valueb
<0.0001
Overall Response Rate (%)a
88.5
73.3
CRc (%)
19.5
7.8
PRd (%)
69.0
65.5
a IRC-evaluated.
b P-value is from unstratified log-rank test.
c Includes 1 patient in the IMBRUVICA + obinutuzumab arm with a complete response with incomplete marrow recovery (CRi)
d PR = nPR +PR.
HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
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20
10
p<0.0001
0
0
3
6
9
12
15
18
21
24
27
30
33
36
(Month)
Nat Risk
IMBRUVICA +
obinutuzumab: 113
109
106
105
99
94
90
85
82
81
28
6
0
chlorambucil +
obinutuzumab: 116
111
109
102
81
67
56
47
35
33
6
5
0
45
Figure 5: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in iLLUMINATE
In the high risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), the
PFS HR was 0.15 [95% CI (0.09, 0.27)].
E1912
The E1912 study, a randomized, multi-center, phase 3 study of IMBRUVICA in combination
with rituximab versus standard fludarabine, cyclophosphamide, and rituximab (FCR)
chemoimmunotherapy (NCT02048813), was conducted in adult patients who were 70 years or
younger with previously untreated CLL or SLL requiring systemic therapy. All patients had a
CLcr > 40 mL/min at baseline. Patients with 17p deletion were excluded. Patients (n =529) were
randomized 2:1 to receive either IMBRUVICA plus rituximab or FCR. IMBRUVICA was
administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was
administered at a dose of 25 mg/m2, and cyclophosphamide was administered at a dose of
250 mg/m2, both on Days 1, 2, and 3 of Cycles 1-6. Rituximab was initiated in Cycle 2 for the
IMBRUVICA plus rituximab arm and in Cycle 1 for the FCR arm and was administered at 50
mg/m2 on Day 1 of the first cycle, 325 mg/m2 on Day 2 of the first cycle, and 500 mg/m2 on Day
1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.
The median age was 58 years (range, 28 to 70 years), 67% were male, 90% were White and 98%
had a ECOG performance status of 0-1. At baseline, 43% of patients were Rai stage 3 or 4 and
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20
10
p<0.0001
0
0
3
6
9
Nat Risk
IMBRUVICA 354
351
349
345
+ rituximab
fludarabine, 175
158
152
148
cyclophosphamide
+ rituximab
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270
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159
125
114
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ftudarabine,
cyclophosphamide
+ riluximab
39
42
45
(Month)
108
79
52
34
20
10
46
59% of patients presented with high risk factors (TP53 mutation [6%], del11q [22%], or
unmutated IGHV [53%]).
With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in
Table 27. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria is shown in
Figure 6.
Table 27: Efficacy Results in Patients with CLL/SLL in E1912
Endpoint
IMBRUVICA + R
N=354
FCR
N=175
Progression-Free Survival
Number of events (%)
41 (12)
44 (25)
Disease progression
39
38
Death events
2
6
Median (95% CI), months
NE (49.4, NE)
NE (47.1, NE)
HR (95% CI)
0.34 (0.22, 0.52)
P-valuea
<0.0001
a P-value is from unstratified log-rank test.
FCR = fludarabine, cyclophosphamide, and rituximab; HR = hazard ratio; R = rituximab; NE = not evaluable.
Figure 6: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in E1912
Reference ID: 5500397
47
With a median follow-up time on study of 49 months, median overall survival was not reached
with a total of 23 deaths: 11 (3%) in the IMBRUVICA plus rituximab and 12 (7%) in the FCR
treatment arms.
Lymphocytosis
Upon initiation of single-agent IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50%
increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of
patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of
IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When
IMBRUVICA was administered in combination, lymphocytosis was 7% with IMBRUVICA +
BR versus 6% with placebo + BR and 7% with IMBRUVICA + obinutuzumab versus 1% with
chlorambucil + obinutuzumab.
14.2
Waldenström’s Macroglobulinemia
The safety and efficacy of IMBRUVICA in patients with WM were demonstrated in two single-
arm trials and one randomized, controlled trial.
Study 1118 and INNOVATE Monotherapy Arm
Study 1118 (NCT01614821), an open-label, multi-center, single-arm trial was conducted in 63
previously treated patients with WM. IMBRUVICA was administered orally at 420 mg once
daily until disease progression or unacceptable toxicity. The responses were assessed by
investigators and an IRC using criteria adopted from the International Workshop of
Waldenström’s Macroglobulinemia.
The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At
baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).
Responses, defined as partial response or better, per IRC are shown in Table 28.
Table 28: Response Rate and Duration of Response (DOR) Based on
IRC Assessment in Patients with WM in Study 1118
Total (N=63)
Response rate (CR+VGPR+PR), (%)
61.9
95% CI (%)
(48.8, 73.9)
Complete Response (CR)
0
Very Good Partial Response (VGPR), (%)
11.1
Partial Response (PR), (%)
50.8
Median duration of response, months (range)
NE (2.8+, 18.8+)
CI = confidence interval; NE = not evaluable.
The median time to response was 1.2 months (range, 0.7-13.4 months).
Reference ID: 5500397
48
The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed
prior rituximab-containing therapy and received single-agent IMBRUVICA. The median age
was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG
performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The
median number of prior treatments was 4 (range, 1 to 7 treatments). With an overall follow-up of
61 months, the response rate observed in the INNOVATE monotherapy arm per IRC assessment
was 77% (0% CR, 29% VGPR, 48% PR). The median duration of response was 33 months
(range, 2.4 to 60.2+ months).
INNOVATE
The INNOVATE study, a randomized, double-blind, placebo-controlled, phase 3 study of
IMBRUVICA or placebo in combination with rituximab (NCT02165397), was conducted in
treatment naïve or previously treated patients with WM. Patients (n = 150) were randomized 1:1
to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until
disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of
375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly
rituximab for 4 consecutive weeks (weeks 17-20). The major efficacy outcome measure is
progression-free survival (PFS) assessed by an IRC with additional efficacy measure of response
rate.
The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were White.
Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of
patients had a baseline ECOG performance status of 2. Forty-five percent of patients were
treatment naïve, and 55% of patients were previously treated. Among previously treated patients,
the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median
serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), and MYD88 L265P mutations were
present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for
mutation status.
An exploratory analysis demonstrated a sustained hemoglobin improvement (defined as increase
of ≥ 2 g/dL over baseline for at least 8 weeks without blood transfusions or growth factor
support) in 65% of patients in the IMBRUVICA + R group and 39% of patients in the
placebo + R group.
With an overall follow-up of 63 months, efficacy results as assessed by an IRC at the time of the
final analysis for INNOVATE are shown in Table 29, and the Kaplan-Meier curves for PFS are
shown in Figure 7.
Reference ID: 5500397
100
90
80
70
60
~
0
(f)
u..
50
c..
40
30
20
10
0
0
Nat Risk
lbr+R:
75
Pbo+R: 75
1--. ' I
' ·I -, -,
• I I --, , _
Median Time (mo)
Hazard Ratio
(95% CI)
Log-Rank p-value
3
6
9
12
73
69
67
66
64
54
48
43
'• -, .
·--. I --•---,_ I
'I-,
'
I -..
' - - - - - I I_ - - -
I - 1- -
I- 11 1 -II--1- - - - <II- I
Pbo+R
lbr+R
20<3
NE
0<250
(0<148-0.420)
-
lbr+R
<.0001
Pbo+R
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
60
60
58
57
56
54
54
49
48
47
44
32
22
15
7
39
33
32
31
27
23
19
19
17
17
15
7
4
3
2
(Month)
49
Table 29: Efficacy Results in Patients with WM by IRC in INNOVATE (Final Analysis)
Endpoint
IMBRUVICA + R
N=75
Placebo + R
N=75
Progression-Free Survival
Number of events (%)
22 (29)
50 (67)
Median (95% CI), months
NE (57.7, NE)
20.3 (13.0, 27.6)
HR (95% CI)
0.25 (0.15, 0.42)
P-valuea
<0.0001
Response Rate (CR+VGPR+PR)b
76%
31%
95% CI (%)
(65, 85)
(21, 42)
Complete Response (CR)
1%
1%
Very Good Partial Response (VGPR)
29%
4%
Partial Response (PR)
45%
25%
Median duration of response, months (range)
NE (1.9+, 58.9+)
NE (4.6+, 49.7+)
CI = confidence interval; HR = hazard ratio; NE = not evaluable; R = rituximab.
a P-value is from the stratified log-rank test.
b P-value associated with response rate was <0.0001.
Figure 7: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with WM in INNOVATE
Reference ID: 5500397
50
Median overall survival was not reached for either treatment arm. With an overall follow-up of
63 months, 9 (12%) patients on IMBRUVICA + R and 10 (13.3%) patients on placebo + R had
died. Forty-seven percent of patients randomized to the placebo + R arm crossed over to receive
IMBRUVICA.
14.3
Chronic Graft versus Host Disease
Study 1129
The safety and efficacy of IMBRUVICA in cGVHD were evaluated in Study 1129
(NCT02195869), an open-label, multi-center, single-arm trial of 42 patients with cGVHD after
failure of first line corticosteroid therapy and requiring additional therapy. IMBRUVICA was
administered orally at 420 mg once daily. The responses were assessed by investigators using the
2005 National Institute of Health (NIH) Consensus Panel Response Criteria with two
modifications to align with the updated 2014 NIH Consensus Panel Response Criteria.
The median age was 56 years (range, 19 to 74 years), 52% were male, and 93% were White. The
most common underlying malignancies leading to transplantation were acute lymphocytic
leukemia, acute myeloid leukemia, and CLL. The median time since cGVHD diagnosis was
14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3 treatments), and
60% of patients had a Karnofsky performance score of ≤ 80. The majority of patients (88 %) had
at least 2 organs involved at baseline, with the most commonly involved organs being mouth
(86%), skin (81%), and gastrointestinal tract (33%). The median daily corticosteroid dose
(prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of patients were
receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.
Prophylaxis for infections were managed per institutional guidelines with 79% of patients
receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole
derivatives.
Efficacy results are shown in Table 30.
Table 30: Best Overall Response Rate (ORR) and Sustained Response Rate
Based on Investigator Assessmenta in Patients with cGVHD in Study 1129
Total (N=42)
ORR
28 (67%)
95% CI
(51%, 80%)
Complete Response (CR)
9 (21%)
Partial Response (PR)
19 (45%)
Sustained response rateb
20 (48%)
CI = confidence interval.
a Investigator assessment based on the 2005 NIH Response Criteria with two modifications (added “not evaluable” for
organs with non-cGVHD abnormalities, and organ score change from 0 to 1 was not considered disease
progression.)
b Sustained response rate is defined as the proportion of patients who achieved a CR or PR that was sustained for at
least 20 weeks.
Reference ID: 5500397
51
The median time to response coinciding with the first scheduled response assessment was
12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all organs involved for
cGVHD (skin, mouth, gastrointestinal tract, and liver).
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42)
of patients on at least 2 consecutive visits.
iMAGINE
The safety and efficacy of IMBRUVICA were evaluated in iMAGINE (NCT03790332), an
open-label, multi-center, single-arm trial of IMBRUVICA for the treatment of pediatric and
young adult patients age 1 year to less than 22 years with moderate or severe cGVHD as defined
by NIH Consensus Criteria. The study included 47 patients who required additional therapy after
failure of one or more prior lines of systemic therapy. All patients had platelets ≥ 30 x 109/L;
absolute neutrophil count ≥ 1.0 x 109/L; AST or ALT ≤ 3 x ULN; total bilirubin of ≤ 1.5 x ULN;
and estimated creatinine clearance ≥ 30 mL/min. Patients were excluded if single organ
genitourinary involvement was the only manifestation of cGVHD.
Patients age 12 years and older were treated with IMBRUVICA 420 mg orally once daily, and
patients age 1 year to less than 12 years were treated with IMBRUVICA 240 mg/m2 orally once
daily. Concomitant treatment with supportive care therapies for cGVHD was permitted. Initiation
of new systemic cGVHD therapy while on study was not permitted.
The median age was 13 years (range, 1 to 19 years). Of the 47 patients, 70% of patients were
male, and 36% were White, 9% were Black or African American, 55% were other or unreported.
The median time since cGVHD diagnosis was 16.1 months, the median number of prior cGVHD
treatments was 2 (range, 1 to 12). The majority of patients (87%) had at least 2 organs involved
at baseline, with lung involvement at baseline in 49% of patients; 26% of patients had a
Karnofsky/Lansky performance score of <80. The median daily corticosteroid dose (prednisone
or prednisone equivalent) at baseline was 0.47 mg/kg/day, and 61% (19 of 31) patients were
receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.
Prophylaxis for infections was managed per institutional guidelines, with 72% of patients
receiving combinations of sulfonamides and trimethoprim and 70% receiving systemic
antifungal agents.
The efficacy of IMBRUVICA was established based on overall response rate (ORR) through
Week 25, where overall response included complete response or partial response according to the
2014 National Institutes of Health (NIH) Consensus Development Project Response Criteria. The
efficacy results are shown in Table 31.
Reference ID: 5500397
52
Table 31: Efficacy Results in Patients with Previously Treated cGVHDa in iMAGINE
Total (N=47)
ORR by Week 25
28 (60%)
95% CI (%)
(44, 74)
Complete Response (CR)
2 (4%)
Partial Response (PR)
26 (55%)
Median duration of response, months (95% CI)b
5.3 (2.8, 8.8)
CI = confidence interval; ORR = overall response rate.
a Assessment based on 2014 NIH Consensus Development Project Response Criteria.
b Based on all responders in the study, calculated from first response to progression, death, or new systemic therapies for
cGVHD.
The median time to first response was 0.9 month (range, 0.9 to 6.1 months). The median time
from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI:
4.6, not evaluable).
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in Lee Symptom Scale overall summary score through Week
25 in 50% (13/26) of patients age 12 years and older.
16 HOW SUPPLIED/STORAGE AND HANDLING
Capsules
The 70 mg capsules are supplied as yellow opaque capsules, marked with “ibr 70 mg” in black
ink, in white HDPE bottles with a child-resistant closure:
• 28 capsules per bottle: NDC 57962-070-28
The 140 mg capsules are supplied as white opaque capsules, marked with “ibr 140 mg” in black
ink, in white HDPE bottles with a child-resistant closure:
• 90 capsules per bottle: NDC 57962-140-09
• 120 capsules per bottle: NDC 57962-140-12
Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C
(59°F to 86°F) permitted (see USP Controlled Room Temperature). Retain in original package
until dispensing.
Tablets
The IMBRUVICA (ibrutinib) tablets are supplied in 3 strengths in the following packaging
configurations:
• 140 mg tablets: Yellow green to green round tablets debossed with “ibr” on one side and
“140” on the other side. Carton of one folded blister card containing two 14-count blister
strips for a total of 28 tablets: NDC 57962-014-28
Reference ID: 5500397
53
• 280 mg tablets: Purple oblong tablets debossed with “ibr” on one side and “280” on the
other side. Carton of one folded blister card containing two 14-count blister strips for a
total of 28 tablets: NDC 57962-280-28
• 420 mg tablets: Yellow green to green oblong tablets debossed with “ibr” on one side and
“420” on the other side. Carton of one folded blister card containing two 14-count blister
strips for a total of 28 tablets: NDC 57962-420-28
Store tablets in original packaging at room temperature 20°C to 25°C (68°F to 77°F). Brief
exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature).
Oral Suspension
The IMBRUVICA (ibrutinib) oral suspension is a white to off-white suspension supplied as
108 mL in a 150 mL amber glass bottle with a pre-inserted bottle adapter and a child-resistant
closure. Each mL contains 70 mg of ibrutinib. The oral suspension bottle is provided in a carton
with two 3 mL reusable oral dosing syringes: NDC 57962-007-12.
Store the oral suspension bottle at 2°C to 25°C (36°F to 77°F). Do not freeze. Dispense in
original sealed container. Do not use if the carton seal is broken or missing.
Discard any unused IMBRUVICA oral suspension remaining 60 days after first opening the
bottle.
17 PATIENT COUNSELING INFORMATION
Advise the patients and caregivers to read the FDA-approved patient labeling (Patient
Information and Instructions for Use).
Hemorrhage:
Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe
headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that
IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and
Precautions (5.1)].
Infections:
Inform patients of the possibility of serious infection, and to report any signs or symptoms
(fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions
(5.2)].
Cardiac arrhythmias, cardiac failure, and sudden death:
Inform patients of the possibility of irregular heart rhythm, heart failure and sudden death.
Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting,
shortness of breath, chest discomfort, or edema [see Warnings and Precautions (5.3)].
Hypertension:
Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which
may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.4)].
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54
Second primary malignancies:
Inform patients that other malignancies have occurred in patients who have been treated with
IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions
(5.6)].
Hepatotoxicity, including drug-induced liver injury:
Inform patients that liver problems, including drug-induced liver injury and abnormalities in
liver tests, may develop during IMBRUVICA treatment. Advise patients to contact their
healthcare provider immediately if they experience abdominal discomfort, dark urine, or
jaundice [see Warnings and Precautions (5.7)].
Tumor lysis syndrome:
Inform patients of the potential risk of tumor lysis syndrome and to report any signs and
symptoms associated with this event to their healthcare provider for evaluation [see Warnings
and Precautions (5.8)].
Embryo-fetal toxicity:
Advise women of the potential risk to a fetus. Advise females of reproductive potential to inform
their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions
(5.9), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with
IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive potential to use effective contraception during
treatment with IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations
(8.3), Nonclinical Toxicology (13.1)].
Lactation:
Advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the
last dose [see Use in Specific Populations (8.2)].
Other Important Information:
Inform patients to take IMBRUVICA orally once daily according to their physician’s
instructions and that the oral dosage (capsules or tablets) should be swallowed whole with a glass
of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the
tablets approximately the same time each day [see Dosage and Administration (2.1)].
Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as
soon as possible on the same day with a return to the normal schedule the following day. Patients
should not take extra doses to make up the missed dose [see Dosage and Administration (2.1)].
For IMBRUVICA oral suspension, instruct patients or caregivers to read and follow the
Instructions for Use for proper preparation, administration, storage and disposal [see Dosage and
Administration (2.1)].
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55
Advise patients of the common side effects associated with IMBRUVICA [see Adverse
Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT
INFORMATION.
Advise patients to inform their health care providers of all concomitant medications, including
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug
Interactions (7)].
Advise patients that they may experience loose stools or diarrhea and should contact their doctor
if their diarrhea persists. Advise patients to maintain adequate hydration [see Adverse Reactions
(6.1)].
Distributed and Marketed by:
Pharmacyclics LLC
South San Francisco, CA 94080 USA
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA 19044 USA
Patent http://www.imbruvica.com
IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC
© Pharmacyclics LLC 2024
© Janssen Biotech, Inc. 2024
20088578
Reference ID: 5500397
PATIENT INFORMATION
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
capsules
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
tablets
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
oral suspension
What is IMBRUVICA?
IMBRUVICA is a prescription medicine used to treat:
•
Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
•
Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
•
Adults with Waldenström’s macroglobulinemia (WM).
•
Adults and children 1 year of age and older with chronic graft versus host disease (cGVHD) after failure of 1 or
more lines of systemic therapy.
It is not known if IMBRUVICA is safe and effective in children under 1 year of age.
Before taking IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:
•
have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned
medical, surgical, or dental procedure.
•
have bleeding problems or are taking a blood thinner medicine.
•
have an infection.
•
have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease,
such as high blood pressure, high cholesterol, or diabetes.
•
have liver problems.
•
are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become
pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA. Tell your
healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA.
o
Females who are able to become pregnant should use effective birth control (contraception) during treatment
with IMBRUVICA and for 1 month after the last dose.
o
Males with female partners who are able to become pregnant should use effective birth control, such as
condoms, during treatment with IMBRUVICA and for 1 month after the last dose.
•
are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for 1 week after
the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how
IMBRUVICA works and can cause side effects.
How should I take or give IMBRUVICA?
•
Take or give IMBRUVICA exactly as your healthcare provider tells you to take or give it.
•
Take or give IMBRUVICA 1 time a day at about the same time each day.
IMBRUVICA comes as capsules, tablets, and oral suspension.
•
If your healthcare provider prescribes IMBRUVICA capsules or tablets:
o
Swallow IMBRUVICA capsules or tablets whole with a glass of water.
o
Do not open, break, or chew IMBRUVICA capsules.
o
Do not cut, crush, or chew IMBRUVICA tablets.
•
If your healthcare provider prescribes IMBRUVICA oral suspension:
o
See the detailed Instructions for Use that comes with IMBRUVICA oral suspension for information about the
correct way to take or give a dose. If you have questions about how to take or give IMBRUVICA oral
suspension, talk to your healthcare provider.
o
Do not use if the carton seal is broken or missing.
•
If you miss a dose of IMBRUVICA, take or give it as soon as you remember on the same day. Take or give the next
dose of IMBRUVICA at the regular time on the next day. Do not take or give extra doses of IMBRUVICA to make up
for a missed dose.
•
If you take too much IMBRUVICA, call your healthcare provider, or go to the nearest hospital emergency room right
away.
What should I avoid while taking IMBRUVICA?
Reference ID: 5500397
You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment
with IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.
What are the possible side effects of IMBRUVICA?
IMBRUVICA may cause serious side effects, including:
•
Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA and can also be serious and
may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your
healthcare provider if you have any signs of bleeding, including:
o blood in your stools or black stools (looks like
tar)
o increased bruising, or small red or purple spots
on the skin
o pink or brown urine
o dizziness
o unexpected bleeding, or bleeding that is severe
or that you cannot control
o weakness
o confusion
o vomit blood or vomit looks like coffee grounds
o cough up blood or blood clots
o change in your speech
o headache that lasts a long time or severe
headache
•
Infections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death.
Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms
of an infection during treatment with IMBRUVICA.
•
Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart
failure and death have happened in people treated with IMBRUVICA, especially in people who have an infection,
an increased risk for heart disease, or have had heart rhythm problems in the past. Your heart function will be
checked before and during treatment with IMBRUVICA. Tell your healthcare provider if you get any symptoms of
heart problems, such as:
o
feeling as if your heart is beating
fast and irregular
o
lightheadedness
o
dizziness
o
shortness of breath
o
swelling of the feet, ankles, or
legs
o
chest discomfort
o
feeling faint
If you develop any of these symptoms, your healthcare provider may do tests to check your heart and may change
your IMBRUVICA dose.
•
High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with
IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to
treat your blood pressure.
•
Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are
common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to
check your blood counts.
•
Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of
the skin or other organs.
•
Liver problems. Liver problems, which may be severe or life-threatening, or lead to death, can happen in people
treated with IMBRUVICA. Your healthcare provider will do blood tests to check your liver before and during
treatment with IMBRUVICA. Tell your healthcare provider or get medical help right away if you have any signs of
liver problems, including stomach pain or discomfort, dark-colored urine, or yellow skin and eyes.
•
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure
and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare
provider may do blood tests to check you for TLS.
The most common side effects of IMBRUVICA in adults with B-cell malignancies (CLL/SLL and WM) include:
o
low platelet count
o
diarrhea
o
tiredness
o
muscle, bone, and joint pain
o
low white blood cell count
o
rash
o
low red blood cell count (anemia)
o
bruising
o
nausea
The most common side effects of IMBRUVICA in adults or children 1 year of age and older with cGVHD
include:
o
tiredness
o
low red blood cell count (anemia)
o
bruising
o
diarrhea
o
low platelet count
o
muscle, bone, and joint pain
o
fever
o
muscle spasms
o
mouth sores (stomatitis)
o
bleeding
o
nausea
o
stomach pain
o
pneumonia
o
headache
Reference ID: 5500397
Diarrhea is a common side effect in people who take IMBRUVICA. Drink plenty of fluids during treatment with
IMBRUVICA to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your
healthcare provider if you have diarrhea that does not go away.
These are not all the possible side effects of IMBRUVICA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store IMBRUVICA?
•
Store IMBRUVICA capsules and tablets at room temperature between 68°F and 77°F (20°C and 25°C).
•
Keep IMBRUVICA capsules in the original container with the lid tightly closed.
•
Keep IMBRUVICA tablets in the original carton.
•
Store IMBRUVICA oral suspension bottle between 36°F and 77°F (2°C and 25°C). Do not freeze.
•
Use IMBRUVICA oral suspension within 60 days after first opening the bottle. Throw away (dispose of) any unused
portion 60 days after opening.
•
IMBRUVICA capsules and oral suspension come in a bottle with a child-resistant cap.
Keep IMBRUVICA and all medicines out of the reach of children.
General information about the safe and effective use of IMBRUVICA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have
the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for
information about IMBRUVICA that is written for health professionals.
What are the ingredients in IMBRUVICA?
Active ingredient: ibrutinib
Inactive ingredients:
IMBRUVICA capsules: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl
sulfate. The 70 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and black ink. The 140 mg
capsule shell contains gelatin, titanium dioxide, and black ink.
IMBRUVICA tablets: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric
oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets),
talc, titanium dioxide, and yellow iron oxide (140 mg and 420 mg tablets).
IMBRUVICA oral suspension: benzyl alcohol, citric acid monohydrate, disodium hydrogen phosphate, hypromellose,
microcrystalline cellulose and carboxymethylcellulose sodium, purified water, and sucralose.
Distributed and Marketed by: Pharmacyclics LLC South San Francisco, CA 94080 USA
Marketed by: Janssen Biotech, Inc. Horsham, PA 19044 USA
© Pharmacyclics LLC 2024
© Janssen Biotech, Inc. 2024
20088578
For more information, go to www.imbruvica.com or call 1-877-877-3536.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 5/2024
Reference ID: 5500397
A
A
INSTRUCTIONS FOR USE
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
oral suspension
This Instructions for Use contains information about how to prepare and take or give a dose of
IMBRUVICA oral suspension.
Read this Instructions for Use before you take or give IMBRUVICA and each time you get a refill. There
may be new information.
This Instructions for Use does not take the place of talking to your healthcare provider about your or your
child’s medical condition or treatment.
Call your healthcare provider or 1-877-877-3536 if you need help or have any questions about how to
take or give IMBRUVICA the right way.
Important information you need to know before taking or giving IMBRUVICA.
•
IMBRUVICA is for oral use only.
•
Take or give IMBRUVICA exactly as your healthcare provider tells you to.
•
If you miss a dose of IMBRUVICA, it can be taken or given as soon as possible on the same day.
Do not take or give more than the prescribed dose in 1 day.
If you or your child take too much IMBRUVICA, call your healthcare provider for help.
•
Keep these instructions for future use.
Each IMBRUVICA carton contains (see Figure A):
•
1 bottle of IMBRUVICA (called ‘bottle’ in this Instructions for Use) with pre-inserted bottle adapter
(called ‘adapter’ in this Instructions for Use). Do not remove the bottle adapter.
•
2 reusable 3 mL oral dosing syringes (called ‘syringe’ in this Instructions for Use) measuring in
0.1 mL increments.
Only use the syringes that come with IMBRUVICA. Do not use the syringes for other
patients or with other medicines.
If you cannot read the markings on the syringes, throw them away and call 1-877-877-3536
to get new ones.
Reference ID: 5500397
A
B-Cap
-
Adapter (Do not remove the
adapter)
3 ml
3 ml
Barrel
-
Plunger
Bottle
Syringes
Preparing and taking or giving a dose of IMBRUVICA
Step 1: Gather and check supplies.
•
Check the prescribed dose in milliliters (mLs).
Find this mL marking on the syringe.
•
If the dose is more than the marking on the
syringe, split the dose between syringes as
prescribed.
•
Gather bottle and syringe(s) (see Figure A).
•
Check the bottle and make sure that the bottle has
IMBRUVICA Oral Suspension printed on it and the
expiration date (“EXP”) has not passed.
Do not use IMBRUVICA after the “EXP” date printed
on the carton and on the bottle.
Do not use if the IMBRUVICA carton seal appears to
be tampered with.
Figure A
Step 2: Record or check the discard date.
•
When opening the bottle for the first time, record
the date that is 60 days from the day the bottle is
opened underneath the words “Discard Date” (see
Figure B).
•
Use IMBRUVICA within 60 days after first opening
the bottle.
Do not use IMBRUVICA past the discard date
recorded on the bottle.
Figure B
Reference ID: 5500397
Ii\
Step 3: Shake the bottle.
•
Shake the bottle well before each use (see Figure
C).
Figure C
Step 4: Remove the cap from the bottle.
•
Press down and twist the cap counterclockwise to
remove it from the bottle (see Figure D).
•
If there is fluid on top of the adapter, you may wipe
it with a clean disposable tissue.
Do not remove the bottle adapter.
Figure D
Step 5: Attach the syringe to the bottle.
•
Make sure the syringe is clean and dry before
use.
•
Push the plunger down all the way.
•
Gently insert tip of the syringe into the adapter.
•
Turn the assembled bottle and syringe upside
down (see Figure E).
Figure E
Reference ID: 5500397
A
Step 6: Fill the syringe.
•
Slowly pull the syringe plunger down, past the
number of mLs for your prescribed dose (see Figure
F).
•
Check for air bubbles and proceed to Step 7 for
instructions on how to remove air bubbles.
Figure F
Step 7: Remove air bubbles and adjust to the prescribed
dose (mL).
•
Hold the syringe and tap the sides to send
bubbles to the tip.
•
With the syringe attached to the bottle, push the
plunger up to remove the air bubbles from the top
(see Figure G).
•
After the bubbles are removed, push the plunger
up until the top of the colored plunger is even with
the markings on the syringe for the prescribed
dose.
Air bubbles must be removed to ensure the correct
dose.
Note: Repeat steps 6 and 7 if any air bubbles remain.
Figure G
Reference ID: 5500397
Step 8: Remove the syringe from the bottle.
•
Turn the assembled bottle upright.
•
Hold the middle of the syringe and carefully
remove it from the bottle (see Figure H).
•
Place the bottle aside.
Do not touch the plunger of the syringe to avoid
accidentally spilling the medicine before you are
ready to take or give the dose.
Note: If more than 1 syringe is needed to take or give the full
dose, repeat steps 5 to 8 with the second syringe to complete
the prescribed dose.
Figure H
Step 9: Take or give IMBRUVICA.
•
Place the tip of the syringe along the inside of the
cheek.
•
Slowly push the plunger all the way in to take or
give the entire dose (see Figure I).
•
Repeat with second syringe if needed to complete
the prescribed dose.
Note: IMBRUVICA must be taken or given as soon as
possible after being drawn from the bottle.
Note: After swallowing the dose of medicine make sure to
drink water.
Figure I
Step 10: Recap the bottle.
•
Place the cap back on the IMBRUVICA bottle (see
Figure J).
•
Make sure the bottle is tightly closed between
each use.
Figure J
Reference ID: 5500397
➔
Step 11: Rinse the syringe.
•
Remove the plunger from the syringe.
•
Rinse the plunger and the syringe only with water
and air dry (see Figure K).
•
Store the syringe in a clean, dry place.
Do not clean the syringe with soap or in the dishwasher.
Figure K
Turn over for more information
How to store IMBRUVICA Oral Suspension
•
Store the bottle between 36°F and 77°F (2°C and 25°C).
Do not freeze.
•
IMBRUVICA oral suspension comes in a bottle with a child-resistant cap.
•
Store IMBRUVICA and all medications out of the reach of children.
How to dispose of IMBRUVICA
Throw away (dispose of) any unused medicine within 60 days after first opening of the
bottle. At the same time, throw away any used or unused syringes.
•
Ask your pharmacist how to properly dispose of the medicine.
•
For syringe disposal, rinse and place in household trash.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed and Marketed by:
Pharmacyclics LLC
South San Francisco, CA 94080 USA
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA 19044 USA
Patent http://www.imbruvica.com
IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC
© 2024 Pharmacyclics LLC
© 2024 Janssen Biotech, Inc.
20080493
Revised: 2/2024
Reference ID: 5500397
| custom-source | 2025-02-12T15:48:09.099585 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205552s043,210563s019,217003s004lbl.pdf', 'application_number': 210563, 'submission_type': 'SUPPL ', 'submission_number': 19} |
80,730 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IMBRUVICA safely and effectively. See full prescribing information for
IMBRUVICA.
IMBRUVICA® (ibrutinib) capsules, for oral use
IMBRUVICA® (ibrutinib) tablets, for oral use
IMBRUVICA® (ibrutinib) oral suspension
Initial U.S. Approval: 2013
----------------------------RECENT MAJOR CHANGES--------------------------
Warnings and Precautions, Hepatotoxicity,
Including Drug-Induced Liver Injury (5.7)
5/2024
----------------------------INDICATIONS AND USAGE---------------------------
IMBRUVICA is a kinase inhibitor indicated for the treatment of:
•
Adult patients with chronic lymphocytic leukemia (CLL)/Small
lymphocytic lymphoma (SLL) (1.1).
•
Adult patients with chronic lymphocytic leukemia (CLL)/Small
lymphocytic lymphoma (SLL) with 17p deletion (1.2).
•
Adult patients with Waldenström’s macroglobulinemia (WM) (1.3).
•
Adult and pediatric patients age 1 year and older with chronic graft versus
host disease (cGVHD) after failure of one or more lines of systemic
therapy (1.4).
-----------------------DOSAGE AND ADMINISTRATION-----------------------
•
CLL/SLL and WM: 420 mg taken orally once daily (2.1).
•
cGVHD:
o Patients 12 years and older: 420 mg taken orally once daily (2.1).
o Patients 1 to less than 12 years of age: 240 mg/m2 taken orally once
daily (up to a dose of 420 mg) (2.1).
Tablets or capsules should be taken orally with a glass of water. Do not open,
break, or chew the capsules. Do not cut, crush, or chew the tablets. See full
prescribing information for oral suspension administration instructions (2.1).
----------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsules: 70 mg and 140 mg (3)
Tablets: 140 mg, 280 mg, and 420 mg (3)
Oral suspension: 70 mg/mL (3)
------------------------------CONTRAINDICATIONS------------------------------
None (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
• Hemorrhage: Monitor for bleeding and manage (5.1).
• Infections: Monitor patients for fever and infections, evaluate promptly,
and treat (5.2).
• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Monitor for
symptoms of arrhythmias and cardiac failure and manage (5.3).
• Hypertension: Monitor blood pressure and treat (5.4).
• Cytopenias: Check complete blood counts monthly (5.5).
• Second Primary Malignancies: Other malignancies have occurred in
patients, including skin cancers, and other carcinomas (5.6).
• Hepatotoxicity, Including Drug-Induced Liver Injury: Monitor hepatic
function throughout treatment (5.7).
• Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.
Monitor and treat for TLS (5.8).
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use effective
contraception (5.9, 8.1, 8.3).
------------------------------ADVERSE REACTIONS-------------------------------
• The most common (≥30%) adverse reactions in patients with B-cell
malignancies are thrombocytopenia, diarrhea, fatigue, musculoskeletal
pain, neutropenia, rash, anemia, bruising, and nausea (6).
• The most common (≥20%) adverse reactions in adult or pediatric patients
with cGVHD are fatigue, anemia, bruising, diarrhea, thrombocytopenia,
musculoskeletal pain, pyrexia, muscle spasms, stomatitis, hemorrhage,
nausea, abdominal pain, pneumonia, and headache (6).
To report SUSPECTED ADVERSE REACTIONS, contact
Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS------------------------------
• CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1).
• CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
(7.2).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
• Lactation: Advise not to breastfeed (8.2).
• Hepatic Impairment: Avoid use of IMBRUVICA in patients with severe
hepatic impairment. In patients with mild or moderate impairment, reduce
IMBRUVICA dose (2.4, 8.6).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma
1.2
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma with 17p deletion
1.3
Waldenström’s Macroglobulinemia
1.4
Chronic Graft versus Host Disease
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2
Dosage Modifications for Adverse Reactions
2.3
Dosage Modifications for Use with CYP3A Inhibitors
2.4
Dosage Modifications for Use in Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hemorrhage
5.2
Infections
5.3
Cardiac Arrhythmias, Cardiac Failure, and Sudden
Death
5.4
Hypertension
5.5
Cytopenias
5.6
Second Primary Malignancies
5.7
Hepatotoxicity, Including Drug-Induced Liver Injury
5.8
Tumor Lysis Syndrome
5.9
Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Effect of CYP3A Inhibitors on Ibrutinib
7.2
Effect of CYP3A Inducers on Ibrutinib
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Plasmapheresis
10 OVERDOSAGE
11
DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Chronic Lymphocytic Leukemia / Small Lymphocytic
Lymphoma
14.2
Waldenström’s Macroglobulinemia
14.3
Chronic Graft versus Host Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5500397
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL).
1.2
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
1.3
Waldenström’s Macroglobulinemia
IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
macroglobulinemia (WM).
1.4
Chronic Graft versus Host Disease
IMBRUVICA is indicated for the treatment of adult and pediatric patients age 1 year and older
with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic
therapy.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s
Macroglobulinemia
The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily
until disease progression or unacceptable toxicity.
For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with
rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).
For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider
administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
Chronic Graft versus Host Disease
The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is
420 mg orally once daily, and for patients 1 to less than 12 years of age with cGVHD is 240
mg/m2 orally once daily (up to a dose of 420 mg), until cGVHD progression, recurrence of an
underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for
the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical
assessment of the individual patient.
Reference ID: 5500397
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Table 1: Recommended dosage based on body surface area (BSA) for patients 1 to less than
12 years of age using either IMBRUVICA capsules/tablets or oral suspension
Recommended dose to achieve 240 mg/m2
BSA* (m2)
Range
Dose (mg) of IMBRUVICA
Capsules/Tablets to Administer
Volume (mL) of IMBRUVICA Oral
Suspension (70 mg/mL) to Administer
> 0.3 to 0.4
-
1.2 mL
> 0.4 to 0.5
-
1.5 mL
> 0.5 to 0.6
-
1.9 mL
> 0.6 to 0.7
-
2.2 mL
> 0.7 to 0.8
210 mg
2.6 mL
> 0.8 to 0.9
210 mg
2.9 mL
> 0.9 to 1
210 mg
3.3 mL
> 1 to 1.1
280 mg
3.6 mL
> 1.1 to 1.2
280 mg
4 mL
> 1.2 to 1.3
280 mg
4.3 mL
> 1.3 to 1.4
350 mg
4.6 mL
> 1.4 to 1.5
350 mg
5 mL
> 1.5 to 1.6
350 mg
5.3 mL
> 1.6
420 mg
6 mL
*BSA = body surface area.
Administration
Administer IMBRUVICA at approximately the same time each day.
Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the
capsules. Do not cut, crush, or chew the tablets.
Follow Instructions for Use for further administration details of IMBRUVICA oral suspension.
If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
on the same day with a return to the normal schedule the following day. Do not take extra doses
of IMBRUVICA to make up for the missed dose.
2.2
Dosage Modifications for Adverse Reactions
For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Once the adverse
reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage
modifications (see Table 2).
Reference ID: 5500397
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Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reactiona,b
Occurrence
Dose Modification for
CLL/SLL, WM, and
Patients 12 Years or older
with cGVHD After
Recovery
Starting Dose = 420 mg
Dose Modification for
Patients 1 Year to less than
12 Years with cGVHD
After Recovery
Starting Dose = 240 mg/m2
Grade 2 cardiac failure
First
Restart at 280 mg dailyc
Restart at 160 mg/m2 dailyc
Second
Restart at 140 mg dailyc
Restart at 80 mg/m2 dailyc
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 cardiac arrhythmias
First
Restart at 280 mg dailyc
Restart at 160 mg/m2 dailyc
Second
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 or 4 cardiac failure
Grade 4 cardiac arrhythmias
First
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Other Grade 3 or 4 non-
hematological toxicitiesd
Grade 3 or 4 neutropenia
with infection or fever
Grade 4 hematological
toxicities
First
Restart at 280 mg daily
Restart at 160 mg/m2 dailyc
Second
Restart at 140 mg daily
Restart at 80 mg/m2 dailyc
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
a [see Warnings and Precautions (5)].
b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.
c Evaluate the benefit-risk before resuming treatment.
d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.
Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA
capsules/tablets or oral suspension
Recommended dose to achieve 160 mg/m2
Recommended dose to achieve 80 mg/m2
BSA* (m2)
Range
Dose (mg) of
IMBRUVICA
Capsules/Tablets to
Administer
Volume (mL) of
IMBRUVICA Oral
Suspension (70
mg/mL) to
Administer
Dose (mg) of
IMBRUVICA
Capsules/Tablets to
Administer
Volume (mL) of
IMBRUVICA Oral
Suspension (70
mg/mL) to
Administer
> 0.3 to 0.4
-
0.8 mL
-
0.4 mL
> 0.4 to 0.5
-
1 mL
-
0.5 mL
> 0.5 to 0.6
-
1.3 mL
-
0.6 mL
> 0.6 to 0.7
-
1.5 mL
-
0.7 mL
Reference ID: 5500397
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*BSA = body surface area.
2.3
Dosage Modifications for Use with CYP3A Inhibitors
Recommended dosage modifications are described below [see Drug Interactions (7.1)]:
Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors
Patient Population
Coadministered Drug
Recommended IMBRUVICA Dosage
B-cell Malignancies
•
Moderate CYP3A inhibitor
280 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Voriconazole 200 mg twice daily
•
Posaconazole suspension 100 mg
once daily, 100 mg twice daily, or
200 mg twice daily
140 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Posaconazole suspension 200 mg
three times daily or 400 mg twice
daily
•
Posaconazole intravenously 300 mg
once daily
•
Posaconazole delayed-release tablets
300 mg once daily
70 mg once daily
Interrupt dose as recommended [see
Dosage and Administration (2.2)].
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
Patients 12 years
and older with
cGVHD
• Moderate CYP3A inhibitor
420 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
> 0.7 to 0.8
140 mg
1.7 mL
70 mg
0.9 mL
> 0.8 to 0.9
140 mg
1.9 mL
70 mg
1 mL
> 0.9 to 1
140 mg
2.2 mL
70 mg
1.1 mL
> 1 to 1.1
140 mg
2.4 mL
70 mg
1.2 mL
> 1.1 to 1.2
210 mg
2.6 mL
-
1.3 mL
> 1.2 to 1.3
210 mg
2.9 mL
-
1.4 mL
> 1.3 to 1.4
210 mg
3.1 mL
-
1.5 mL
> 1.4 to 1.5
210 mg
3.3 mL
140 mg
1.7 mL
> 1.5 to 1.6
280 mg
3.5 mL
140 mg
1.8 mL
> 1.6
280 mg
4 mL
140 mg
2 mL
Reference ID: 5500397
6
Patient Population
Coadministered Drug
Recommended IMBRUVICA Dosage
•
Voriconazole 200 mg twice daily
•
Posaconazole suspension 100 mg
once daily, 100 mg twice daily, or
200 mg twice daily
280 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Posaconazole suspension 200 mg
three times daily or 400 mg twice
daily
•
Posaconazole intravenously 300 mg
once daily
•
Posaconazole delayed-release tablets
300 mg once daily
140 mg once daily
Interrupt dose as recommended [see
Dosage and Administration (2.2)].
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
Patients 1 year to
less than 12 years of
age with cGVHD
•
Moderate CYP3A inhibitors
240 mg/m2 once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Voriconazole for suspension 9 mg/kg
(maximum dose: 350 mg) twice daily
160 mg/m2 once daily
•
Posaconazole at any dosage
80 mg/m2 once daily
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage
and Administration (2.1), Drug Interactions (7.1)].
2.4
Dosage Modifications for Use in Hepatic Impairment
Adult Patients with B-cell Malignancies
The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-
Pugh class A).
The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-
Pugh class B).
Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C)
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Reference ID: 5500397
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Patients with cGVHD
The recommended dosage is 140 mg daily for patients 12 years of age and older with total
bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to
Gilbert’s syndrome).
The recommended dosage is 80 mg/m2 daily for patients 1 to less than 12 years of age with total
bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of
non-hepatic origin or due to Gilbert’s syndrome) [see Use in Specific Populations (8.6), Clinical
Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Capsules:
Each 70 mg capsule is a yellow, opaque capsule marked with “ibr 70 mg” in black ink.
Each 140 mg capsule is a white, opaque capsule marked with “ibr 140 mg” in black ink.
Tablets:
Each 140 mg tablet is a yellow green to green round tablet debossed with “ibr” on one side and
“140” on the other side.
Each 280 mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on the
other side.
Each 420 mg tablet is a yellow green to green oblong tablet debossed with “ibr” on one side and
“420” on the other side.
Oral Suspension:
70 mg/mL, white to off-white suspension.
4
CONTRAINDICATIONS
None
5
WARNINGS AND PRECAUTIONS
5.1
Hemorrhage
Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage
(≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage
[including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural
hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who
received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and
petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients
who received IMBRUVICA, respectively [see Adverse Reactions (6.1)].
The mechanism for the bleeding events is not well understood.
Reference ID: 5500397
8
Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the
risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received
IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The
addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to
4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased
this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy
when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-
surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
5.2
Infections
Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with
IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-
cell malignancies who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1,
6.2)]. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii
pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis
according to standard of care in patients who are at increased risk for opportunistic infections.
Monitor and evaluate patients for fever and infections and treat appropriately.
5.3
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death
Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA.
Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received
IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved
monotherapy or combination regimens. These adverse reactions occurred in patients with and
without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities
may be at greater risk of these events.
Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial
fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was
reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in
patients who received IMBRUVICA in unapproved monotherapy or combination regimens.
These events have occurred particularly in patients with cardiac risk factors including
hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients
with acute infections [see Adverse Reactions (6.1)].
Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias
and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for
patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest
pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and
cardiac failure appropriately, follow dose modification guidelines [see Dosage and
Administration (2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.
Reference ID: 5500397
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5.4
Hypertension
Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received
IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients [see
Adverse Reactions (6.1)]. Based on data from a subset of these patients (N=1,124), the median
time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years
of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98
months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or
greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9%
(year 4-5); the overall incidence for the 5-year period was 11%.
Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive
medication throughout treatment with IMBRUVICA as appropriate, and follow dosage
modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration
(2.2)].
5.5
Cytopenias
In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3
or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3
or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions (6.1)].
Monitor complete blood counts monthly.
5.6
Second Primary Malignancies
Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the
1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials [see
Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma
skin cancer (6%).
5.7
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced
liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors,
including IMBRUVICA.
Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA.
For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for
liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected,
withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA.
5.8
Tumor Lysis Syndrome
Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse
Reactions (6.2)]. Assess the baseline risk (e.g., high tumor burden) and take appropriate
precautions. Monitor patients closely and treat as appropriate.
Reference ID: 5500397
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5.9
Embryo-Fetal Toxicity
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of
organogenesis caused embryo-fetal toxicity including malformations at exposures that were
3-20 times higher than those reported in patients with hematologic malignancies. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.
[see Use in Specific Populations (8.1)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Hemorrhage [see Warnings and Precautions (5.1)]
• Infections [see Warnings and Precautions (5.2)]
• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions
(5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Cytopenias [see Warnings and Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
• Hepatotoxicity, including DILI [see Warnings and Precautions (5.7)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely variable conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
another drug and may not reflect the rates observed in practice.
Unless otherwise specified, the pooled safety population described in the WARNINGS AND
PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered
as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally
once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with
other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In
this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and
68% were exposed for greater than one year. The most common adverse reactions (≥ 30%) were
thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising,
and nausea.
Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received
IMBRUVICA in unapproved monotherapy or combination regimens.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The data described below reflect exposure to IMBRUVICA in one single-arm, open-label
clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE,
Reference ID: 5500397
11
RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total,
including n=1,133 patients exposed to IMBRUVICA). In general, patients with creatinine
clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless
of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or
ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients
with previously treated CLL/SLL. RESONATE included 386 randomized patients with
previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab.
RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65
years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574
randomized patients with previously treated CLL or SLL who received IMBRUVICA in
combination with BR or placebo in combination with BR. iLLUMINATE included 228
randomized patients with treatment naïve CLL/SLL who were 65 years or older or with
coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or
chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously
untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination
with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR).
The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%)
were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia,
bruising, and nausea.
Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment
due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia,
arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in
approximately 9% of patients.
Study 1102
Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent
IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of
≥ 10% with a median duration of treatment of 15.6 months are presented in Table 5 and Table 6.
Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
CLL/SLL (N=51) in Study 1102
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
Constipation
Nausea
Stomatitis
Vomiting
Abdominal pain
Dyspepsia
59
22
20
20
18
14
12
4
2
2
0
2
0
0
Skin and subcutaneous
Bruising
51
2
Reference ID: 5500397
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†One patient death due to histiocytic sarcoma.
Table 6: Treatment-Emergent* Hematologic Laboratory Abnormalities
in Patients with CLL/SLL (N=51) in Study 1102
Percent of Patients (N=51)
All Grades (%)
Grade 3 or 4 (%)
Platelets decreased
69
12
Neutrophils decreased
53
26
Hemoglobin decreased
43
0
* Based on laboratory measurements per IWCLL criteria and adverse reactions.
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.
tissue disorders
Rash
Petechiae
25
16
0
0
Infections and infestations
Upper respiratory tract infection
Sinusitis
Skin infection
Pneumonia
Urinary tract infection
47
22
16
12
12
2
6
6
10
2
General disorders and
administration site
conditions
Fatigue
Pyrexia
Peripheral edema
Asthenia
Chills
33
24
22
14
12
6
2
0
6
0
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain
Arthralgia
Muscle spasms
25
24
18
6
0
2
Respiratory, thoracic and
mediastinal disorders
Cough
Oropharyngeal pain
Dyspnea
22
14
12
0
0
0
Nervous system disorders
Dizziness
Headache
20
18
0
2
Vascular disorders
Hypertension
16
8
Metabolism and nutrition
disorders
Decreased appetite
16
2
Neoplasms benign,
malignant, unspecified
Second malignancies
10
2†
Reference ID: 5500397
13
RESONATE
Adverse reactions and laboratory abnormalities described below in Table 7 and Table 8 reflect
exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.
Table 7: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
Arm in Patients with CLL/SLL in RESONATE
Body System
Adverse Reaction
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
48
4
18
2
Nausea
26
2
18
0
Stomatitis*
17
1
6
1
Constipation
15
0
9
0
Vomiting
14
0
6
1
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
28
2
18
1
Arthralgia
17
1
7
0
Muscle spasms
13
0
8
0
Skin and subcutaneous tissue
disorders
Rash*
24
3
13
0
Petechiae
14
0
1
0
Bruising*
12
0
1
0
General disorders and
administration site conditions
Pyrexia
24
2
15
2†
Respiratory, thoracic and
mediastinal disorders
Cough
19
0
23
1
Dyspnea
12
2
10
1
Infections and infestations
Upper respiratory tract
infection
16
1
11
2†
Pneumonia*
15
12†
13
10†
Sinusitis*
11
1
6
0
Urinary tract infection
10
4
5
1
Reference ID: 5500397
14
Body System
Adverse Reaction
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Nervous system disorders
Headache
14
1
6
0
Dizziness
11
0
5
0
Injury, poisoning and
procedural complications
Contusion
11
0
3
0
Eye disorders
Vision blurred
10
0
3
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a
fatal outcome in the ofatumumab arm.
Table 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients
with CLL/SLL in RESONATE
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Neutrophils decreased
51
23
57
26
Platelets decreased
52
5
45
10
Hemoglobin decreased
36
0
21
0
Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia
(8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.
RESONATE-2
Adverse reactions and laboratory abnormalities described below in Table 9 and Table 10 reflect
exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to
chlorambucil was 7.1 months in RESONATE-2.
Table 9: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
Arm in Patients with CLL/SLL in RESONATE-2
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
42
4
17
0
Nausea
22
1
39
1
Reference ID: 5500397
15
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Constipation
16
1
16
0
Stomatitis*
14
1
4
1
Vomiting
13
0
20
1
Abdominal pain
13
3
11
1
Dyspepsia
11
0
2
0
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
36
4
20
0
Arthralgia
16
1
7
1
Muscle spasms
11
0
5
0
General disorders and
administration site conditions
Fatigue
30
1
38
5
Peripheral edema
19
1
9
0
Pyrexia
17
0
14
2
Respiratory, thoracic and
mediastinal disorders
Cough
22
0
15
0
Dyspnea
10
1
10
0
Skin and subcutaneous tissue
disorders
Rash*
21
4
12
2
Bruising*
19
0
7
0
Eye disorders
Dry eye
17
0
5
0
Lacrimation increased
13
0
6
0
Vision blurred
13
0
8
0
Visual acuity reduced
11
0
2
0
Infections and infestations
Upper respiratory tract
infection
17
2
17
2
Skin infection*
15
2
3
1
Pneumonia*
14
8
7
4
Urinary tract infections
10
1
8
1
Vascular disorders
Hypertension*
14
4
1
0
Nervous system disorders
Headache
12
1
10
2
Dizziness
11
0
12
1
Reference ID: 5500397
16
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Investigations
Weight decreased
10
0
12
0
Subjects with multiple events for a given ADR term are counted once only for each ADR term.
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with
CLL/SLL in RESONATE-2
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Neutrophils Decreased
55
28
67
31
Platelets Decreased
47
7
58
14
Hemoglobin Decreased
36
0
39
2
Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm vs 3% in the chlorambucil arm) and neutropenia
(11% in the IMBRUVICA arm vs 12% in the chlorambucil arm) occurred in patients.
HELIOS
Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + BR with a
median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in
HELIOS in patients with previously treated CLL/SLL.
Reference ID: 5500397
17
Table 11: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the
IMBRUVICA Arm in Patients with CLL/SLL in HELIOS
Body System
Adverse Reaction
IMBRUVICA + BR
(N=287)
Placebo + BR
(N=287)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Blood and lymphatic
system disorders
Neutropenia*
66
61
60
56†
Thrombocytopenia*
34
16
26
16
Gastrointestinal disorders
Diarrhea
36
2
23
1
Abdominal pain
12
1
8
<1
Skin and subcutaneous
tissue disorders
Rash*
32
4
25
1
Bruising *
20
<1
8
<1
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
29
2
20
0
Muscle spasms
12
<1
5
0
General disorders and
administration site
conditions
Pyrexia
25
4
22
2
Vascular disorders
Hemorrhage*
19
2†
9
1
Hypertension*
11
5
5
2
Infections and infestations
Bronchitis
13
2
10
3
Skin infection*
10
3
6
2
Metabolism and nutrition
disorders
Hyperuricemia
10
2
6
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
<1 used for frequency above 0 and below 0.5%.
† Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in
the placebo + BR arm.
Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and
2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was
3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR.
Reference ID: 5500397
18
iLLUMINATE
Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA +
obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil +
obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously
untreated CLL/SLL.
Table 12: Adverse Reactions Reported in ≥ 10% of Patients
in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATE
Body System
Adverse Reaction
IMBRUVICA +
Obinutuzumab
(N=113)
Chlorambucil +
Obinutuzumab
(N=115)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Blood and lymphatic system
disorders
Neutropenia*
48
39
64
48
Thrombocytopenia*
36
19
28
11
Anemia
17
4
25
8
Skin and subcutaneous tissue
disorders
Rash*
36
3
11
0
Bruising*
32
3
3
0
Gastrointestinal disorders
Diarrhea
34
3
10
0
Constipation
16
0
12
1
Nausea
12
0
30
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
33
1
23
3
Arthralgia
22
1
10
0
Muscle spasms
13
0
6
0
Respiratory, thoracic and
mediastinal disorders
Cough
27
1
12
0
Injury, poisoning and
procedural complications
Infusion related reaction
25
2
58
8
Vascular disorders
Hemorrhage*
25
1
9
0
Hypertension*
17
4
4
3
Reference ID: 5500397
19
Body System
Adverse Reaction
IMBRUVICA +
Obinutuzumab
(N=113)
Chlorambucil +
Obinutuzumab
(N=115)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
General disorders and
administration site conditions
Pyrexia
19
2
26
1
Fatigue
18
0
17
2
Peripheral edema
12
0
7
0
Infections and infestations
Pneumonia*
16
9
9
4†
Upper respiratory tract
infection
14
1
6
0
Skin infection*
13
1
3
0
Urinary tract infection
12
3
7
1
Nasopharyngitis
12
0
3
0
Conjunctivitis
11
0
2
0
Metabolism and nutrition
disorders
Hyperuricemia
13
1
0
0
Cardiac disorders
Atrial fibrillation
12
5
0
0
Psychiatric disorders
Insomnia
12
0
4
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
† Includes one event with a fatal outcome.
E1912
Adverse reactions described below in Table 13 reflect exposure to IMBRUVICA + rituximab
with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in
E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.
Reference ID: 5500397
20
Table 13: Adverse Reactions Reported in ≥ 15% of Patients
in the IMBRUVICA Arm in Patients with CLL/SLL in E1912
Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
General disorders and
administration site conditions
Fatigue
80
2
78
3
Peripheral edema
28
1
17
0
Pyrexia
27
1
27
1
Pain
23
2
8
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
61
5
35
2
Arthralgia
41
5
10
1
Gastrointestinal disorders
Diarrhea
53
4
27
1
Nausea
40
1
64
1
Stomatitis*
22
1
8
1
Abdominal pain*
19
2
10
1
Vomiting
18
2
28
0
Constipation
17
0
32
0
Skin and subcutaneous tissue
disorders
Rash*
49
4
29
5
Bruising*
36
1
4
1
Vascular disorders
Hypertension*
42
19
22
6
Hemorrhage*
31
2
8
1
Nervous system disorders
Headache
40
1
27
1
Dizziness
21
1
13
1
Peripheral neuropathy*
19
1
13
1
Respiratory, thoracic and
mediastinal disorders
Cough
32
0
25
0
Dyspnea
22
2
21
1
Reference ID: 5500397
21
Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Infections and infestations
Upper respiratory tract
infection
29
1
19
2
Skin infection*
16
1
3
1
Metabolism and nutrition
disorders
Hyperuricemia
19
1
4
0
Decreased appetite
15
0
20
1
Psychiatric disorders
Insomnia
16
1
19
1
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
Table 14: Select Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from
Baseline in Patients Receiving IMBRUVICA (E1912)
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Hematology abnormalities
Neutrophils decreased
Platelets decreased
Hemoglobin decreased
53
43
26
30
7
0
70
69
51
44
25
2
Chemistry abnormalities
Creatinine increased
Bilirubin increased
AST increased
38
30
25
1
2
3
17
15
23
1
0
<1
Based on laboratory measurements per IWCLL criteria.
Waldenström’s Macroglobulinemia
The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials
(Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial
(INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA. Study 1118
included 63 patients with previously treated WM who received single agent IMBRUVICA.
INNOVATE included 150 patients with treatment naïve or previously treated WM who received
IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm
Reference ID: 5500397
22
included 31 patients with previously treated WM who received IMBRUVICA after failure of
prior rituximab-containing therapy.
The most common adverse reactions in Studies 1118 and INNOVATE (≥ 20%) were
neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and
nausea.
Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE
discontinued treatment due to adverse reactions. The most common adverse reaction leading to
discontinuation was atrial fibrillation. Adverse reactions leading to dose reduction occurred in
14% of patients.
Study 1118 and INNOVATE Monotherapy Arm
Adverse reactions and laboratory abnormalities described below in Table 15 and Table 16 reflect
exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 and 33 months
in the INNOVATE Monotherapy Arm.
Table 15: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM
in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
Nausea
Stomatitis*
Constipation
Gastroesophageal reflux disease
38
21
15
12
12
2
0
0
1
0
Skin and subcutaneous tissue
disorders
Bruising*
Rash*
28
21
1
1
Vascular disorders
Hemorrhage*
Hypertension*
28
14
0
4
General disorders and
administrative site conditions
Fatigue
Pyrexia
18
12
2
2
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
Muscle spasms
21
19
0
0
Infections and infestations
Upper respiratory tract infection
Skin infection*
Sinusitis*
Pneumonia*
19
18
16
13
0
3
0
5
Nervous system disorders
Headache
Dizziness
14
13
0
0
Respiratory, thoracic and
mediastinal disorders
Cough
13
0
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Reference ID: 5500397
23
Table 16: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Percent of Patients (N=94)
All Grades (%)
Grade 3 or 4 (%)
Platelets Decreased
38
11
Neutrophils Decreased
43
16
Hemoglobin Decreased
21
6
Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients.
INNOVATE
Adverse reactions described below in Table 17 reflect exposure to IMBRUVICA + R with a
median duration of 25.8 months and exposure to placebo + R with a median duration of
15.5 months in patients with treatment naïve or previously treated WM in INNOVATE.
Table 17: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the
IMBRUVICA Arm in Patients with WM in INNOVATE
Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades
(%)
Grade 3 or
Higher
(%)
All Grades
(%)
Grade 3 or
Higher
(%)
Skin and subcutaneous tissue
disorders
Bruising*
37
1
5
0
Rash*
24
1
11
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
35
4
21
3
Arthralgia
24
3
11
1
Muscle spasms
17
0
12
1
Vascular disorders
Hemorrhage*
32
3
17
4†
Hypertension*
20
13
5
4
Gastrointestinal disorders
Diarrhea
28
0
15
1
Nausea
21
0
12
0
Dyspepsia
16
0
1
0
Constipation
13
1
11
1
Infections and infestations
Pneumonia*
19
13
5
3
Reference ID: 5500397
24
Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades
(%)
Grade 3 or
Higher
(%)
All Grades
(%)
Grade 3 or
Higher
(%)
Skin infection*
17
3
3
0
Urinary tract infection
13
0
0
0
Bronchitis
12
3
7
0
Influenza
12
0
7
1
Viral upper respiratory tract
infection
11
0
7
0
General disorders and
administration site conditions
Peripheral edema
17
0
12
1
Respiratory, thoracic, and
mediastinal disorders
Cough
17
0
11
0
Blood and lymphatic system
disorders
Neutropenia*
16
12
11
4
Cardiac disorders
Atrial fibrillation
15
12
3
1
Nervous system disorders
Dizziness
11
0
7
0
Psychiatric disorders
Insomnia
11
0
4
0
Metabolism and nutrition
disorders
Hypokalemia
11
0
1
1
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes one event with a fatal outcome.
Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR.
Chronic Graft versus Host Disease
Study 1129
The data described below reflect exposure to IMBRUVICA in an open-label clinical trial
(Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid
therapy and required additional therapy [see Clinical Studies (14.3)].
Reference ID: 5500397
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The most common adverse reactions in Study 1129 (≥ 20%) were fatigue, bruising, diarrhea,
thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia.
Atrial fibrillation occurred in one patient (2%) which was Grade 3.
Twenty-four percent of patients receiving IMBRUVICA in Study 1129 discontinued treatment
due to adverse reactions. The most common adverse reactions leading to discontinuation were
fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.
Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect
exposure to IMBRUVICA with a median duration of 4.4 months in Study 1129.
Table 18: Non-Hematologic Adverse Reactions in ≥ 10% of Adult Patients with cGVHD in
Study 1129 (N=42)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher
(%)
General disorders and
administration site
conditions
Fatigue
Pyrexia
Edema peripheral
57
17
12
12
5
0
Skin and subcutaneous tissue
disorders
Bruising*
Rash*
40
12
0
0
Gastrointestinal disorders
Diarrhea
Stomatitis*
Nausea
Constipation
36
29
26
12
10
2
0
0
Musculoskeletal and
connective tissue disorders
Muscle spasms
Musculoskeletal pain*
29
14
2
5
Vascular disorders
Hemorrhage*
26
0
Infections and infestations
Pneumonia*
Upper respiratory tract infection
Sepsis*
21
19
10
14†
0
10
Nervous system disorders
Headache
17
5
Injury, poisoning and
procedural complications
Fall
17
0
Respiratory, thoracic and
mediastinal disorders
Cough
Dyspnea
14
12
0
2
Metabolism and nutrition
disorders
Hypokalemia
12
7
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes 2 events with a fatal outcome.
Reference ID: 5500397
26
Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities
in Adult Patients with cGVHD in Study 1129 (N=42)
Percent of Patients (N=42)
All Grades (%)
Grade 3 or 4 (%)
Platelets decreased
33
0
Neutrophils decreased
10
10
Hemoglobin decreased
24
2
Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.
iMAGINE
The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric
and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or
more lines of systemic therapy. Patients age 12 years and older were treated with IMBRUVICA
420 mg orally once daily, and patients age 1 year to less than 12 years were treated with
IMBRUVICA 240 mg/m2 orally once daily [see Clinical Studies (14.3)]. The median duration of
exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months).
Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious
adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis.
Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis
and acute respiratory distress syndrome (ARDS).
Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of
patients. Adverse reactions which resulted in permanent discontinuation in at least two patients
included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in
19% of patients. Adverse reactions which required dose reduction in at least two patients
included stomatitis.
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia,
musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis,
thrombocytopenia, and headache.
Table 20 summarizes the adverse reactions in iMAGINE.
Table 20: Adverse Reactions (≥ 10%) in Patients with Previously Treated cGVHD Who
Received IMBRUVICA in iMAGINE
Body System
Adverse Reaction
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
General disorders and administration site conditions
Pyrexia
30
11
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Body System
Adverse Reaction
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*
30
2
Osteonecrosis
11
9
Gastrointestinal disorders
Diarrhea
28
2
Abdominal pain*
23
4
Stomatitis*
23
9
Vomiting
19
2
Nausea
19
4
Infections and infestations
Pneumonia*
23
13
Skin infection*
17
4
Sepsis*
11
9†
Nervous system disorders
Headache
21
2
Skin and subcutaneous tissue disorders
Rash*
19
2
Pruritus
13
0
Petechiae
13
0
Respiratory, thoracic and mediastinal disorders
Cough
19
2
Vascular disorders
Hemorrhage*
17
0
Hypertension*
11
4
Blood and lymphatic system disorders
Hypokalemia
15
6
Hypogammaglobulinemia*
11
0
Cardiac Disorders
Sinus tachycardia
11
0
Investigations
Alanine aminotransferase increased
11
2
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes 1 fatal outcome.
Table 21 summarizes the laboratory abnormalities in iMAGINE.
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Table 21: Select Hematologic Laboratory Abnormalities (≥ 10%) That Worsened from
Baseline in Patients with Previously Treated cGVHD Who Received
IMBRUVICA in iMAGINE
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
Hemoglobin decreased
49
13
Platelets decreased
21
4
Neutrophils decreased
13
6
Treatment-emergent Grade 4 neutropenia occurred in 3% of patients.
Additional Important Adverse Reactions
Cardiovascular Events
Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA
(n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with
IMBRUVICA and 5.3 months for 958 patients in the control arm). The incidence of ventricular
tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation,
ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade
3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in
the control arm. The incidence of atrial fibrillation and atrial flutter of any grade was 8.4%
versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with
IMBRUVICA compared to patients in the control arm. In addition, the incidence of cardiac
failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater was 1.2% versus 0.3% in
patients treated with IMBRUVICA compared to patients in the control arm.
The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke,
cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3
or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in
the control arm, respectively.
Diarrhea
In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for
1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm),
diarrhea of any grade occurred at a rate of 43% of patients treated with IMBRUVICA compared
to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of
IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%)
of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.
Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0
to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414)
versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients
compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus
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89% had complete resolution, and 15% versus 11% had not reported resolution at time of
analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median
time from onset to resolution in IMBRUVICA-treated subjects was 7 days (range, 1 to 655)
versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days
(range, 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the control
arm, respectively.
Visual Disturbance
In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for
1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm),
blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with
IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control
arm (5% Grade 1 and < 1% Grade 2 and 3).
Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0
to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-treated patients compared to the
control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had
complete resolution and 40% versus 29% had not reported resolution at the time of analysis in
IMBRUVICA-treated patients compared to the control arm, respectively. The median time from
onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in
IMBRUVICA-treated subjects compared to the control arm, respectively.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of IMBRUVICA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
• Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic
cirrhosis, drug-induced liver injury
• Respiratory disorders: interstitial lung disease
• Metabolic and nutrition disorders: tumor lysis syndrome
• Immune system disorders: anaphylactic shock, angioedema, urticaria
• Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis,
panniculitis, neutrophilic dermatoses, cutaneous vasculitis
• Infections: hepatitis B reactivation
• Nervous system disorders: peripheral neuropathy
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7
DRUG INTERACTIONS
7.1
Effect of CYP3A Inhibitors on Ibrutinib
The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase
ibrutinib plasma concentrations [see Clinical Pharmacology (12.3)]. Increased ibrutinib
concentrations may increase the risk of drug-related toxicity.
Dose modifications of IMBRUVICA are recommended when used concomitantly with
posaconazole, voriconazole and moderate CYP3A inhibitors [see Dosage and Administration
(2.3)].
Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these
inhibitors will be used short-term (such as anti-infectives for seven days or less) [see Dosage and
Administration (2.3)].
Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or
moderate inhibitors of CYP3A.
7.2
Effect of CYP3A Inducers on Ibrutinib
The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib
concentrations. Avoid coadministration with strong CYP3A inducers [see Clinical Pharmacology
(12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
IMBRUVICA can cause fetal harm based on findings from animal studies. There are no
available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major
birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to
pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the
clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities
(see Data). Advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of
10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral
malformations (heart and major vessels) and increased resorptions and post-implantation loss.
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The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with
CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or
greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is
approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at
doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated
with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated
with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is
approximately 2.8 times the exposure in patients with CLL/SLL or WM administered a dose of
420 mg daily.
8.2
Lactation
Risk Summary
There is no information regarding the presence of ibrutinib or its metabolites in human milk, the
effects on the breastfed child, or the effects on milk production. Because of the potential for
serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment
with IMBRUVICA and for 1 week after the last dose.
8.3
Females and Males of Reproductive Potential
IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with
IMBRUVICA and for 1 month after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during
treatment with IMBRUVICA and for 1 month following the last dose.
8.4
Pediatric Use
Chronic GVHD
The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD
after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older.
Use of IMBRUVICA for this indication is supported by evidence from iMAGINE, a study which
included pediatric patients age 1 year and older with previously treated cGVHD, including
patients in the following age groups: one patient 1 year to less than 2 years of age, 20 patients 2
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years to less than 12 years of age, and 19 patients 12 years to less than 17 years of age.
Additional supportive efficacy data was provided from Study 1129 in adults [see Adverse
Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].
The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that
in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based
on body-surface area (BSA) [see Dosage and Administration (2.1)].
The safety and effectiveness of IMBRUVICA have not been established for this indication in
pediatric patients less than 1 year of age.
Mature B-cell Non-Hodgkin Lymphoma
The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were
assessed but have not been established based on an open-label, randomized study
(NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years,
with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for
futility. In the randomized population, major hemorrhage and discontinuation of
chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus
chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.
CLL/SLL, CLL/SLL with 17p deletion, WM
The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in
CLL/SLL, CLL/SLL with 17p deletion, or WM.
8.5
Geriatric Use
Of 992 patients in clinical studies of IMBRUVICA for B-cell malignancies or cGVHD, 62%
were ≥ 65 years of age, while 22% were ≥ 75 years of age [see Clinical Studies (14.1, 14.2,
14.3)]. No overall differences in effectiveness were observed between younger and older
patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension,
and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA
[see Adverse Reactions (6.1)].
8.6
Hepatic Impairment
Adult Patients with B-cell Malignancies
Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C). The
safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic
impairment by Child-Pugh criteria.
Reduce the recommended dose when administering IMBRUVICA to patients with mild or
moderate hepatic impairment (Child-Pugh class A and B). Monitor patients more frequently for
adverse reactions of IMBRUVICA [see Dosage and Administration (2.4), Clinical
Pharmacology (12.3)].
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Patients with cGVHD
Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x ULN (unless of non-
hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering
IMBRUVICA to patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin
or due to Gilbert’s syndrome) [see Dosage and Administration (2.4)].
8.7
Plasmapheresis
Management of hyperviscosity in WM patients may include plasmapheresis before and during
treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
10 OVERDOSAGE
There is no specific experience in the management of ibrutinib overdose in patients. One healthy
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of
1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide
appropriate supportive treatment.
11 DESCRIPTION
Ibrutinib is a kinase inhibitor. It is a white to off-white solid with the empirical formula
C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide,
soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-
[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-
propen-1-one and has the following structure:
IMBRUVICA (ibrutinib) is available as immediate-release oral capsules, immediate-release oral
tablets, and immediate-release oral suspension.
IMBRUVICA (ibrutinib) capsules for oral use are available in the following dosage strengths: 70
mg and 140 mg. Each capsule contains ibrutinib (active ingredient) and the following inactive
ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium
lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg
capsule only), and black ink.
N
N
N
N
NH2
(R)
O
N
O
-0
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IMBRUVICA (ibrutinib) tablets for oral use are available in the following dosage strengths: 140
mg, 280 mg, and 420 mg. Each tablet contains ibrutinib (active ingredient) and the following
inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film
coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets),
polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets), talc, titanium dioxide,
and yellow iron oxide (140 mg and 420 mg tablets).
IMBRUVICA (ibrutinib) oral suspension contains 70 mg/mL ibrutinib (active ingredient) and
the following inactive ingredients: benzyl alcohol, citric acid monohydrate, disodium hydrogen
phosphate, hypromellose, microcrystalline cellulose and carboxymethylcellulose sodium,
purified water and sucralose.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a
covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK
enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and
cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results
in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical
studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as
cell migration and substrate adhesion in vitro.
12.2
Pharmacodynamics
In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in
peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of
≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).
In adult patients with cGVHD, 93% occupancy of the BTK active site in peripheral blood
mononuclear cells was observed at the ibrutinib recommended dose. The mean BTK occupancy
in pediatric patients ranged from 95.1% to 99.6%.
In vitro Platelet Aggregation
Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at
4.6 µM (2026 ng/mL), 0.8 µM (352 ng/mL), and 3 µM (1321 ng/mL) in blood samples from
healthy donors, donors taking warfarin, and donors with severe renal dysfunction,
respectively. Ibrutinib did not show meaningful inhibition of platelet aggregation for ADP,
arachidonic acid, ristocetin, and TRAP-6.
Cardiac Electrophysiology
At a single dose 4 times the maximum recommended dose (1680 mg), IMBRUVICA did not
prolong the QT interval to any clinically relevant extent.
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12.3
Pharmacokinetics
Ibrutinib exposure increases with doses up to 840 mg (2 times the maximum approved
recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC
(% coefficient of variation) observed in patients at 420 mg with CLL/SLL is
708 (71%) ng×h/mL, with WM is 707 (72%) ng×h/mL, and in adult patients with previously
treated cGVHD is 1159 (50%) ng×h/mL. Steady-state concentrations of ibrutinib without
CYP3A inhibitors were achieved with an accumulation ratio of 1 to 1.6 after 1 week of multiple
daily doses of 420 mg.
Absorption
Absolute bioavailability of ibrutinib in fasted condition was 2.9% (90% CI: 2.1, 3.9) in healthy
subjects. Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 2 hours.
Effect of Food
The administration of IMBRUVICA with a high-fat and high-calorie meal (800 calories to
1,000 calories with approximately 50% of total caloric content of the meal from fat) increased
ibrutinib Cmax by 2- to 4-fold and AUC by approximately 2-fold, compared with administration
of ibrutinib after overnight fasting.
In vitro studies suggest that ibrutinib is not a substrate of p-glycoprotein (P-gp) or breast cancer
resistance protein (BCRP).
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no
concentration dependence in the range of 50 ng/mL to 1000 ng/mL. The volume of distribution
(Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was
approximately 10,000 L.
Elimination
Intravenous clearance was 62 L/h in fasted conditions and 76 L/h in fed conditions. In line with
the high first-pass effect, the apparent oral clearance is 2000 L/h in fasted conditions and
1000 L/h in fed conditions. The half-life of ibrutinib is 4 hours to 6 hours.
Metabolism
Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites
primarily by cytochrome P450 (CYP) 3A and to a minor extent by CYP2D6. The active
metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK
approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent
ratio for PCI-45227 at steady-state is 1 to 2.8.
Excretion
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral
administration of radiolabeled ibrutinib, 90% of radioactivity was excreted within 168 hours,
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with 80% excreted in the feces and less than 10% eliminated in urine. Unchanged ibrutinib
accounted for 1% of the radiolabeled excreted dose in feces and none in urine, with the
remainder of the excreted dose being metabolites.
Specific Populations
Age and Sex
Age and sex have no clinically meaningful effect on ibrutinib pharmacokinetics.
Patients with Renal Impairment
Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by
Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. No data is available in
patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.
Patients with Hepatic Impairment
The AUC of ibrutinib increased 2.7-fold in subjects with mild hepatic impairment (Child-Pugh
class A), 8.2-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and
9.8-fold in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with
normal liver function. The Cmax of ibrutinib increased 5.2-fold in mild hepatic impairment,
8.8-fold in moderate hepatic impairment and 7-fold in severe hepatic impairment relative to
subjects with normal liver function [see Use in Specific Populations (8.6)].
Pediatric Patients
In pediatric patients with cGVHD treated with ibrutinib at 240 mg/m2 once daily (patients age
≥ 1 to < 12 years) or 420 mg once daily (patients age ≥ 12 years), the geometric mean (%CV)
steady state AUC and Cmax in patients age ≥ 1 to < 12 years is 467 (102%) ng×h/mL and 65.7
(96%) ng/mL, respectively, and in patients age ≥ 12 to < 17 years is 966 (78%) ng×h/mL and
149 (79%) ng/mL, respectively.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole
(strong CYP3A inhibitor) increased the Cmax of ibrutinib by 29-fold and AUC by 24-fold. The
coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady
state Cmax of ibrutinib by 6.7-fold and AUC by 5.7-fold. Simulations under fed conditions
suggest that posaconazole (strong CYP3A inhibitor) may increase the AUC of ibrutinib 3-fold to
10-fold.
The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased
steady state Cmax of ibrutinib by 3.4-fold and AUC by 3-fold.
Effect of CYP3A Inducers on Ibrutinib: The coadministration of rifampin (strong CYP3A
inducer) decreased the Cmax of ibrutinib by more than 13-fold and AUC by more than 10-fold.
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Simulations suggest that efavirenz (moderate CYP3A inducer) may decrease the AUC of
ibrutinib by 3-fold.
In Vitro Studies
Effect of Ibrutinib on CYP Substrates: In vitro studies suggest that ibrutinib and PCI-45227 are
unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib
and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses.
Effect of Ibrutinib on Substrates of Transporters: In vitro studies suggest that ibrutinib may
inhibit BCRP and P-gp transport at clinical doses. The coadministration of oral P-gp or BCRP
substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ibrutinib was not carcinogenic in a 6-month rasH2 mouse study at oral doses up to
2000 mg/kg/day resulting in exposures approximately 32 (males) to 52 (females) times higher
than the exposure in humans at a dose of 420 mg daily [see Warnings and Precautions (5.6)].
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during
pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female
rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats
continued until end of study. No effects on fertility or reproductive capacities were observed in
male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose
[HED] 16 mg/kg).
14 CLINICAL STUDIES
14.1
Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma
The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one
uncontrolled trial and five randomized, controlled trials.
Study 1102
Study 1102 (NCT01105247), an open-label, multi-center trial, was conducted in 48 previously
treated CLL patients. IMBRUVICA was administered orally at 420 mg once daily until disease
progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version
of the International Workshop on CLL Criteria by an Independent Review Committee.
The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At
baseline, 46% of subjects had at least one tumor ≥ 5 cm.
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The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients
achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR
was not reached.
RESONATE
The RESONATE study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA
versus ofatumumab (NCT01578707), was conducted in patients with previously treated CLL or
SLL. Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until
disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg,
followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4
additional doses. Fifty-seven patients randomized to ofatumumab crossed over following
progression to receive IMBRUVICA.
The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were White. All
patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with
CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median
number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at
least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.
Efficacy results for RESONATE are shown in Table 22 and the Kaplan-Meier curves for PFS,
assessed by an IRC according to IWCLL criteria, and OS are shown in Figure 1 and Figure 2,
respectively.
Table 22: Efficacy Results in Patients with CLL/SLL in RESONATE
Endpoint
IMBRUVICA
N=195
Ofatumumab
N=196
Progression-Free Survivalb
Number of events (%)
35 (17.9)
111 (56.6)
Disease progression
26
93
Death events
9
18
Median (95% CI), months
NE
8.1 (7.2, 8.3)
HR (95% CI)
0.22 (0.15, 0.32)
Overall Survivala
Number of deaths (%)
16 (8.2)
33 (16.8)
HR (95% CI)
0.43 (0.24, 0.79)
Overall Response Rateb
42.6%
4.1%
a Median OS not evaluable for either arm.
b IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
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0
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183
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40
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3
6
9
12
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(Month)
Nat Risk
IMBRUVICA: 195
191
184
11 S
32
s
0
Ofatumumab: 196
183
164
88
21
3
0
39
Figure 1: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in RESONATE
Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with
CLL/SLL in RESONATE
Reference ID: 5500397
40
63-Month Follow-Up
With an overall follow-up of 63 months, the median investigator-assessed PFS per IWCLL
criteria was 44.1 months [95% CI (38.5, 56.9)] in the IMBRUVICA arm and 8.1 months
[95% CI (7.8, 8.3)] in the ofatumumab arm. Overall response rate as assessed by investigators
was 87.2% in the IMBRUVICA arm versus 22.4% in the ofatumumab arm.
CLL/SLL with 17p deletion (del 17p CLL/SLL) in RESONATE
RESONATE included 127 patients with del 17p CLL/SLL. The median age was 67 years (range,
30 to 84 years), 62% were male, and 88% were White. All patients had a baseline ECOG
performance status of 0 or 1. PFS and ORR were assessed by an IRC. Efficacy results for del 17p
CLL/SLL are shown in Table 23.
Table 23: Efficacy Results in Patients with del 17p CLL/SLL in RESONATE
Endpoint
IMBRUVICA
N=63
Ofatumumab
N=64
Progression-Free Survivala
Number of events (%)
16 (25.4)
38 (59.4)
Disease progression
12
31
Death events
4
7
Median (95% CI), months
NE
5.8 (5.3, 7.9)
HR (95% CI)
0.25 (0.14, 0.45)
Overall Response Ratea
47.6%
4.7%
a IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NE = not evaluable.
63-Month Follow-Up
With an overall follow-up of 63 months, the median investigator-assessed PFS in patients with
del 17p per IWCLL criteria was 40.6 months [95% CI (25.4, 44.6)] in the IMBRUVICA arm and
6.2 months [95% CI (4.6, 8.1)] in the ofatumumab arm. Overall response rate as assessed by
investigators in patients with del 17p was 88.9% in the IMBRUVICA arm versus 18.8% in the
ofatumumab arm.
RESONATE-2
The RESONATE-2 study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA
versus chlorambucil (NCT01722487), was conducted in patients with treatment naïve CLL or
SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either
IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil
at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12
cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were White.
Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an
Reference ID: 5500397
41
ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with
SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating
CLL therapy include: progressive marrow failure demonstrated by anemia and/or
thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or
symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).
With a median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and
21 (15.8%) in IMBRUVICA and chlorambucil treatment arms, respectively]. With 41% of
patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT
patient population resulted in a statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and
2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)]
in the IMBRUVICA and chlorambucil arms, respectively.
Efficacy results for RESONATE-2 are shown in Table 24 and the Kaplan-Meier curve for PFS,
assessed by an IRC according to IWCLL criteria is shown in Figure 3.
Table 24: Efficacy Results in Patients with CLL/SLL in RESONATE-2
Endpoint
IMBRUVICA
N=136
Chlorambucil
N=133
Progression-Free Survivala
Number of events (%)
15 (11.0)
64 (48.1)
Disease progression
12
57
Death events
3
7
Median (95% CI), months
NE
18.9 (14.1, 22.0)
HRb (95% CI)
0.16 (0.09, 0.28)
Overall Response Ratea (CR + PR)
82.4%
35.3%
P-value
<0.0001
a IRC evaluated; five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved
complete response.
b HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
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20
10 p<0.0001
0
0
3
6
9
12
15
18
21
24
27 (Month)
Nat Risk
IMBRUVICA:
136
133
130
126
122
98
66
21
2
0
chlorambucil: 133
121
95
85
74
49
34
10
0
0
42
Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in RESONATE-2
55-Month Follow-Up
With an overall follow-up of 55 months, the median PFS was not reached in the IMBRUVICA
arm.
HELIOS
The HELIOS study, a randomized, double-blind, placebo-controlled phase 3 study of
IMBRUVICA in combination with bendamustine and rituximab (BR) (NCT01611090), was
conducted in patients with previously treated CLL or SLL. Patients (n = 578) were randomized
1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease
progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day
cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2
and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles, and all patients had a CLcr ≥ 40
mL/min at baseline. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day
1, and 500 mg/m2 Cycles 2 through 6, Day 1.
The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments).
At baseline, 56% of patients had at least one tumor > 5 cm and 26% presented with del11q.
Efficacy results for HELIOS are shown in Table 25 and the Kaplan-Meier curves for PFS are
shown in Figure 4.
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80
60
40
20
0
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IMBRUVICA + BR
Placebo+ BR
p<0.0001
0
289
289
0
4
8
12
264
247
200
259
234
117
IMBRUVICA + BR
I
I
16
I
20
24
Months
127
52
5
59
17
3
- - -.& - -
Placebo+ BR
IMBRUVICA + BR
'• Placebo+ BR
28
32
36
0
0
0
0
0
0
43
Table 25: Efficacy Results in Patients with CLL/SLL in HELIOS
Endpoint
IMBRUVICA + BR
N=289
Placebo + BR
N=289
Progression-Free Survivala
Number of events (%)
56 (19.4)
183 (63.3)
Median (95% CI), months
NE
13.3 (11.3, 13.9)
HR (95% CI)
0.20 (0.15, 0.28)
Overall Response Ratea
82.7%
67.8%
a IRC evaluated; twenty-four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm
achieved complete response.
BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in HELIOS
iLLUMINATE
The iLLUMINATE study, a randomized, multi-center, phase 3 study of IMBRUVICA in
combination with obinutuzumab versus chlorambucil in combination with obinutuzumab
(NCT02264574), was conducted in patients with treatment naïve CLL or SLL. Patients were 65
Reference ID: 5500397
44
years of age or older or < 65 years of age with coexisting medical conditions, reduced renal
function as measured by creatinine clearance < 70 mL/min, or presence of del 17p/TP53
mutation. Patients (n = 229) were randomized 1:1 to receive either IMBRUVICA 420 mg daily
until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on
Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1,000 mg of
obinutuzumab on Days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5
subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided
between Day 1 (100 mg) and Day 2 (900 mg).
The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were White. All
patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). The trial enrolled
214 patients with CLL and 15 patients with SLL. At baseline, 65% of patients presented with
CLL/SLL with high risk factors (del 17p/TP53 mutation [18%], del 11q [15%], or unmutated
immunoglobulin heavy-chain variable region (unmutated IGHV) [54%]). The most common
reasons for initiating CLL therapy included: lymphadenopathy (38%), night sweats (34%),
progressive marrow failure (31%), fatigue (29%), splenomegaly (25%), and progressive
lymphocytosis (21%).
With a median follow-up time on study of 31 months, efficacy results for iLLUMINATE
assessed by an IRC according to IWCLL criteria are shown in Table 26, and the Kaplan-Meier
curve for PFS is shown in Figure 5.
Table 26: Efficacy Results in Patients with CLL/SLL in iLLUMINATE
Endpoint
IMBRUVICA +
Obinutuzumab
N=113
Chlorambucil +
Obinutuzumab
N=116
Progression-Free Survivala
Number of events (%)
24 (21)
74 (64)
Disease progression
11
64
Death events
13
10
Median (95% CI), months
NE
19.0 (15.1, 22.1)
HR (95% CI)
0.23 (0.15, 0.37)
P-valueb
<0.0001
Overall Response Rate (%)a
88.5
73.3
CRc (%)
19.5
7.8
PRd (%)
69.0
65.5
a IRC-evaluated.
b P-value is from unstratified log-rank test.
c Includes 1 patient in the IMBRUVICA + obinutuzumab arm with a complete response with incomplete marrow recovery (CRi)
d PR = nPR +PR.
HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
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30
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20
10
p<0.0001
0
0
3
6
9
12
15
18
21
24
27
30
33
36
(Month)
Nat Risk
IMBRUVICA +
obinutuzumab: 113
109
106
105
99
94
90
85
82
81
28
6
0
chlorambucil +
obinutuzumab: 116
111
109
102
81
67
56
47
35
33
6
5
0
45
Figure 5: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in iLLUMINATE
In the high risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), the
PFS HR was 0.15 [95% CI (0.09, 0.27)].
E1912
The E1912 study, a randomized, multi-center, phase 3 study of IMBRUVICA in combination
with rituximab versus standard fludarabine, cyclophosphamide, and rituximab (FCR)
chemoimmunotherapy (NCT02048813), was conducted in adult patients who were 70 years or
younger with previously untreated CLL or SLL requiring systemic therapy. All patients had a
CLcr > 40 mL/min at baseline. Patients with 17p deletion were excluded. Patients (n =529) were
randomized 2:1 to receive either IMBRUVICA plus rituximab or FCR. IMBRUVICA was
administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was
administered at a dose of 25 mg/m2, and cyclophosphamide was administered at a dose of
250 mg/m2, both on Days 1, 2, and 3 of Cycles 1-6. Rituximab was initiated in Cycle 2 for the
IMBRUVICA plus rituximab arm and in Cycle 1 for the FCR arm and was administered at 50
mg/m2 on Day 1 of the first cycle, 325 mg/m2 on Day 2 of the first cycle, and 500 mg/m2 on Day
1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.
The median age was 58 years (range, 28 to 70 years), 67% were male, 90% were White and 98%
had a ECOG performance status of 0-1. At baseline, 43% of patients were Rai stage 3 or 4 and
Reference ID: 5500397
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80
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60
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40
30
20
10
p<0.0001
0
0
3
6
9
Nat Risk
IMBRUVICA 354
351
349
345
+ rituximab
fludarabine, 175
158
152
148
cyclophosphamide
+ rituximab
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307
270
227
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159
125
114
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ftudarabine,
cyclophosphamide
+ riluximab
39
42
45
(Month)
108
79
52
34
20
10
46
59% of patients presented with high risk factors (TP53 mutation [6%], del11q [22%], or
unmutated IGHV [53%]).
With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in
Table 27. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria is shown in
Figure 6.
Table 27: Efficacy Results in Patients with CLL/SLL in E1912
Endpoint
IMBRUVICA + R
N=354
FCR
N=175
Progression-Free Survival
Number of events (%)
41 (12)
44 (25)
Disease progression
39
38
Death events
2
6
Median (95% CI), months
NE (49.4, NE)
NE (47.1, NE)
HR (95% CI)
0.34 (0.22, 0.52)
P-valuea
<0.0001
a P-value is from unstratified log-rank test.
FCR = fludarabine, cyclophosphamide, and rituximab; HR = hazard ratio; R = rituximab; NE = not evaluable.
Figure 6: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in E1912
Reference ID: 5500397
47
With a median follow-up time on study of 49 months, median overall survival was not reached
with a total of 23 deaths: 11 (3%) in the IMBRUVICA plus rituximab and 12 (7%) in the FCR
treatment arms.
Lymphocytosis
Upon initiation of single-agent IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50%
increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of
patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of
IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When
IMBRUVICA was administered in combination, lymphocytosis was 7% with IMBRUVICA +
BR versus 6% with placebo + BR and 7% with IMBRUVICA + obinutuzumab versus 1% with
chlorambucil + obinutuzumab.
14.2
Waldenström’s Macroglobulinemia
The safety and efficacy of IMBRUVICA in patients with WM were demonstrated in two single-
arm trials and one randomized, controlled trial.
Study 1118 and INNOVATE Monotherapy Arm
Study 1118 (NCT01614821), an open-label, multi-center, single-arm trial was conducted in 63
previously treated patients with WM. IMBRUVICA was administered orally at 420 mg once
daily until disease progression or unacceptable toxicity. The responses were assessed by
investigators and an IRC using criteria adopted from the International Workshop of
Waldenström’s Macroglobulinemia.
The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At
baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).
Responses, defined as partial response or better, per IRC are shown in Table 28.
Table 28: Response Rate and Duration of Response (DOR) Based on
IRC Assessment in Patients with WM in Study 1118
Total (N=63)
Response rate (CR+VGPR+PR), (%)
61.9
95% CI (%)
(48.8, 73.9)
Complete Response (CR)
0
Very Good Partial Response (VGPR), (%)
11.1
Partial Response (PR), (%)
50.8
Median duration of response, months (range)
NE (2.8+, 18.8+)
CI = confidence interval; NE = not evaluable.
The median time to response was 1.2 months (range, 0.7-13.4 months).
Reference ID: 5500397
48
The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed
prior rituximab-containing therapy and received single-agent IMBRUVICA. The median age
was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG
performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The
median number of prior treatments was 4 (range, 1 to 7 treatments). With an overall follow-up of
61 months, the response rate observed in the INNOVATE monotherapy arm per IRC assessment
was 77% (0% CR, 29% VGPR, 48% PR). The median duration of response was 33 months
(range, 2.4 to 60.2+ months).
INNOVATE
The INNOVATE study, a randomized, double-blind, placebo-controlled, phase 3 study of
IMBRUVICA or placebo in combination with rituximab (NCT02165397), was conducted in
treatment naïve or previously treated patients with WM. Patients (n = 150) were randomized 1:1
to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until
disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of
375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly
rituximab for 4 consecutive weeks (weeks 17-20). The major efficacy outcome measure is
progression-free survival (PFS) assessed by an IRC with additional efficacy measure of response
rate.
The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were White.
Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of
patients had a baseline ECOG performance status of 2. Forty-five percent of patients were
treatment naïve, and 55% of patients were previously treated. Among previously treated patients,
the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median
serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), and MYD88 L265P mutations were
present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for
mutation status.
An exploratory analysis demonstrated a sustained hemoglobin improvement (defined as increase
of ≥ 2 g/dL over baseline for at least 8 weeks without blood transfusions or growth factor
support) in 65% of patients in the IMBRUVICA + R group and 39% of patients in the
placebo + R group.
With an overall follow-up of 63 months, efficacy results as assessed by an IRC at the time of the
final analysis for INNOVATE are shown in Table 29, and the Kaplan-Meier curves for PFS are
shown in Figure 7.
Reference ID: 5500397
100
90
80
70
60
~
0
(f)
u..
50
c..
40
30
20
10
0
0
Nat Risk
lbr+R:
75
Pbo+R: 75
1--. ' I
' ·I -, -,
• I I --, , _
Median Time (mo)
Hazard Ratio
(95% CI)
Log-Rank p-value
3
6
9
12
73
69
67
66
64
54
48
43
'• -, .
·--. I --•---,_ I
'I-,
'
I -..
' - - - - - I I_ - - -
I - 1- -
I- 11 1 -II--1- - - - <II- I
Pbo+R
lbr+R
20<3
NE
0<250
(0<148-0.420)
-
lbr+R
<.0001
Pbo+R
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
60
60
58
57
56
54
54
49
48
47
44
32
22
15
7
39
33
32
31
27
23
19
19
17
17
15
7
4
3
2
(Month)
49
Table 29: Efficacy Results in Patients with WM by IRC in INNOVATE (Final Analysis)
Endpoint
IMBRUVICA + R
N=75
Placebo + R
N=75
Progression-Free Survival
Number of events (%)
22 (29)
50 (67)
Median (95% CI), months
NE (57.7, NE)
20.3 (13.0, 27.6)
HR (95% CI)
0.25 (0.15, 0.42)
P-valuea
<0.0001
Response Rate (CR+VGPR+PR)b
76%
31%
95% CI (%)
(65, 85)
(21, 42)
Complete Response (CR)
1%
1%
Very Good Partial Response (VGPR)
29%
4%
Partial Response (PR)
45%
25%
Median duration of response, months (range)
NE (1.9+, 58.9+)
NE (4.6+, 49.7+)
CI = confidence interval; HR = hazard ratio; NE = not evaluable; R = rituximab.
a P-value is from the stratified log-rank test.
b P-value associated with response rate was <0.0001.
Figure 7: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with WM in INNOVATE
Reference ID: 5500397
50
Median overall survival was not reached for either treatment arm. With an overall follow-up of
63 months, 9 (12%) patients on IMBRUVICA + R and 10 (13.3%) patients on placebo + R had
died. Forty-seven percent of patients randomized to the placebo + R arm crossed over to receive
IMBRUVICA.
14.3
Chronic Graft versus Host Disease
Study 1129
The safety and efficacy of IMBRUVICA in cGVHD were evaluated in Study 1129
(NCT02195869), an open-label, multi-center, single-arm trial of 42 patients with cGVHD after
failure of first line corticosteroid therapy and requiring additional therapy. IMBRUVICA was
administered orally at 420 mg once daily. The responses were assessed by investigators using the
2005 National Institute of Health (NIH) Consensus Panel Response Criteria with two
modifications to align with the updated 2014 NIH Consensus Panel Response Criteria.
The median age was 56 years (range, 19 to 74 years), 52% were male, and 93% were White. The
most common underlying malignancies leading to transplantation were acute lymphocytic
leukemia, acute myeloid leukemia, and CLL. The median time since cGVHD diagnosis was
14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3 treatments), and
60% of patients had a Karnofsky performance score of ≤ 80. The majority of patients (88 %) had
at least 2 organs involved at baseline, with the most commonly involved organs being mouth
(86%), skin (81%), and gastrointestinal tract (33%). The median daily corticosteroid dose
(prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of patients were
receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.
Prophylaxis for infections were managed per institutional guidelines with 79% of patients
receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole
derivatives.
Efficacy results are shown in Table 30.
Table 30: Best Overall Response Rate (ORR) and Sustained Response Rate
Based on Investigator Assessmenta in Patients with cGVHD in Study 1129
Total (N=42)
ORR
28 (67%)
95% CI
(51%, 80%)
Complete Response (CR)
9 (21%)
Partial Response (PR)
19 (45%)
Sustained response rateb
20 (48%)
CI = confidence interval.
a Investigator assessment based on the 2005 NIH Response Criteria with two modifications (added “not evaluable” for
organs with non-cGVHD abnormalities, and organ score change from 0 to 1 was not considered disease
progression.)
b Sustained response rate is defined as the proportion of patients who achieved a CR or PR that was sustained for at
least 20 weeks.
Reference ID: 5500397
51
The median time to response coinciding with the first scheduled response assessment was
12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all organs involved for
cGVHD (skin, mouth, gastrointestinal tract, and liver).
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42)
of patients on at least 2 consecutive visits.
iMAGINE
The safety and efficacy of IMBRUVICA were evaluated in iMAGINE (NCT03790332), an
open-label, multi-center, single-arm trial of IMBRUVICA for the treatment of pediatric and
young adult patients age 1 year to less than 22 years with moderate or severe cGVHD as defined
by NIH Consensus Criteria. The study included 47 patients who required additional therapy after
failure of one or more prior lines of systemic therapy. All patients had platelets ≥ 30 x 109/L;
absolute neutrophil count ≥ 1.0 x 109/L; AST or ALT ≤ 3 x ULN; total bilirubin of ≤ 1.5 x ULN;
and estimated creatinine clearance ≥ 30 mL/min. Patients were excluded if single organ
genitourinary involvement was the only manifestation of cGVHD.
Patients age 12 years and older were treated with IMBRUVICA 420 mg orally once daily, and
patients age 1 year to less than 12 years were treated with IMBRUVICA 240 mg/m2 orally once
daily. Concomitant treatment with supportive care therapies for cGVHD was permitted. Initiation
of new systemic cGVHD therapy while on study was not permitted.
The median age was 13 years (range, 1 to 19 years). Of the 47 patients, 70% of patients were
male, and 36% were White, 9% were Black or African American, 55% were other or unreported.
The median time since cGVHD diagnosis was 16.1 months, the median number of prior cGVHD
treatments was 2 (range, 1 to 12). The majority of patients (87%) had at least 2 organs involved
at baseline, with lung involvement at baseline in 49% of patients; 26% of patients had a
Karnofsky/Lansky performance score of <80. The median daily corticosteroid dose (prednisone
or prednisone equivalent) at baseline was 0.47 mg/kg/day, and 61% (19 of 31) patients were
receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.
Prophylaxis for infections was managed per institutional guidelines, with 72% of patients
receiving combinations of sulfonamides and trimethoprim and 70% receiving systemic
antifungal agents.
The efficacy of IMBRUVICA was established based on overall response rate (ORR) through
Week 25, where overall response included complete response or partial response according to the
2014 National Institutes of Health (NIH) Consensus Development Project Response Criteria. The
efficacy results are shown in Table 31.
Reference ID: 5500397
52
Table 31: Efficacy Results in Patients with Previously Treated cGVHDa in iMAGINE
Total (N=47)
ORR by Week 25
28 (60%)
95% CI (%)
(44, 74)
Complete Response (CR)
2 (4%)
Partial Response (PR)
26 (55%)
Median duration of response, months (95% CI)b
5.3 (2.8, 8.8)
CI = confidence interval; ORR = overall response rate.
a Assessment based on 2014 NIH Consensus Development Project Response Criteria.
b Based on all responders in the study, calculated from first response to progression, death, or new systemic therapies for
cGVHD.
The median time to first response was 0.9 month (range, 0.9 to 6.1 months). The median time
from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI:
4.6, not evaluable).
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in Lee Symptom Scale overall summary score through Week
25 in 50% (13/26) of patients age 12 years and older.
16 HOW SUPPLIED/STORAGE AND HANDLING
Capsules
The 70 mg capsules are supplied as yellow opaque capsules, marked with “ibr 70 mg” in black
ink, in white HDPE bottles with a child-resistant closure:
• 28 capsules per bottle: NDC 57962-070-28
The 140 mg capsules are supplied as white opaque capsules, marked with “ibr 140 mg” in black
ink, in white HDPE bottles with a child-resistant closure:
• 90 capsules per bottle: NDC 57962-140-09
• 120 capsules per bottle: NDC 57962-140-12
Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C
(59°F to 86°F) permitted (see USP Controlled Room Temperature). Retain in original package
until dispensing.
Tablets
The IMBRUVICA (ibrutinib) tablets are supplied in 3 strengths in the following packaging
configurations:
• 140 mg tablets: Yellow green to green round tablets debossed with “ibr” on one side and
“140” on the other side. Carton of one folded blister card containing two 14-count blister
strips for a total of 28 tablets: NDC 57962-014-28
Reference ID: 5500397
53
• 280 mg tablets: Purple oblong tablets debossed with “ibr” on one side and “280” on the
other side. Carton of one folded blister card containing two 14-count blister strips for a
total of 28 tablets: NDC 57962-280-28
• 420 mg tablets: Yellow green to green oblong tablets debossed with “ibr” on one side and
“420” on the other side. Carton of one folded blister card containing two 14-count blister
strips for a total of 28 tablets: NDC 57962-420-28
Store tablets in original packaging at room temperature 20°C to 25°C (68°F to 77°F). Brief
exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature).
Oral Suspension
The IMBRUVICA (ibrutinib) oral suspension is a white to off-white suspension supplied as
108 mL in a 150 mL amber glass bottle with a pre-inserted bottle adapter and a child-resistant
closure. Each mL contains 70 mg of ibrutinib. The oral suspension bottle is provided in a carton
with two 3 mL reusable oral dosing syringes: NDC 57962-007-12.
Store the oral suspension bottle at 2°C to 25°C (36°F to 77°F). Do not freeze. Dispense in
original sealed container. Do not use if the carton seal is broken or missing.
Discard any unused IMBRUVICA oral suspension remaining 60 days after first opening the
bottle.
17 PATIENT COUNSELING INFORMATION
Advise the patients and caregivers to read the FDA-approved patient labeling (Patient
Information and Instructions for Use).
Hemorrhage:
Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe
headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that
IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and
Precautions (5.1)].
Infections:
Inform patients of the possibility of serious infection, and to report any signs or symptoms
(fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions
(5.2)].
Cardiac arrhythmias, cardiac failure, and sudden death:
Inform patients of the possibility of irregular heart rhythm, heart failure and sudden death.
Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting,
shortness of breath, chest discomfort, or edema [see Warnings and Precautions (5.3)].
Hypertension:
Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which
may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.4)].
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54
Second primary malignancies:
Inform patients that other malignancies have occurred in patients who have been treated with
IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions
(5.6)].
Hepatotoxicity, including drug-induced liver injury:
Inform patients that liver problems, including drug-induced liver injury and abnormalities in
liver tests, may develop during IMBRUVICA treatment. Advise patients to contact their
healthcare provider immediately if they experience abdominal discomfort, dark urine, or
jaundice [see Warnings and Precautions (5.7)].
Tumor lysis syndrome:
Inform patients of the potential risk of tumor lysis syndrome and to report any signs and
symptoms associated with this event to their healthcare provider for evaluation [see Warnings
and Precautions (5.8)].
Embryo-fetal toxicity:
Advise women of the potential risk to a fetus. Advise females of reproductive potential to inform
their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions
(5.9), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with
IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive potential to use effective contraception during
treatment with IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations
(8.3), Nonclinical Toxicology (13.1)].
Lactation:
Advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the
last dose [see Use in Specific Populations (8.2)].
Other Important Information:
Inform patients to take IMBRUVICA orally once daily according to their physician’s
instructions and that the oral dosage (capsules or tablets) should be swallowed whole with a glass
of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the
tablets approximately the same time each day [see Dosage and Administration (2.1)].
Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as
soon as possible on the same day with a return to the normal schedule the following day. Patients
should not take extra doses to make up the missed dose [see Dosage and Administration (2.1)].
For IMBRUVICA oral suspension, instruct patients or caregivers to read and follow the
Instructions for Use for proper preparation, administration, storage and disposal [see Dosage and
Administration (2.1)].
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55
Advise patients of the common side effects associated with IMBRUVICA [see Adverse
Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT
INFORMATION.
Advise patients to inform their health care providers of all concomitant medications, including
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug
Interactions (7)].
Advise patients that they may experience loose stools or diarrhea and should contact their doctor
if their diarrhea persists. Advise patients to maintain adequate hydration [see Adverse Reactions
(6.1)].
Distributed and Marketed by:
Pharmacyclics LLC
South San Francisco, CA 94080 USA
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA 19044 USA
Patent http://www.imbruvica.com
IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC
© Pharmacyclics LLC 2024
© Janssen Biotech, Inc. 2024
20088578
Reference ID: 5500397
PATIENT INFORMATION
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
capsules
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
tablets
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
oral suspension
What is IMBRUVICA?
IMBRUVICA is a prescription medicine used to treat:
•
Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
•
Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
•
Adults with Waldenström’s macroglobulinemia (WM).
•
Adults and children 1 year of age and older with chronic graft versus host disease (cGVHD) after failure of 1 or
more lines of systemic therapy.
It is not known if IMBRUVICA is safe and effective in children under 1 year of age.
Before taking IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:
•
have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned
medical, surgical, or dental procedure.
•
have bleeding problems or are taking a blood thinner medicine.
•
have an infection.
•
have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease,
such as high blood pressure, high cholesterol, or diabetes.
•
have liver problems.
•
are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become
pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA. Tell your
healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA.
o
Females who are able to become pregnant should use effective birth control (contraception) during treatment
with IMBRUVICA and for 1 month after the last dose.
o
Males with female partners who are able to become pregnant should use effective birth control, such as
condoms, during treatment with IMBRUVICA and for 1 month after the last dose.
•
are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for 1 week after
the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how
IMBRUVICA works and can cause side effects.
How should I take or give IMBRUVICA?
•
Take or give IMBRUVICA exactly as your healthcare provider tells you to take or give it.
•
Take or give IMBRUVICA 1 time a day at about the same time each day.
IMBRUVICA comes as capsules, tablets, and oral suspension.
•
If your healthcare provider prescribes IMBRUVICA capsules or tablets:
o
Swallow IMBRUVICA capsules or tablets whole with a glass of water.
o
Do not open, break, or chew IMBRUVICA capsules.
o
Do not cut, crush, or chew IMBRUVICA tablets.
•
If your healthcare provider prescribes IMBRUVICA oral suspension:
o
See the detailed Instructions for Use that comes with IMBRUVICA oral suspension for information about the
correct way to take or give a dose. If you have questions about how to take or give IMBRUVICA oral
suspension, talk to your healthcare provider.
o
Do not use if the carton seal is broken or missing.
•
If you miss a dose of IMBRUVICA, take or give it as soon as you remember on the same day. Take or give the next
dose of IMBRUVICA at the regular time on the next day. Do not take or give extra doses of IMBRUVICA to make up
for a missed dose.
•
If you take too much IMBRUVICA, call your healthcare provider, or go to the nearest hospital emergency room right
away.
What should I avoid while taking IMBRUVICA?
Reference ID: 5500397
You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment
with IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.
What are the possible side effects of IMBRUVICA?
IMBRUVICA may cause serious side effects, including:
•
Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA and can also be serious and
may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your
healthcare provider if you have any signs of bleeding, including:
o blood in your stools or black stools (looks like
tar)
o increased bruising, or small red or purple spots
on the skin
o pink or brown urine
o dizziness
o unexpected bleeding, or bleeding that is severe
or that you cannot control
o weakness
o confusion
o vomit blood or vomit looks like coffee grounds
o cough up blood or blood clots
o change in your speech
o headache that lasts a long time or severe
headache
•
Infections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death.
Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms
of an infection during treatment with IMBRUVICA.
•
Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart
failure and death have happened in people treated with IMBRUVICA, especially in people who have an infection,
an increased risk for heart disease, or have had heart rhythm problems in the past. Your heart function will be
checked before and during treatment with IMBRUVICA. Tell your healthcare provider if you get any symptoms of
heart problems, such as:
o
feeling as if your heart is beating
fast and irregular
o
lightheadedness
o
dizziness
o
shortness of breath
o
swelling of the feet, ankles, or
legs
o
chest discomfort
o
feeling faint
If you develop any of these symptoms, your healthcare provider may do tests to check your heart and may change
your IMBRUVICA dose.
•
High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with
IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to
treat your blood pressure.
•
Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are
common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to
check your blood counts.
•
Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of
the skin or other organs.
•
Liver problems. Liver problems, which may be severe or life-threatening, or lead to death, can happen in people
treated with IMBRUVICA. Your healthcare provider will do blood tests to check your liver before and during
treatment with IMBRUVICA. Tell your healthcare provider or get medical help right away if you have any signs of
liver problems, including stomach pain or discomfort, dark-colored urine, or yellow skin and eyes.
•
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure
and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare
provider may do blood tests to check you for TLS.
The most common side effects of IMBRUVICA in adults with B-cell malignancies (CLL/SLL and WM) include:
o
low platelet count
o
diarrhea
o
tiredness
o
muscle, bone, and joint pain
o
low white blood cell count
o
rash
o
low red blood cell count (anemia)
o
bruising
o
nausea
The most common side effects of IMBRUVICA in adults or children 1 year of age and older with cGVHD
include:
o
tiredness
o
low red blood cell count (anemia)
o
bruising
o
diarrhea
o
low platelet count
o
muscle, bone, and joint pain
o
fever
o
muscle spasms
o
mouth sores (stomatitis)
o
bleeding
o
nausea
o
stomach pain
o
pneumonia
o
headache
Reference ID: 5500397
Diarrhea is a common side effect in people who take IMBRUVICA. Drink plenty of fluids during treatment with
IMBRUVICA to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your
healthcare provider if you have diarrhea that does not go away.
These are not all the possible side effects of IMBRUVICA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store IMBRUVICA?
•
Store IMBRUVICA capsules and tablets at room temperature between 68°F and 77°F (20°C and 25°C).
•
Keep IMBRUVICA capsules in the original container with the lid tightly closed.
•
Keep IMBRUVICA tablets in the original carton.
•
Store IMBRUVICA oral suspension bottle between 36°F and 77°F (2°C and 25°C). Do not freeze.
•
Use IMBRUVICA oral suspension within 60 days after first opening the bottle. Throw away (dispose of) any unused
portion 60 days after opening.
•
IMBRUVICA capsules and oral suspension come in a bottle with a child-resistant cap.
Keep IMBRUVICA and all medicines out of the reach of children.
General information about the safe and effective use of IMBRUVICA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have
the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for
information about IMBRUVICA that is written for health professionals.
What are the ingredients in IMBRUVICA?
Active ingredient: ibrutinib
Inactive ingredients:
IMBRUVICA capsules: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl
sulfate. The 70 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and black ink. The 140 mg
capsule shell contains gelatin, titanium dioxide, and black ink.
IMBRUVICA tablets: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric
oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets),
talc, titanium dioxide, and yellow iron oxide (140 mg and 420 mg tablets).
IMBRUVICA oral suspension: benzyl alcohol, citric acid monohydrate, disodium hydrogen phosphate, hypromellose,
microcrystalline cellulose and carboxymethylcellulose sodium, purified water, and sucralose.
Distributed and Marketed by: Pharmacyclics LLC South San Francisco, CA 94080 USA
Marketed by: Janssen Biotech, Inc. Horsham, PA 19044 USA
© Pharmacyclics LLC 2024
© Janssen Biotech, Inc. 2024
20088578
For more information, go to www.imbruvica.com or call 1-877-877-3536.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 5/2024
Reference ID: 5500397
A
A
INSTRUCTIONS FOR USE
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
oral suspension
This Instructions for Use contains information about how to prepare and take or give a dose of
IMBRUVICA oral suspension.
Read this Instructions for Use before you take or give IMBRUVICA and each time you get a refill. There
may be new information.
This Instructions for Use does not take the place of talking to your healthcare provider about your or your
child’s medical condition or treatment.
Call your healthcare provider or 1-877-877-3536 if you need help or have any questions about how to
take or give IMBRUVICA the right way.
Important information you need to know before taking or giving IMBRUVICA.
•
IMBRUVICA is for oral use only.
•
Take or give IMBRUVICA exactly as your healthcare provider tells you to.
•
If you miss a dose of IMBRUVICA, it can be taken or given as soon as possible on the same day.
Do not take or give more than the prescribed dose in 1 day.
If you or your child take too much IMBRUVICA, call your healthcare provider for help.
•
Keep these instructions for future use.
Each IMBRUVICA carton contains (see Figure A):
•
1 bottle of IMBRUVICA (called ‘bottle’ in this Instructions for Use) with pre-inserted bottle adapter
(called ‘adapter’ in this Instructions for Use). Do not remove the bottle adapter.
•
2 reusable 3 mL oral dosing syringes (called ‘syringe’ in this Instructions for Use) measuring in
0.1 mL increments.
Only use the syringes that come with IMBRUVICA. Do not use the syringes for other
patients or with other medicines.
If you cannot read the markings on the syringes, throw them away and call 1-877-877-3536
to get new ones.
Reference ID: 5500397
A
B-Cap
-
Adapter (Do not remove the
adapter)
3 ml
3 ml
Barrel
-
Plunger
Bottle
Syringes
Preparing and taking or giving a dose of IMBRUVICA
Step 1: Gather and check supplies.
•
Check the prescribed dose in milliliters (mLs).
Find this mL marking on the syringe.
•
If the dose is more than the marking on the
syringe, split the dose between syringes as
prescribed.
•
Gather bottle and syringe(s) (see Figure A).
•
Check the bottle and make sure that the bottle has
IMBRUVICA Oral Suspension printed on it and the
expiration date (“EXP”) has not passed.
Do not use IMBRUVICA after the “EXP” date printed
on the carton and on the bottle.
Do not use if the IMBRUVICA carton seal appears to
be tampered with.
Figure A
Step 2: Record or check the discard date.
•
When opening the bottle for the first time, record
the date that is 60 days from the day the bottle is
opened underneath the words “Discard Date” (see
Figure B).
•
Use IMBRUVICA within 60 days after first opening
the bottle.
Do not use IMBRUVICA past the discard date
recorded on the bottle.
Figure B
Reference ID: 5500397
Ii\
Step 3: Shake the bottle.
•
Shake the bottle well before each use (see Figure
C).
Figure C
Step 4: Remove the cap from the bottle.
•
Press down and twist the cap counterclockwise to
remove it from the bottle (see Figure D).
•
If there is fluid on top of the adapter, you may wipe
it with a clean disposable tissue.
Do not remove the bottle adapter.
Figure D
Step 5: Attach the syringe to the bottle.
•
Make sure the syringe is clean and dry before
use.
•
Push the plunger down all the way.
•
Gently insert tip of the syringe into the adapter.
•
Turn the assembled bottle and syringe upside
down (see Figure E).
Figure E
Reference ID: 5500397
A
Step 6: Fill the syringe.
•
Slowly pull the syringe plunger down, past the
number of mLs for your prescribed dose (see Figure
F).
•
Check for air bubbles and proceed to Step 7 for
instructions on how to remove air bubbles.
Figure F
Step 7: Remove air bubbles and adjust to the prescribed
dose (mL).
•
Hold the syringe and tap the sides to send
bubbles to the tip.
•
With the syringe attached to the bottle, push the
plunger up to remove the air bubbles from the top
(see Figure G).
•
After the bubbles are removed, push the plunger
up until the top of the colored plunger is even with
the markings on the syringe for the prescribed
dose.
Air bubbles must be removed to ensure the correct
dose.
Note: Repeat steps 6 and 7 if any air bubbles remain.
Figure G
Reference ID: 5500397
Step 8: Remove the syringe from the bottle.
•
Turn the assembled bottle upright.
•
Hold the middle of the syringe and carefully
remove it from the bottle (see Figure H).
•
Place the bottle aside.
Do not touch the plunger of the syringe to avoid
accidentally spilling the medicine before you are
ready to take or give the dose.
Note: If more than 1 syringe is needed to take or give the full
dose, repeat steps 5 to 8 with the second syringe to complete
the prescribed dose.
Figure H
Step 9: Take or give IMBRUVICA.
•
Place the tip of the syringe along the inside of the
cheek.
•
Slowly push the plunger all the way in to take or
give the entire dose (see Figure I).
•
Repeat with second syringe if needed to complete
the prescribed dose.
Note: IMBRUVICA must be taken or given as soon as
possible after being drawn from the bottle.
Note: After swallowing the dose of medicine make sure to
drink water.
Figure I
Step 10: Recap the bottle.
•
Place the cap back on the IMBRUVICA bottle (see
Figure J).
•
Make sure the bottle is tightly closed between
each use.
Figure J
Reference ID: 5500397
➔
Step 11: Rinse the syringe.
•
Remove the plunger from the syringe.
•
Rinse the plunger and the syringe only with water
and air dry (see Figure K).
•
Store the syringe in a clean, dry place.
Do not clean the syringe with soap or in the dishwasher.
Figure K
Turn over for more information
How to store IMBRUVICA Oral Suspension
•
Store the bottle between 36°F and 77°F (2°C and 25°C).
Do not freeze.
•
IMBRUVICA oral suspension comes in a bottle with a child-resistant cap.
•
Store IMBRUVICA and all medications out of the reach of children.
How to dispose of IMBRUVICA
Throw away (dispose of) any unused medicine within 60 days after first opening of the
bottle. At the same time, throw away any used or unused syringes.
•
Ask your pharmacist how to properly dispose of the medicine.
•
For syringe disposal, rinse and place in household trash.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed and Marketed by:
Pharmacyclics LLC
South San Francisco, CA 94080 USA
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA 19044 USA
Patent http://www.imbruvica.com
IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC
© 2024 Pharmacyclics LLC
© 2024 Janssen Biotech, Inc.
20080493
Revised: 2/2024
Reference ID: 5500397
| custom-source | 2025-02-12T15:48:09.915280 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205552s043,210563s019,217003s004lbl.pdf', 'application_number': 205552, 'submission_type': 'SUPPL ', 'submission_number': 43} |
80,732 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IMBRUVICA safely and effectively. See full prescribing information for
IMBRUVICA.
IMBRUVICA® (ibrutinib) capsules, for oral use
IMBRUVICA® (ibrutinib) tablets, for oral use
IMBRUVICA® (ibrutinib) oral suspension
Initial U.S. Approval: 2013
----------------------------RECENT MAJOR CHANGES--------------------------
Warnings and Precautions, Hepatotoxicity,
Including Drug-Induced Liver Injury (5.7)
5/2024
----------------------------INDICATIONS AND USAGE---------------------------
IMBRUVICA is a kinase inhibitor indicated for the treatment of:
•
Adult patients with chronic lymphocytic leukemia (CLL)/Small
lymphocytic lymphoma (SLL) (1.1).
•
Adult patients with chronic lymphocytic leukemia (CLL)/Small
lymphocytic lymphoma (SLL) with 17p deletion (1.2).
•
Adult patients with Waldenström’s macroglobulinemia (WM) (1.3).
•
Adult and pediatric patients age 1 year and older with chronic graft versus
host disease (cGVHD) after failure of one or more lines of systemic
therapy (1.4).
-----------------------DOSAGE AND ADMINISTRATION-----------------------
•
CLL/SLL and WM: 420 mg taken orally once daily (2.1).
•
cGVHD:
o Patients 12 years and older: 420 mg taken orally once daily (2.1).
o Patients 1 to less than 12 years of age: 240 mg/m2 taken orally once
daily (up to a dose of 420 mg) (2.1).
Tablets or capsules should be taken orally with a glass of water. Do not open,
break, or chew the capsules. Do not cut, crush, or chew the tablets. See full
prescribing information for oral suspension administration instructions (2.1).
----------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsules: 70 mg and 140 mg (3)
Tablets: 140 mg, 280 mg, and 420 mg (3)
Oral suspension: 70 mg/mL (3)
------------------------------CONTRAINDICATIONS------------------------------
None (4)
------------------------WARNINGS AND PRECAUTIONS-----------------------
• Hemorrhage: Monitor for bleeding and manage (5.1).
• Infections: Monitor patients for fever and infections, evaluate promptly,
and treat (5.2).
• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Monitor for
symptoms of arrhythmias and cardiac failure and manage (5.3).
• Hypertension: Monitor blood pressure and treat (5.4).
• Cytopenias: Check complete blood counts monthly (5.5).
• Second Primary Malignancies: Other malignancies have occurred in
patients, including skin cancers, and other carcinomas (5.6).
• Hepatotoxicity, Including Drug-Induced Liver Injury: Monitor hepatic
function throughout treatment (5.7).
• Tumor Lysis Syndrome (TLS): Assess baseline risk and take precautions.
Monitor and treat for TLS (5.8).
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use effective
contraception (5.9, 8.1, 8.3).
------------------------------ADVERSE REACTIONS-------------------------------
• The most common (≥30%) adverse reactions in patients with B-cell
malignancies are thrombocytopenia, diarrhea, fatigue, musculoskeletal
pain, neutropenia, rash, anemia, bruising, and nausea (6).
• The most common (≥20%) adverse reactions in adult or pediatric patients
with cGVHD are fatigue, anemia, bruising, diarrhea, thrombocytopenia,
musculoskeletal pain, pyrexia, muscle spasms, stomatitis, hemorrhage,
nausea, abdominal pain, pneumonia, and headache (6).
To report SUSPECTED ADVERSE REACTIONS, contact
Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS------------------------------
• CYP3A Inhibitors: Modify IMBRUVICA dose as described (2.3, 7.1).
• CYP3A Inducers: Avoid coadministration with strong CYP3A inducers
(7.2).
-----------------------USE IN SPECIFIC POPULATIONS------------------------
• Lactation: Advise not to breastfeed (8.2).
• Hepatic Impairment: Avoid use of IMBRUVICA in patients with severe
hepatic impairment. In patients with mild or moderate impairment, reduce
IMBRUVICA dose (2.4, 8.6).
See 17 for PATIENT COUNSELING INFORMATION and FDA
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma
1.2
Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma with 17p deletion
1.3
Waldenström’s Macroglobulinemia
1.4
Chronic Graft versus Host Disease
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2
Dosage Modifications for Adverse Reactions
2.3
Dosage Modifications for Use with CYP3A Inhibitors
2.4
Dosage Modifications for Use in Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hemorrhage
5.2
Infections
5.3
Cardiac Arrhythmias, Cardiac Failure, and Sudden
Death
5.4
Hypertension
5.5
Cytopenias
5.6
Second Primary Malignancies
5.7
Hepatotoxicity, Including Drug-Induced Liver Injury
5.8
Tumor Lysis Syndrome
5.9
Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Effect of CYP3A Inhibitors on Ibrutinib
7.2
Effect of CYP3A Inducers on Ibrutinib
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Plasmapheresis
10 OVERDOSAGE
11
DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Chronic Lymphocytic Leukemia / Small Lymphocytic
Lymphoma
14.2
Waldenström’s Macroglobulinemia
14.3
Chronic Graft versus Host Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5500397
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL).
1.2
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia
(CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
1.3
Waldenström’s Macroglobulinemia
IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s
macroglobulinemia (WM).
1.4
Chronic Graft versus Host Disease
IMBRUVICA is indicated for the treatment of adult and pediatric patients age 1 year and older
with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic
therapy.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s
Macroglobulinemia
The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily
until disease progression or unacceptable toxicity.
For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with
rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).
For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider
administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
Chronic Graft versus Host Disease
The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is
420 mg orally once daily, and for patients 1 to less than 12 years of age with cGVHD is 240
mg/m2 orally once daily (up to a dose of 420 mg), until cGVHD progression, recurrence of an
underlying malignancy, or unacceptable toxicity. When a patient no longer requires therapy for
the treatment of cGVHD, IMBRUVICA should be discontinued considering the medical
assessment of the individual patient.
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Table 1: Recommended dosage based on body surface area (BSA) for patients 1 to less than
12 years of age using either IMBRUVICA capsules/tablets or oral suspension
Recommended dose to achieve 240 mg/m2
BSA* (m2)
Range
Dose (mg) of IMBRUVICA
Capsules/Tablets to Administer
Volume (mL) of IMBRUVICA Oral
Suspension (70 mg/mL) to Administer
> 0.3 to 0.4
-
1.2 mL
> 0.4 to 0.5
-
1.5 mL
> 0.5 to 0.6
-
1.9 mL
> 0.6 to 0.7
-
2.2 mL
> 0.7 to 0.8
210 mg
2.6 mL
> 0.8 to 0.9
210 mg
2.9 mL
> 0.9 to 1
210 mg
3.3 mL
> 1 to 1.1
280 mg
3.6 mL
> 1.1 to 1.2
280 mg
4 mL
> 1.2 to 1.3
280 mg
4.3 mL
> 1.3 to 1.4
350 mg
4.6 mL
> 1.4 to 1.5
350 mg
5 mL
> 1.5 to 1.6
350 mg
5.3 mL
> 1.6
420 mg
6 mL
*BSA = body surface area.
Administration
Administer IMBRUVICA at approximately the same time each day.
Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the
capsules. Do not cut, crush, or chew the tablets.
Follow Instructions for Use for further administration details of IMBRUVICA oral suspension.
If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible
on the same day with a return to the normal schedule the following day. Do not take extra doses
of IMBRUVICA to make up for the missed dose.
2.2
Dosage Modifications for Adverse Reactions
For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Once the adverse
reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage
modifications (see Table 2).
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Table 2: Recommended Dosage Modifications for Adverse Reactions
Adverse Reactiona,b
Occurrence
Dose Modification for
CLL/SLL, WM, and
Patients 12 Years or older
with cGVHD After
Recovery
Starting Dose = 420 mg
Dose Modification for
Patients 1 Year to less than
12 Years with cGVHD
After Recovery
Starting Dose = 240 mg/m2
Grade 2 cardiac failure
First
Restart at 280 mg dailyc
Restart at 160 mg/m2 dailyc
Second
Restart at 140 mg dailyc
Restart at 80 mg/m2 dailyc
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 cardiac arrhythmias
First
Restart at 280 mg dailyc
Restart at 160 mg/m2 dailyc
Second
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Grade 3 or 4 cardiac failure
Grade 4 cardiac arrhythmias
First
Discontinue IMBRUVICA
Discontinue IMBRUVICA
Other Grade 3 or 4 non-
hematological toxicitiesd
Grade 3 or 4 neutropenia
with infection or fever
Grade 4 hematological
toxicities
First
Restart at 280 mg daily
Restart at 160 mg/m2 dailyc
Second
Restart at 140 mg daily
Restart at 80 mg/m2 dailyc
Third
Discontinue IMBRUVICA
Discontinue IMBRUVICA
a [see Warnings and Precautions (5)].
b Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or
International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.
c Evaluate the benefit-risk before resuming treatment.
d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.
Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA
capsules/tablets or oral suspension
Recommended dose to achieve 160 mg/m2
Recommended dose to achieve 80 mg/m2
BSA* (m2)
Range
Dose (mg) of
IMBRUVICA
Capsules/Tablets to
Administer
Volume (mL) of
IMBRUVICA Oral
Suspension (70
mg/mL) to
Administer
Dose (mg) of
IMBRUVICA
Capsules/Tablets to
Administer
Volume (mL) of
IMBRUVICA Oral
Suspension (70
mg/mL) to
Administer
> 0.3 to 0.4
-
0.8 mL
-
0.4 mL
> 0.4 to 0.5
-
1 mL
-
0.5 mL
> 0.5 to 0.6
-
1.3 mL
-
0.6 mL
> 0.6 to 0.7
-
1.5 mL
-
0.7 mL
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*BSA = body surface area.
2.3
Dosage Modifications for Use with CYP3A Inhibitors
Recommended dosage modifications are described below [see Drug Interactions (7.1)]:
Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors
Patient Population
Coadministered Drug
Recommended IMBRUVICA Dosage
B-cell Malignancies
•
Moderate CYP3A inhibitor
280 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Voriconazole 200 mg twice daily
•
Posaconazole suspension 100 mg
once daily, 100 mg twice daily, or
200 mg twice daily
140 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Posaconazole suspension 200 mg
three times daily or 400 mg twice
daily
•
Posaconazole intravenously 300 mg
once daily
•
Posaconazole delayed-release tablets
300 mg once daily
70 mg once daily
Interrupt dose as recommended [see
Dosage and Administration (2.2)].
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
Patients 12 years
and older with
cGVHD
• Moderate CYP3A inhibitor
420 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
> 0.7 to 0.8
140 mg
1.7 mL
70 mg
0.9 mL
> 0.8 to 0.9
140 mg
1.9 mL
70 mg
1 mL
> 0.9 to 1
140 mg
2.2 mL
70 mg
1.1 mL
> 1 to 1.1
140 mg
2.4 mL
70 mg
1.2 mL
> 1.1 to 1.2
210 mg
2.6 mL
-
1.3 mL
> 1.2 to 1.3
210 mg
2.9 mL
-
1.4 mL
> 1.3 to 1.4
210 mg
3.1 mL
-
1.5 mL
> 1.4 to 1.5
210 mg
3.3 mL
140 mg
1.7 mL
> 1.5 to 1.6
280 mg
3.5 mL
140 mg
1.8 mL
> 1.6
280 mg
4 mL
140 mg
2 mL
Reference ID: 5500397
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Patient Population
Coadministered Drug
Recommended IMBRUVICA Dosage
•
Voriconazole 200 mg twice daily
•
Posaconazole suspension 100 mg
once daily, 100 mg twice daily, or
200 mg twice daily
280 mg once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Posaconazole suspension 200 mg
three times daily or 400 mg twice
daily
•
Posaconazole intravenously 300 mg
once daily
•
Posaconazole delayed-release tablets
300 mg once daily
140 mg once daily
Interrupt dose as recommended [see
Dosage and Administration (2.2)].
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
Patients 1 year to
less than 12 years of
age with cGVHD
•
Moderate CYP3A inhibitors
240 mg/m2 once daily
Modify dose as recommended [see
Dosage and Administration (2.2)].
•
Voriconazole for suspension 9 mg/kg
(maximum dose: 350 mg) twice daily
160 mg/m2 once daily
•
Posaconazole at any dosage
80 mg/m2 once daily
•
Other strong CYP3A inhibitors
Avoid concomitant use.
If these inhibitors will be used short-
term (such as anti-infectives for seven
days or less), interrupt IMBRUVICA.
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage
and Administration (2.1), Drug Interactions (7.1)].
2.4
Dosage Modifications for Use in Hepatic Impairment
Adult Patients with B-cell Malignancies
The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-
Pugh class A).
The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-
Pugh class B).
Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C)
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
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Patients with cGVHD
The recommended dosage is 140 mg daily for patients 12 years of age and older with total
bilirubin level >1.5 to 3 x upper limit of normal (ULN) (unless of non-hepatic origin or due to
Gilbert’s syndrome).
The recommended dosage is 80 mg/m2 daily for patients 1 to less than 12 years of age with total
bilirubin level >1.5 to 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of
non-hepatic origin or due to Gilbert’s syndrome) [see Use in Specific Populations (8.6), Clinical
Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Capsules:
Each 70 mg capsule is a yellow, opaque capsule marked with “ibr 70 mg” in black ink.
Each 140 mg capsule is a white, opaque capsule marked with “ibr 140 mg” in black ink.
Tablets:
Each 140 mg tablet is a yellow green to green round tablet debossed with “ibr” on one side and
“140” on the other side.
Each 280 mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on the
other side.
Each 420 mg tablet is a yellow green to green oblong tablet debossed with “ibr” on one side and
“420” on the other side.
Oral Suspension:
70 mg/mL, white to off-white suspension.
4
CONTRAINDICATIONS
None
5
WARNINGS AND PRECAUTIONS
5.1
Hemorrhage
Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage
(≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage
[including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural
hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who
received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and
petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients
who received IMBRUVICA, respectively [see Adverse Reactions (6.1)].
The mechanism for the bleeding events is not well understood.
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Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the
risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received
IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The
addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to
4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased
this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy
when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-
surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].
5.2
Infections
Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with
IMBRUVICA therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-
cell malignancies who received IMBRUVICA in clinical trials [see Adverse Reactions (6.1,
6.2)]. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii
pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis
according to standard of care in patients who are at increased risk for opportunistic infections.
Monitor and evaluate patients for fever and infections and treat appropriately.
5.3
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death
Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA.
Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received
IMBRUVICA in clinical trials, including in patients who received IMBRUVICA in unapproved
monotherapy or combination regimens. These adverse reactions occurred in patients with and
without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities
may be at greater risk of these events.
Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial
fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was
reported in 1.3% of 4,896 patients who received IMBRUVICA in clinical trials, including in
patients who received IMBRUVICA in unapproved monotherapy or combination regimens.
These events have occurred particularly in patients with cardiac risk factors including
hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients
with acute infections [see Adverse Reactions (6.1)].
Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias
and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for
patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest
pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and
cardiac failure appropriately, follow dose modification guidelines [see Dosage and
Administration (2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.
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5.4
Hypertension
Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received
IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients [see
Adverse Reactions (6.1)]. Based on data from a subset of these patients (N=1,124), the median
time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years
of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98
months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or
greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9%
(year 4-5); the overall incidence for the 5-year period was 11%.
Monitor blood pressure in patients treated with IMBRUVICA, initiate or adjust anti-hypertensive
medication throughout treatment with IMBRUVICA as appropriate, and follow dosage
modification guidelines for Grade 3 or higher hypertension [see Dosage and Administration
(2.2)].
5.5
Cytopenias
In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3
or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3
or 4 anemia in 2.8%, based on laboratory measurements [see Adverse Reactions (6.1)].
Monitor complete blood counts monthly.
5.6
Second Primary Malignancies
Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the
1,476 patients with B-cell malignancies who received IMBRUVICA in clinical trials [see
Adverse Reactions (6.1)]. The most frequent second primary malignancy was non-melanoma
skin cancer (6%).
5.7
Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced
liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors,
including IMBRUVICA.
Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA.
For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for
liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected,
withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA.
5.8
Tumor Lysis Syndrome
Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse
Reactions (6.2)]. Assess the baseline risk (e.g., high tumor burden) and take appropriate
precautions. Monitor patients closely and treat as appropriate.
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5.9
Embryo-Fetal Toxicity
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a
pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of
organogenesis caused embryo-fetal toxicity including malformations at exposures that were
3-20 times higher than those reported in patients with hematologic malignancies. Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.
[see Use in Specific Populations (8.1)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Hemorrhage [see Warnings and Precautions (5.1)]
• Infections [see Warnings and Precautions (5.2)]
• Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions
(5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Cytopenias [see Warnings and Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
• Hepatotoxicity, including DILI [see Warnings and Precautions (5.7)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely variable conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
another drug and may not reflect the rates observed in practice.
Unless otherwise specified, the pooled safety population described in the WARNINGS AND
PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered
as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally
once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with
other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In
this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and
68% were exposed for greater than one year. The most common adverse reactions (≥ 30%) were
thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising,
and nausea.
Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received
IMBRUVICA in unapproved monotherapy or combination regimens.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The data described below reflect exposure to IMBRUVICA in one single-arm, open-label
clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE,
Reference ID: 5500397
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RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total,
including n=1,133 patients exposed to IMBRUVICA). In general, patients with creatinine
clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless
of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or
ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients
with previously treated CLL/SLL. RESONATE included 386 randomized patients with
previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab.
RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65
years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574
randomized patients with previously treated CLL or SLL who received IMBRUVICA in
combination with BR or placebo in combination with BR. iLLUMINATE included 228
randomized patients with treatment naïve CLL/SLL who were 65 years or older or with
coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or
chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously
untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination
with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR).
The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%)
were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia,
bruising, and nausea.
Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment
due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia,
arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in
approximately 9% of patients.
Study 1102
Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent
IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of
≥ 10% with a median duration of treatment of 15.6 months are presented in Table 5 and Table 6.
Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
CLL/SLL (N=51) in Study 1102
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
Constipation
Nausea
Stomatitis
Vomiting
Abdominal pain
Dyspepsia
59
22
20
20
18
14
12
4
2
2
0
2
0
0
Skin and subcutaneous
Bruising
51
2
Reference ID: 5500397
12
†One patient death due to histiocytic sarcoma.
Table 6: Treatment-Emergent* Hematologic Laboratory Abnormalities
in Patients with CLL/SLL (N=51) in Study 1102
Percent of Patients (N=51)
All Grades (%)
Grade 3 or 4 (%)
Platelets decreased
69
12
Neutrophils decreased
53
26
Hemoglobin decreased
43
0
* Based on laboratory measurements per IWCLL criteria and adverse reactions.
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.
tissue disorders
Rash
Petechiae
25
16
0
0
Infections and infestations
Upper respiratory tract infection
Sinusitis
Skin infection
Pneumonia
Urinary tract infection
47
22
16
12
12
2
6
6
10
2
General disorders and
administration site
conditions
Fatigue
Pyrexia
Peripheral edema
Asthenia
Chills
33
24
22
14
12
6
2
0
6
0
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain
Arthralgia
Muscle spasms
25
24
18
6
0
2
Respiratory, thoracic and
mediastinal disorders
Cough
Oropharyngeal pain
Dyspnea
22
14
12
0
0
0
Nervous system disorders
Dizziness
Headache
20
18
0
2
Vascular disorders
Hypertension
16
8
Metabolism and nutrition
disorders
Decreased appetite
16
2
Neoplasms benign,
malignant, unspecified
Second malignancies
10
2†
Reference ID: 5500397
13
RESONATE
Adverse reactions and laboratory abnormalities described below in Table 7 and Table 8 reflect
exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab
with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.
Table 7: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
Arm in Patients with CLL/SLL in RESONATE
Body System
Adverse Reaction
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
48
4
18
2
Nausea
26
2
18
0
Stomatitis*
17
1
6
1
Constipation
15
0
9
0
Vomiting
14
0
6
1
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
28
2
18
1
Arthralgia
17
1
7
0
Muscle spasms
13
0
8
0
Skin and subcutaneous tissue
disorders
Rash*
24
3
13
0
Petechiae
14
0
1
0
Bruising*
12
0
1
0
General disorders and
administration site conditions
Pyrexia
24
2
15
2†
Respiratory, thoracic and
mediastinal disorders
Cough
19
0
23
1
Dyspnea
12
2
10
1
Infections and infestations
Upper respiratory tract
infection
16
1
11
2†
Pneumonia*
15
12†
13
10†
Sinusitis*
11
1
6
0
Urinary tract infection
10
4
5
1
Reference ID: 5500397
14
Body System
Adverse Reaction
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Nervous system disorders
Headache
14
1
6
0
Dizziness
11
0
5
0
Injury, poisoning and
procedural complications
Contusion
11
0
3
0
Eye disorders
Vision blurred
10
0
3
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a
fatal outcome in the ofatumumab arm.
Table 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients
with CLL/SLL in RESONATE
IMBRUVICA
(N=195)
Ofatumumab
(N=191)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Neutrophils decreased
51
23
57
26
Platelets decreased
52
5
45
10
Hemoglobin decreased
36
0
21
0
Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA arm vs 3% in the ofatumumab arm) and neutropenia
(8% in the IMBRUVICA arm vs 8% in the ofatumumab arm) occurred in patients.
RESONATE-2
Adverse reactions and laboratory abnormalities described below in Table 9 and Table 10 reflect
exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to
chlorambucil was 7.1 months in RESONATE-2.
Table 9: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated
Arm in Patients with CLL/SLL in RESONATE-2
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
42
4
17
0
Nausea
22
1
39
1
Reference ID: 5500397
15
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Constipation
16
1
16
0
Stomatitis*
14
1
4
1
Vomiting
13
0
20
1
Abdominal pain
13
3
11
1
Dyspepsia
11
0
2
0
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
36
4
20
0
Arthralgia
16
1
7
1
Muscle spasms
11
0
5
0
General disorders and
administration site conditions
Fatigue
30
1
38
5
Peripheral edema
19
1
9
0
Pyrexia
17
0
14
2
Respiratory, thoracic and
mediastinal disorders
Cough
22
0
15
0
Dyspnea
10
1
10
0
Skin and subcutaneous tissue
disorders
Rash*
21
4
12
2
Bruising*
19
0
7
0
Eye disorders
Dry eye
17
0
5
0
Lacrimation increased
13
0
6
0
Vision blurred
13
0
8
0
Visual acuity reduced
11
0
2
0
Infections and infestations
Upper respiratory tract
infection
17
2
17
2
Skin infection*
15
2
3
1
Pneumonia*
14
8
7
4
Urinary tract infections
10
1
8
1
Vascular disorders
Hypertension*
14
4
1
0
Nervous system disorders
Headache
12
1
10
2
Dizziness
11
0
12
1
Reference ID: 5500397
16
Body System
Adverse Reaction
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Investigations
Weight decreased
10
0
12
0
Subjects with multiple events for a given ADR term are counted once only for each ADR term.
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with
CLL/SLL in RESONATE-2
IMBRUVICA
(N=135)
Chlorambucil
(N=132)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Neutrophils Decreased
55
28
67
31
Platelets Decreased
47
7
58
14
Hemoglobin Decreased
36
0
39
2
Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm vs 3% in the chlorambucil arm) and neutropenia
(11% in the IMBRUVICA arm vs 12% in the chlorambucil arm) occurred in patients.
HELIOS
Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + BR with a
median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in
HELIOS in patients with previously treated CLL/SLL.
Reference ID: 5500397
17
Table 11: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the
IMBRUVICA Arm in Patients with CLL/SLL in HELIOS
Body System
Adverse Reaction
IMBRUVICA + BR
(N=287)
Placebo + BR
(N=287)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Blood and lymphatic
system disorders
Neutropenia*
66
61
60
56†
Thrombocytopenia*
34
16
26
16
Gastrointestinal disorders
Diarrhea
36
2
23
1
Abdominal pain
12
1
8
<1
Skin and subcutaneous
tissue disorders
Rash*
32
4
25
1
Bruising *
20
<1
8
<1
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
29
2
20
0
Muscle spasms
12
<1
5
0
General disorders and
administration site
conditions
Pyrexia
25
4
22
2
Vascular disorders
Hemorrhage*
19
2†
9
1
Hypertension*
11
5
5
2
Infections and infestations
Bronchitis
13
2
10
3
Skin infection*
10
3
6
2
Metabolism and nutrition
disorders
Hyperuricemia
10
2
6
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
<1 used for frequency above 0 and below 0.5%.
† Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm and 1 event of neutropenia with a fatal outcome in
the placebo + BR arm.
Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and
2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was
3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR.
Reference ID: 5500397
18
iLLUMINATE
Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA +
obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil +
obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously
untreated CLL/SLL.
Table 12: Adverse Reactions Reported in ≥ 10% of Patients
in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATE
Body System
Adverse Reaction
IMBRUVICA +
Obinutuzumab
(N=113)
Chlorambucil +
Obinutuzumab
(N=115)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Blood and lymphatic system
disorders
Neutropenia*
48
39
64
48
Thrombocytopenia*
36
19
28
11
Anemia
17
4
25
8
Skin and subcutaneous tissue
disorders
Rash*
36
3
11
0
Bruising*
32
3
3
0
Gastrointestinal disorders
Diarrhea
34
3
10
0
Constipation
16
0
12
1
Nausea
12
0
30
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
33
1
23
3
Arthralgia
22
1
10
0
Muscle spasms
13
0
6
0
Respiratory, thoracic and
mediastinal disorders
Cough
27
1
12
0
Injury, poisoning and
procedural complications
Infusion related reaction
25
2
58
8
Vascular disorders
Hemorrhage*
25
1
9
0
Hypertension*
17
4
4
3
Reference ID: 5500397
19
Body System
Adverse Reaction
IMBRUVICA +
Obinutuzumab
(N=113)
Chlorambucil +
Obinutuzumab
(N=115)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
General disorders and
administration site conditions
Pyrexia
19
2
26
1
Fatigue
18
0
17
2
Peripheral edema
12
0
7
0
Infections and infestations
Pneumonia*
16
9
9
4†
Upper respiratory tract
infection
14
1
6
0
Skin infection*
13
1
3
0
Urinary tract infection
12
3
7
1
Nasopharyngitis
12
0
3
0
Conjunctivitis
11
0
2
0
Metabolism and nutrition
disorders
Hyperuricemia
13
1
0
0
Cardiac disorders
Atrial fibrillation
12
5
0
0
Psychiatric disorders
Insomnia
12
0
4
0
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
† Includes one event with a fatal outcome.
E1912
Adverse reactions described below in Table 13 reflect exposure to IMBRUVICA + rituximab
with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in
E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.
Reference ID: 5500397
20
Table 13: Adverse Reactions Reported in ≥ 15% of Patients
in the IMBRUVICA Arm in Patients with CLL/SLL in E1912
Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
General disorders and
administration site conditions
Fatigue
80
2
78
3
Peripheral edema
28
1
17
0
Pyrexia
27
1
27
1
Pain
23
2
8
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
61
5
35
2
Arthralgia
41
5
10
1
Gastrointestinal disorders
Diarrhea
53
4
27
1
Nausea
40
1
64
1
Stomatitis*
22
1
8
1
Abdominal pain*
19
2
10
1
Vomiting
18
2
28
0
Constipation
17
0
32
0
Skin and subcutaneous tissue
disorders
Rash*
49
4
29
5
Bruising*
36
1
4
1
Vascular disorders
Hypertension*
42
19
22
6
Hemorrhage*
31
2
8
1
Nervous system disorders
Headache
40
1
27
1
Dizziness
21
1
13
1
Peripheral neuropathy*
19
1
13
1
Respiratory, thoracic and
mediastinal disorders
Cough
32
0
25
0
Dyspnea
22
2
21
1
Reference ID: 5500397
21
Body System
Adverse Reaction
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or
Higher (%)
All Grades
(%)
Grade 3 or
Higher (%)
Infections and infestations
Upper respiratory tract
infection
29
1
19
2
Skin infection*
16
1
3
1
Metabolism and nutrition
disorders
Hyperuricemia
19
1
4
0
Decreased appetite
15
0
20
1
Psychiatric disorders
Insomnia
16
1
19
1
The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm.
* Includes multiple ADR terms.
Table 14: Select Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from
Baseline in Patients Receiving IMBRUVICA (E1912)
IMBRUVICA + Rituximab
(N=352)
Fludarabine +
Cyclophosphamide +
Rituximab
(N=158)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Hematology abnormalities
Neutrophils decreased
Platelets decreased
Hemoglobin decreased
53
43
26
30
7
0
70
69
51
44
25
2
Chemistry abnormalities
Creatinine increased
Bilirubin increased
AST increased
38
30
25
1
2
3
17
15
23
1
0
<1
Based on laboratory measurements per IWCLL criteria.
Waldenström’s Macroglobulinemia
The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials
(Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial
(INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA. Study 1118
included 63 patients with previously treated WM who received single agent IMBRUVICA.
INNOVATE included 150 patients with treatment naïve or previously treated WM who received
IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm
Reference ID: 5500397
22
included 31 patients with previously treated WM who received IMBRUVICA after failure of
prior rituximab-containing therapy.
The most common adverse reactions in Studies 1118 and INNOVATE (≥ 20%) were
neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and
nausea.
Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE
discontinued treatment due to adverse reactions. The most common adverse reaction leading to
discontinuation was atrial fibrillation. Adverse reactions leading to dose reduction occurred in
14% of patients.
Study 1118 and INNOVATE Monotherapy Arm
Adverse reactions and laboratory abnormalities described below in Table 15 and Table 16 reflect
exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 and 33 months
in the INNOVATE Monotherapy Arm.
Table 15: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM
in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher (%)
Gastrointestinal disorders
Diarrhea
Nausea
Stomatitis*
Constipation
Gastroesophageal reflux disease
38
21
15
12
12
2
0
0
1
0
Skin and subcutaneous tissue
disorders
Bruising*
Rash*
28
21
1
1
Vascular disorders
Hemorrhage*
Hypertension*
28
14
0
4
General disorders and
administrative site conditions
Fatigue
Pyrexia
18
12
2
2
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain*
Muscle spasms
21
19
0
0
Infections and infestations
Upper respiratory tract infection
Skin infection*
Sinusitis*
Pneumonia*
19
18
16
13
0
3
0
5
Nervous system disorders
Headache
Dizziness
14
13
0
0
Respiratory, thoracic and
mediastinal disorders
Cough
13
0
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Reference ID: 5500397
23
Table 16: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Percent of Patients (N=94)
All Grades (%)
Grade 3 or 4 (%)
Platelets Decreased
38
11
Neutrophils Decreased
43
16
Hemoglobin Decreased
21
6
Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients.
INNOVATE
Adverse reactions described below in Table 17 reflect exposure to IMBRUVICA + R with a
median duration of 25.8 months and exposure to placebo + R with a median duration of
15.5 months in patients with treatment naïve or previously treated WM in INNOVATE.
Table 17: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the
IMBRUVICA Arm in Patients with WM in INNOVATE
Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades
(%)
Grade 3 or
Higher
(%)
All Grades
(%)
Grade 3 or
Higher
(%)
Skin and subcutaneous tissue
disorders
Bruising*
37
1
5
0
Rash*
24
1
11
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain*
35
4
21
3
Arthralgia
24
3
11
1
Muscle spasms
17
0
12
1
Vascular disorders
Hemorrhage*
32
3
17
4†
Hypertension*
20
13
5
4
Gastrointestinal disorders
Diarrhea
28
0
15
1
Nausea
21
0
12
0
Dyspepsia
16
0
1
0
Constipation
13
1
11
1
Infections and infestations
Pneumonia*
19
13
5
3
Reference ID: 5500397
24
Body System
Adverse Reaction
IMBRUVICA + R
(N=75)
Placebo + R
(N=75)
All Grades
(%)
Grade 3 or
Higher
(%)
All Grades
(%)
Grade 3 or
Higher
(%)
Skin infection*
17
3
3
0
Urinary tract infection
13
0
0
0
Bronchitis
12
3
7
0
Influenza
12
0
7
1
Viral upper respiratory tract
infection
11
0
7
0
General disorders and
administration site conditions
Peripheral edema
17
0
12
1
Respiratory, thoracic, and
mediastinal disorders
Cough
17
0
11
0
Blood and lymphatic system
disorders
Neutropenia*
16
12
11
4
Cardiac disorders
Atrial fibrillation
15
12
3
1
Nervous system disorders
Dizziness
11
0
7
0
Psychiatric disorders
Insomnia
11
0
4
0
Metabolism and nutrition
disorders
Hypokalemia
11
0
1
1
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes one event with a fatal outcome.
Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR.
Chronic Graft versus Host Disease
Study 1129
The data described below reflect exposure to IMBRUVICA in an open-label clinical trial
(Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid
therapy and required additional therapy [see Clinical Studies (14.3)].
Reference ID: 5500397
25
The most common adverse reactions in Study 1129 (≥ 20%) were fatigue, bruising, diarrhea,
thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia.
Atrial fibrillation occurred in one patient (2%) which was Grade 3.
Twenty-four percent of patients receiving IMBRUVICA in Study 1129 discontinued treatment
due to adverse reactions. The most common adverse reactions leading to discontinuation were
fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.
Adverse reactions and laboratory abnormalities described below in Table 18 and Table 19 reflect
exposure to IMBRUVICA with a median duration of 4.4 months in Study 1129.
Table 18: Non-Hematologic Adverse Reactions in ≥ 10% of Adult Patients with cGVHD in
Study 1129 (N=42)
Body System
Adverse Reaction
All Grades
(%)
Grade 3 or
Higher
(%)
General disorders and
administration site
conditions
Fatigue
Pyrexia
Edema peripheral
57
17
12
12
5
0
Skin and subcutaneous tissue
disorders
Bruising*
Rash*
40
12
0
0
Gastrointestinal disorders
Diarrhea
Stomatitis*
Nausea
Constipation
36
29
26
12
10
2
0
0
Musculoskeletal and
connective tissue disorders
Muscle spasms
Musculoskeletal pain*
29
14
2
5
Vascular disorders
Hemorrhage*
26
0
Infections and infestations
Pneumonia*
Upper respiratory tract infection
Sepsis*
21
19
10
14†
0
10
Nervous system disorders
Headache
17
5
Injury, poisoning and
procedural complications
Fall
17
0
Respiratory, thoracic and
mediastinal disorders
Cough
Dyspnea
14
12
0
2
Metabolism and nutrition
disorders
Hypokalemia
12
7
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes 2 events with a fatal outcome.
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Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities
in Adult Patients with cGVHD in Study 1129 (N=42)
Percent of Patients (N=42)
All Grades (%)
Grade 3 or 4 (%)
Platelets decreased
33
0
Neutrophils decreased
10
10
Hemoglobin decreased
24
2
Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.
iMAGINE
The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric
and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or
more lines of systemic therapy. Patients age 12 years and older were treated with IMBRUVICA
420 mg orally once daily, and patients age 1 year to less than 12 years were treated with
IMBRUVICA 240 mg/m2 orally once daily [see Clinical Studies (14.3)]. The median duration of
exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months).
Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious
adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis.
Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis
and acute respiratory distress syndrome (ARDS).
Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of
patients. Adverse reactions which resulted in permanent discontinuation in at least two patients
included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in
19% of patients. Adverse reactions which required dose reduction in at least two patients
included stomatitis.
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia,
musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis,
thrombocytopenia, and headache.
Table 20 summarizes the adverse reactions in iMAGINE.
Table 20: Adverse Reactions (≥ 10%) in Patients with Previously Treated cGVHD Who
Received IMBRUVICA in iMAGINE
Body System
Adverse Reaction
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
General disorders and administration site conditions
Pyrexia
30
11
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Body System
Adverse Reaction
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*
30
2
Osteonecrosis
11
9
Gastrointestinal disorders
Diarrhea
28
2
Abdominal pain*
23
4
Stomatitis*
23
9
Vomiting
19
2
Nausea
19
4
Infections and infestations
Pneumonia*
23
13
Skin infection*
17
4
Sepsis*
11
9†
Nervous system disorders
Headache
21
2
Skin and subcutaneous tissue disorders
Rash*
19
2
Pruritus
13
0
Petechiae
13
0
Respiratory, thoracic and mediastinal disorders
Cough
19
2
Vascular disorders
Hemorrhage*
17
0
Hypertension*
11
4
Blood and lymphatic system disorders
Hypokalemia
15
6
Hypogammaglobulinemia*
11
0
Cardiac Disorders
Sinus tachycardia
11
0
Investigations
Alanine aminotransferase increased
11
2
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
† Includes 1 fatal outcome.
Table 21 summarizes the laboratory abnormalities in iMAGINE.
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Table 21: Select Hematologic Laboratory Abnormalities (≥ 10%) That Worsened from
Baseline in Patients with Previously Treated cGVHD Who Received
IMBRUVICA in iMAGINE
IMBRUVICA
(N=47)
All Grades
(%)
Grade 3 or 4
(%)
Hemoglobin decreased
49
13
Platelets decreased
21
4
Neutrophils decreased
13
6
Treatment-emergent Grade 4 neutropenia occurred in 3% of patients.
Additional Important Adverse Reactions
Cardiovascular Events
Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA
(n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with
IMBRUVICA and 5.3 months for 958 patients in the control arm). The incidence of ventricular
tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation,
ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade
3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in
the control arm. The incidence of atrial fibrillation and atrial flutter of any grade was 8.4%
versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with
IMBRUVICA compared to patients in the control arm. In addition, the incidence of cardiac
failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater was 1.2% versus 0.3% in
patients treated with IMBRUVICA compared to patients in the control arm.
The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke,
cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3
or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in
the control arm, respectively.
Diarrhea
In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for
1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm),
diarrhea of any grade occurred at a rate of 43% of patients treated with IMBRUVICA compared
to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of
IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%)
of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.
Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0
to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414)
versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients
compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus
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89% had complete resolution, and 15% versus 11% had not reported resolution at time of
analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median
time from onset to resolution in IMBRUVICA-treated subjects was 7 days (range, 1 to 655)
versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days
(range, 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the control
arm, respectively.
Visual Disturbance
In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for
1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm),
blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with
IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control
arm (5% Grade 1 and < 1% Grade 2 and 3).
Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0
to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-treated patients compared to the
control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had
complete resolution and 40% versus 29% had not reported resolution at the time of analysis in
IMBRUVICA-treated patients compared to the control arm, respectively. The median time from
onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in
IMBRUVICA-treated subjects compared to the control arm, respectively.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of IMBRUVICA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
• Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic
cirrhosis, drug-induced liver injury
• Respiratory disorders: interstitial lung disease
• Metabolic and nutrition disorders: tumor lysis syndrome
• Immune system disorders: anaphylactic shock, angioedema, urticaria
• Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis,
panniculitis, neutrophilic dermatoses, cutaneous vasculitis
• Infections: hepatitis B reactivation
• Nervous system disorders: peripheral neuropathy
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7
DRUG INTERACTIONS
7.1
Effect of CYP3A Inhibitors on Ibrutinib
The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase
ibrutinib plasma concentrations [see Clinical Pharmacology (12.3)]. Increased ibrutinib
concentrations may increase the risk of drug-related toxicity.
Dose modifications of IMBRUVICA are recommended when used concomitantly with
posaconazole, voriconazole and moderate CYP3A inhibitors [see Dosage and Administration
(2.3)].
Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these
inhibitors will be used short-term (such as anti-infectives for seven days or less) [see Dosage and
Administration (2.3)].
Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or
moderate inhibitors of CYP3A.
7.2
Effect of CYP3A Inducers on Ibrutinib
The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib
concentrations. Avoid coadministration with strong CYP3A inducers [see Clinical Pharmacology
(12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
IMBRUVICA can cause fetal harm based on findings from animal studies. There are no
available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major
birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to
pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the
clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities
(see Data). Advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data
Animal Data
Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of
10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral
malformations (heart and major vessels) and increased resorptions and post-implantation loss.
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The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with
CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or
greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is
approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at
doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated
with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated
with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is
approximately 2.8 times the exposure in patients with CLL/SLL or WM administered a dose of
420 mg daily.
8.2
Lactation
Risk Summary
There is no information regarding the presence of ibrutinib or its metabolites in human milk, the
effects on the breastfed child, or the effects on milk production. Because of the potential for
serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment
with IMBRUVICA and for 1 week after the last dose.
8.3
Females and Males of Reproductive Potential
IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with
IMBRUVICA and for 1 month after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during
treatment with IMBRUVICA and for 1 month following the last dose.
8.4
Pediatric Use
Chronic GVHD
The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD
after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older.
Use of IMBRUVICA for this indication is supported by evidence from iMAGINE, a study which
included pediatric patients age 1 year and older with previously treated cGVHD, including
patients in the following age groups: one patient 1 year to less than 2 years of age, 20 patients 2
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years to less than 12 years of age, and 19 patients 12 years to less than 17 years of age.
Additional supportive efficacy data was provided from Study 1129 in adults [see Adverse
Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].
The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that
in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based
on body-surface area (BSA) [see Dosage and Administration (2.1)].
The safety and effectiveness of IMBRUVICA have not been established for this indication in
pediatric patients less than 1 year of age.
Mature B-cell Non-Hodgkin Lymphoma
The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were
assessed but have not been established based on an open-label, randomized study
(NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years,
with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for
futility. In the randomized population, major hemorrhage and discontinuation of
chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus
chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.
CLL/SLL, CLL/SLL with 17p deletion, WM
The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in
CLL/SLL, CLL/SLL with 17p deletion, or WM.
8.5
Geriatric Use
Of 992 patients in clinical studies of IMBRUVICA for B-cell malignancies or cGVHD, 62%
were ≥ 65 years of age, while 22% were ≥ 75 years of age [see Clinical Studies (14.1, 14.2,
14.3)]. No overall differences in effectiveness were observed between younger and older
patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension,
and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA
[see Adverse Reactions (6.1)].
8.6
Hepatic Impairment
Adult Patients with B-cell Malignancies
Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C). The
safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic
impairment by Child-Pugh criteria.
Reduce the recommended dose when administering IMBRUVICA to patients with mild or
moderate hepatic impairment (Child-Pugh class A and B). Monitor patients more frequently for
adverse reactions of IMBRUVICA [see Dosage and Administration (2.4), Clinical
Pharmacology (12.3)].
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Patients with cGVHD
Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x ULN (unless of non-
hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering
IMBRUVICA to patients with total bilirubin level > 1.5 to 3 x ULN (unless of non-hepatic origin
or due to Gilbert’s syndrome) [see Dosage and Administration (2.4)].
8.7
Plasmapheresis
Management of hyperviscosity in WM patients may include plasmapheresis before and during
treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
10 OVERDOSAGE
There is no specific experience in the management of ibrutinib overdose in patients. One healthy
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of
1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide
appropriate supportive treatment.
11 DESCRIPTION
Ibrutinib is a kinase inhibitor. It is a white to off-white solid with the empirical formula
C25H24N6O2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide,
soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-
[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-
propen-1-one and has the following structure:
IMBRUVICA (ibrutinib) is available as immediate-release oral capsules, immediate-release oral
tablets, and immediate-release oral suspension.
IMBRUVICA (ibrutinib) capsules for oral use are available in the following dosage strengths: 70
mg and 140 mg. Each capsule contains ibrutinib (active ingredient) and the following inactive
ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium
lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg
capsule only), and black ink.
N
N
N
N
NH2
(R)
O
N
O
-0
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IMBRUVICA (ibrutinib) tablets for oral use are available in the following dosage strengths: 140
mg, 280 mg, and 420 mg. Each tablet contains ibrutinib (active ingredient) and the following
inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film
coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets),
polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets), talc, titanium dioxide,
and yellow iron oxide (140 mg and 420 mg tablets).
IMBRUVICA (ibrutinib) oral suspension contains 70 mg/mL ibrutinib (active ingredient) and
the following inactive ingredients: benzyl alcohol, citric acid monohydrate, disodium hydrogen
phosphate, hypromellose, microcrystalline cellulose and carboxymethylcellulose sodium,
purified water and sucralose.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a
covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK
enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and
cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results
in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical
studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as
cell migration and substrate adhesion in vitro.
12.2
Pharmacodynamics
In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in
peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of
≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).
In adult patients with cGVHD, 93% occupancy of the BTK active site in peripheral blood
mononuclear cells was observed at the ibrutinib recommended dose. The mean BTK occupancy
in pediatric patients ranged from 95.1% to 99.6%.
In vitro Platelet Aggregation
Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at
4.6 µM (2026 ng/mL), 0.8 µM (352 ng/mL), and 3 µM (1321 ng/mL) in blood samples from
healthy donors, donors taking warfarin, and donors with severe renal dysfunction,
respectively. Ibrutinib did not show meaningful inhibition of platelet aggregation for ADP,
arachidonic acid, ristocetin, and TRAP-6.
Cardiac Electrophysiology
At a single dose 4 times the maximum recommended dose (1680 mg), IMBRUVICA did not
prolong the QT interval to any clinically relevant extent.
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12.3
Pharmacokinetics
Ibrutinib exposure increases with doses up to 840 mg (2 times the maximum approved
recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC
(% coefficient of variation) observed in patients at 420 mg with CLL/SLL is
708 (71%) ng×h/mL, with WM is 707 (72%) ng×h/mL, and in adult patients with previously
treated cGVHD is 1159 (50%) ng×h/mL. Steady-state concentrations of ibrutinib without
CYP3A inhibitors were achieved with an accumulation ratio of 1 to 1.6 after 1 week of multiple
daily doses of 420 mg.
Absorption
Absolute bioavailability of ibrutinib in fasted condition was 2.9% (90% CI: 2.1, 3.9) in healthy
subjects. Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 2 hours.
Effect of Food
The administration of IMBRUVICA with a high-fat and high-calorie meal (800 calories to
1,000 calories with approximately 50% of total caloric content of the meal from fat) increased
ibrutinib Cmax by 2- to 4-fold and AUC by approximately 2-fold, compared with administration
of ibrutinib after overnight fasting.
In vitro studies suggest that ibrutinib is not a substrate of p-glycoprotein (P-gp) or breast cancer
resistance protein (BCRP).
Distribution
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no
concentration dependence in the range of 50 ng/mL to 1000 ng/mL. The volume of distribution
(Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was
approximately 10,000 L.
Elimination
Intravenous clearance was 62 L/h in fasted conditions and 76 L/h in fed conditions. In line with
the high first-pass effect, the apparent oral clearance is 2000 L/h in fasted conditions and
1000 L/h in fed conditions. The half-life of ibrutinib is 4 hours to 6 hours.
Metabolism
Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites
primarily by cytochrome P450 (CYP) 3A and to a minor extent by CYP2D6. The active
metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK
approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent
ratio for PCI-45227 at steady-state is 1 to 2.8.
Excretion
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral
administration of radiolabeled ibrutinib, 90% of radioactivity was excreted within 168 hours,
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with 80% excreted in the feces and less than 10% eliminated in urine. Unchanged ibrutinib
accounted for 1% of the radiolabeled excreted dose in feces and none in urine, with the
remainder of the excreted dose being metabolites.
Specific Populations
Age and Sex
Age and sex have no clinically meaningful effect on ibrutinib pharmacokinetics.
Patients with Renal Impairment
Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by
Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. No data is available in
patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.
Patients with Hepatic Impairment
The AUC of ibrutinib increased 2.7-fold in subjects with mild hepatic impairment (Child-Pugh
class A), 8.2-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and
9.8-fold in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with
normal liver function. The Cmax of ibrutinib increased 5.2-fold in mild hepatic impairment,
8.8-fold in moderate hepatic impairment and 7-fold in severe hepatic impairment relative to
subjects with normal liver function [see Use in Specific Populations (8.6)].
Pediatric Patients
In pediatric patients with cGVHD treated with ibrutinib at 240 mg/m2 once daily (patients age
≥ 1 to < 12 years) or 420 mg once daily (patients age ≥ 12 years), the geometric mean (%CV)
steady state AUC and Cmax in patients age ≥ 1 to < 12 years is 467 (102%) ng×h/mL and 65.7
(96%) ng/mL, respectively, and in patients age ≥ 12 to < 17 years is 966 (78%) ng×h/mL and
149 (79%) ng/mL, respectively.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of multiple doses of ketoconazole
(strong CYP3A inhibitor) increased the Cmax of ibrutinib by 29-fold and AUC by 24-fold. The
coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady
state Cmax of ibrutinib by 6.7-fold and AUC by 5.7-fold. Simulations under fed conditions
suggest that posaconazole (strong CYP3A inhibitor) may increase the AUC of ibrutinib 3-fold to
10-fold.
The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased
steady state Cmax of ibrutinib by 3.4-fold and AUC by 3-fold.
Effect of CYP3A Inducers on Ibrutinib: The coadministration of rifampin (strong CYP3A
inducer) decreased the Cmax of ibrutinib by more than 13-fold and AUC by more than 10-fold.
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Simulations suggest that efavirenz (moderate CYP3A inducer) may decrease the AUC of
ibrutinib by 3-fold.
In Vitro Studies
Effect of Ibrutinib on CYP Substrates: In vitro studies suggest that ibrutinib and PCI-45227 are
unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib
and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses.
Effect of Ibrutinib on Substrates of Transporters: In vitro studies suggest that ibrutinib may
inhibit BCRP and P-gp transport at clinical doses. The coadministration of oral P-gp or BCRP
substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their concentrations.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ibrutinib was not carcinogenic in a 6-month rasH2 mouse study at oral doses up to
2000 mg/kg/day resulting in exposures approximately 32 (males) to 52 (females) times higher
than the exposure in humans at a dose of 420 mg daily [see Warnings and Precautions (5.6)].
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.
Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during
pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female
rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats
continued until end of study. No effects on fertility or reproductive capacities were observed in
male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose
[HED] 16 mg/kg).
14 CLINICAL STUDIES
14.1
Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma
The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in one
uncontrolled trial and five randomized, controlled trials.
Study 1102
Study 1102 (NCT01105247), an open-label, multi-center trial, was conducted in 48 previously
treated CLL patients. IMBRUVICA was administered orally at 420 mg once daily until disease
progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version
of the International Workshop on CLL Criteria by an Independent Review Committee.
The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At
baseline, 46% of subjects had at least one tumor ≥ 5 cm.
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The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients
achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR
was not reached.
RESONATE
The RESONATE study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA
versus ofatumumab (NCT01578707), was conducted in patients with previously treated CLL or
SLL. Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until
disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg,
followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4
additional doses. Fifty-seven patients randomized to ofatumumab crossed over following
progression to receive IMBRUVICA.
The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were White. All
patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with
CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median
number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at
least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.
Efficacy results for RESONATE are shown in Table 22 and the Kaplan-Meier curves for PFS,
assessed by an IRC according to IWCLL criteria, and OS are shown in Figure 1 and Figure 2,
respectively.
Table 22: Efficacy Results in Patients with CLL/SLL in RESONATE
Endpoint
IMBRUVICA
N=195
Ofatumumab
N=196
Progression-Free Survivalb
Number of events (%)
35 (17.9)
111 (56.6)
Disease progression
26
93
Death events
9
18
Median (95% CI), months
NE
8.1 (7.2, 8.3)
HR (95% CI)
0.22 (0.15, 0.32)
Overall Survivala
Number of deaths (%)
16 (8.2)
33 (16.8)
HR (95% CI)
0.43 (0.24, 0.79)
Overall Response Rateb
42.6%
4.1%
a Median OS not evaluable for either arm.
b IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
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183
116
38
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0
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161
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40
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20
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3
6
9
12
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(Month)
Nat Risk
IMBRUVICA: 195
191
184
11 S
32
s
0
Ofatumumab: 196
183
164
88
21
3
0
39
Figure 1: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in RESONATE
Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with
CLL/SLL in RESONATE
Reference ID: 5500397
40
63-Month Follow-Up
With an overall follow-up of 63 months, the median investigator-assessed PFS per IWCLL
criteria was 44.1 months [95% CI (38.5, 56.9)] in the IMBRUVICA arm and 8.1 months
[95% CI (7.8, 8.3)] in the ofatumumab arm. Overall response rate as assessed by investigators
was 87.2% in the IMBRUVICA arm versus 22.4% in the ofatumumab arm.
CLL/SLL with 17p deletion (del 17p CLL/SLL) in RESONATE
RESONATE included 127 patients with del 17p CLL/SLL. The median age was 67 years (range,
30 to 84 years), 62% were male, and 88% were White. All patients had a baseline ECOG
performance status of 0 or 1. PFS and ORR were assessed by an IRC. Efficacy results for del 17p
CLL/SLL are shown in Table 23.
Table 23: Efficacy Results in Patients with del 17p CLL/SLL in RESONATE
Endpoint
IMBRUVICA
N=63
Ofatumumab
N=64
Progression-Free Survivala
Number of events (%)
16 (25.4)
38 (59.4)
Disease progression
12
31
Death events
4
7
Median (95% CI), months
NE
5.8 (5.3, 7.9)
HR (95% CI)
0.25 (0.14, 0.45)
Overall Response Ratea
47.6%
4.7%
a IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NE = not evaluable.
63-Month Follow-Up
With an overall follow-up of 63 months, the median investigator-assessed PFS in patients with
del 17p per IWCLL criteria was 40.6 months [95% CI (25.4, 44.6)] in the IMBRUVICA arm and
6.2 months [95% CI (4.6, 8.1)] in the ofatumumab arm. Overall response rate as assessed by
investigators in patients with del 17p was 88.9% in the IMBRUVICA arm versus 18.8% in the
ofatumumab arm.
RESONATE-2
The RESONATE-2 study, a randomized, multicenter, open-label, phase 3 study of IMBRUVICA
versus chlorambucil (NCT01722487), was conducted in patients with treatment naïve CLL or
SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either
IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil
at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12
cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were White.
Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an
Reference ID: 5500397
41
ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with
SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating
CLL therapy include: progressive marrow failure demonstrated by anemia and/or
thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or
symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).
With a median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and
21 (15.8%) in IMBRUVICA and chlorambucil treatment arms, respectively]. With 41% of
patients switching from chlorambucil to IMBRUVICA, the overall survival analysis in the ITT
patient population resulted in a statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and
2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)]
in the IMBRUVICA and chlorambucil arms, respectively.
Efficacy results for RESONATE-2 are shown in Table 24 and the Kaplan-Meier curve for PFS,
assessed by an IRC according to IWCLL criteria is shown in Figure 3.
Table 24: Efficacy Results in Patients with CLL/SLL in RESONATE-2
Endpoint
IMBRUVICA
N=136
Chlorambucil
N=133
Progression-Free Survivala
Number of events (%)
15 (11.0)
64 (48.1)
Disease progression
12
57
Death events
3
7
Median (95% CI), months
NE
18.9 (14.1, 22.0)
HRb (95% CI)
0.16 (0.09, 0.28)
Overall Response Ratea (CR + PR)
82.4%
35.3%
P-value
<0.0001
a IRC evaluated; five subjects (3.7%) in the IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved
complete response.
b HR = hazard ratio; NE = not evaluable.
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20
10 p<0.0001
0
0
3
6
9
12
15
18
21
24
27 (Month)
Nat Risk
IMBRUVICA:
136
133
130
126
122
98
66
21
2
0
chlorambucil: 133
121
95
85
74
49
34
10
0
0
42
Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in RESONATE-2
55-Month Follow-Up
With an overall follow-up of 55 months, the median PFS was not reached in the IMBRUVICA
arm.
HELIOS
The HELIOS study, a randomized, double-blind, placebo-controlled phase 3 study of
IMBRUVICA in combination with bendamustine and rituximab (BR) (NCT01611090), was
conducted in patients with previously treated CLL or SLL. Patients (n = 578) were randomized
1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with BR until disease
progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day
cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2
and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles, and all patients had a CLcr ≥ 40
mL/min at baseline. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day
1, and 500 mg/m2 Cycles 2 through 6, Day 1.
The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments).
At baseline, 56% of patients had at least one tumor > 5 cm and 26% presented with del11q.
Efficacy results for HELIOS are shown in Table 25 and the Kaplan-Meier curves for PFS are
shown in Figure 4.
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80
60
40
20
0
Subjects at risk
IMBRUVICA + BR
Placebo+ BR
p<0.0001
0
289
289
0
4
8
12
264
247
200
259
234
117
IMBRUVICA + BR
I
I
16
I
20
24
Months
127
52
5
59
17
3
- - -.& - -
Placebo+ BR
IMBRUVICA + BR
'• Placebo+ BR
28
32
36
0
0
0
0
0
0
43
Table 25: Efficacy Results in Patients with CLL/SLL in HELIOS
Endpoint
IMBRUVICA + BR
N=289
Placebo + BR
N=289
Progression-Free Survivala
Number of events (%)
56 (19.4)
183 (63.3)
Median (95% CI), months
NE
13.3 (11.3, 13.9)
HR (95% CI)
0.20 (0.15, 0.28)
Overall Response Ratea
82.7%
67.8%
a IRC evaluated; twenty-four subjects (8.3%) in the IMBRUVICA + BR arm and six subjects (2.1%) in the placebo + BR arm
achieved complete response.
BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio; NE = not evaluable.
Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in HELIOS
iLLUMINATE
The iLLUMINATE study, a randomized, multi-center, phase 3 study of IMBRUVICA in
combination with obinutuzumab versus chlorambucil in combination with obinutuzumab
(NCT02264574), was conducted in patients with treatment naïve CLL or SLL. Patients were 65
Reference ID: 5500397
44
years of age or older or < 65 years of age with coexisting medical conditions, reduced renal
function as measured by creatinine clearance < 70 mL/min, or presence of del 17p/TP53
mutation. Patients (n = 229) were randomized 1:1 to receive either IMBRUVICA 420 mg daily
until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on
Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1,000 mg of
obinutuzumab on Days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5
subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided
between Day 1 (100 mg) and Day 2 (900 mg).
The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were White. All
patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). The trial enrolled
214 patients with CLL and 15 patients with SLL. At baseline, 65% of patients presented with
CLL/SLL with high risk factors (del 17p/TP53 mutation [18%], del 11q [15%], or unmutated
immunoglobulin heavy-chain variable region (unmutated IGHV) [54%]). The most common
reasons for initiating CLL therapy included: lymphadenopathy (38%), night sweats (34%),
progressive marrow failure (31%), fatigue (29%), splenomegaly (25%), and progressive
lymphocytosis (21%).
With a median follow-up time on study of 31 months, efficacy results for iLLUMINATE
assessed by an IRC according to IWCLL criteria are shown in Table 26, and the Kaplan-Meier
curve for PFS is shown in Figure 5.
Table 26: Efficacy Results in Patients with CLL/SLL in iLLUMINATE
Endpoint
IMBRUVICA +
Obinutuzumab
N=113
Chlorambucil +
Obinutuzumab
N=116
Progression-Free Survivala
Number of events (%)
24 (21)
74 (64)
Disease progression
11
64
Death events
13
10
Median (95% CI), months
NE
19.0 (15.1, 22.1)
HR (95% CI)
0.23 (0.15, 0.37)
P-valueb
<0.0001
Overall Response Rate (%)a
88.5
73.3
CRc (%)
19.5
7.8
PRd (%)
69.0
65.5
a IRC-evaluated.
b P-value is from unstratified log-rank test.
c Includes 1 patient in the IMBRUVICA + obinutuzumab arm with a complete response with incomplete marrow recovery (CRi)
d PR = nPR +PR.
HR = hazard ratio; NE = not evaluable.
Reference ID: 5500397
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30
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20
10
p<0.0001
0
0
3
6
9
12
15
18
21
24
27
30
33
36
(Month)
Nat Risk
IMBRUVICA +
obinutuzumab: 113
109
106
105
99
94
90
85
82
81
28
6
0
chlorambucil +
obinutuzumab: 116
111
109
102
81
67
56
47
35
33
6
5
0
45
Figure 5: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in iLLUMINATE
In the high risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), the
PFS HR was 0.15 [95% CI (0.09, 0.27)].
E1912
The E1912 study, a randomized, multi-center, phase 3 study of IMBRUVICA in combination
with rituximab versus standard fludarabine, cyclophosphamide, and rituximab (FCR)
chemoimmunotherapy (NCT02048813), was conducted in adult patients who were 70 years or
younger with previously untreated CLL or SLL requiring systemic therapy. All patients had a
CLcr > 40 mL/min at baseline. Patients with 17p deletion were excluded. Patients (n =529) were
randomized 2:1 to receive either IMBRUVICA plus rituximab or FCR. IMBRUVICA was
administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was
administered at a dose of 25 mg/m2, and cyclophosphamide was administered at a dose of
250 mg/m2, both on Days 1, 2, and 3 of Cycles 1-6. Rituximab was initiated in Cycle 2 for the
IMBRUVICA plus rituximab arm and in Cycle 1 for the FCR arm and was administered at 50
mg/m2 on Day 1 of the first cycle, 325 mg/m2 on Day 2 of the first cycle, and 500 mg/m2 on Day
1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.
The median age was 58 years (range, 28 to 70 years), 67% were male, 90% were White and 98%
had a ECOG performance status of 0-1. At baseline, 43% of patients were Rai stage 3 or 4 and
Reference ID: 5500397
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80
70
60
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40
30
20
10
p<0.0001
0
0
3
6
9
Nat Risk
IMBRUVICA 354
351
349
345
+ rituximab
fludarabine, 175
158
152
148
cyclophosphamide
+ rituximab
•
I'll 1 '11111111 IIIUI '1111;II I I ,
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145
134
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+ rituximab
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21
24
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30
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324
307
270
227
185
159
125
114
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79
64
51
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ftudarabine,
cyclophosphamide
+ riluximab
39
42
45
(Month)
108
79
52
34
20
10
46
59% of patients presented with high risk factors (TP53 mutation [6%], del11q [22%], or
unmutated IGHV [53%]).
With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in
Table 27. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria is shown in
Figure 6.
Table 27: Efficacy Results in Patients with CLL/SLL in E1912
Endpoint
IMBRUVICA + R
N=354
FCR
N=175
Progression-Free Survival
Number of events (%)
41 (12)
44 (25)
Disease progression
39
38
Death events
2
6
Median (95% CI), months
NE (49.4, NE)
NE (47.1, NE)
HR (95% CI)
0.34 (0.22, 0.52)
P-valuea
<0.0001
a P-value is from unstratified log-rank test.
FCR = fludarabine, cyclophosphamide, and rituximab; HR = hazard ratio; R = rituximab; NE = not evaluable.
Figure 6: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with CLL/SLL in E1912
Reference ID: 5500397
47
With a median follow-up time on study of 49 months, median overall survival was not reached
with a total of 23 deaths: 11 (3%) in the IMBRUVICA plus rituximab and 12 (7%) in the FCR
treatment arms.
Lymphocytosis
Upon initiation of single-agent IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50%
increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of
patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of
IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When
IMBRUVICA was administered in combination, lymphocytosis was 7% with IMBRUVICA +
BR versus 6% with placebo + BR and 7% with IMBRUVICA + obinutuzumab versus 1% with
chlorambucil + obinutuzumab.
14.2
Waldenström’s Macroglobulinemia
The safety and efficacy of IMBRUVICA in patients with WM were demonstrated in two single-
arm trials and one randomized, controlled trial.
Study 1118 and INNOVATE Monotherapy Arm
Study 1118 (NCT01614821), an open-label, multi-center, single-arm trial was conducted in 63
previously treated patients with WM. IMBRUVICA was administered orally at 420 mg once
daily until disease progression or unacceptable toxicity. The responses were assessed by
investigators and an IRC using criteria adopted from the International Workshop of
Waldenström’s Macroglobulinemia.
The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were White. All
patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was
74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At
baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).
Responses, defined as partial response or better, per IRC are shown in Table 28.
Table 28: Response Rate and Duration of Response (DOR) Based on
IRC Assessment in Patients with WM in Study 1118
Total (N=63)
Response rate (CR+VGPR+PR), (%)
61.9
95% CI (%)
(48.8, 73.9)
Complete Response (CR)
0
Very Good Partial Response (VGPR), (%)
11.1
Partial Response (PR), (%)
50.8
Median duration of response, months (range)
NE (2.8+, 18.8+)
CI = confidence interval; NE = not evaluable.
The median time to response was 1.2 months (range, 0.7-13.4 months).
Reference ID: 5500397
48
The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed
prior rituximab-containing therapy and received single-agent IMBRUVICA. The median age
was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG
performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The
median number of prior treatments was 4 (range, 1 to 7 treatments). With an overall follow-up of
61 months, the response rate observed in the INNOVATE monotherapy arm per IRC assessment
was 77% (0% CR, 29% VGPR, 48% PR). The median duration of response was 33 months
(range, 2.4 to 60.2+ months).
INNOVATE
The INNOVATE study, a randomized, double-blind, placebo-controlled, phase 3 study of
IMBRUVICA or placebo in combination with rituximab (NCT02165397), was conducted in
treatment naïve or previously treated patients with WM. Patients (n = 150) were randomized 1:1
to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until
disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of
375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly
rituximab for 4 consecutive weeks (weeks 17-20). The major efficacy outcome measure is
progression-free survival (PFS) assessed by an IRC with additional efficacy measure of response
rate.
The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were White.
Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of
patients had a baseline ECOG performance status of 2. Forty-five percent of patients were
treatment naïve, and 55% of patients were previously treated. Among previously treated patients,
the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median
serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), and MYD88 L265P mutations were
present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for
mutation status.
An exploratory analysis demonstrated a sustained hemoglobin improvement (defined as increase
of ≥ 2 g/dL over baseline for at least 8 weeks without blood transfusions or growth factor
support) in 65% of patients in the IMBRUVICA + R group and 39% of patients in the
placebo + R group.
With an overall follow-up of 63 months, efficacy results as assessed by an IRC at the time of the
final analysis for INNOVATE are shown in Table 29, and the Kaplan-Meier curves for PFS are
shown in Figure 7.
Reference ID: 5500397
100
90
80
70
60
~
0
(f)
u..
50
c..
40
30
20
10
0
0
Nat Risk
lbr+R:
75
Pbo+R: 75
1--. ' I
' ·I -, -,
• I I --, , _
Median Time (mo)
Hazard Ratio
(95% CI)
Log-Rank p-value
3
6
9
12
73
69
67
66
64
54
48
43
'• -, .
·--. I --•---,_ I
'I-,
'
I -..
' - - - - - I I_ - - -
I - 1- -
I- 11 1 -II--1- - - - <II- I
Pbo+R
lbr+R
20<3
NE
0<250
(0<148-0.420)
-
lbr+R
<.0001
Pbo+R
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
60
60
58
57
56
54
54
49
48
47
44
32
22
15
7
39
33
32
31
27
23
19
19
17
17
15
7
4
3
2
(Month)
49
Table 29: Efficacy Results in Patients with WM by IRC in INNOVATE (Final Analysis)
Endpoint
IMBRUVICA + R
N=75
Placebo + R
N=75
Progression-Free Survival
Number of events (%)
22 (29)
50 (67)
Median (95% CI), months
NE (57.7, NE)
20.3 (13.0, 27.6)
HR (95% CI)
0.25 (0.15, 0.42)
P-valuea
<0.0001
Response Rate (CR+VGPR+PR)b
76%
31%
95% CI (%)
(65, 85)
(21, 42)
Complete Response (CR)
1%
1%
Very Good Partial Response (VGPR)
29%
4%
Partial Response (PR)
45%
25%
Median duration of response, months (range)
NE (1.9+, 58.9+)
NE (4.6+, 49.7+)
CI = confidence interval; HR = hazard ratio; NE = not evaluable; R = rituximab.
a P-value is from the stratified log-rank test.
b P-value associated with response rate was <0.0001.
Figure 7: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients
with WM in INNOVATE
Reference ID: 5500397
50
Median overall survival was not reached for either treatment arm. With an overall follow-up of
63 months, 9 (12%) patients on IMBRUVICA + R and 10 (13.3%) patients on placebo + R had
died. Forty-seven percent of patients randomized to the placebo + R arm crossed over to receive
IMBRUVICA.
14.3
Chronic Graft versus Host Disease
Study 1129
The safety and efficacy of IMBRUVICA in cGVHD were evaluated in Study 1129
(NCT02195869), an open-label, multi-center, single-arm trial of 42 patients with cGVHD after
failure of first line corticosteroid therapy and requiring additional therapy. IMBRUVICA was
administered orally at 420 mg once daily. The responses were assessed by investigators using the
2005 National Institute of Health (NIH) Consensus Panel Response Criteria with two
modifications to align with the updated 2014 NIH Consensus Panel Response Criteria.
The median age was 56 years (range, 19 to 74 years), 52% were male, and 93% were White. The
most common underlying malignancies leading to transplantation were acute lymphocytic
leukemia, acute myeloid leukemia, and CLL. The median time since cGVHD diagnosis was
14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3 treatments), and
60% of patients had a Karnofsky performance score of ≤ 80. The majority of patients (88 %) had
at least 2 organs involved at baseline, with the most commonly involved organs being mouth
(86%), skin (81%), and gastrointestinal tract (33%). The median daily corticosteroid dose
(prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of patients were
receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.
Prophylaxis for infections were managed per institutional guidelines with 79% of patients
receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole
derivatives.
Efficacy results are shown in Table 30.
Table 30: Best Overall Response Rate (ORR) and Sustained Response Rate
Based on Investigator Assessmenta in Patients with cGVHD in Study 1129
Total (N=42)
ORR
28 (67%)
95% CI
(51%, 80%)
Complete Response (CR)
9 (21%)
Partial Response (PR)
19 (45%)
Sustained response rateb
20 (48%)
CI = confidence interval.
a Investigator assessment based on the 2005 NIH Response Criteria with two modifications (added “not evaluable” for
organs with non-cGVHD abnormalities, and organ score change from 0 to 1 was not considered disease
progression.)
b Sustained response rate is defined as the proportion of patients who achieved a CR or PR that was sustained for at
least 20 weeks.
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51
The median time to response coinciding with the first scheduled response assessment was
12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all organs involved for
cGVHD (skin, mouth, gastrointestinal tract, and liver).
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42)
of patients on at least 2 consecutive visits.
iMAGINE
The safety and efficacy of IMBRUVICA were evaluated in iMAGINE (NCT03790332), an
open-label, multi-center, single-arm trial of IMBRUVICA for the treatment of pediatric and
young adult patients age 1 year to less than 22 years with moderate or severe cGVHD as defined
by NIH Consensus Criteria. The study included 47 patients who required additional therapy after
failure of one or more prior lines of systemic therapy. All patients had platelets ≥ 30 x 109/L;
absolute neutrophil count ≥ 1.0 x 109/L; AST or ALT ≤ 3 x ULN; total bilirubin of ≤ 1.5 x ULN;
and estimated creatinine clearance ≥ 30 mL/min. Patients were excluded if single organ
genitourinary involvement was the only manifestation of cGVHD.
Patients age 12 years and older were treated with IMBRUVICA 420 mg orally once daily, and
patients age 1 year to less than 12 years were treated with IMBRUVICA 240 mg/m2 orally once
daily. Concomitant treatment with supportive care therapies for cGVHD was permitted. Initiation
of new systemic cGVHD therapy while on study was not permitted.
The median age was 13 years (range, 1 to 19 years). Of the 47 patients, 70% of patients were
male, and 36% were White, 9% were Black or African American, 55% were other or unreported.
The median time since cGVHD diagnosis was 16.1 months, the median number of prior cGVHD
treatments was 2 (range, 1 to 12). The majority of patients (87%) had at least 2 organs involved
at baseline, with lung involvement at baseline in 49% of patients; 26% of patients had a
Karnofsky/Lansky performance score of <80. The median daily corticosteroid dose (prednisone
or prednisone equivalent) at baseline was 0.47 mg/kg/day, and 61% (19 of 31) patients were
receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline.
Prophylaxis for infections was managed per institutional guidelines, with 72% of patients
receiving combinations of sulfonamides and trimethoprim and 70% receiving systemic
antifungal agents.
The efficacy of IMBRUVICA was established based on overall response rate (ORR) through
Week 25, where overall response included complete response or partial response according to the
2014 National Institutes of Health (NIH) Consensus Development Project Response Criteria. The
efficacy results are shown in Table 31.
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52
Table 31: Efficacy Results in Patients with Previously Treated cGVHDa in iMAGINE
Total (N=47)
ORR by Week 25
28 (60%)
95% CI (%)
(44, 74)
Complete Response (CR)
2 (4%)
Partial Response (PR)
26 (55%)
Median duration of response, months (95% CI)b
5.3 (2.8, 8.8)
CI = confidence interval; ORR = overall response rate.
a Assessment based on 2014 NIH Consensus Development Project Response Criteria.
b Based on all responders in the study, calculated from first response to progression, death, or new systemic therapies for
cGVHD.
The median time to first response was 0.9 month (range, 0.9 to 6.1 months). The median time
from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI:
4.6, not evaluable).
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in Lee Symptom Scale overall summary score through Week
25 in 50% (13/26) of patients age 12 years and older.
16 HOW SUPPLIED/STORAGE AND HANDLING
Capsules
The 70 mg capsules are supplied as yellow opaque capsules, marked with “ibr 70 mg” in black
ink, in white HDPE bottles with a child-resistant closure:
• 28 capsules per bottle: NDC 57962-070-28
The 140 mg capsules are supplied as white opaque capsules, marked with “ibr 140 mg” in black
ink, in white HDPE bottles with a child-resistant closure:
• 90 capsules per bottle: NDC 57962-140-09
• 120 capsules per bottle: NDC 57962-140-12
Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C
(59°F to 86°F) permitted (see USP Controlled Room Temperature). Retain in original package
until dispensing.
Tablets
The IMBRUVICA (ibrutinib) tablets are supplied in 3 strengths in the following packaging
configurations:
• 140 mg tablets: Yellow green to green round tablets debossed with “ibr” on one side and
“140” on the other side. Carton of one folded blister card containing two 14-count blister
strips for a total of 28 tablets: NDC 57962-014-28
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• 280 mg tablets: Purple oblong tablets debossed with “ibr” on one side and “280” on the
other side. Carton of one folded blister card containing two 14-count blister strips for a
total of 28 tablets: NDC 57962-280-28
• 420 mg tablets: Yellow green to green oblong tablets debossed with “ibr” on one side and
“420” on the other side. Carton of one folded blister card containing two 14-count blister
strips for a total of 28 tablets: NDC 57962-420-28
Store tablets in original packaging at room temperature 20°C to 25°C (68°F to 77°F). Brief
exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature).
Oral Suspension
The IMBRUVICA (ibrutinib) oral suspension is a white to off-white suspension supplied as
108 mL in a 150 mL amber glass bottle with a pre-inserted bottle adapter and a child-resistant
closure. Each mL contains 70 mg of ibrutinib. The oral suspension bottle is provided in a carton
with two 3 mL reusable oral dosing syringes: NDC 57962-007-12.
Store the oral suspension bottle at 2°C to 25°C (36°F to 77°F). Do not freeze. Dispense in
original sealed container. Do not use if the carton seal is broken or missing.
Discard any unused IMBRUVICA oral suspension remaining 60 days after first opening the
bottle.
17 PATIENT COUNSELING INFORMATION
Advise the patients and caregivers to read the FDA-approved patient labeling (Patient
Information and Instructions for Use).
Hemorrhage:
Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe
headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that
IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and
Precautions (5.1)].
Infections:
Inform patients of the possibility of serious infection, and to report any signs or symptoms
(fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions
(5.2)].
Cardiac arrhythmias, cardiac failure, and sudden death:
Inform patients of the possibility of irregular heart rhythm, heart failure and sudden death.
Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting,
shortness of breath, chest discomfort, or edema [see Warnings and Precautions (5.3)].
Hypertension:
Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which
may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.4)].
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Second primary malignancies:
Inform patients that other malignancies have occurred in patients who have been treated with
IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions
(5.6)].
Hepatotoxicity, including drug-induced liver injury:
Inform patients that liver problems, including drug-induced liver injury and abnormalities in
liver tests, may develop during IMBRUVICA treatment. Advise patients to contact their
healthcare provider immediately if they experience abdominal discomfort, dark urine, or
jaundice [see Warnings and Precautions (5.7)].
Tumor lysis syndrome:
Inform patients of the potential risk of tumor lysis syndrome and to report any signs and
symptoms associated with this event to their healthcare provider for evaluation [see Warnings
and Precautions (5.8)].
Embryo-fetal toxicity:
Advise women of the potential risk to a fetus. Advise females of reproductive potential to inform
their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions
(5.9), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with
IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations (8.3)].
Advise males with female partners of reproductive potential to use effective contraception during
treatment with IMBRUVICA and for 1 month after the last dose [see Use in Specific Populations
(8.3), Nonclinical Toxicology (13.1)].
Lactation:
Advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the
last dose [see Use in Specific Populations (8.2)].
Other Important Information:
Inform patients to take IMBRUVICA orally once daily according to their physician’s
instructions and that the oral dosage (capsules or tablets) should be swallowed whole with a glass
of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the
tablets approximately the same time each day [see Dosage and Administration (2.1)].
Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as
soon as possible on the same day with a return to the normal schedule the following day. Patients
should not take extra doses to make up the missed dose [see Dosage and Administration (2.1)].
For IMBRUVICA oral suspension, instruct patients or caregivers to read and follow the
Instructions for Use for proper preparation, administration, storage and disposal [see Dosage and
Administration (2.1)].
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55
Advise patients of the common side effects associated with IMBRUVICA [see Adverse
Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT
INFORMATION.
Advise patients to inform their health care providers of all concomitant medications, including
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug
Interactions (7)].
Advise patients that they may experience loose stools or diarrhea and should contact their doctor
if their diarrhea persists. Advise patients to maintain adequate hydration [see Adverse Reactions
(6.1)].
Distributed and Marketed by:
Pharmacyclics LLC
South San Francisco, CA 94080 USA
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA 19044 USA
Patent http://www.imbruvica.com
IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC
© Pharmacyclics LLC 2024
© Janssen Biotech, Inc. 2024
20088578
Reference ID: 5500397
PATIENT INFORMATION
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
capsules
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
tablets
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
oral suspension
What is IMBRUVICA?
IMBRUVICA is a prescription medicine used to treat:
•
Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
•
Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
•
Adults with Waldenström’s macroglobulinemia (WM).
•
Adults and children 1 year of age and older with chronic graft versus host disease (cGVHD) after failure of 1 or
more lines of systemic therapy.
It is not known if IMBRUVICA is safe and effective in children under 1 year of age.
Before taking IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:
•
have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned
medical, surgical, or dental procedure.
•
have bleeding problems or are taking a blood thinner medicine.
•
have an infection.
•
have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease,
such as high blood pressure, high cholesterol, or diabetes.
•
have liver problems.
•
are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. If you are able to become
pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA. Tell your
healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA.
o
Females who are able to become pregnant should use effective birth control (contraception) during treatment
with IMBRUVICA and for 1 month after the last dose.
o
Males with female partners who are able to become pregnant should use effective birth control, such as
condoms, during treatment with IMBRUVICA and for 1 month after the last dose.
•
are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA and for 1 week after
the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how
IMBRUVICA works and can cause side effects.
How should I take or give IMBRUVICA?
•
Take or give IMBRUVICA exactly as your healthcare provider tells you to take or give it.
•
Take or give IMBRUVICA 1 time a day at about the same time each day.
IMBRUVICA comes as capsules, tablets, and oral suspension.
•
If your healthcare provider prescribes IMBRUVICA capsules or tablets:
o
Swallow IMBRUVICA capsules or tablets whole with a glass of water.
o
Do not open, break, or chew IMBRUVICA capsules.
o
Do not cut, crush, or chew IMBRUVICA tablets.
•
If your healthcare provider prescribes IMBRUVICA oral suspension:
o
See the detailed Instructions for Use that comes with IMBRUVICA oral suspension for information about the
correct way to take or give a dose. If you have questions about how to take or give IMBRUVICA oral
suspension, talk to your healthcare provider.
o
Do not use if the carton seal is broken or missing.
•
If you miss a dose of IMBRUVICA, take or give it as soon as you remember on the same day. Take or give the next
dose of IMBRUVICA at the regular time on the next day. Do not take or give extra doses of IMBRUVICA to make up
for a missed dose.
•
If you take too much IMBRUVICA, call your healthcare provider, or go to the nearest hospital emergency room right
away.
What should I avoid while taking IMBRUVICA?
Reference ID: 5500397
You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment
with IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.
What are the possible side effects of IMBRUVICA?
IMBRUVICA may cause serious side effects, including:
•
Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA and can also be serious and
may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your
healthcare provider if you have any signs of bleeding, including:
o blood in your stools or black stools (looks like
tar)
o increased bruising, or small red or purple spots
on the skin
o pink or brown urine
o dizziness
o unexpected bleeding, or bleeding that is severe
or that you cannot control
o weakness
o confusion
o vomit blood or vomit looks like coffee grounds
o cough up blood or blood clots
o change in your speech
o headache that lasts a long time or severe
headache
•
Infections can happen during treatment with IMBRUVICA. These infections can be serious and may lead to death.
Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms
of an infection during treatment with IMBRUVICA.
•
Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart
failure and death have happened in people treated with IMBRUVICA, especially in people who have an infection,
an increased risk for heart disease, or have had heart rhythm problems in the past. Your heart function will be
checked before and during treatment with IMBRUVICA. Tell your healthcare provider if you get any symptoms of
heart problems, such as:
o
feeling as if your heart is beating
fast and irregular
o
lightheadedness
o
dizziness
o
shortness of breath
o
swelling of the feet, ankles, or
legs
o
chest discomfort
o
feeling faint
If you develop any of these symptoms, your healthcare provider may do tests to check your heart and may change
your IMBRUVICA dose.
•
High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with
IMBRUVICA. Your healthcare provider may start you on blood pressure medicine or change current medicines to
treat your blood pressure.
•
Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are
common with IMBRUVICA, but can also be severe. Your healthcare provider should do monthly blood tests to
check your blood counts.
•
Second primary cancers. New cancers have happened during treatment with IMBRUVICA, including cancers of
the skin or other organs.
•
Liver problems. Liver problems, which may be severe or life-threatening, or lead to death, can happen in people
treated with IMBRUVICA. Your healthcare provider will do blood tests to check your liver before and during
treatment with IMBRUVICA. Tell your healthcare provider or get medical help right away if you have any signs of
liver problems, including stomach pain or discomfort, dark-colored urine, or yellow skin and eyes.
•
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure
and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare
provider may do blood tests to check you for TLS.
The most common side effects of IMBRUVICA in adults with B-cell malignancies (CLL/SLL and WM) include:
o
low platelet count
o
diarrhea
o
tiredness
o
muscle, bone, and joint pain
o
low white blood cell count
o
rash
o
low red blood cell count (anemia)
o
bruising
o
nausea
The most common side effects of IMBRUVICA in adults or children 1 year of age and older with cGVHD
include:
o
tiredness
o
low red blood cell count (anemia)
o
bruising
o
diarrhea
o
low platelet count
o
muscle, bone, and joint pain
o
fever
o
muscle spasms
o
mouth sores (stomatitis)
o
bleeding
o
nausea
o
stomach pain
o
pneumonia
o
headache
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Diarrhea is a common side effect in people who take IMBRUVICA. Drink plenty of fluids during treatment with
IMBRUVICA to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your
healthcare provider if you have diarrhea that does not go away.
These are not all the possible side effects of IMBRUVICA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store IMBRUVICA?
•
Store IMBRUVICA capsules and tablets at room temperature between 68°F and 77°F (20°C and 25°C).
•
Keep IMBRUVICA capsules in the original container with the lid tightly closed.
•
Keep IMBRUVICA tablets in the original carton.
•
Store IMBRUVICA oral suspension bottle between 36°F and 77°F (2°C and 25°C). Do not freeze.
•
Use IMBRUVICA oral suspension within 60 days after first opening the bottle. Throw away (dispose of) any unused
portion 60 days after opening.
•
IMBRUVICA capsules and oral suspension come in a bottle with a child-resistant cap.
Keep IMBRUVICA and all medicines out of the reach of children.
General information about the safe and effective use of IMBRUVICA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have
the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for
information about IMBRUVICA that is written for health professionals.
What are the ingredients in IMBRUVICA?
Active ingredient: ibrutinib
Inactive ingredients:
IMBRUVICA capsules: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl
sulfate. The 70 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and black ink. The 140 mg
capsule shell contains gelatin, titanium dioxide, and black ink.
IMBRUVICA tablets: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric
oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets),
talc, titanium dioxide, and yellow iron oxide (140 mg and 420 mg tablets).
IMBRUVICA oral suspension: benzyl alcohol, citric acid monohydrate, disodium hydrogen phosphate, hypromellose,
microcrystalline cellulose and carboxymethylcellulose sodium, purified water, and sucralose.
Distributed and Marketed by: Pharmacyclics LLC South San Francisco, CA 94080 USA
Marketed by: Janssen Biotech, Inc. Horsham, PA 19044 USA
© Pharmacyclics LLC 2024
© Janssen Biotech, Inc. 2024
20088578
For more information, go to www.imbruvica.com or call 1-877-877-3536.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 5/2024
Reference ID: 5500397
A
A
INSTRUCTIONS FOR USE
IMBRUVICA (im-BRU-vih-kuh)
(ibrutinib)
oral suspension
This Instructions for Use contains information about how to prepare and take or give a dose of
IMBRUVICA oral suspension.
Read this Instructions for Use before you take or give IMBRUVICA and each time you get a refill. There
may be new information.
This Instructions for Use does not take the place of talking to your healthcare provider about your or your
child’s medical condition or treatment.
Call your healthcare provider or 1-877-877-3536 if you need help or have any questions about how to
take or give IMBRUVICA the right way.
Important information you need to know before taking or giving IMBRUVICA.
•
IMBRUVICA is for oral use only.
•
Take or give IMBRUVICA exactly as your healthcare provider tells you to.
•
If you miss a dose of IMBRUVICA, it can be taken or given as soon as possible on the same day.
Do not take or give more than the prescribed dose in 1 day.
If you or your child take too much IMBRUVICA, call your healthcare provider for help.
•
Keep these instructions for future use.
Each IMBRUVICA carton contains (see Figure A):
•
1 bottle of IMBRUVICA (called ‘bottle’ in this Instructions for Use) with pre-inserted bottle adapter
(called ‘adapter’ in this Instructions for Use). Do not remove the bottle adapter.
•
2 reusable 3 mL oral dosing syringes (called ‘syringe’ in this Instructions for Use) measuring in
0.1 mL increments.
Only use the syringes that come with IMBRUVICA. Do not use the syringes for other
patients or with other medicines.
If you cannot read the markings on the syringes, throw them away and call 1-877-877-3536
to get new ones.
Reference ID: 5500397
A
B-Cap
-
Adapter (Do not remove the
adapter)
3 ml
3 ml
Barrel
-
Plunger
Bottle
Syringes
Preparing and taking or giving a dose of IMBRUVICA
Step 1: Gather and check supplies.
•
Check the prescribed dose in milliliters (mLs).
Find this mL marking on the syringe.
•
If the dose is more than the marking on the
syringe, split the dose between syringes as
prescribed.
•
Gather bottle and syringe(s) (see Figure A).
•
Check the bottle and make sure that the bottle has
IMBRUVICA Oral Suspension printed on it and the
expiration date (“EXP”) has not passed.
Do not use IMBRUVICA after the “EXP” date printed
on the carton and on the bottle.
Do not use if the IMBRUVICA carton seal appears to
be tampered with.
Figure A
Step 2: Record or check the discard date.
•
When opening the bottle for the first time, record
the date that is 60 days from the day the bottle is
opened underneath the words “Discard Date” (see
Figure B).
•
Use IMBRUVICA within 60 days after first opening
the bottle.
Do not use IMBRUVICA past the discard date
recorded on the bottle.
Figure B
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Ii\
Step 3: Shake the bottle.
•
Shake the bottle well before each use (see Figure
C).
Figure C
Step 4: Remove the cap from the bottle.
•
Press down and twist the cap counterclockwise to
remove it from the bottle (see Figure D).
•
If there is fluid on top of the adapter, you may wipe
it with a clean disposable tissue.
Do not remove the bottle adapter.
Figure D
Step 5: Attach the syringe to the bottle.
•
Make sure the syringe is clean and dry before
use.
•
Push the plunger down all the way.
•
Gently insert tip of the syringe into the adapter.
•
Turn the assembled bottle and syringe upside
down (see Figure E).
Figure E
Reference ID: 5500397
A
Step 6: Fill the syringe.
•
Slowly pull the syringe plunger down, past the
number of mLs for your prescribed dose (see Figure
F).
•
Check for air bubbles and proceed to Step 7 for
instructions on how to remove air bubbles.
Figure F
Step 7: Remove air bubbles and adjust to the prescribed
dose (mL).
•
Hold the syringe and tap the sides to send
bubbles to the tip.
•
With the syringe attached to the bottle, push the
plunger up to remove the air bubbles from the top
(see Figure G).
•
After the bubbles are removed, push the plunger
up until the top of the colored plunger is even with
the markings on the syringe for the prescribed
dose.
Air bubbles must be removed to ensure the correct
dose.
Note: Repeat steps 6 and 7 if any air bubbles remain.
Figure G
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Step 8: Remove the syringe from the bottle.
•
Turn the assembled bottle upright.
•
Hold the middle of the syringe and carefully
remove it from the bottle (see Figure H).
•
Place the bottle aside.
Do not touch the plunger of the syringe to avoid
accidentally spilling the medicine before you are
ready to take or give the dose.
Note: If more than 1 syringe is needed to take or give the full
dose, repeat steps 5 to 8 with the second syringe to complete
the prescribed dose.
Figure H
Step 9: Take or give IMBRUVICA.
•
Place the tip of the syringe along the inside of the
cheek.
•
Slowly push the plunger all the way in to take or
give the entire dose (see Figure I).
•
Repeat with second syringe if needed to complete
the prescribed dose.
Note: IMBRUVICA must be taken or given as soon as
possible after being drawn from the bottle.
Note: After swallowing the dose of medicine make sure to
drink water.
Figure I
Step 10: Recap the bottle.
•
Place the cap back on the IMBRUVICA bottle (see
Figure J).
•
Make sure the bottle is tightly closed between
each use.
Figure J
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➔
Step 11: Rinse the syringe.
•
Remove the plunger from the syringe.
•
Rinse the plunger and the syringe only with water
and air dry (see Figure K).
•
Store the syringe in a clean, dry place.
Do not clean the syringe with soap or in the dishwasher.
Figure K
Turn over for more information
How to store IMBRUVICA Oral Suspension
•
Store the bottle between 36°F and 77°F (2°C and 25°C).
Do not freeze.
•
IMBRUVICA oral suspension comes in a bottle with a child-resistant cap.
•
Store IMBRUVICA and all medications out of the reach of children.
How to dispose of IMBRUVICA
Throw away (dispose of) any unused medicine within 60 days after first opening of the
bottle. At the same time, throw away any used or unused syringes.
•
Ask your pharmacist how to properly dispose of the medicine.
•
For syringe disposal, rinse and place in household trash.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed and Marketed by:
Pharmacyclics LLC
South San Francisco, CA 94080 USA
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA 19044 USA
Patent http://www.imbruvica.com
IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC
© 2024 Pharmacyclics LLC
© 2024 Janssen Biotech, Inc.
20080493
Revised: 2/2024
Reference ID: 5500397
| custom-source | 2025-02-12T15:48:10.443311 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205552s043,210563s019,217003s004lbl.pdf', 'application_number': 217003, 'submission_type': 'SUPPL ', 'submission_number': 4} |
80,733 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PYZCHIVA safely and effectively. See full prescribing information for
PYZCHIVA.
PYZCHIVA® (ustekinumab-ttwe) injection, for subcutaneous or
intravenous use
Initial U.S. Approval: 2024
PYZCHIVA (ustekinumab-ttwe) is biosimilar* to STELARA (ustekinumab)
-----------------------------INDICATIONS AND USAGE-------------------------
PYZCHIVA is a human interleukin-12 and -23 antagonist indicated for the
treatment of:
Adult patients with:
•
moderate to severe plaque psoriasis (PsO) who are candidates for
phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
•
moderately to severely active Crohn's disease (CD). (1.3)
•
moderately to severely active ulcerative colitis. (1.4)
Pediatric patients 6 years and older with:
•
moderate to severe plaque psoriasis, who are candidates for
phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
------------------------DOSAGE AND ADMINISTRATION---------------------
Psoriasis Adult Subcutaneous Recommended Dosage (2.1):
Weight Range (kilograms)
Recommended Dosage
less than or equal to 100 kg
45 mg administered subcutaneously
initially and 4 weeks later,
followed by 45 mg administered
subcutaneously every 12 weeks
greater than 100 kg
90 mg administered subcutaneously
initially and 4 weeks later,
followed by 90 mg administered
subcutaneously every 12 weeks
Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended
Dosage (2.1):
Weight-based dosing is recommended at the initial dose, 4 weeks later, then
every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
greater than 100 kg
90 mg
Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):
•
The recommended dosage is 45 mg administered subcutaneously
initially and 4 weeks later, followed by 45 mg administered
subcutaneously every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis
weighing greater than 100 kg, the recommended dosage is 90 mg
administered subcutaneously initially and 4 weeks later, followed by 90
mg administered subcutaneously every 12 weeks.
Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended
Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4
weeks later, then every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co
existent moderate-to-severe plaque
psoriasis
90 mg
Crohn's Disease and Ulcerative Colitis Initial Adult Intravenous
Recommended Dosage (2.3): A single intravenous infusion using weight-
based dosing:
Weight Range (kilograms)
Dose
up to 55 kg
260 mg (2 vials)
greater than 55 kg to 85 kg
390 mg (3 vials)
greater than 85 kg
520 mg (4 vials)
Crohn's Disease and Ulcerative Colitis Maintenance Adult Subcutaneous
Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the
initial intravenous dose, then every 8 weeks thereafter.
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Subcutaneous Injection (3)
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled
syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
Intravenous Infusion (3)
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
-------------------------------CONTRAINDICATIONS-----------------------------
•
Clinically significant hypersensitivity to ustekinumab products or to any
of the excipients in PYZCHIVA. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
•
Infections: Serious infections have occurred. Avoid starting
PYZCHIVA during any clinically important active infection. If a
serious infection or clinically significant infection develops, discontinue
PYZCHIVA until the infection resolves. (5.1)
•
Theoretical Risk for Particular Infections: Serious infections from
mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG)
vaccinations have been reported in patients genetically deficient in IL
12/IL-23. Consider diagnostic tests for these infections as dictated by
clinical circumstances. (5.2)
•
Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment
with PYZCHIVA. Initiate treatment of latent TB before administering
PYZCHIVA. (5.3)
•
Malignancies: Ustekinumab products may increase risk of malignancy.
The safety of ustekinumab products in patients with a history of or a
known malignancy has not been evaluated. (5.4)
•
Hypersensitivity Reactions: If an anaphylactic or other clinically
significant hypersensitivity reaction occurs, institute appropriate therapy
and discontinue PYZCHIVA. (5.5)
•
Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is
suspected, treat promptly and discontinue PYZCHIVA. (5.6)
•
Immunizations: Avoid use of live vaccines in patients during treatment
with PYZCHIVA. (5.7)
•
Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic
pneumonia and cryptogenic organizing pneumonia have been reported
during post-approval use of ustekinumab products. If diagnosis is
confirmed, discontinue PYZCHIVA and institute appropriate treatment.
(5.8)
-------------------------------ADVERSE REACTIONS-----------------------------
Most common adverse reactions are:
•
Psoriasis QDVRSKDU\QJLWLVXSSHUUHVSLUDWRU\WUDFWLQIHFWLRQ
headache, and fatigue. (6.1)
•
Crohn's Disease, induction YRPLWLQJ
•
Crohn's Disease, maintenance QDVRSKDU\QJLWLVLQMHFWLRQVLWH
erythema, vulvovaginal candidiasis/mycotic infection, bronchitis,
pruritus, urinary tract infection, and sinusitis. (6.1)
•
Ulcerative colitis, induction QDVRSKDU\QJLWLV
•
Ulcerative colitis, maintenance QDVRSKDU\QJLWLVKHDGDFKH
abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at
1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
*Biosimilar means that the biological product is approved based on data
demonstrating that it is highly similar to an FDA-approved biological product,
known as a reference product, and that there are no clinically meaningful
differences between the biosimilar product and the reference product.
Biosimilarity of PYZCHIVA has been demonstrated for the condition(s) of
use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and
route(s) of administration described in its Full Prescribing Information
Revised: 12/2024
Reference ID: 5500909
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Plaque Psoriasis (PsO)
1.2 Psoriatic Arthritis (PsA)
1.3 Crohn's Disease (CD)
1.4 Ulcerative Colitis
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage in Plaque Psoriasis
2.2 Recommended Dosage in Psoriatic Arthritis
2.3 Recommended Dosage in Crohn's Disease and Ulcerative Colitis
2.4 General Considerations for Administration
2.5 Instructions for Administration of PYZCHIVA Prefilled Syringes
Equipped with Needle Safety Guard
2.6 Preparation and Administration of PYZCHIVA 130 mg/26 mL (5
mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative
Colitis)
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Infections
5.2 Theoretical Risk for Vulnerability to Particular Infections
5.3 Pre-treatment Evaluation for Tuberculosis
5.4 Malignancies
5.5 Hypersensitivity Reactions
5.6 Posterior Reversible Encephalopathy Syndrome (PRES)
5.7 Immunizations
5.8 Noninfectious Pneumonia
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Concomitant Therapies
7.2 CYP450 Substrates
7.3 Allergen Immunotherapy
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Adult Plaque Psoriasis
14.2 Pediatric Plaque Psoriasis
14.3 Psoriatic Arthritis
14.4 Crohn's Disease
14.5 Ulcerative Colitis
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5500909
1
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Plaque Psoriasis (PsO)
PYZCHIVA is indicated for the treatment of adults and pediatric patients 6 years of age and older with
moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
1.2
Psoriatic Arthritis (PsA)
PYZCHIVA is indicated for the treatment of adults and pediatric patients 6 years of age and older with
active psoriatic arthritis.
1.3
Crohn's Disease (CD)
PYZCHIVA is indicated for the treatment of adult patients with moderately to severely active Crohn's
disease.
1.4
Ulcerative Colitis
PYZCHIVA is indicated for the treatment of adult patients with moderately to severely active ulcerative
colitis.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage in Plaque Psoriasis
Subcutaneous Adult Dosage Regimen
•
For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks
later, followed by 45 mg every 12 weeks.
•
For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks
later, followed by 90 mg every 12 weeks.
In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg
resulted in greater efficacy in these subjects [see Clinical Studies (14)].
Subcutaneous Pediatric Dosage Regimen
Administer PYZCHIVA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of PYZCHIVA for pediatric patients (6–17 years old) with plaque psoriasis
based on body weight is shown below (Table 1).
Reference ID: 5500909
Table 1:
Recommended Dose of PYZCHIVA for Subcutaneous Injection in Pediatric Patients (6–17 years old)
with Plaque Psoriasis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
more than 100 kg
90 mg
For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose
(0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the single-dose vial.
Table 2:
Injection volumes of PYZCHIVA45 mg/0.5 mL single-dose vials for pediatric patients (6–17 years
old) with plaque psoriasis and pediatric patients (6-17 years old) with psoriatic arthritis
* weighing less
than 60 kg
Body Weight (kg) at the time of
dosing
Dose (mg)
Volume of injection (mL)
15
11.3
0.12
16
12
0.13
17
12.8
0.14
18
13.5
0.15
19
14.3
0.16
20
15
0.17
21
15.8
0.17
22
16.5
0.18
23
17.3
0.19
24
18
0.20
25
18.8
0.21
26
19.5
0.22
27
20.3
0.22
28
21
0.23
29
21.8
0.24
30
22.5
0.25
31
23.3
0.26
32
24
0.27
33
24.8
0.27
34
25.5
0.28
35
26.3
0.29
36
27
0.30
37
27.8
0.31
38
28.5
0.32
39
29.3
0.32
40
30
0.33
41
30.8
0.34
42
31.5
0.35
43
32.3
0.36
44
33
0.37
45
33.8
0.37
46
34.5
0.38
47
35.3
0.39
48
36
0.40
49
36.8
0.41
50
37.5
0.42
51
38.3
0.42
52
39
0.43
53
39.8
0.44
54
40.5
0.45
55
41.3
0.46
Reference ID: 5500909
56
42
0.46
57
42.8
0.47
58
43.5
0.48
59
44.3
0.49
* Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen.
2.2
Recommended Dosage in Psoriatic Arthritis
Subcutaneous Adult Dosage Regimen
•
The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the
recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
Subcutaneous Pediatric Dosage Regimen
Administer PYZCHIVA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of PYZCHIVA for pediatric patients (6 to 17 years old) with psoriatic arthritis,
based on body weight, is shown below (Table 3).
Table 3:
Recommended Dose of PYZCHIVA for Subcutaneous Injection in Pediatric Patients (6 to 17 years
old) with Psoriatic Arthritis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg*
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co-existent moderate-to-severe plaque
90 mg
psoriasis
* For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the
appropriate volume from the single-dose vial.
2.3
Recommended Dosage in Crohn's Disease and Ulcerative Colitis
Intravenous Induction Adult Dosage Regimen
A single intravenous infusion dose of PYZCHIVA using the weight-based dosage regimen specified in
Table 4 [see Dosage and Administration (2.6)].
Reference ID: 5500909
Table 4:
Initial Intravenous Dosage of PYZCHIVA
Body Weight of Patient at the time of dosing
Dose
Number of 130 mg/26 mL
(5 mg/mL) PYZCHIVA vials
55 kg or less
260 mg
2
more than 55 kg to 85 kg
390 mg
3
more than 85 kg
520 mg
4
Subcutaneous Maintenance Adult Dosage Regimen
The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the
initial intravenous dose, then every 8 weeks thereafter.
2.4
General Considerations for Administration
•
PYZCHIVA is intended for use under the guidance and supervision of a healthcare provider.
PYZCHIVA should only be administered to patients who will be closely monitored and have
regular follow-up visits with a healthcare provider. The appropriate dose should be determined by
a healthcare provider using the patient's current weight at the time of dosing. In pediatric patients,
it is recommended that PYZCHIVA be administered by a healthcare provider. If a healthcare
provider determines that it is appropriate, a patient may self-inject or a caregiver may inject
PYZCHIVA after proper training in subcutaneous injection technique. Instruct patients to follow
the directions provided in the Medication Guide [see Medication Guide].
•
It is recommended that each injection be administered at a different anatomic location (such as
upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and
not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-
dose vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended.
•
Prior to administration, visually inspect PYZCHIVA for particulate matter and discoloration.
PYZCHIVA is a clear, colorless to light yellow, sterile and preservative-free solution. Do not use
PYZCHIVA if it is discolored or cloudy, or if other particulate matter is present. PYZCHIVA does
not contain preservatives; therefore, discard any unused product remaining in the vial and/or
syringe.
Reference ID: 5500909
Viewing window
Body
Needle guard wings
Plunger
Needle cover
Needle
Label
Plunger head
2.5
Instructions for Administration of PYZCHIVA Prefilled Syringes Equipped with Needle
Safety Guard
Refer to the diagram below for the provided instructions.
•
Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER
HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the
prefilled syringe if it is dropped without the NEEDLE COVER in place.
•
Inject PYZCHIVA subcutaneously as recommended [see Dosage and Administration (2.1, 2.2,
2.3)].
•
Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is
completely between the needle guard wings. Injection of the entire prefilled syringe contents is
necessary to activate the needle guard.
•
After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the
skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up
until the entire needle is covered by the needle guard, as shown by the illustration below:
Reference ID: 5500909
•
Used syringes should be placed in a puncture-resistant container.
2.6
Preparation and Administration of PYZCHIVA 130 mg/26 mL (5 mg/mL) Vial for
Intravenous Infusion (Crohn's Disease and Ulcerative Colitis)
PYZCHIVA solution for intravenous infusion must be diluted, prepared and infused by a healthcare
professional using aseptic technique.
1.
Calculate the dose and the number of PYZCHIVA vials needed based on patient weight (Table 4).
Each 26 mL vial of PYZCHIVA contains 130 mg of ustekinumab-ttwe.
2.
:LWKGUDZDQGWKHQGLVFDUGDYROXPHRIWKH 6RGLXP&KORULGH,QMHFWLRQ863IURPWKH
250 mL infusion bag equal to the volume of PYZCHIVA to be added (discard 26 mL sodium
chloride for each vial of PYZCHIVA needed, for 2 vials- discard 52 mL, for 3 vials- discard 78
mL, 4 vials- GLVFDUGP/ $OWHUQDWLYHO\DP/LQIXVLRQEDJFRQWDLQLQJ6RGLXP
Chloride Injection, USP may be used.
3.
Withdraw 26 mL of PYZCHIVA from each vial needed and add it to the 250 mL infusion bag.
The final volume in the infusion bag should be 250 mL. Gently mix. Protect from light.
4.
Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles,
discoloration or foreign particles are observed.
5.
Infuse the diluted solution over a period of at least one hour. Once diluted in the infusion bag, the
infusion should be completely administered within 36 hours at room temperature up to 30°C
(86°F) .
6.
Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore
size 0.2 micrometer).
7.
Do not infuse PYZCHIVA concomitantly in the same intravenous line with other agents.
8.
PYZCHIVA does not contain preservatives. Each vial is for one-time use in only one patient.
Discard any remaining solution. Dispose any unused medicinal product in accordance with local
requirements.
Reference ID: 5500909
Storage
•
The diluted infusion solution may be kept at room temperature up to 30°C (86°F) for up to 36
hours including infusion period.
•
If necessary, the diluted infusion solution may be stored refrigerated at 2ºC to 8ºC (36ºF to
46ºF) for up to 15 days. After removal from refrigeration, the diluted solution may be stored at
room temperature at up to 30°C (86°F) for an additional 24 hours including infusion period.
Storage time at refrigerated or room temperature begins once the diluted solution has been
prepared. Do not freeze. Protect from light. Discard any unused portion of the infusion solution.
3
DOSAGE FORMS AND STRENGTHS
PYZCHIVA (ustekinumab-ttwe) is a clear, colorless to light yellow, sterile and preservative-free
solution.
Subcutaneous Injection
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
Intravenous Infusion
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
4
CONTRAINDICATIONS
PYZCHIVA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab
products or to any of the excipients in PYZCHIVA [see Warnings and Precautions (5.5)].
5
WARNINGS AND PRECAUTIONS
5.1
Infections
Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious
bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab
products [see Adverse Reactions (6.1, 6.3)].
Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in
clinical trials included the following:
•
Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis,
osteomyelitis, viral infections, gastroenteritis and urinary tract infections.
•
Psoriatic arthritis: cholecystitis.
•
Crohn's disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria
meningitis.
•
Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.
Reference ID: 5500909
Avoid initiating treatment with PYZCHIVA in patients with any clinically important active infection
until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to
initiating use of PYZCHIVA in patients with a chronic infection or a history of recurrent infection.
Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on
treatment with PYZCHIVA and discontinue PYZCHIVA for serious or clinically significant infections
until the infection resolves or is adequately treated.
5.2
Theoretical Risk for Vulnerability to Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections
from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including
nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal
outcomes have been reported in such patients.
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with
ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic
testing (e.g., tissue culture, stool culture, as dictated by clinical circumstances).
5.3
Pre-treatment Evaluation for Tuberculosis
Evaluate patients for tuberculosis infection prior to initiating treatment with PYZCHIVA.
Avoid administering PYZCHIVA to patients with active tuberculosis infection. Initiate treatment of
latent tuberculosis prior to administering PYZCHIVA. Consider anti-tuberculosis therapy prior to
initiation of PYZCHIVA in patients with a past history of latent or active tuberculosis in whom an
adequate course of treatment cannot be confirmed. Closely monitor patients receiving PYZCHIVA for
signs and symptoms of active tuberculosis during and after treatment.
5.4
Malignancies
Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies
were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)].
In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical
Toxicology (13)].
The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy
or who have a known malignancy.
There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell
carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing
non-melanoma skin cancer. Monitor all patients receiving PYZCHIVA for the appearance of non-
melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history
of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse
Reactions (6.1)].
Reference ID: 5500909
5.5
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with
ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically
significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue PYZCHIVA.
5.6
Posterior Reversible Encephalopathy Syndrome (PRES)
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior
Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported
in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn's disease. Clinical
presentation included headaches, seizures, confusion, visual disturbances, and imaging changes
consistent with PRES a few days to several months after ustekinumab product initiation. A few cases
reported latency of a year or longer. Patients recovered with supportive care following withdrawal of
ustekinumab products.
Monitor all patients treated with PYZCHIVA for signs and symptoms of PRES. If PRES is suspected,
promptly administer appropriate treatment and discontinue PYZCHIVA.
5.7
Immunizations
Prior to initiating therapy with PYZCHIVA, patients should receive all age-appropriate immunizations
as recommended by current immunization guidelines. Patients being treated with PYZCHIVA should
avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with PYZCHIVA or
for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is
advised when administering live vaccines to household contacts of patients receiving PYZCHIVA
because of the potential risk for shedding from the household contact and transmission to patient.
Non-live vaccinations received during a course of PYZCHIVA may not elicit an immune response
sufficient to prevent disease.
5.8
Noninfectious Pneumonia
Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have
been reported during post-approval use of ustekinumab products. Clinical presentations included cough,
dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included
respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and
in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue PYZCHIVA and
institute appropriate treatment [see Adverse Reactions (6.3)].
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the label:
•
Infections [see Warnings and Precautions (5.1)]
•
Malignancies [see Warnings and Precautions (5.4)]
Reference ID: 5500909
•
Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
•
Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]
•
Noninfectious Pneumonia [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Adult Subjects with Plaque Psoriasis
The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including
2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two
years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at
least five years.
Table 5 VXPPDUL]HVWKHDGYHUVHUHDFWLRQVWKDWRFFXUUHGDWDUDWHRIDWOHDVWwith higher rates in the
ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see
Clinical Studies (14)].
Table 5:
$GYHUVH5HDFWLRQV5HSRUWHGE\RI6XEMHFWV with Plaque Psoriasis and at Higher Rates in the
Ustekinumab Groups through Week 12 in Ps STUDY 1 and Ps STUDY 2
Ustekinumab
Placebo
45 mg
90 mg
Subjects treated
665
664
666
Nasopharyngitis
Upper respiratory tract infection
Headache
Fatigue
Back pain
Dizziness
Pharyngolaryngeal pain
Pruritus
Injection site erythema
Myalgia
8
Depression
$GYHUVHUHDFWLRQVWKDWRFFXUUHGDWUDWHVOHVVWKDQLQWKHcontrolled period of Ps STUDIES 1 and 2
through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions
(pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).
One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions
(5.6)].
Reference ID: 5500909
Infections
In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of
12.6 weeks for placebo-treated subjects and 13.4 weeks for ustekinumab-WUHDWHGVXEMHFWV RI
ustekinumab-treated subjects reported infections (1.39 per subject-year of follow-up) compared with
RISODFHER-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in
RIustekinumab-treated subjects (0.01 per subject-year of follow-XS DQGLQRISODFHER
treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)].
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2
years), representing 8998 subject-\HDUVRIH[SRVXUHRIustekinumab-treated subjects reported
infections (0.87 per subject-years of follow-XS 6HULRXVLQIHFWLRQVZHUHUHSRUWHGLQRIVXEMHFWV
(0.01 per subject-years of follow-up).
Malignancies
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2
years, representing 8998 subject-\HDUVRIH[SRVXUH RIustekinumab-treated subjects reported
malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non
PHODQRPDVNLQFDQFHUZDVUHSRUWHGLQRIustekinumab-treated subjects (0.52 per hundred subject-
years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies
other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and
breast. Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the
controlled and uncontrolled portions of trials were similar in type and number to what would be
expected in the general U.S. population according to the SEER database (adjusted for age, gender and
race).1
Pediatric Subjects with Plaque Psoriasis
The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe
plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17
years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old.
The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque
psoriasis.
Psoriatic Arthritis
The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-
controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab
in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher
incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects
when compared with placebo- WUHDWHGVXEMHFWV YVIRUDUWKUDOJLDDQGYVIRUQDXVHD
YVIRUGHQWDOLQIHFWLRQV LQWKHSODFHER-controlled portions of the PsA clinical trials.
Crohn's Disease
Reference ID: 5500909
The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn's
disease (Crohn's Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to
450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials. These
1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab
formulation but were not included in the efficacy analyses. In trials CD-1 and CD-2 there were 470
subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and
466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in
either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90
mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may
have received other concomitant therapies including aminosalicylates, immunomodulatory agents
[azathioprine (AZA), 6- mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone
or budesonide), and/or antibiotics for their Crohn's disease [see Clinical Studies (14.4)].
The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult
psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in
trial CD-3 are listed in Table 6 and Table 7, respectively.
Table 6:
Common adverse reactions through Week 8 in Trials CD-1 and CD-2 occurring in RI
ustekinumab-treated subjects and higher than placebo
Ustekinumab
6 mg/kg single intravenous
Placebo
induction dose
N=466
N=470
Vomiting
Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia
YV DFQH YV DQGSUXULWXV YV
Table 7:
Common adverse reactions through Week 44 in Trial CD-RFFXUULQJLQRIustekinumab
treated subjects and higher than placebo
Ustekinumab
90 mg subcutaneous maintenance
Placebo
dose every 8 weeks
N=133
N=131
Nasopharyngitis
Injection site erythema
0
Vulvovaginal candidiasis/mycotic
infection
Bronchitis
Pruritus
Urinary tract infection
Sinusitis
Infections
In subjects with Crohn's disease, serious or other clinically significant infections included anal abscess,
gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were
reported in one patient each [see Warnings and Precautions (5.1)].
Reference ID: 5500909
Malignancies
With up to one year of treatment in the Crohn's disease clinical trialsRIustekinumab-treated
subjects (0.36 events per hundred patient-\HDUV DQGRISODFHER-treated subjects (0.58 events per
hundred patient-years) developed non- melanoma skin cancer. Malignancies other than non-melanoma
VNLQFDQFHUVRFFXUUHGLQRIustekinumab-treated subjects (0.27 events per hundred patient-years)
and in none of the placebo-treated subjects.
Hypersensitivity Reactions Including Anaphylaxis
In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One
patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness
RIEUHDWKDQGIOXVKLQJ DIWHUDVLQJOHVXEFXWDQHRXVDGPLQLVWUDWLRQ RIsubjects receiving
subcutaneous ustekinumab). In addition, one subject experienced signs and symptoms consistent with or
related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body
temperature) after the initial intravenous ustekinumab GRVH RIsubjects receiving intravenous
ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases
symptoms resolved within an hour.
Ulcerative Colitis
The safety of ustekinumab was evaluated in two randomized, double-blind, placebo- controlled clinical
trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to
severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of ustekinumab
in subjects with ulcerative colitis was consistent with the safety profile seen across all approved
LQGLFDWLRQV$GYHUVHUHDFWLRQVUHSRUWHGLQDWOHDVWRIustekinumab-treated subjects and at a higher
rate than placebo were:
•
Induction (UC- QDVRSKDU\QJLWLV YV
•
Maintenance (UC-2): QDVRSKDU\QJLWLV YV KHDGDFKH YV DEGRPLQDOSDLQ
YV LQIOXHQ]D YV IHYHU YV GLDUUKHD YV VLQXVLWLV YV
IDWLJXH YV DQGQDXVHD YV
Infections
In subjects with ulcerative colitis, serious or other clinically significant infections included
gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one
subject each [see Warnings and Precautions (5.1)].
Malignancies
With up to one year of treatment in the ulcerative colitis clinical trialsRIustekinumab-treated
subjects (0.48 events per hundred patient-\HDUV DQGRISODFHER-treated subjects (0.00 events per
hundred patient-years) developed non- melanoma skin cancer. Malignancies other than non-melanoma
Reference ID: 5500909
VNLQFDQFHUVRFFXUUHGLQRIustekinumab-treated subjects (0.64 events per hundred patient-years)
DQGRISODFHER-treated subjects (0.40 events per hundred patient-years).
6.2
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of
the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug
antibodies in the studies described below with the incidence of anti-drug antibodies in other studies,
including those of ustekinumab or of other ustekinumab products.
$SSUR[LPDWHO\WRRIVXEMHFWVWUHDWHGZLWKustekinumab in plaque psoriasis and psoriatic
arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In plaque
psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum
ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who
were positive for antibodies to ustekinumab had neutralizing antibodies.
In Crohn's disease and ulcerative colitis clinical trials DQGRIVXEMHFWVUHVSHFWLYHO\
developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No
apparent association between the development of antibodies to ustekinumab and the development of
injection site reactions was seen.
6.3
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of ustekinumab products.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product
exposure.
Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema),
other hypersensitivity reactions (including rash and urticaria).
Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections
and tuberculosis).
Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and
cryptogenic organizing pneumonia.
Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.
7
DRUG INTERACTIONS
7.1
Concomitant Therapies
Reference ID: 5500909
In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive
agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not
appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis
induction trials, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately
RIVXEMHFWVDQGFRUWLFRVWHURLGVZHUHXVHGFRQFRPLWDQWO\LQDSSUR[LPDWHO\DQGRI&URKQ
V
disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to
influence the overall safety or efficacy of ustekinumab.
7.2
CYP450 Substrates
The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL
1, IL-71)Į,)1 GXULQJFKURQLFLQIODPPDWLRQ7KXVuse of ustekinumab products, antagonists of IL
12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of
PYZCHIVA in patients who are receiving concomitant CYP450 substrates, particularly those with a
narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the
individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP
substrates.
A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical
Pharmacology (12.3)].
7.3
Allergen Immunotherapy
Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy.
Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease
tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy.
Therefore, caution should be exercised in patients receiving or who have received allergen
immunotherapy, particularly for anaphylaxis.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Limited data from observational studies, published case reports, and postmarketing surveillance on the
use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major
birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody
across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore,
ustekinumab products may be transferred to the developing fetus (see Clinical Considerations). In
animal reproductive and developmental toxicity studies, no adverse developmental effects were
observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than
100 times the maximum recommended human dose (MRHD).
The background risk of major birth defects and miscarriage for the indicated population(s) are unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.
Reference ID: 5500909
general population, the estimated background risk of major birth defects and miscarriage of clinically
UHFRJQL]HGSUHJQDQFLHVLVWRDQGWRUHVSHFWLYHO\
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Because ustekinumab products may theoretically interfere with immune response to infections, consider
risks and benefits prior to administering live vaccines to infants exposed to PYZCHIVA in utero. There
are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the
duration of persistence of ustekinumab products in infant serum after birth. Although a specific
timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown,
consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance
of the product.
Data
Animal Data
Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No
teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that
were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period
of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100
times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for
4 weeks.
In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant
cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures
greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery.
Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and
one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or
immunological development were observed in the neonates from birth through six months of age.
8.2
Lactation
Risk Summary
Limited data from published literature suggests that ustekinumab is present in human breast milk. There
are no available data on the effects of ustekinumab products on milk production. The effects of local
gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products
are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products have
been identified in the published literature or postmarketing experience.
The developmental and health benefits of breastfeeding should be considered along with the mother's
clinical need for PYZCHIVA and any potential adverse effects on the breastfed child from PYZCHIVA
or from the underlying maternal condition.
Reference ID: 5500909
8.4
Pediatric Use
Plaque Psoriasis
The safety and effectiveness of PYZCHIVA have been established for the treatment of moderate to
severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or
systemic therapy.
Use of PYZCHIVA in pediatric patients 12 to less than 17 years of age is supported by evidence from a
multicenter, randomized, 60 week trial (Ps STUDY 3) of ustekinumab that included a 12 week, double-
blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older [see
Adverse Reactions (6.1), Clinical Studies (14.2)].
Use of PYZCHIVA in pediatric patients 6 to 11 years of age is supported by evidence from an open-
label, single-arm, efficacy, safety and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44
subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
The safety and effectiveness of PYZCHIVA have not been established in pediatric patients less than 6
years of age with plaque psoriasis.
Psoriatic Arthritis
The safety and effectiveness of PYZCHIVA have been established for treatment of psoriatic arthritis in
pediatric patients 6 to 17 years old.
Use of PYZCHIVA in these age groups is supported by evidence from adequate and well controlled
trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with
psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab
from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects
12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally
comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with
psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with
PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2,
14.3)].
The safety and effectiveness of PYZCHIVA have not been established in pediatric patients less than 6
years old with psoriatic arthritis.
Crohn's Disease and Ulcerative Colitis
The safety and effectiveness of PYZCHIVA have not been established in pediatric patients with Crohn's
disease or ulcerative colitis.
8.5
Geriatric Use
Reference ID: 5500909
Of the 6709 subjects exposed to ustekinumab, a total of 340 were 65 years of age or older (183 subjects
with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn's disease and 34
subjects with ulcerative colitis), and 40 subjects were 75 years of age or older. Clinical trials of
ustekinumab did not include sufficient numbers of subjects 65 years of age and older to determine
whether they respond differently from younger adult subjects.
10
OVERDOSAGE
Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting
toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or
effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison
Help line (1-800-222-1222) or a medical toxicologist for additional overdose management
recommendations.
11
DESCRIPTION
Ustekinumab-ttweDKXPDQ,J*țPRQRFORQDODQWLERG\LVDKXPDQLQWHUOHXNLQ-12 and -23 antagonist.
Using DNA recombinant technology, ustekinumab-ttwe is produced in a Chinese hamster ovary cell
line. The manufacturing process contains steps for the clearance of viruses. Ustekinumab-ttwe is
comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to
149,690 Daltons.
PYZCHIVA (ustekinumab-ttwe) injection is a clear, colorless to light yellow, sterile and preservative-
free solution with pH of 5.7– 6.3.
PYZCHIVA for Subcutaneous Use
Available as 45 mg of ustekinumab-ttwe in 0.5 mL and 90 mg of ustekinumab-ttwe in 1 mL, supplied as
a sterile solution in a single-dose prefilled syringe with a 29 gauge fixed ½ inch needle and as 45 mg of
ustekinumab-ttwe in 0.5 mL in a single-dose Type I glass vial with a coated stopper. The syringe is
fitted with a passive needle guard and a needle cover.
Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab-ttwe, histidine (0.095 mg), histidine
hydrochloride monohydrate (0.405 mg), polysorbate 80 (0.02 mg), and sucrose (42.5 mg).
Each 1 mL prefilled syringe delivers 90 mg ustekinumab-ttwe, histidine (0.19 mg), histidine
hydrochloride monohydrate (0.81 mg), polysorbate 80 (0.04 mg), and sucrose (85 mg).
PYZCHIVA for Intravenous Infusion
Available as 130 mg of ustekinumab-ttwe in 26 mL, supplied as a single-dose Type I glass vial with a
coated stopper.
Reference ID: 5500909
Each 26 mL vial delivers 130 mg ustekinumab-ttwe, edetate disodium (0.52 mg), histidine (20 mg),
histidine hydrochloride monohydrate (27 mg), methionine (10.4 mg), polysorbate 80 (10.4 mg) and
sucrose (2,210 mg).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ustekinumab products are KXPDQ,J*ԕPRQRFORQDODQWLERGies that bind with specificity to the p40
protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring
cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation
and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab products were shown to
disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these
cytokines with a shared cell- surface receptor chain, IL-5ȕ7KHF\WRNLQHV,/-12 and IL-23 have
been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's
disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the
p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective.
12.2
Pharmacodynamics
Plaque Psoriasis
In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets
IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in
subjects with plaque psoriasis.
Ulcerative Colitis
In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed
between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The
response rate approached a plateau at the ustekinumab exposures associated with the recommended
dosing regimen for maintenance treatment [see Clinical Studies (14.5)].
12.3
Pharmacokinetics
Absorption
In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration
(Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg
(N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days)
following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that
observed in subjects with plaque psoriasis.
Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-
state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state
trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to
Reference ID: 5500909
100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90
mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when
given subcutaneously every 12 weeks.
Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab
concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn's disease, and 129.1 ± 27.6 mcg/mL in
subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing
of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was
achieved by the start of the second maintenance dose. There was no apparent accumulation in
ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ± SD steady-
state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn's disease, and 3.3 ± 2.3 mcg/mL
in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks.
Distribution
Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the
FHQWUDOFRPSDUWPHQWZDV/ &, LQsubjects ZLWK&URKQ
VGLVHDVHDQG/ &,
2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady-state was 4.6 L
in subjects with Crohn's disease and 4.4 L in subjects with ulcerative colitis.
Elimination
The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials
following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance
RIXVWHNLQXPDEZDV /GD\ &, LQsubjects with Crohn's disease and 0.19 L/day
&, LQsubjects with ulcerative colitis with an estimated median terminal half-life of
approximately 19 days for both IBD (Crohn's disease and ulcerative colitis) populations.
These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn's
disease and ulcerative colitis.
Metabolism
The metabolic pathway of ustekinumab products has QRWEHHQFKDUDFWHUL]HG$VDKXPDQ,J*ț
monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino
acids via catabolic pathways in the same manner as endogenous IgG.
Specific Populations
Weight
When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100
kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg
or less. The median trough serum concentrations of ustekinumab in subjects of higher weight (greater
than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less)
in the 45 mg group.
Reference ID: 5500909
Age: Geriatric Population
A population pharmacokinetic analysis (N=106/1937 subjects with plaque psoriasis greater than or equal
to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab.
There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution)
in subjects older than 65 years old.
Age: Pediatric Population
Following multiple recommended doses of ustekinumab in pediatric subjects 6 to 17 years of age with
plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At
Week 28, the mean ±SD steady-state trough serum ustekinumab concentrations were 0.36 ± 0.26
mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric subjects 6 to 11 years of age and pediatric
subjects 12 to 17 years of age.
Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque
psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult
subjects with PsA after administration of ustekinumab.
Drug Interaction Studies
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study
using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter
human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).
No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9
substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam
(CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved
recommended dosage in subjects with Crohn’s disease [see Drug Interactions (7.2)].
Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by
concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects
with psoriatic arthritis.
In subjects with Crohn's disease and ulcerative colitis, population pharmacokinetic analyses did not
indicate changes in ustekinumab clearance with concomitant use of corticosteroids or
immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted
by concomitant use of these medications.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of
ustekinumab products. Published literature showed that administration of murine IL-12 caused an anti-
Reference ID: 5500909
tumor effect in mice that contained transplanted tumors and IL-12/IL- 23p40 knockout mice or mice
treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically
manipulated to be deficient in both IL-12 and IL- 23 or IL-12 alone developed UV-induced skin cancers
earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in
mouse models for malignancy risk in humans is unknown.
No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab
at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and
during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated
females.
No effects on fertility were observed in female mice that were administered an analogous IL-12/IL
23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and
during early pregnancy.
13.2
Animal Toxicology and/or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg
ustekinumab twice weekly for 26 weeks had a bacterial infection.
14
CLINICAL STUDIES
14.1
Adult Plaque Psoriasis
Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2)
enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum
ERG\VXUIDFHDUHDLQYROYHPHQWRIDQG3VRULDVLV$UHDDQG6HYHULW\,QGH[ 3$6, VFRUHDQG
who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or
pustular psoriasis were excluded from the trials.
Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same
design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg
or 90 mg of ustekinumab. Subjects randomized to ustekinumab received 45 mg or 90 mg doses,
regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4
crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16.
In both trials, subjects in all treatment groups had a median baseline PASI score ranging from
DSSUR[LPDWHO\WR%DVHOLQH3*$VFRUHZDVPDUNHGRUVHYHUHLQRIVXEMHFWVLQ3V678'<
DQGRIVXEMHFWVLQ3V678'<$SSUR[LPDWHO\WZR-thirds of all subjects had received prior
SKRWRWKHUDS\ KDGUHFHLYHGHLWKHUSULRUFRQYHQWLRQDOV\VWHPLFRUELRORJLFWKHUDS\IRUWKHWUHDWPHQW
RISVRULDVLVZLWKUHFHLYLQJSULRUFRQYHQWLRQDOV\VWHPLFWKHUDS\DQGUHFHLYLQJSULRUELRORJLF
therapy. A total of RIVXEMHFWVKDGDKLVWRU\RISVRULDWLFDUWKULWLV
,QERWKWULDOVWKHHQGSRLQWVZHUHWKHSURSRUWLRQRIVXEMHFWVZKRDFKLHYHGDWOHDVWDUHGXFWLRQLQ
PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the
Physician's Global Assessment (PGA). The PGA is a 6- category scale ranging from 0 (cleared) to 5
Reference ID: 5500909
(severe) that indicates the physician's overall assessment of psoriasis focusing on plaque
thickness/induration, erythema, and scaling.
Clinical Response
The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.
Table 8:
Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
Ustekinumab
Ustekinumab
Placebo
45 mg
90 mg
Placebo
45 mg
90 mg
Subjects randomized
255
255
256
410
409
411
PASI 75 response
171
170
273
311
PGA of Cleared or Minimal
151
156
277
300
Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab
among these subgroups.
In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg
doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90
mg dosing compared with 45 mg dosing (Table 9 below).
Table 9:
Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and
Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
Ustekinumab
Ustekinumab
Placebo
45 mg
90 mg
Placebo
45 mg
90 mg
Subjects
255
255
256
410
409
411
randomized
PASI 75 response*
kg
6/166
124/168
107/164
12/290
218/297
225/289
>100 kg
2/89
47/87
63/92
3/120
55/112
86/121
PGA of Cleared or Minimal *
kg
7/166
108/168
103/164
14/290
220/297
216/289
>100 kg
3/89
43/87
53/92
4/120
57/112
84/121
* Subjects were dosed with trial medication at Weeks 0 and 4.
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at
Week 40 to either continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of
WKHUDS\ SODFHERDW:HHN $W:HHN RIVXEMHFWVUH-randomized to ustekinumab
WUHDWPHQWZHUH3$6,UHVSRQGHUVFRPSDUHGZLWK RIVXEMHFWVUH-randomized to placebo
(treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the
subjects randomized to treatment withdrawal was 16 weeks.
14.2
Pediatric Plaque Psoriasis
Reference ID: 5500909
A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric
VXEMHFWVWR\HDUVRIDJHZLWKDPLQLPXP%6$LQYROYHPHQWRID3$6,VFRUHJUHDWHUWKDQRU
equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or
systemic therapy and whose disease was inadequately controlled by topical therapy.
Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36),
or one-half the recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4
followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for
subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects
weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive
ustekinumab at the recommended dose or one-half the recommended dose.
Of the pediatric VXEMHFWVDSSUR[LPDWHO\KDGSULRUH[SRVXUHWRSKRWRWKHUDS\RUFRQYHQWLRQDO
V\VWHPLFWKHUDS\DQGDSSUR[LPDWHO\KDGSULRUH[SRVXUHWRELRORJLFV
The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1),
PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first
administration of trial agent.
Clinical Response
The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10.
Table 10:
Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3
Ps STUDY 3
Placebo
Ustekinumab*
Q
Q
N
37
36
PGA
PGA of cleared (0) or minimal (1)
PASI
PASI 75 responders
4
PASI 90 responders
* Using the weight-based dosage regimen specified in Table 1 and Table 2.
14.3
Psoriatic Arthritis
The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA
STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 18 years
RIDJHDQGROGHUZLWKDFWLYH3V$ VZRllen joints and WHQGHUMRLQWV GHVSLWHQRQVWHURLGDODQWL
inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Subjects in these trials
had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA were enrolled, including
polyartLFXODUDUWKULWLVZLWKWKHDEVHQFHRIUKHXPDWRLGQRGXOHV VSRQG\OLWLVZLWKSHULSKHUDODUWKULWLV
DV\PPHWULFSHULSKHUDODUWKULWLV GLVWDOLQWHUSKDODQJHDOLQYROYHPHQW DQGDUWKULWLV
PXWLODQV 2YHUDQGRIWKHsubjects, respectively, had enthesitis and dactylitis at
baseline.
Reference ID: 5500909
Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo
subcutaneously at Weeks 0 and 4 followed E\HYHU\ZHHNV TZ GRVLQJ$SSUR[LPDWHO\RI
subjects FRQWLQXHGRQVWDEOHGRVHVRI07; PJZHHN 7KHSULPDU\HQGSRLQt was the percentage of
subjects achieving ACR 20 response at Week 24.
,Q3V$678'<DQG3V$678'<DQGRIWKHsubjects, respectively, had been previously
treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-Į
agent was not allowed,Q3V$678'< Q RIWKHsubjects had been previously treated with
71)EORFNHURIZKRPRYHUKDGGLVFRQWLQXHGWKHLU71)EORFNHUWUHDWPHQWIRUODFNRIHIILFDF\RU
intolerance at any time.
Clinical Response
In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the
ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70
responses were also higher in the ustekinumab 45 mg and 90 mg groups, although the difference was
only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with ustekinumab
alone or in combination with methotrexate. Responses were similar in subjects UHJDUGOHVVRISULRU71)Į
exposure.
Table 11:
ACR 20, ACR 50, ACR 70 an
Placebo
d PASI 75 responses in PsA S
PsA STUDY 1
Ustekinumab
45 mg
90 mg
TUDY 1 and
Placebo
PsA STUDY 2 at Week 24
PsA STUDY 2
Ustekinumab
45 mg
90 mg
Number of subjects
Randomized
206
205
204
104
103
105
ACR 20 UHVSRQVH1
101
ACR 50 UHVSRQVH1
18
ACR 70 UHVSRQVH1
Number of subjects with
%6$
146
145
149
80
80
81
PASI 75 UHVSRQVH1
*Number of subjects ZLWK%6$SVRULDVLVVNLQLQYROYHPHQWDWEDVHOLQH
The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1.
Reference ID: 5500909
~
'o'
~
V, .... s
·=
(II
(l.,
60
40
20
0
PsASTUDY I
Weeks~
-o- Placebo•(n=206)
_.,_ Ustekinumab•45mg•(n=205),I
-
Ustekinumab•90mg•(n=204)
Figure 1: Percent of subjects achieving ACR 20 response through Week 24
The results of the components of the ACR response criteria are shown in Table 12.
Table 12:
Mean change from baseline in ACR components at Week 24
PsA STUDY 1
Ustekinumab
Placebo
45 mg
90 mg
(N = 206)
(N = 205)
(N = 204)
Number of swollen jointsa
Baseline
15
12
13
Mean Change at Week 24
-3
-5
-6
Number of tender jointsb
Baseline
25
22
23
Mean Change at Week 24
-4
-8
-9
Subject's assessment of painc
Baseline
6.1
6.2
6.6
Mean Change at Week 24
-0.5
-2.0
-2.6
Subject global assessmentc
Baseline
6.1
6.3
6.4
Mean Change at Week 24
-0.5
-2.0
-2.5
Physician global assessmentc
Baseline
5.8
5.7
6.1
Reference ID: 5500909
Mean Change at Week 24
-1.4
-2.6
-3.1
Disability index (HAQ)d
Baseline
1.2
1.2
1.2
Mean Change at Week 24
-0.1
-0.3
-0.4
CRP (mg/dL)e
Baseline
1.6
1.7
1.8
Mean Change at Week 24
0.01
-0.5
-0.8
a
Number of swollen joints counted (0–66)
b
Number of tender joints counted (0–68)
c
Visual analogue scale; 0= best, 10=worst.
d
Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to perform the
following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
e
CRP: (Normal Range 0.0–1.0 mg/dL)
An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared
with placebo at Week 24.
Physical Function
Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated
with placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ-DI responders
LPSURYHPHQWLQ+$4-DI score) was greater in the ustekinumab 45 mg and 90 mg groups
compared to placebo at Week 24.
14.4
Crohn's Disease
Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult
subjects with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI]
score of 220 to 450). There were two 8-week intravenous induction trials (CD-1 and CD-2) followed by
a 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of
therapy. Subjects in CD- 1 had failed or were intolerant to treatment with one or more TNF blockers,
while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or
corticosteroids, but never failed treatment with a TNF blocker.
Trials CD-1 and CD-2
In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627)
were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in
CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and
clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials,
subjects were randomized to receive a single intravenous administration of ustekinumab at either
approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended).
In trial CD-1, subjects KDGIDLOHGRUZHUHLQWROHUDQWWRSULRUWUHDWPHQWZLWKD71)EORFNHU subjects
had an inadequate initial response (primary non-UHVSRQGHUV UHVSRQGHGEXWVXEVHTXHQWO\ORVW
response (secondary non-UHVSRQGHUV DQGZHUHLQWROHUDQWWRD71)EORFNHU2IWKHVHsubjects
IDLOHGRUZHUHLQWROHUDQWWRRQH71)EORFNHUDQGKDGIDLOHGRUSULRU71)EORFNHUV$WEDVHOLQH
Reference ID: 5500909
and throughout the trialDSSUR[LPDWHO\RIWKHsubjects ZHUHUHFHLYLQJFRUWLFRVWHURLGVDQGRI
the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score
was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group.
In trial CD-2, subjects KDGIDLOHGRUZHUHLQWROHUDQWWRSULRUWUHDWPHQWZLWKFRUWLFRVWHURLGV RI
subjects), at least one immunomodulator (6-MP, AZA, MTX; 68 of subjects), or both (49 of
subjects). Additionall\ QHYHUUHFHLYHGD71)EORFNHUDQGSUHYLRXVO\UHFHLYHGEXWKDGQRW
failed a TNF blocker. At baseline, and throughout the trialDSSUR[LPDWHO\ RIWKHsubjects were
UHFHLYLQJFRUWLFRVWHURLGVDQGRIWKHsubjects were receiving immunomodulators (AZA, 6-MP,
MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group.
In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended
dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at
Week 8 compared to placebo (see Table 13 for clinical response and remission rates). Clinical response
and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to
improve through Week 8.
Reference ID: 5500909
Table 13:
Induction of Clinical Response and Remission in CD-1* and CD-2**
CD-1
CD-2
n = 741
n = 627
Treatment
Treatment
Placebo
Ustekinumab†
difference
Placebo
Ustekinumab†
difference
N = 247
N = 249
DQG Cl
N = 209
N = 209
DQG Cl
Clinical Response
53
a
b
(100 point), Week 6
Clinical Remission,
b
b
Week 8
Clinical Response
b
121 b
(100 point), Week 8
70 Point Response,
a
b
Week 6
70 Point Response,
a
b
Week 3
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being
in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points
*
Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy
**
Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA,
MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker.
†
Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
a
S
b
p < 0.001
Trial CD-3
The maintenance trial (CD-3), evaluated 388 subjects ZKRDFKLHYHGFOLQLFDOUHVSRQVH 100 point
reduction in CDAI score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2.
Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab
every 8 weeks or placebo for 44 weeks (see Table 14).
Table 14:
Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)
Placebo*
N = 131**
90 mg ustekinumab
every 8 weeks
N = 128**
Treatment
difference
DQG &,
Clinical Remission
†
Clinical Response
Clinical Remission in subjects in remission at
the start of maintenance therapyb
a
52/78 †
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in
clinical remission
*
The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start
of maintenance therapy.
**
Subjects who achieved clinical response to ustekinumab at the end of the induction trial.
†
p < 0.01
a
S
b
Subjects in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not
account for any other time point during maintenance therapy.
$W:HHNRI subjects who received ustekinumab were corticosteroid-free and in clinical
UHPLVVLRQFRPSDUHGWRRIsubjects in the placebo group.
Reference ID: 5500909
At Week 0 of trial CD- ustekinumab-treated subjects who previously failed or were
LQWROHUDQWWR71)EORFNHUWKHUDSLHVZHUHLQFOLQLFDOUHPLVVLRQDQG RI these subjects were in
FOLQLFDOUHPLVVLRQDW:HHN,QWKHSODFHERDUP subjects were in clinical remission at
:HHNZKLOH RIWKHVHsubjects were in remission at Week 44.
At Week 0 of trial CD- ustekinumab-treated subjects who had previously failed
immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and
RIWKHVHsubjects were in clinical remission at Week ,QWKHSODFHERDUP RI
these subjects ZHUHLQFOLQLFDOUHPLVVLRQDW:HHNZKLOH ZHUHLQUHPLVVLRQDW:HHN,Q
the subset of these subjects ZKRZHUHDOVRQDwYHWR71)EORFNHUV RIustekinumab-treated
subjects ZHUHLQFOLQLFDOUHPLVVLRQDW:HHNDVFRPSDUHGWR LQWKHSODFHERDUP
Subjects who were not in clinical response 8 weeks after ustekinumab induction were not included in the
primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg
subcutaneous injection of ustekinumab upon entry into trial CD-3. Of these subjects
achieved clinical response eight weeks later and were followed for the duration of the trial.
14.5
Ulcerative Colitis
Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1
and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who
had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab),
corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was
followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of
52 weeks of therapy.
Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores
that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on
centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active
ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo
HQGRVFRS\VXEVFRUH$QHQGRVFRS\VFRUHRIZDVGHILQHGE\PDUNHGHU\WKHPDDEVHQWYDVFXODU
pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At
baseline, subjects KDGDPHGLDQ0D\RVFRUHRI ZLWKRIsubjects having moderate disease (Mayo
score 6– DQGKDYLQJVHYHUHGLVHDVH 0D\RVFRUH–12).
Subjects in these trials may have received other concomitant therapies including aminosalicylates,
immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).
Reference ID: 5500909
Trial UC-1
In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab
of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in
UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. A total
RIKDGIDLOHGDWOHDVWRQHELRORJLFDQGKDGIDLOHGERWKD71)EORFNHUDQGDQLQWHJULQUHFHSWRU
EORFNHU2IWKHWRWDOSRSXODWLRQKDGIDiled corticosteroids or immunomodulators but were
biologic-QDwYHDQGDQDGGLWLRQDOKDGSUHYLRXVO\UHFHLYHGEXWKDGQRWIDLOHGDELRORJLF$WLQGXFWLRQ
baseline and throughout the trialDSSUR[LPDWHO\subjects ZHUHUHFHLYLQJRUDOFRUWLFRVWHURLGV
subjects were receiving immunomodulators (AZA, 6-03RU07; DQG subjects were receiving
aminosalicylates.
The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo
stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo
endoscopy subscore of 0 or 1 (Mayo endoscopy subscore of 0 defined as normal or inactive disease and
Mayo subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability) is
provided in Table 15.
The secondary endpoints were clinical response, endoscopic improvement, and histologic-endoscopic
PXFRVDOLPSURYHPHQW&OLQLFDOUHVSRQVHZLWKDGHILQLWLRQRI SRLQWVDQGGHFUHDVHLQ
modified Mayo score, defined as 3-component Mayo score without the Physician's Global Assessment,
ZLWKHLWKHUDGHFUHDVHIURPEDVHOLQHLQWKHUHFWDOEOHHGLQJVXEVFRUHRUDUHFWDOEOHHGLQJVXEVFRUHRI
or 1), endoscopic improvement with a definition of Mayo endoscopy subscore of 0 or 1, and histologic-
endoscopic mucosal improvement with a definition of combined endoscopic improvement and
histologic improvement of the colon tissue [neutrophil infiltration in RIFU\SWVQRFU\SW
destruction, and no erosions, ulcerations, or granulation tissue]) are provided in Table 15.
In UC-1, a significantly greater proportion of subjects treated with ustekinumab (at the recommended
dose of approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic
improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 15).
Table 15:
Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1
Endpoint
Placebo
N = 319
Ustekinumab†
N = 322
Treatment
difference and
97.&,a
N
N
Clinical Remission*
22
62
b
Bio-naïveᄾ
14/151
36/147
Prior biologic failure
7/161
24/166
Endoscopic Improvement§
40
80
b
Bio-naïveᄾ
28/151
43/147
Prior biologic failure
11/161
34/166
Clinical Response¶
99
186
b
Bio-naïveᄾ
55/151
94/147
Prior biologic failure
42/161
86/166
Histologic-Endoscopic
Mucosal
26
54
b
Reference ID: 5500909
Endpoint
Placebo
N = 319
Ustekinumab†
N = 322
Treatment
difference and
97.&,a
N
N
Improvement‡
Bio-naïveᄾ
19/151
30/147
Prior biologic failure
6/161
21/166
†
Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
ᄾ
An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics.
*
Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo
endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
§
Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
¶
Clinical response was defined as a decrease from baseline in the modified Mayo score by DQGSRLQWVZLWKHLWKHUD
decrease from baseline in the rectal bleeding subscore RUDUHFWDOEOHHGLQJVXEVFRUHRIRU
‡
Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0
RU DQGKLVWRORJLFLPSURYHPHQWRIWKHFRORQWLVVXH QHXWURSKLOLQILOWUDWLRQLQ RIFU\SWVQRFU\SWGHVWUXFWLRQDQGQR
erosions, ulcerations, or granulation tissue).
a
$GMXVWHGWUHDWPHQWGLIIHUHQFH &,
b
p < 0.001
The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to
disease progression and long-term outcomes was not evaluated during UC-1.
Rectal Bleeding and Stool Frequency Subscores
Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in
ustekinumab-treated subjects.
Trial UC-2
The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following
the intravenous administration of either induction dose of ustekinumab in UC-1. These subjects were
randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8
weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks.
The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary
endpoints included the proportion of subjects maintaining clinical response at Week 44, the proportion
of subjects with endoscopic improvement at Week 44, the proportion of subjects with corticosteroid-free
clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44
among subjects who achieved clinical remission 8 weeks after induction.
Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the
recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16.
Reference ID: 5500909
Table 16:
Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction
Dose)
Endpoint
Placebo*
N = 175†
90 mg ustekinumab
every 8 weeks N = 176
Treatment
GLIIHUHQFHDQG
CI
N
N
Clinical Remission**
46
79
a
Bio-naïveᄾ
30/84
39/79
Prior biologic failure
16/88
37/91
Maintenance of Clinical
Response at Week 44†
84
130
a
Bio-naïveᄾ
49/84
62/79
Prior biologic failure
35/88
64/91
Endoscopic Improvement§
47
83
a
Bio-naïveᄾ
29/84
42/79
Prior biologic failure
18/88
38/91
Corticosteroid-free Clinical
Remission‡
45
76
a
Bio-naïveᄾ
30/84
38/79
Prior biologic failure
15/88
35/91
Maintenance of Clinical
Remission at Week 44 in
subjects who achieved clinical
remission 8 weeks after
induction
18/50
27/41
b
Bio-naïveᄾ
12/27
14/20
Prior biologic failure
6/23
12/18
ᄾ
An additional 3 subjects on placebo and 6 subjects on ustekinumab had been exposed to, but had not failed, biologics.
*
The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the
start of maintenance therapy.
**
Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo
endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
‡
Clinical response was defined as a decrease from baseline in the modified Mayo score by DQGSRLQWVZLWKHLWKHUD
decrease from baseline in the rectal bleeding subscore RUDUHFWDOEOHHGLQJVXEVFRUHRIRU
§
Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
‡
Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44.
a
p =<0.001
b
p=0.004
Reference ID: 5500909
Other Endpoints
Week 16 Responders to Ustekinumab Induction
Subjects who were not in clinical response 8 weeks after induction with ustekinumab in UC- 1 were not
included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive
a 90 mg subcutaneous injection of ustekinumab at Week 8. Of these subjects DFKLHYHG
clinical response eight weeks later (Week 16) and received ustekinumab 90 mg subcutaneously every 8
weeks during the UC-WULDO$W:HHNWKHUHZHUH subjects who maintained clinical
UHVSRQVHDQGWKHUHZHUH ZKRDFKLHYHGFOLQLFDOUHPLVVLRQ
Histologic-Endoscopic Mucosal Improvement at Week 44
The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance
treatment in UC-ZDV DPRQJsubjects on ustekinumab DQG LQsubjects on
placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC
2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2.
Endoscopic Normalization
Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of
0. At Week 8 in UC-HQGRVFRSLFQRUPDOL]DWLRQZDVDFKLHYHGLQ RIsubjects treated with
ustekinumab DQG RIsubjects in the placebo group. At Week 44 of UC-2, endoscopic
QRUPDOL]DWLRQZDVDFKLHYHGLQ RIsubjects treated with ustekinumab DQGLQ
of subjects in placebo group.
15
REFERENCES
1
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov)
SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973–2007) -
Linked To County Attributes - Total U.S., 1969– 2007 Counties, National Cancer Institute,
DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010,
based on the November 2009 submission.
16
HOW SUPPLIED/STORAGE AND HANDLING
PYZCHIVA (ustekinumab-ttwe) injection is a clear, colorless to light yellow, sterile and preservative-
free solution. It is supplied as individually packaged, single-dose prefilled syringe or single-dose vial.
For Subcutaneous Use
Prefilled Syringes
•
45 mg/0.5 mL (NDC 61314-651-01)
•
90 mg/mL (NDC 61314-652-01)
Reference ID: 5500909
Each prefilled syringe is equipped with a 29 gauge fixed ½ inch needle, a needle safety guard, and a
needle cover that is not made with natural rubber latex.
Single-dose Vial
•
45 mg/0.5 mL (NDC 61314-651-94)
For Intravenous Infusion
Single-dose Vial
•
130 mg/26 mL (5 mg/mL) (NDC 61314-654-94)
Storage and Stability
Store PYZCHIVA vials, and prefilled syringes refrigerated between 2°C to 8°C (36°F to 46°F). Store
PYZCHIVA vials upright. Keep the product in the original carton to protect from light until the time of
use. Do not freeze. Do not shake.
If needed, individual prefilled syringes may be stored at room temperature up to 30°C (86°F) for a
maximum single period of up to 35 days in the original carton to protect from light. If not used within 35
days of room temperature storage, discard the prefilled syringe. The prefilled syringe may be returned to
the refrigerator one time only for a maximum of 60 days. If not used within 60 days, discard the
prefilled syringe. Record the date when the prefilled syringe is removed from and returned to the
refrigerator on the carton in the space provided.
Do not use PYZCHIVA after the expiration date on the carton or on the prefilled syringe.
17
PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and
Instructions for Use).
Infections
Inform patients that PYZCHIVA may lower the ability of their immune system to fight infections and
to contact their healthcare provider immediately if they develop any signs or symptoms of infection [see
Warnings and Precautions (5.1)].
Malignancies
Inform patients of the risk of developing malignancies while receiving PYZCHIVA [see Warnings and
Precautions (5.4)].
Hypersensitivity Reactions
Reference ID: 5500909
•
Advise patients to seek immediate medical attention if they experience any signs or symptoms
of serious hypersensitivity reactions and discontinue PYZCHIVA [see Warnings and
Precautions (5.5)].
Posterior Reversible Encephalopathy Syndrome (PRES)
Inform patients to immediately contact their healthcare provider if they experience signs and symptoms
of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and
Precautions (5.6)].
Immunizations
Inform patients that PYZCHIVA can interfere with the usual response to immunizations and that they
should avoid live vaccines [see Warnings and Precautions (5.7)].
Administration
Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.
Manufactured by:
Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for:
Sandoz Inc.
Princeton, NJ 08540
Reference ID: 5500909
MEDICATION GUIDE
PYZCHIVA® (Piz-chi-va)
(ustekinumab-ttwe)
injection, for subcutaneous or intravenous use
What is the most important information I should know about PYZCHIVA?
PYZCHIVA is a medicine that affects your immune system. PYZCHIVA can increase your risk of having serious side
effects, including:
Serious infections: PYZCHIVA may lower the ability of your immune system to fight infections and may increase your
risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB),
and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their
infection.
•
Your doctor should check you for TB before starting PYZCHIVA.
•
If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment
with PYZCHIVA and during treatment with PYZCHIVA.
•
Your doctor should watch you closely for signs and symptoms of TB while you are being treated with PYZCHIVA.
You should not start taking PYZCHIVA if you have any kind of infection unless your doctor says it is okay.
Before starting PYZCHIVA, tell your doctor if you:
•
think you have an infection or have symptoms of an infection such as:
o
fever, sweat, or chills
o
weight loss
o
muscle aches
o
warm, red, or painful skin or sores on your body
o
cough
o
diarrhea or stomach pain
o
shortness of breath
o
burning when you urinate or urinate more often than normal
o
blood in phlegm
o
feel very tired
•
are being treated for an infection or have any open cuts.
•
get a lot of infections or have infections that keep coming back.
•
have TB, or have been in close contact with someone with TB.
After starting PYZCHIVA, call your doctor right away if you have any symptoms of an infection (see above). These
may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications.
PYZCHIVA can make you more likely to get infections or make an infection that you have worse. People who have a
genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are
at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People
who take PYZCHIVA may also be more likely to get these infections.
Cancers. PYZCHIVA may decrease the activity of your immune system and increase your risk for certain types of
cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab
products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with
PYZCHIVA, tell your doctor if you develop any new skin growths.
Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain and can
cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your
doctor right away if you have any new or worsening medical problems including:
o
headache
o
confusion
o
seizures
o
vision problems
What is PYZCHIVA?
PYZCHIVA is a prescription medicine used to treat:
•
adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or
pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).
•
adults and children 6 years and older with active psoriatic arthritis.
•
adults 18 years and older with moderately to severely active Crohn's disease.
•
adults 18 years and older with moderately to severely active ulcerative colitis.
It is not known if PYZCHIVA is safe and effective in children less than 6 years of age.
Do not take PYZCHIVA if you are allergic to ustekinumab products or any of the ingredients in PYZCHIVA. See the
end of this Medication Guide for a complete list of ingredients in PYZCHIVA.
Before you receive PYZCHIVA, tell your doctor about all of your medical conditions, including if you:
•
have any of the conditions or symptoms listed in the section "What is the most important information I should
know about PYZCHIVA?"
•
ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.
•
have recently received or are scheduled to receive an immunization (vaccine). People who take PYZCHIVA should
not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some
types of live vaccines can spread to people with a weakened immune system, and can cause serious problems.
Reference ID: 5500909
You should not receive the BCG vaccine during the one year before receiving PYZCHIVA or one year after
you stop receiving PYZCHIVA.
•
have any new or changing lesions within psoriasis areas or on normal skin.
•
are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as
well for you during treatment with PYZCHIVA. PYZCHIVA may also increase your risk of having an allergic
reaction to an allergy shot.
•
receive or have received phototherapy for your psoriasis.
•
are pregnant or plan to become pregnant. It is not known if PYZCHIVA can harm your unborn baby. You and your
doctor should decide if you will receive PYZCHIVA. See “What should I avoid while using PYZCHIVA?”
•
received PYZCHIVA while you were pregnant. It is important that you tell your baby’s healthcare provider before
any vaccinations are given to your baby.
•
are breastfeeding or plan to breastfeed. PYZCHIVA can pass into your breast milk.
•
Talk to your doctor about the best way to feed your baby if you receive PYZCHIVA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins,
and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I use PYZCHIVA?
•
Use PYZCHIVA exactly as your doctor tells you to.
•
Adults with Crohn's disease and ulcerative colitis will receive the first dose of PYZCHIVA through a vein in the arm
(intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full
dose of medicine. You will then receive PYZCHIVA as an injection under the skin (subcutaneous injection) 8
weeks after the first dose of PYZCHIVA, as described below.
•
Adults with psoriasis or psoriatic arthritis and children 6 years and older with psoriasis or psoriatic arthritis will
receive PYZCHIVA as an injection under the skin (subcutaneous injection) as described below.
•
Injecting PYZCHIVA under your skin
o
PYZCHIVA is intended for use under the guidance and supervision of your doctor. In children 6 years and
older, it is recommended that PYZCHIVA be administered by a healthcare provider. If your doctor decides that
you or a caregiver may give your injections of PYZCHIVA at home, you should receive training on the right
way to prepare and inject PYZCHIVA. Your doctor will determine the right dose of PYZCHIVA for you, the
amount for each injection, and how often you should receive it. Do not try to inject PYZCHIVA yourself until
you or your caregiver have been shown how to inject PYZCHIVA by your doctor or nurse.
o
Inject PYZCHIVA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or
stomach area (abdomen).
o
Do not give an injection in an area of the skin that is tender, bruised, red or hard.
o
Use a different injection site each time you use PYZCHIVA.
o
If you inject more PYZCHIVA than prescribed, call your doctor right away.
o
Be sure to keep all of your scheduled follow-up appointments.
Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to
prepare and inject a dose of PYZCHIVA, and how to properly throw away (dispose of) used needles, and
syringes. The syringe, needle, and vial must never be re-used. After the rubber stopper is punctured,
PYZCHIVA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore,
throw away any unused portion of PYZCHIVA.
What should I avoid while using PYZCHIVA?
You should not receive a live vaccine while taking PYZCHIVA. See "Before you receive PYZCHIVA, tell your doctor
about all of your medical conditions, including if you:"
What are the possible side effects of PYZCHIVA?
PYZCHIVA may cause serious side effects, including:
y
See "What is the most important information I should know about PYZCHIVA?"
•
Serious allergic reactions. Serious allergic reactions can occur with PYZCHIVA. Stop using PYZCHIVA and get
medical help right away if you have any of the following symptoms of a serious allergic reaction:
o
feeling faint
o
chest tightness
o
swelling of your face, eyelids, tongue, or throat
o
skin rash
•
Lung inflammation. Cases of lung inflammation have happened in some people who receive ustekinumab
products, and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right
away if you develop shortness of breath or a cough that doesn't go away during treatment with PYZCHIVA.
Common side effects of PYZCHIVA include:
Reference ID: 5500909
•
nasal congestion, sore throat, and runny nose
•
redness at the injection site
y
upper respiratory infections
y
vaginal yeast infections
y
fever
y
urinary tract infections
y
headache
y
sinus infection
y
tiredness
y
bronchitis
y
itching
y
diarrhea
•
nausea and vomiting
y
stomach pain
These are not all of the possible side effects of PYZCHIVA. Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Sandoz Inc. at 1-800-525-8747.
How should I store PYZCHIVA?
•
Store PYZCHIVA vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Store PYZCHIVA vials standing up straight.
•
Store PYZCHIVA in the original carton to protect it from light until time to use it.
•
Do not freeze PYZCHIVA.
•
Do not shake PYZCHIVA.
•
If needed, individual PYZCHIVA prefilled syringes may be stored at room temperature up to 86ºF (30°C) for a
maximum single period of up to 35 days in the original carton to protect from light.
•
Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space
provided.
•
You may return the prefilled syringe to the refrigerator 1 time only for a maximum of 60 days, either during the 35
day period or at the end of the 35-day period.
•
Record the date when the prefilled syringe is returned to the refrigerator on the carton.
•
Discard the prefilled syringe if not used within 35 days of room temperature storage and you did not return it to the
refrigerator, or if it has been returned to the refrigerator and is not used within 60 days.
•
Do not use PYZCHIVA after the expiration date on the carton or on the prefilled syringe.
Keep PYZCHIVA and all medicines out of the reach of children.
General information about the safe and effective use of PYZCHIVA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PYZCHIVA
for a condition for which it was not prescribed. Do not give PYZCHIVA to other people, even if they have the same
symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about PYZCHIVA
that was written for health professionals.
What are the ingredients in PYZCHIVA?
Active ingredient: ustekinumab-ttwe
Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains histidine, histidine hydrochloride
monohydrate, polysorbate 80, and sucrose. Single-dose vial for subcutaneous use contains histidine, histidine
hydrochloride monohydrate, polysorbate 80, and sucrose. Single-dose vial for intravenous infusion contains edetate
disodium, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, and sucrose.
Manufactured by: Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for: Sandoz Inc.
Princeton, NJ 08540
For more information, call 1-800-525-8747.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
Reference ID: 5500909
INSTRUCTIONS FOR USE
PYZCHIVA® (Piz-chi-va)
(ustekinumab-ttwe)
injection, for subcutaneous use
Instructions for injecting PYZCHIVA using a prefilled syringe.
Read this Instructions for Use before you start using PYZCHIVA. Your doctor or nurse
should show you how to prepare and give your injection of PYZCHIVA the right way.
If you cannot give yourself the injection:
•
ask your doctor or nurse to help you, or
•
ask someone who has been trained by a doctor or nurse to give your injections.
Do not try to inject PYZCHIVA yourself until you have been shown how to inject PYZCHIVA by
your doctor, nurse or health professional.
Important information:
•
Before you start, check the carton to make sure that it is the right dose. You will have
either 45 mg or 90 mg as prescribed by your doctor.
ƕ
If your dose is 45 mg, you will receive one 45 mg prefilled syringe.
ƕ
If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg
prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you
will need to give yourself two injections, one right after the other.
•
Children 12 years of age and older with psoriasis who weigh 132 pounds (60 kg) or more may
use a prefilled syringe.
•
Check the expiration date on the prefilled syringe and carton. Do not use PYZCHIVA after
the expiration date has passed. If the expiration date has passed or if the prefilled syringe
has been stored above 86ºF (30ºC), call your doctor or pharmacist, or call Sandoz Inc. at
1-800-525-8747 for help.
•
Make sure the syringe is not damaged. Do not use the prefilled syringe if it is damaged.
•
Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should
look clear and colorless to light yellow.
•
Do not use if it is frozen, discolored, cloudy or has particles. Get a new prefilled syringe.
•
Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may
damage your PYZCHIVA medicine. If your prefilled syringe has been shaken, do not use it.
Get a new prefilled syringe.
•
To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard
that is automatically activated to cover the needle after you have given your injection. Do
not pull back on the plunger at any time.
Storage information
•
Store PYZCHIVA in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Store PYZCHIVA in the original carton to protect from light until the time of use.
•
Do not freeze PYZCHIVA.
•
If needed, individual prefilled syringes may be stored at room temperature up to 86ºF (30ºC)
for a maximum single period of up to 35 days in the original carton to protect from light.
•
Record the date when the prefilled syringe is removed from the refrigerator on the carton in
the space provided.
•
You may return the prefilled syringe to the refrigerator 1 time only for a maximum of 60 days,
either during the 35-day period or at the end of the 35-day period.
•
Record the date when the prefilled syringe is returned to the refrigerator on the carton.
•
Discard the prefilled syringe if not used within 35 days of room temperature storage and you
Reference ID: 5500909
PYZCHIVA prefilled syringe
Viewing window
Needle cover
Needle
Adhesive
bandage
Body
Label
Antiseptic
Cotton ball
FDA-cleared sharps
wipes
or gauze pads
disposal container
Needle guard wings
Plunger
Plunger head
did not return it to the refrigerator, or if it has been returned to the refrigerator and is not used
within 60 days.
Gather the supplies you will need to prepare and to give your injection. (See Figure A)
You will need:
•
antiseptic wipes
•
cotton balls or gauze pads
•
adhesive bandage
•
your prescribed dose of PYZCHIVA (See Figure B)
•
FDA-cleared sharps disposal container. See "Step 4: Dispose of the syringe."
Figure A
Figure B
Step 1: Prepare the injection
•
Choose a well-lit, clean, flat work surface.
•
Leave PYZCHIVA prefilled syringe at room temperature for about 30 minutes before injecting.
Do not warm the prefilled syringe in any other way (for example, do not warm it in a
microwave or in hot water).
•
Wash your hands well with soap and warm water.
•
Hold the prefilled syringe with the covered needle pointing upward.
Step 2: Prepare your injection site
•
Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs).
If a caregiver is giving you the injection, the outer area of the upper arms may also be used.
(See Figure C)
Reference ID: 5500909
~
•
Use a different injection site for each injection. Do not give an injection in an area of
the skin that is tender, bruised, red or hard.
•
Clean the skin with an antiseptic wipe where you plan to give your injection.
•
Do not touch this area again before giving the injection. Let your skin dry before injecting.
•
Do not fan or blow on the clean area.
Figure C
*Areas in gray are recommended injection sites.
Step 3: Inject PYZCHIVA
•
Remove the needle cover when you are ready to inject your PYZCHIVA.
•
Do not touch the plunger or plunger head while removing the needle cover.
•
Hold the body of the prefilled syringe with one hand, and pull the needle cover straight off.
(See Figure D)
•
Put the needle cover in the trash.
•
You may also see a drop of liquid at the end of the needle. This is normal.
•
Do not touch the needle or let it touch anything.
•
Do not use the prefilled syringe if it is dropped without the needle cover in place. Call your
doctor, nurse or health professional for instructions.
Figure D
•
Hold the body of the prefilled syringe in one hand between the thumb and index fingers. (See
Reference ID: 5500909
45°
Figure E)
Figure E
•
Do not pull back on the plunger at any time.
•
Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
•
Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree
angle. (See Figure F)
Figure F
•
Inject all of the liquid by using your thumb to push in the plunger until the plunger head is
completely between the needle guard wings. (See Figure G)
Reference ID: 5500909
Needle guard wings
Figure G
•
When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take
the needle out of the skin and let go of the skin.
•
Slowly take your thumb off the plunger head. This will let the empty syringe move up until the
entire needle is covered by the needle guard. (See Figure H)
Figure H
•
When the needle is pulled out of your skin, there may be a little bleeding at the injection
site. This is normal. You can press a cotton ball or gauze pad to the injection site if
needed. Do not rub the injection site. You may cover the injection site with a small adhesive
bandage, if necessary.
If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg
prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need
Reference ID: 5500909
to give yourself a second injection right after the first. Repeat Steps 1 to 3 for the second
injection using a new syringe. Choose a different site for the second injection.
Step 4: Dispose of the syringe.
•
Put the syringe in an FDA-cleared sharps disposal container right away after use. Do not
throw away (dispose of) loose syringes in your household trash.
•
If you do not have an FDA-cleared sharps disposal container, you may use a household
container that is:
ƕ
made of heavy-duty plastic,
ƕ
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come
out,
ƕ
upright and stable during use,
ƕ
leak-resistant,
ƕ
and properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be local
or state laws about how to throw away syringes and needles. For more information about safe
sharps disposal, and for specific information about sharps disposal in the state that you live
in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your sharps disposal container.
•
If you have any questions, talk to your doctor or pharmacist.
Keep PYZCHIVA and all medicines out of the reach of children.
Manufactured by:
Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for:
Sandoz Inc.
Princeton, NJ 08540
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised 12/2024
Reference ID: 5500909
INSTRUCTIONS FOR USE
PYZCHIVA® (Piz-chi-va)
(ustekinumab-ttwe)
injection, for subcutaneous use
Instructions for injecting PYZCHIVA from a vial.
Read this Instructions for Use before you start using PYZCHIVA. Your doctor or nurse
should show you how to prepare, measure your dose, and give your injection of
PYZCHIVA the right way.
If you cannot give yourself the injection:
•
ask your doctor or nurse to help you, or
•
ask someone who has been trained by a doctor or nurse to give your injections.
Do not try to inject PYZCHIVA yourself until you have been shown how to inject PYZCHIVA by
your doctor, nurse or health professional.
Important information:
•
Before you start, check the carton to make sure that it is the right dose. You will have
either 45 mg or 90 mg as prescribed by your doctor.
ƕ
If your dose is 45 mg or less you will receive one 45 mg vial.
ƕ
If your dose is 90 mg, you will receive two 45 mg vials and you will need to give
yourself two injections, one right after the other.
•
Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45
mg.
•
Check the expiration date on the vial and carton. If the expiration date has passed, do not use it.
If the expiration date has passed, call your doctor or pharmacist, or call Sandoz Inc. at 1-800
525-8747 for help.
•
Check the vial for any particles or discoloration. Your vial should look clear and colorless to light
yellow.
•
Do not use if it is frozen, discolored, cloudy or has particles. Get a new vial.
•
Do not shake the vial at any time. Shaking your vial may damage your PYZCHIVA medicine. If
your vial has been shaken, do not use it. Get a new vial.
•
Do not use a PYZCHIVA vial more than one time, even if there is medicine left in the vial. After
the rubber stopper is punctured, PYZCHIVA can become contaminated by harmful bacteria
which could cause an infection if re-used. Therefore, throw away any unused PYZCHIVA after
you give your injection.
•
Safely throw away (dispose of) PYZCHIVA vials after use.
•
Do not re-use syringes or needles. See "Step 6: Dispose of needles and syringes."
•
To avoid needle-stick injuries, do not recap needles.
Storage information
•
Store PYZCHIVA in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Store PYZCHIVA vials standing up straight.
•
Store PYZCHIVA in the original carton to protect from light until the time of use.
•
Do not freeze PYZCHIVA.
Gather the supplies you will need to prepare PYZCHIVA and to give your injection. (See
Figure A)
You will need:
•
a syringe with the needle attached, you will need a prescription from your healthcare provider to
get syringes with the needles attached from your pharmacy.
Reference ID: 5500909
g
,
□ (5) 0
tr
Adhesive
Antiseptic
Cotton ball
PYZCHIVA
Syringe and Attached Needle
FDA-cleared sharps
bandage
wipes
or gauze pads
Vial
disposal container
) \
•
antiseptic wipes
•
cotton balls or gauze pads
•
adhesive bandage
•
your prescribed dose of PYZCHIVA
•
FDA-cleared sharps disposal container. See "Step 6: Dispose of needles and syringes."
Figure A
Step 1: Prepare the injection.
•
Choose a well-lit, clean, flat work surface.
•
Wash your hands well with soap and warm water.
Step 2: Prepare your injection site
•
Choose an injection site around your stomach area (abdomen), buttocks, and upper legs
(thighs).
•
If a caregiver is giving you the injection, the outer area of the upper arms may also be used.
(See Figure B)
•
Use a different injection site for each injection. Do not give an injection in an area of the skin
that is tender, bruised, red or hard.
•
Clean the skin with an antiseptic wipe where you plan to give your injection.
•
Do not touch this area again before giving the injection. Let your skin dry before injecting.
•
Do not fan or blow on the clean area.
Figure B
*Areas in gray are recommended injection sites.
Reference ID: 5500909
g
Step 3: Prepare the vial.
•
Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber
stopper. (See Figure C)
Figure C
•
Clean the rubber stopper with an antiseptic swab. (See Figure D)
Figure D
•
Do not touch the rubber stopper after you clean it.
•
Put the vial on a flat surface.
Step 4: Prepare the syringe
•
Pick up the syringe with the needle attached.
•
Remove the cap that covers the needle. (See Figure E)
•
Throw the needle cap away. Do not touch the needle or allow the needle to touch anything.
Figure E
Reference ID: 5500909
•
Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor.
•
Hold the vial between your thumb and index (pointer) finger.
•
Use your other hand to push the syringe needle through the center of the rubber
stopper. (See Figure F)
Figure F
•
Push down on the plunger until all of the air has gone from the syringe into the vial.
•
Turn the vial and the syringe upside down. (See Figure G)
•
Hold the PYZCHIVA vial with one hand.
•
It is important that the needle is always in the liquid in order to prevent air bubbles forming in the
syringe.
•
Pull back on the syringe plunger with your other hand.
•
Fill the syringe until the black tip of the plunger lines up with the mark that matches your
prescribed dose.
Figure G
Reference ID: 5500909
I~))
•
Do not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it
has any air bubbles inside.
•
If there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the
top. (See Figure H)
•
Slowly press the plunger up until all of the air bubbles are out of the syringe (but none of the
liquid is out).
•
Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch
anything.
Figure H
Step 5: Inject PYZCHIVA
•
Hold the barrel of the syringe in one hand, between the thumb and index fingers.
•
Do not pull back on the plunger at any time.
Reference ID: 5500909
g
•
Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
•
Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree
angle. (See Figure I)
Figure I
•
Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and
evenly, keeping the skin gently pinched.
•
When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J)
Figure J
•
When the needle is pulled out of your skin, there may be a little bleeding at the injection site.
This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not
Reference ID: 5500909
rub the injection site. You may cover the injection site with a small adhesive bandage, if
necessary.
If your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a
second injection right after the first. Repeat Steps 1 to 5 using a new syringe. Choose a
different site for the second injection.
Step 6: Dispose of the needles and syringes.
•
Do not re-use a syringe or needle.
•
To avoid needle-stick injuries, do not recap a needle.
•
Put your needles and syringes in an FDA-cleared sharps disposal container right away after use.
Do not throw away (dispose of) loose needles and syringes in your household trash.
•
If you do not have an FDA-cleared sharps disposal container, you may use a household
container that is:
ƕ
made of heavy-duty plastic
ƕ
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come
out
ƕ
upright and stable during use
ƕ
leak-resistant,
ƕ
and properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be local or
state laws about how to throw away syringes and needles. For more information about safe
sharps disposal, and for specific information about sharps disposal in the state that you live in,
go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your sharps disposal container.
•
Throw away the vial into the container where you put the syringes and needles.
•
If you have any questions, talk to your doctor or pharmacist.
Keep PYZCHIVA and all medicines out of reach IURP children.
Manufactured by:
Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for:
Sandoz Inc.
Princeton, NJ 08540
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued 12/2024
Reference ID: 5500909
| custom-source | 2025-02-12T15:48:10.516894 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761373s002,761425s002lbl.pdf', 'application_number': 761373, 'submission_type': 'SUPPL ', 'submission_number': 2} |
80,737 |
_______________________________________________________________________________________________________________________________________
______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AUGMENTIN ES-600, safely and effectively. See full prescribing
information for AUGMENTIN ES-600.
AUGMENTIN ES-600® (amoxicillin and clavulanate potassium) for oral
suspension
Initial U.S. Approval: 2001
---------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
12/2024
Dosage and Administration, Dosage in Pediatric Patients (2.2)
12/2024
Warnings and Precautions,
Drug-Induced Enterocolitis Syndrome (DIES) (5.3)
5/2024
----------------------------INDICATIONS AND USAGE--------------------------
AUGMENTIN ES-600 is a combination of amoxicillin, a penicillin-class
antibacterial and clavulanate potassium, a beta-lactamase inhibitor, indicated
for the treatment of pediatric patients aged 3 months to 12 years weighing less
than or equal to 40 kg with
Recurrent or persistent acute otitis media due to S. pneumoniae (penicillin
MICs less than or equal to 2 mcg/mL), H. influenzae (including
beta-lactamase-producing strains), or M. catarrhalis (including beta-
lactamase-producing strains) characterized by the following risk factors
(1): Antibacterial exposure for acute otitis media within the preceding 3
months, and either of the following: 1) age 2 years, or younger or 2)
daycare attendance.
Limitations of Use
AUGMENTIN ES-600 is not indicated for the treatment of acute otitis media
due to S. pneumoniae with penicillin MIC greater than or equal to 4 mcg/mL.
Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin.
Therapy may be instituted prior to obtaining the results from bacteriological
studies when there is reason to believe the infection may involve both S.
pneumoniae (penicillin MIC less than or equal to 2 mcg/mL) and the
beta-lactamase-producing organisms listed above. (1)
Usage
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of AUGMENTIN ES-600 and other antibacterial drugs,
AUGMENTIN ES-600 should be used only to treat or prevent infections that
are proven or strongly suspected to be caused by bacteria. (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
Pediatric Patients aged 3 months to 12 years weighing less than or equal to
40 kg: 90 mg/kg/day divided every 12 hours, administered for 10 days. (2)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
For oral suspension: 600 mg/42.9 mg per 5 mL. (3)
-------------------------------CONTRAINDICATIONS-----------------------------
History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-
Johnson syndrome) to AUGMENTIN ES-600 or any other beta-lactams
(e.g., penicillins or cephalosporins). (4.1)
History of cholestatic jaundice/hepatic dysfunction associated with
AUGMENTIN ES-600. (4.2)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Serious (including fatal) hypersensitivity reactions: Discontinue
AUGMENTIN ES-600 if a reaction occurs and institute appropriate
therapy. (5.1)
Severe cutaneous adverse reactions (SCAR): Monitor closely. Discontinue
if rash progresses. (5.2)
Drug-induced enterocolitis syndrome (DIES) has been reported with use of
amoxicillin, a component of AUGMENTIN ES-600. If this occurs,
discontinue AUGMENTIN ES-600 and institute appropriate therapy. (5.3)
Hepatic dysfunction and cholestatic jaundice: Discontinue if
signs/symptoms of hepatitis occur. Monitor liver function tests in patients
with hepatic impairment. (5.4)
Clostridioides difficile-associated diarrhea (CDAD) (ranging from mild
diarrhea to fatal colitis): Evaluate patients if diarrhea occurs. (5.5)
Patients with mononucleosis who receive AUGMENTIN ES-600 develop
skin rash. Avoid AUGMENTIN ES-600 use in these patients. (5.6)
------------------------------ADVERSE REACTIONS------------------------------
The most frequently reported adverse reactions (incidence rate > 4 %) were
coughing, vomiting, contact dermatitis (i.e., diaper rash), fever, upper
respiratory tract infection, and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
USAntibiotics, LLC at 1-844-454-5532 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
Co-administration with probenecid is not recommended. (7.1)
Concomitant use of AUGMENTIN ES-600 with oral anticoagulants may
increase the prolongation of prothrombin time. (7.2)
Co-administration with allopurinol increases the risk of rash. (7.3)
AUGMENTIN ES-600 may reduce efficacy of oral contraceptives. (7.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
7
DRUG INTERACTIONS
2
DOSAGE AND ADMINISTRATION
7.1 Probenecid
2.1 Important Administration Instructions
7.2 Oral Anticoagulants
2.2 Dosage in Pediatric Patients
7.3 Allopurinol
2.3 Dosage in Adult Patients
7.4 Oral Contraception
2.4 Dosage in Patients with Hepatic Impairment
7.5 Effects on Laboratory Tests
2.5 Preparation of the Oral Suspension
8
USE IN SPECIFIC POPULATIONS
2.6 Switching between Dosage Forms and between Strengths
8.1 Pregnancy
3
DOSAGE FORMS AND STRENGTHS
8.2 Lactation
4
CONTRAINDICATIONS
8.4 Pediatric Use
4.1 Serious Hypersensitivity Reactions
10 OVERDOSAGE
4.2 Cholestatic Jaundice/Hepatic Dysfunction
11 DESCRIPTION
5
WARNINGS AND PRECAUTIONS
12 CLINICAL PHARMACOLOGY
5.1 Serious Allergic Reactions, Including Anaphylaxis
12.1 Mechanism of Action
5.2 Severe Cutaneous Adverse Reactions
12.3 Pharmacokinetics
5.3 Drug-Induced Enterocolitis Syndrome (DIES)
12.4 Microbiology
5.4 Hepatic Dysfunction
13 NONCLINICAL TOXICOLOGY
5.5 Clostridioides difficile-Associated Diarrhea (CDAD)
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.6 Skin Rash in Patients with Mononucleosis
14 CLINICAL STUDIES
5.7 Potential for Microbial Overgrowth
15 REFERENCES
5.8 Phenylketonurics
16 HOW SUPPLIED/STORAGE AND HANDLING
5.9 Development of Drug-Resistant Bacteria
17 PATIENT COUNSELING INFORMATION
6
ADVERSE REACTIONS
6.1 Clinical Trial Experience
*Sections or subsections omitted from the Full Prescribing Information are not
6.2 Postmarketing Experience
listed
1
Reference ID: 5500248
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
AUGMENTIN ES-600 is indicated for the treatment of pediatric patients aged 3 months to 12
years weighing less than or equal to 40 kg with:
Recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs less than
or equal to 2 mcg/mL), H. influenzae (including beta-lactamase-producing strains), or M.
catarrhalis (including beta-lactamase-producing strains) characterized by the following
risk factors:
- Antibacterial drug exposure for acute otitis media within the preceding 3 months, and
either of the following: 1) age 2 years, or younger or 2) day care attendance [see
Microbiology (12.4)].
Limitations of Use
AUGMENTIN ES-600 is not indicated for the treatment of acute otitis media due to S.
pneumoniae with penicillin MIC greater than or equal to 4 mcg/mL. Acute otitis media due to S.
pneumoniae alone can be treated with amoxicillin. Therapy may be instituted prior to obtaining
the results from bacteriological studies when there is reason to believe the infection may involve
both S. pneumoniae (penicillin MIC less than or equal to 2 mcg/mL) and the
beta-lactamase-producing organisms listed above.
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
AUGMENTIN ES-600 and other antibacterial drugs, AUGMENTIN ES-600 should be used only
to treat or prevent infections that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information are available, they should be considered in
selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
To minimize the potential for gastrointestinal intolerance, AUGMENTIN ES-600 should be
taken at the start of a meal. Absorption of clavulanate potassium may be enhanced when
AUGMENTIN ES-600 is administered at the start of a meal.
2.2 Dosage in Pediatric Patients
Pediatric patients aged 3 months to 12 years weighing less than or equal to 40 kg: Based on the
amoxicillin component (600 mg/5 mL), the recommended dose of AUGMENTIN ES-600 is 90
mg/kg/day divided every 12 hours, administered for 10 days (see Table 1 as a general example
guideline for attainment of this dosage). This dose provides 6.4 mg/kg/day of the clavulanic acid
component.
Reference ID: 5500248
2
Table 1: General Dosage Guidelines for AUGMENTIN ES-600 in Pediatric Patients
Body Weight (kg)
Volume of AUGMENTIN ES-600 for oral
suspension providing 90 mg/kg/day
8
3 mL twice daily
12
4.5 mL twice daily
16
6 mL twice daily
20
7.5 mL twice daily
24
9 mL twice daily
28
10.5 mL twice daily
32
12 mL twice daily
36
13.5 mL twice daily
40
15 mL twice daily
Pediatric patients weighing greater than 40 kg: Experience with AUGMENTIN ES-600 in this
group is not available.
2.3 Dosage in Adult Patients
Experience with AUGMENTIN ES-600 in adults is not available and adults who have difficulty
swallowing should not be given AUGMENTIN ES-600 in place of the 500 mg or 875 mg tablet
of AUGMENTIN.
2.4 Dosage in Patients with Hepatic Impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at
regular intervals [see Warnings and Precautions (5.4)].
2.5 Preparation of the Oral Suspension
Prepare the suspension at time of dispensing as follows: Tap bottle until all powder flows freely.
Measure the total amount of water (see Table 2) to be added in two parts. Add approximately 2/3
of the total amount of water for reconstitution, replace cap and shake vigorously to suspend
powder. Add remainder of the water (that had been measured), replace cap and again shake
vigorously.
Table 2: Volume of Water for Reconstituting AUGMENTIN ES-600
Bottle Size
Amount of Water
Required for Reconstitution
75 mL
70 mL
125 mL
110 mL
200 mL
180 mL
Each 5 mL will contain 600 mg of amoxicillin as the trihydrate, and 42.9 mg of clavulanic acid
as the potassium salt.
Reference ID: 5500248
3
Shake oral suspension well before each use. Suspension must be refrigerated. Discard after 10
days. Suspension is off-white at time of reconstitution; some color change is normal during the
dosing period.
Flavoring Information: For patients who wish to alter the taste of AUGMENTIN ES-600,
immediately after reconstitution, 1 drop of FLAVORx® (apple, banana cream, bubble gum,
cherry, or watermelon flavor) may be added for every 5 mL of AUGMENTIN ES-600. The
resulting suspension is stable for 10 days under refrigeration. Stability of AUGMENTIN ES-600
when mixed with other flavors other than the 5 flavors listed above has not been evaluated.
2.6 Switching between Dosage Forms and between Strengths
AUGMENTIN ES-600 does not contain the same amount of clavulanic acid (as the potassium
salt) as any of the other suspensions of AUGMENTIN. AUGMENTIN ES-600 contains 42.9 mg
of clavulanic acid per 5 mL, whereas the 200 mg/28.5 mg per 5 mL suspension of
AUGMENTIN contains 28.5 mg clavulanic acid per 5 mL and the 400 mg/57 mg per 5 mL
suspension of AUGMENTIN contains 57 mg clavulanic acid per 5 mL. Therefore, the 200
mg/28.5 mg per 5 mL and 400 mg/57 mg per 5 mL suspensions of AUGMENTIN should not be
substituted for AUGMENTIN ES-600 as they are not interchangeable.
3 DOSAGE FORMS AND STRENGTHS
Augmentin ES 600 for Oral Suspension: 600 mg/42.9 mg per 5 mL: Strawberry cream-flavored
for oral suspension (each 5 mL of reconstituted suspension contains 600 mg of amoxicillin as the
trihydrate, and 42.9 mg of clavulanic acid as the potassium salt).
4 CONTRAINDICATIONS
4.1 Serious Hypersensitivity Reactions
AUGMENTIN ES-600 is contraindicated in patients with a history of serious hypersensitivity
reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate, or to
other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).
4.2 Cholestatic Jaundice/Hepatic Dysfunction
AUGMENTIN ES-600 is contraindicated in patients with a previous history of cholestatic
jaundice/hepatic dysfunction associated with treatment with amoxicillin and clavulanate
potassium.
5 WARNINGS AND PRECAUTIONS
5.1 Serious Allergic Reactions, including Anaphylaxis
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in
patients receiving beta-lactam antibacterials, including AUGMENTIN ES-600. These reactions
are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a
history of sensitivity to multiple allergens. Before initiating therapy with AUGMENTIN ES-600,
Reference ID: 5500248
4
careful inquiry should be made concerning previous hypersensitivity reactions to penicillins,
cephalosporins, or other allergens. If an allergic reaction occurs, discontinue AUGMENTIN ES
600 and institute appropriate therapy.
5.2 Severe Cutaneous Adverse Reactions
AUGMENTIN ES-600 may cause severe cutaneous adverse reactions (SCAR), such as Stevens-
Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and
systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If
patients develop a skin rash, they should be monitored closely, and AUGMENTIN ES-600
discontinued if lesions progress.
5.3 Drug-Induced Enterocolitis Syndrome (DIES)
Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a
component of AUGMENTIN ES-600 [see Adverse Reactions (6.2)], with most cases occurring in
pediatric patients 18 years of age. DIES is a non-IgE mediated hypersensitivity reaction
characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of
skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock,
diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES
occurs, discontinue AUGMENTIN ES-600 and institute appropriate therapy.
5.4 Hepatic Dysfunction
Use AUGMENTIN ES-600 with caution in patients with evidence of hepatic dysfunction.
Hepatic toxicity associated with the use of AUGMENTIN ES-600 is usually reversible. Deaths
have been reported (fewer than one death reported per estimated four million prescriptions
worldwide). These have generally been cases associated with serious underlying diseases or
concomitant medications [see Contraindications (4.2) and Adverse Reactions (6.2)].
5.5 Clostridioides difficile-Associated Diarrhea (CDAD)
Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including AUGMENTIN ES-600, and may range in severity from mild
diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon
leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these
infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must
be considered in all patients who present with diarrhea following antibacterial drug use. Careful
medical history is necessary since CDAD has been reported to occur over two months after the
administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against
C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
Reference ID: 5500248
5
5.6 Skin Rash in Patients with Mononucleosis
A high percentage of patients with mononucleosis who receive amoxicillin develop an
erythematous skin rash. Avoid AUGMENTIN ES-600 use in patients with mononucleosis.
5.7 Potential for Microbial Overgrowth
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind
during therapy. If superinfections occur (usually involving Pseudomonas spp. or Candida spp.),
the drug should be discontinued, and appropriate therapy instituted.
5.8 Phenylketonurics
AUGMENTIN ES-600 contains aspartame which contains phenylalanine. Each 5 mL of
suspension of AUGMENTIN ES-600 contains 7 mg phenylalanine.
5.9 Development of Drug-Resistant Bacteria
Prescribing AUGMENTIN ES-600 in the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication is unlikely to provide benefit to the patient and increases
the risk of the development of drug-resistant bacteria.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in labeling:
Anaphylactic reactions [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions (SCAR) [see Warnings and Precautions (5.2)]
Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3)]
Hepatic Dysfunction [see Warnings and Precautions (5.4)]
Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.5)]
Skin Rash in Patients with Mononucleosis [see Warnings and Precautions (5.6)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Two clinical trials evaluated the safety of a 10-day treatment course of AUGMENTIN ES-600
90/6.4 mg/kg/day, divided every 12 hours, in pediatric patients with acute otitis media [see
Clinical Studies (14)]. The first trial involved 521 pediatric patients (3 months to 50 months)
and the second trial involved 450 pediatric patients (3 months to 12 years). In the intent-to
treat population of the first trial of 521 patients, the most frequently reported adverse events
were vomiting (7%), fever (6%), contact dermatitis (i.e., diaper rash) (6%), upper respiratory
tract infection (4%), and diarrhea (4%). Protocol-defined diarrhea (i.e., 3 or more watery
Reference ID: 5500248
6
stools in one day or 2 watery stools per day for 2 consecutive days as recorded on diary cards)
occurred in 13% of patients.
The primary objective of the second study was to compare the safety of AUGMENTIN ES-600
(90/6.4 mg/kg/day, divided every 12 hours) to AUGMENTIN (45/6.4 mg/kg/day, divided every
12 hours) for ten days. There was no statistically significant difference between treatments in the
proportion of patients with 1 or more adverse events. The most frequently reported adverse
reactions for AUGMENTIN ES-600 and the comparator of AUGMENTIN were coughing (12%
versus 7%), vomiting (7% versus 8%), contact dermatitis (i.e., diaper rash, 6% versus 5%), fever
(6% versus 4%), and upper respiratory infection (3% versus 9%), respectively. The frequencies
of protocol-defined diarrhea with AUGMENTIN ES-600 (11%) and AUGMENTIN (9%) were
not statistically different. Two patients in the group treated with AUGMENTIN ES-600 and one
patient in the group treated with AUGMENTIN were withdrawn due to diarrhea.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of
AUGMENTIN products, including AUGMENTIN ES-600. Because these reactions are reported
voluntarily from a population of unknown size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Gastrointestinal: Drug-induced enterocolitis syndrome (DIES), diarrhea, nausea, vomiting,
indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis,
enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis
symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.3,
5.5)].
Immune: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock),
angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis,
arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and
Precautions (5.1)].
Skin and Appendages: Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS,
AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis [see Warnings and Precautions
(5.1, 5.2, 5.6)].
Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated
with ampicillin-class antibacterials. Hepatic dysfunction, including increases in serum
transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been
infrequently reported with AUGMENTIN or AUGMENTIN ES-600. It has been reported more
commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings
on liver biopsy have consisted of cholestatic, hepatocellular, or mixed cholestatic-hepatocellular
changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks
after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually
reversible. Deaths have been reported [see Contraindications (4.2), Warnings and Precautions
(5.4)].
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Renal: Interstitial nephritis and hematuria have been reported. Crystalluria has also been reported
[see Overdosage (10)].
Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia,
thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported
during therapy with penicillins. These reactions are usually reversible on discontinuation of
therapy and are believed to be hypersensitivity phenomena. There have been reports of increased
prothrombin time in patients receiving AUGMENTIN and anticoagulant therapy concomitantly.
Central Nervous System: Agitation, anxiety, behavioral changes, aseptic meningitis, confusion,
convulsions, dizziness, insomnia, and reversible hyperactivity have been reported.
Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most
reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or
dental cleaning in most cases.
7 DRUG INTERACTIONS
7.1 Probenecid
Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with
AUGMENTIN ES-600 may result in increased and prolonged blood levels of amoxicillin. Co-
administration of probenecid is not recommended.
7.2 Oral Anticoagulants
Abnormal prolongation of prothrombin time (increased international normalized ratio [INR])
has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate
monitoring should be undertaken when anticoagulants are prescribed concurrently.
Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level
of anticoagulation.
7.3 Allopurinol
The concurrent administration of allopurinol and amoxicillin increases substantially the
incidence of rashes in patients receiving both drugs as compared to patients receiving
amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to
allopurinol or the hyperuricemia present in these patients. There are no data with
AUGMENTIN ES-600 and allopurinol administered concurrently.
7.4 Oral Contraceptives
AUGMENTIN ES-600 may affect intestinal flora, leading to lower estrogen reabsorption and
reduced efficacy of combined oral estrogen/progesterone contraceptives.
7.5 Effects on Laboratory Tests
High urine concentrations of amoxicillin may result in false-positive reactions when testing for
the presence of glucose in urine using CLINITEST®, Benedict’s Solution, or Fehling’s
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8
Solution. Since this effect may also occur with AUGMENTIN ES-600, it is recommended that
glucose tests based on enzymatic glucose oxidase reactions be used.
Following administration of amoxicillin to pregnant women, a transient decrease in plasma
concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol
has been noted.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data from published epidemiologic studies and pharmacovigilance case reports over
several decades of use with amoxicillin and clavulanate during pregnancy have not established a
drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. A study
in women with preterm prelabor rupture of membranes (PPROM) reported that prophylactic
treatment with amoxicillin and clavulanate may be associated with an increased risk of
necrotizing enterocolitis in neonates (see Data). Reproduction studies performed in pregnant
rodents, given up to approximately 2 times the amount of amoxicillin and 15 times the amount of
clavulanate in the Maximum Human Recommended Dose (MHRD) of AUGMENTIN ES-600,
revealed no evidence of harm to the fetus (see Data).
The background risk of major birth defects and miscarriage for the indicated populations is
unknown. All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
One randomized, controlled trial included 4,826 pregnant women with premature rupture of fetal
membranes who were randomly assigned to 250 mg erythromycin (n=1,197), 250 mg
amoxicillin and 125 mg clavulanic acid (amoxicillin and clavulanate, n=1,212), amoxicillin and
clavulanate and erythromycin (n=1,192), or placebo (n=1,225) four times daily for 10 days or
until delivery. Amoxicillin and clavulanate was associated with a significantly increased rate of
proven neonatal necrotizing enterocolitis: 1.9% (n = 24) in the amoxicillin and clavulanate only
group versus 0.5% (n = 6) in the placebo group (p = 0.001), and 1.8% (n = 44) in the any
amoxicillin and clavulanate group versus 0.7% (n =17) in the no amoxicillin and clavulanate
group (p = 0.0005).
Animal Data
Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate (2:1
ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no
evidence of harm to the fetus due to amoxicillin and clavulanate. The amoxicillin doses in
rodents (based on body surface area and assuming a 20 kg child) were approximately 2 times
(rats) or equal to (mice) the recommended clinical AUGMENTIN ES-600 dose of 90/6.4
mg/kg/day. For clavulanate, these dose multiples were approximately 15 times and 7.5 times the
recommended daily dose of AUGMENTIN ES-600.
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8.2 Lactation
Risk Summary
Data from a published clinical lactation study report that amoxicillin is present in human milk.
There are reports of diarrhea, irritability, and rash in infants exposed to amoxicillin and
clavulanate through breast milk; therefore, infants exposed to AUGMENTIN ES-600 should be
monitored for these symptoms. There are no data on the effects of amoxicillin and clavulanate on
milk production. The developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for AUGMENTIN ES-600 and any potential adverse
effects on the breastfed child from AUGMENTIN ES-600 or from the underlying maternal
condition.
8.4 Pediatric Use
Acute Otitis Media
The safety and effectiveness of AUGMENTIN ES-600 have been established in pediatric
patients aged 3 months to 12 years weighing less than or equal to 40 kg, for the treatment of
acute otitis media, and the information on this use is discussed throughout the labeling.
The safety and effectiveness of AUGMENTIN ES-600 in pediatric patients younger than 3
months of age have not been established.
The safety and effectiveness of Augmentin ES-600 have not been established in pediatric
patients aged 3 months to 12 years weighing more than 40 kg.
Acute Bacterial Sinusitis
The safety and effectiveness of AUGMENTIN ES-600 have been established for the treatment of
pediatric patients (3 months to 12 years of age) with acute bacterial sinusitis. This use is
supported by evidence from adequate and well-controlled studies of AUGMENTIN XRTM
Extended Release Tablets in adults with acute bacterial sinusitis, studies of AUGMENTIN ES
600 in pediatric patients with acute otitis media, and by similar pharmacokinetics of amoxicillin
and clavulanate in pediatric patients taking AUGMENTIN ES-600 [see Clinical Pharmacology
(12)] and adults taking AUGMENTIN XR.
10 OVERDOSAGE
Following overdosage, patients have experienced primarily gastrointestinal symptoms including
stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have
also been observed in a small number of patients.
In the case of overdosage, discontinue AUGMENTIN ES-600, treat symptomatically, and
institute supportive measures as required. If the overdosage is very recent and there is no
contraindication, an attempt at emesis or other means of removal of drug from the stomach may
be performed. A prospective study of 51 pediatric patients at a poison control center suggested
that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical
symptoms and do not require gastric emptying.1
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10
-0
H
O
H¾COOH
HO
I
N
CH
3
--9---CONH--~
CH
NH
S
'
2
H
H
Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of
patients after overdosage with amoxicillin.
Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin
overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and
diuresis should be maintained to reduce the risk of amoxicillin crystalluria.
Renal impairment appears to be reversible with cessation of drug administration. High blood
levels may occur more readily in patients with impaired renal function because of decreased
renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are
removed from the circulation by hemodialysis [see Dosage and Administration (2)].
11 DESCRIPTION
AUGMENTIN ES-600 is an oral antibacterial combination consisting of the semisynthetic
antibacterial amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium
salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin
nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16H19N3O5S•3H2O,
and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)-6-[(R )-(-)-2-Amino
2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2
carboxylic acid trihydrate and may be represented structurally as:
Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam
structurally related to the penicillins and possesses the ability to inactivate a wide variety of
beta-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly
active against the clinically important plasmid-mediated beta-lactamases frequently responsible
for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium
molecular formula is C8H8KNO5 and the molecular weight is 237.25. Chemically, clavulanate
potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]
heptane-2-carboxylate and may be represented structurally as:
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11
Following constitution, each 5 mL of oral suspension contains 600 mg of amoxicillin as the
trihydrate and 42.9 mg of clavulanic acid (equivalent to 51.1 mg of clavulanate potassium).
Inactive Ingredients: Aspartame, colloidal silicon dioxide, silicon dioxide, sodium
carboxymethylcellulose, strawberry cream flavor, and xanthan gum [see Warnings and
Precautions (5.8)]. Each 5 mL of reconstituted AUGMENTIN ES-600 contains approximately 9
mg of potassium and 4 mg of sodium.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
AUGMENTIN ES-600 is an antibacterial drug [see Microbiology (12.4)].
12.3
Pharmacokinetics
The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric
patients, 8 months to 11 years, given AUGMENTIN ES-600 at an amoxicillin dose of 45 mg/kg
q12h with a snack or meal. The mean plasma amoxicillin and clavulanate pharmacokinetic
parameter values are listed in Table 3.
Table 3. Mean (±SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter
Values Following Administration of 45 mg/kg of AUGMENTIN ES-600 Every 12 Hours to
Pediatric Patients
Parameter
Amoxicillin
Clavulanate
Cmax (mcg/mL)
15.7 ± 7.7
1.7 ± 0.9
Tmax (hr)
2.0 (1.0 to 4.0)
1.1 (1.0 to 4.0)
AUC0-T (mcg*hr/mL)
59.8 ± 20.0
4.0 ± 1.9
T½ (hr)
1.4 ± 0.3
1.1 ± 0.3
CL/F (L/hr/kg)
0.9 ± 0.4
1.1 ± 1.1
* Arithmetic mean ± standard deviation, except Tmax values which are medians (ranges).
The effect of food on the oral absorption of AUGMENTIN ES-600 has not been studied.
Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic
acid are excreted unchanged in urine during the first 6 hours after administration of 10 mL of
250 mg/5 mL suspension of AUGMENTIN.
Neither component in AUGMENTIN ES-600 is highly protein-bound; clavulanic acid has been
found to be approximately 25% bound to human serum and amoxicillin approximately 18%
bound.
Oral administration of a single dose of AUGMENTIN ES-600 at 45 mg/kg (based on the
amoxicillin component) to pediatric patients, 9 months to 8 years, yielded the following
pharmacokinetic data for amoxicillin in plasma and middle ear fluid (MEF):
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Table 4. Amoxicillin Concentrations in Plasma and Middle Ear Fluid Following
Administration of 45 mg/kg of AUGMENTIN ES-600 to Pediatric Patients*
Timepoint
Amoxicillin concentration
in plasma (mcg/mL)
Amoxicillin concentration
in MEF (mcg/mL)
1 hour
mean
median
range
7.7
9.3
1.5 to 14.0
(n = 5)
3.2
3.5
0.2 to 5.5
(n = 4)
2 hour
mean
median
range
15.7
13.0
11.0 to 25.0
(n = 7)
3.3
2.4
1.9 to 6
(n = 5)
3 hour
mean
median
range
13.0
12.0
5.5 to 21.0
(n = 5)
5.8
6.5
3.9 to 7.4
(n = 5)
*Dose administered immediately prior to eating.
Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain
and spinal fluid. The results of experiments involving the administration of clavulanic acid to
animals suggest that this compound, like amoxicillin, is well distributed in body tissues.
Drug Interaction Studies
Clinical Studies
Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal
excretion of clavulanic acid.
12.4
Microbiology
Mechanism of Action
Amoxicillin is a semisynthetic antibacterial with a broad spectrum of bactericidal activity against
many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to
degradation by beta-lactamases, and therefore, its spectrum of activity does not include
organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to
penicillin, which possesses the ability to inactivate a wide range of beta-lactamase enzymes
commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it
has good activity against the clinically important plasmid-mediated beta-lactamases frequently
found responsible for transferred drug resistance.
The clavulanic acid component of AUGMENTIN ES-600 protects amoxicillin from degradation
by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to
include many bacteria normally resistant to amoxicillin and other beta-lactam antibacterials.
Thus, AUGMENTIN ES-600 possesses the distinctive properties of a broad spectrum
antibacterial and a beta-lactamase inhibitor.
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Antimicrobial Activity Amoxicillin/clavulanic acid has been shown to be active against most
isolates of the following microorganisms, both in vitro and in clinical infections [see Indications
and Usage (1)].
Gram-positive bacteria:
Streptococcus pneumoniae (including isolates with penicillin MICs less than or equal to
2 mcg/mL)
Gram-negative bacteria:
Haemophilus influenzae including beta-lactamase-producing isolates)
Moraxella catarrhalis (including beta-lactamase-producing isolates)
The following in vitro data are available, but their clinical significance is unknown. At least 90%
of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less
than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the safety
and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms
have not been established in adequate and well-controlled trials.
Gram-positive bacteria:
Staphylococcus aureus (including beta-lactamase-producing isolates)
Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to
amoxicillin/clavulanic acid.
Streptococcus pyogenes
S. pyogenes do not produce beta-lactamase, and therefore, are susceptible to amoxicillin alone.
Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin
alone in treating certain clinical infections due to S. pyogenes.
Susceptibility Test Methods:
For specific information regarding susceptibility test interpretive criteria and associated test
methods and quality control standards recognized by FDA for this drug, please see:
https://www.fda.gov/STIC.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Amoxicillin and clavulanate (4:1 ratio formulation of amoxicillin:clavulanate) was non
mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay.
Amoxicillin and clavulanate was weakly positive in the mouse lymphoma assay, but the trend
toward increased mutation frequencies in this assay occurred at concentrations that were also
associated with decreased cell survival. Amoxicillin and clavulanate was negative in the mouse
micronucleus test, and in the dominant lethal assay in mice. Clavulanate potassium alone was
tested in the Ames bacterial mutation assay and in the mouse micronucleus test and was
negative in each of these assays.
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Amoxicillin and clavulanate (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of
up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance
in rats. Based on body surface area (assuming a 20 kg child), this dose of amoxicillin is
approximately 2 times the recommended clinical AUGMENTIN ES-600 dose of
90/6.4 mg/kg/day. For clavulanate, the dose multiple is approximately 15 times higher than
the recommended clinical daily dose, also based on body surface area.
14 CLINICAL STUDIES
Two clinical studies were conducted in pediatric patients with acute otitis media. A non-
comparative, open-label study assessed the bacteriologic and clinical efficacy of
AUGMENTIN ES-600 (90/6.4 mg/kg/day, divided every 12 hours) for 10 days in 521 pediatric
patients (3 to 50 months) with acute otitis media. The primary objective was to assess
bacteriological response in children with acute otitis media due to S. pneumoniae with
amoxicillin/clavulanic acid MICs of 4 mcg/mL. The study sought the enrollment of patients with
the following risk factors: Failure of antibacterial therapy for acute otitis media in the previous 3
months, history of recurrent episodes of acute otitis media, 2 years or younger, or daycare
attendance. Prior to receiving AUGMENTIN ES-600, all patients had tympanocentesis to obtain
middle ear fluid for bacteriological evaluation. Patients from whom S. pneumoniae (alone or in
combination with other bacteria) was isolated had a second tympanocentesis 4 to 6 days after the
start of therapy. Clinical assessments were planned for all patients during treatment (4 to 6 days
after starting therapy), as well as 2 to 4 days post-treatment and 15 to 18 days post-treatment.
Bacteriological success was defined as the absence of the pretreatment pathogen from the on-
therapy tympanocentesis specimen. Clinical success was defined as improvement or resolution of
signs and symptoms. Clinical failure was defined as lack of improvement or worsening of signs
and/or symptoms at any time following at least 72 hours of AUGMENTIN ES-600; patients who
received an additional systemic antibacterial drug for otitis media after 3 days of therapy were
considered clinical failures. Bacteriological eradication on therapy (day 4 to 6 visit) in the per
protocol population is summarized in Table 5.
Table 5. Bacteriologic Eradication Rates in the Per Protocol Population
Bacteriologic Eradication on Therapy
Pathogen
n/N
%
95% CI*
All S. pneumoniae
121/123
98
(94.3, 99.8)
S. pneumoniae with penicillin
MIC equal to 2 mcg/mL
19/19
100
(82.4, 100.0)
S. pneumoniae with penicillin
MIC equal to 4 mcg/mL
12/14
86
(57.2, 98.2)
H. influenzae
75/81
93
(84.6, 97.2)
M. catarrhalis
11/11
100
(71.5, 100.0)
* CI equals confidence intervals; 95% CIs are not adjusted for multiple comparisons.
Clinical assessments were made in the per protocol population 2 to 4 days post-therapy and 15 to
18 days post-therapy. Patients who responded to therapy 2 to 4 days post-therapy were followed
for 15 to 18 days post-therapy to assess them for acute otitis media. Non-responders at 2 to 4
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15
days post-therapy were considered failures at the latter timepoint. The clinical assessments in the
per protocol population are presented in Table 6.
Table 6. Clinical Assessments in the Per Protocol Population (Includes S. pneumoniae
Patients with Penicillin MICs equal to 2 or 4 mcg/mL*)
2 to 4 Days Post-Therapy (Primary
Endpoint)
Pathogen
n/N
%
95% CI†
All S. pneumoniae
122/137
89
(82.6, 93.7)
S. pneumoniae with penicillin
MIC equal to 2 mcg/mL
17/20
85
(62.1, 96.8)
S. pneumoniae with penicillin
MIC equal to 4 mcg/mL
11/14
79
(49.2, 95.3)
H. influenzae
141/162
87
(80.9, 91.8)
M. catarrhalis
22/26
85
(65.1, 95.6)
15 to 18 Days Post-Therapy‡
(Secondary Endpoint)
Pathogen
n/N
%
95% CI†
All S. pneumoniae
95/136
70
(61.4, 77.4)
S. pneumoniae with penicillin
MIC equal to 2 mcg/mL
11/20
55
(31.5, 76.9)
S. pneumoniae with penicillin
MIC equal to 4 mcg/mL
5/14
36
(12.8, 64.9)
H. influenzae
106/156
68
(60.0, 75.2)
M. catarrhalis
14/25
56
(34.9, 75.6)
* S. pneumoniae strains with penicillin MICs of 2 or 4 mcg/mL are considered resistant to
penicillin.
† CI equals confidence intervals; 95% CIs are not adjusted for multiple comparisons.
‡ Clinical assessments at 15 to 18 days post-therapy may have been confounded by viral
infections and new episodes of acute otitis media with time elapsed post-treatment.
In the intent-to-treat analysis, overall clinical outcomes at 2 to 4 days and 15 to 18 days post-
treatment in patients with S. pneumoniae with penicillin MIC equal to 2 mcg/mL and 4 mcg/mL
were 29/41 (71%) and 17/41 (42%), respectively.
15 REFERENCES
1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and
cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;
30:66-67.
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16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
AUGMENTIN ES-600 (amoxicillin and clavulanate potassium) for oral suspension is a
strawberry cream-flavored powder for oral suspension. Following constitution, each 5 mL of oral
suspension contains 600 mg of amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the
potassium salt.
AUGMENTIN ES-600 is supplied as follows:
NDC 81964-003-51
75 mL bottle
NDC 81964-003-69
125 mL bottle
NDC 81964-003-54
200 mL bottle
Storage
Store dry powder for oral suspension at or below 25°C (77°F). Dispense in original container.
Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days.
17 PATIENT COUNSELING INFORMATION
Administration Instructions
Inform patients to take AUGMENTIN ES-600 every 12 hours with a meal or snack to reduce the
possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3
days, they should call their doctor [see Dosage and Administration (2.1), Warnings and
Precautions (5.5)].
Allergic Reactions
Counsel patients that AUGMENTIN ES-600 contains a penicillin class drug product that can cause
allergic reactions in some individuals [see Warnings and Precautions (5.1, 5.3)].
Severe Cutaneous Adverse Reactions (SCAR)
Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to
stop taking AUGMENTIN ES-600 immediately and promptly report the first signs or symptoms
of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions
(5.2)].
Diarrhea
Counsel patients that diarrhea is a common problem caused by antibacterial drugs, including
AUGMENTIN ES-600, which usually ends when the antibacterial is discontinued. Sometimes
after starting treatment with antibacterial drugs, patients can develop watery and bloody stools
(with or without stomach cramps and fever) even as late as 2 or more months after having taken
the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon
as possible [see Warnings and Precautions (5.5)].
Phenylketonuria
Counsel patients with phenylketonuria: Each 5 mL of suspension of AUGMENTIN ES-600
contains 7 mg phenylalanine [see Warnings and Precautions (5.8)].
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17
Antibacterial Resistance
Patients should be counseled that antibacterial drugs, including AUGMENTIN ES-600, should
only be used to treat bacterial infections. Antibacterial drugs do not treat viral infections (e.g.,
the common cold). When AUGMENTIN ES-600 is prescribed to treat a bacterial infection,
patients should be told that although it is common to feel better early in the course of therapy, the
medication should be taken exactly as directed. Skipping doses or not completing the full course
of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the
likelihood that bacteria will develop resistance and will not be treatable by AUGMENTIN ES
600 or other antibacterial drugs in the future [see Warnings and Precautions (5.9)].
Storage Instructions
Keep suspension refrigerated. Shake well before using. When dosing a child with the suspension
(liquid) of AUGMENTIN ES-600, use a dosing spoon or medicine dropper. Be sure to rinse the
spoon or dropper after each use. Bottles of suspension of AUGMENTIN ES-600 may contain
more liquid than required. Follow your doctor’s instructions about the amount to use and the
days of treatment your child requires. Discard any unused medicine.
Manufactured by:
USAntibiotics, LLC
Bristol, TN 37620 (USA)
AUGMENTIN ES-600 and AUGMENTIN XR are registered trademarks of GlaxoSmithKline
and are licensed to USAntibiotics, LLC.
CLINITEST is a registered trademark of Miles, Inc.
FLAVORx is a registered trademark of FLAVORx. Inc.
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1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AUGMENTIN XR safely and effectively. See full prescribing
information for AUGMENTIN XR.
AUGMENTIN XR® (amoxicillin and clavulanate potassium)
extended- release tablets, for oral use.
Initial U.S. Approval: 2002
----------------------------RECENT MAJOR CHANGES------------------------
Indications and Usage (1)
12/2024
Warnings and Precautions,
Drug-Induced Enterocolitis Syndrome (DIES) (5.3)
5/2024
----------------------------INDICATIONS AND USAGE-----------------------
AUGMENTIN XR is a combination of amoxicillin, a penicillin-class
antibacterial and clavulanate potassium, a beta-lactamase inhibitor,
indicated for treatment of adults and pediatric patients weighing greater than
or equal to 40 kg who are able to swallow tablets with
• community-acquired pneumonia or
• acute bacterial sinusitis
due to confirmed, or suspected beta-lactamase-producing pathogens (i.e.,
H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae, or
methicillin-susceptible S. aureus) and S. pneumoniae with reduced
susceptibility to penicillin (i.e., penicillin MICs equal to 2 mcg/mL). (1)
Limitations of Use
AUGMENTIN XR is not indicated for the treatment of infections due to S.
pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL. Data
are limited with regard to infections due to S. pneumoniae with penicillin
MICs greater than or equal to 4 mcg/mL. (1)
Usage
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of AUGMENTIN XR and other antibacterial drugs,
AUGMENTIN XR should be used only to treat or prevent infections that
are proven or strongly suspected to be caused by bacteria. (1)
-----------------------DOSAGE AND ADMINISTRATION--------------------
Adults and Pediatric Patients weighing greater than or equal to 40 kg who are
able to swallow tablets: The recommended dosage of AUGMENTIN XR is
4,000 mg/250 mg daily in divided doses at the start of a meal according to
the following table. (2)
Indication
Dose
Duration
Acute bacterial sinusitis
Two (1,000 mg/62.5 mg)
tablets every 12 hours
10 days
Community‑acquired pneumonia
Two (1,000 mg/62.5 mg)
tablets every 12 hours
7 to 10 days
----------------------DOSAGE FORMS AND STRENGTHS-------------------
Extended-release Tablets: 1,000 mg/62.5 mg (3)
-------------------------------CONTRAINDICATIONS---------------------------
• History of a serious hypersensitivity reaction (e.g., anaphylaxis or
Stevens-Johnson syndrome) to AUGMENTIN XR or to other beta-
lactams (e.g., penicillins or cephalosporins). (4.1)
• History of cholestatic jaundice/hepatic dysfunction associated with
AUGMENTIN XR. (4.2)
• In patients with severe renal impairment (creatinine clearance less than
30 mL/min) and in hemodialysis patients. (4.3)
-------------------------WARNINGS AND PRECAUTIONS--------------------
• Serious (including fatal) hypersensitivity reactions: Discontinue
AUGMENTIN XR if a reaction occurs and institute appropriate therapy.
(5.1)
• Severe cutaneous adverse reactions (SCAR): Monitor closely.
Discontinue if rash progresses. (5.2)
• Drug-induced enterocolitis syndrome (DIES) has been reported with use
of amoxicillin, a component of AUGMENTIN XR. If this occurs,
discontinue AUGMENTIN XR and institute appropriate therapy. (5.3)
• Hepatic dysfunction and cholestatic jaundice: Discontinue if
signs/symptoms of hepatitis occur. Monitor liver function tests in
patients with hepatic impairment. (5.4)
• Clostridioides difficile-associated diarrhea (CDAD): Evaluate patients if
diarrhea occurs. (5.5)
• Patients with mononucleosis who receive AUGMENTIN XR develop
skin rash. Avoid AUGMENTIN XR use in these patients. (5.6)
-------------------------------ADVERSE REACTIONS---------------------------
The most frequently reported adverse reactions were (incidence > 2 %)
diarrhea, vaginal mycosis nausea, and loose stools. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
USAntibiotics, LLC at 1-844-454-5532 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS----------------------------
• Co-administration with probenecid is not recommended. (7.1)
• Concomitant use of AUGMENTIN XR and oral anticoagulants
may increase the prolongation of prothrombin time. (7.2)
• Co-administration with allopurinol increases the risk of rash. (7.3)
• AUGMENTIN XR may reduce efficacy of oral contraceptives. (7.4)
--------------------------USE IN SPECIFIC POPULATIONS-------------------
• Renal Impairment: AUGMENTIN XR has not been studied in patients
with renal impairment. (8.6)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
2.2 Dosage in Adult Patients
2.3 Dosage in Pediatric Patients
2.4 Dosage in Patients with Hepatic Impairment
2.5 Switching between Dosage Forms and Between Strengths
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1 Serious Hypersensitivity Reactions
4.2 Cholestatic Jaundice/Hepatic Dysfunction
4.3 Renal Impairment
5
WARNINGS AND PRECAUTIONS
5.1 Serious Allergic Reactions, Including Anaphylaxis
5.2 Severe Cutaneous Adverse Reactions
5.3 Drug-Induced Enterocolitis Syndrome (DIES)
5.4 Hepatic Dysfunction
5.5 Clostridioides difficile-Associated Diarrhea (CDAD)
5.6 Skin Rash in Patients with Mononucleosis
5.7 Potential for Microbial Overgrowth
5.8 Development of Drug-Resistant Bacteria
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Probenecid
7.2 Oral Anticoagulants
7.3 Allopurinol
7.4 Oral Contraceptives
7.5 Effects on Laboratory Tests
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Acute Bacterial Sinusitis
14.2 Community-Acquired Pneumonia
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
AUGMENTIN XR is indicated for the treatment of infections in adults and pediatric patients
weighing greater than or equal to 40 kg who are able to swallow tablets with:
• community-acquired pneumonia or
• acute bacterial sinusitis
due to confirmed, or suspected beta-lactamase-producing pathogens (i.e., H. influenzae, M.
catarrhalis, H. parainfluenzae, K. pneumoniae, or methicillin-susceptible S. aureus) and S.
pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs equal to 2 mcg/mL).
Limitations of Use
AUGMENTIN XR is not indicated for the treatment of infections due to S. pneumoniae with
penicillin MICs greater than or equal to 4 mcg/mL. Data are limited with regard to infections due
to S. pneumoniae with penicillin MICs greater than or equal to 4 mcg/mL [see Clinical Studies
(14)].
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
AUGMENTIN XR and other antibacterial drugs, AUGMENTIN XR should be used only to treat
or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
When culture and susceptibility information are available, they should be considered in selecting
or modifying antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
In patients with community-acquired pneumonia in whom penicillin-resistant S. pneumoniae is
suspected, bacteriological studies should be performed to determine the causative organisms
and their susceptibility when AUGMENTIN XR is prescribed.
Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain
of S. pneumoniae plus a beta-lactamase-producing pathogen can be treated with another
AUGMENTIN (amoxicillin and clavulanate potassium) product containing lower daily doses of
amoxicillin (i.e., 500 mg every 8 hours or 875 mg every 12 hours). Acute bacterial sinusitis or
community-acquired pneumonia due to S. pneumoniae alone can be treated with amoxicillin.
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
AUGMENTIN XR should be taken at the start of a meal to enhance the absorption of
amoxicillin and to minimize the potential for gastrointestinal intolerance. AUGMENTIN XR is
not recommended to be taken with a high-fat meal because clavulanate absorption is decreased
[see Clinical Pharmacology (12.3)].
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3
2.2 Dosage in Adult Patients
The recommended dosage of AUGMENTIN XR is 4,000 mg/250 mg daily in divided doses
according to the following table:
Table 1: Recommended Dosage of AUGMENTIN XR in Adult Patients
Indication
Dose
Duration
Acute bacterial sinusitis
Two (1,000 mg/62.5 mg)
tablets every 12 hours
10 days
Community‑acquired pneumonia
Two (1,000 mg/62.5 mg)
tablets every 12 hours
7 to 10 days
AUGMENTIN XR can be split in half along the score line for patients with difficulty
swallowing the tablets whole. Both halves of the tablet must be taken immediately.
2.3 Dosage in Pediatric Patients
Pediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose
[see Dosage and Administration (2.2) and Use in Specific Populations (8.4)].
2.4 Dosage in Patients with Hepatic Impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at
regular intervals [see Warnings and Precautions (5.4)].
2.5 Switching between Dosage Forms and between Strengths
AUGMENTIN XR is NOT substitutable on a mg-to-mg basis with other formulations of
AUGMENTIN. In addition, the extended-release tablets provide an extended time course of
plasma amoxicillin concentrations compared to immediate-release tablets. Thus, two
AUGMENTIN 500 mg tablets are not equivalent to one AUGMENTIN XR 1,000 mg tablet.
3 DOSAGE FORMS AND STRENGTHS
•
AUGMENTIN XR Extended-Release Tablets; 1,000 mg/62.5 mg: Each white, oval film-
coated bilayer scored tablet, debossed with AUGMENTIN XR, contains 1,000 mg of
amoxicillin (as amoxicillin sodium and amoxicillin trihydrate) and 62.5 mg clavulanic acid
as the potassium salt.
4 CONTRAINDICATIONS
4.1 Serious Hypersensitivity Reactions
AUGMENTIN XR is contraindicated in patients with a history of serious hypersensitivity
reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to
other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).
4.2 Cholestatic Jaundice/Hepatic Dysfunction
AUGMENTIN XR is contraindicated in patients with a previous history of cholestatic
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jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium.
4.3 Renal Impairment
AUGMENTIN XR is contraindicated in patients with severe renal impairment (creatinine
clearance less than 30 mL/min) and in hemodialysis patients.
5 WARNINGS AND PRECAUTIONS
5.1 Serious Allergic Reactions, Including Anaphylaxis
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in
patients receiving AUGMENTIN XR. These reactions are more likely to occur in individuals
with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.
Before initiating therapy with AUGMENTIN XR, careful inquiry should be made regarding
previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an
allergic reaction occurs, discontinue AUGMENTIN XR and institute appropriate therapy.
5.2 Severe Cutaneous Adverse Reactions
AUGMENTIN XR may cause severe cutaneous adverse reactions (SCAR), such as Stevens-
Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and
systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If
patients develop a skin rash, they should be monitored closely, and AUGMENTIN XR
discontinued if lesions progress.
5.3 Drug-Induced Enterocolitis Syndrome (DIES)
Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a
component of AUGMENTIN XR [see Adverse Reactions (6.2)], with most cases occurring in
pediatric patients ≤ 18 years of age. DIES is a non-IgE mediated hypersensitivity reaction
characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of
skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock,
diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES
occurs, discontinue AUGMENTIN XR and institute appropriate therapy.
5.4 Hepatic Dysfunction
Use AUGMENTIN XR with caution in patients with evidence of hepatic dysfunction. Hepatic
toxicity associated with the use of Augmentin XR is usually reversible. Deaths have been
reported (fewer than one death reported per estimated four million prescriptions worldwide).
These have generally been cases associated with serious underlying diseases or concomitant
medications [see Contraindications (4.2), and Adverse Reactions (6.2)].
5.5 Clostridioides difficile-Associated Diarrhea (CDAD)
Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including AUGMENTIN XR, and may range in severity from mild diarrhea
to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
overgrowth of C. difficile.
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C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-
producing strains of C. difficile cause increased morbidity and mortality, as these infections can
be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in
all patients who present with diarrhea following antibacterial drug use. Careful medical history is
necessary since CDAD has been reported to occur over two months after the administration of
antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C.
difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be
instituted as clinically indicated.
5.6 Skin Rash in Patients with Mononucleosis
A high percentage of patients with mononucleosis who receive amoxicillin develop an
erythematous skin rash. Avoid AUGMENTIN XR use in patients with mononucleosis.
5.7 Potential for Microbial Overgrowth
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind
during therapy. If superinfections occur (usually involving Pseudomonas spp. or Candida spp.),
the drug should be discontinued and/or appropriate therapy instituted.
5.8 Development of Drug-Resistant Bacteria
Prescribing AUGMENTIN XR in the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication is unlikely to provide benefit to the patient and increases
the risk of the development of drug-resistant bacteria.
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•
Anaphylactic reactions [see Warnings and Precautions (5.1)]
•
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
•
Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5.3)]
•
Hepatic Dysfunction [see Warnings and Precautions (5.4)]
•
Clostridioides difficile-associated diarrhea (CDAD) [see Warnings and Precautions (5.5)]
•
Skin Rash in Patients with Mononucleosis [see Warnings and Precautions (5.6)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
In clinical trials, 5,643 patients have been treated with AUGMENTIN XR. The most frequently
reported adverse reactions which were suspected or probably drug-related were diarrhea (15%),
vaginal mycosis (3%), nausea (2%), and loose stools (2%). AUGMENTIN XR had a higher rate
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of diarrhea which required corrective therapy (4% versus 3% for AUGMENTIN XR and all
comparators, respectively). Two percent of patients discontinued therapy because of drug-
related adverse reactions.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of
AUGMENTIN products, including AUGMENTIN XR. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Gastrointestinal: Drug-induced enterocolitis syndrome (DIES), diarrhea, nausea, vomiting,
indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis,
enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis
symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.3,
5.5)].
Immune: Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock),
angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis,
arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and
Precautions (5.1)].
Skin and Appendages: Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS,
AGEP, exfoliative dermatitis, and linear IgA bullous dermatosis [see Warnings and Precautions
(5.1, 5.2, 5.6)].
Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated
with ampicillin-class antibacterials, but the significance of these findings is unknown. Hepatic
dysfunction, including hepatitis and cholestatic jaundice, [see Contraindications (4.2)], increases
in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has
been reported with AUGMENTIN or AUGMENTIN XR. It has been reported more commonly
in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver
biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-
hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or
several weeks after therapy has been discontinued. The hepatic dysfunction, which may be
severe, is usually reversible. Deaths have been reported [see Contraindications (4.2), Warnings
and Precautions (5.4)].
Renal: Interstitial nephritis, hematuria, and crystalluria have been reported [see Overdosage
(10)].
Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia,
thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported
during therapy with penicillins. These reactions are usually reversible on discontinuation of
therapy and are believed to be hypersensitivity phenomena. There have been reports of increased
prothrombin time in patients receiving AUGMENTIN and anticoagulant therapy concomitantly.
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Central Nervous System: Agitation, anxiety, behavioral changes, aseptic meningitis, confusion,
convulsions, dizziness, headache, insomnia, and reversible hyperactivity have been reported.
Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most
reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or
dental cleaning in most cases.
7 DRUG INTERACTIONS
7.1 Probenecid
Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with
AUGMENTIN XR may result in increased and prolonged blood levels of amoxicillin. Co-
administration of probenecid is not recommended.
7.2 Oral Anticoagulants
Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has
been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring
should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose
of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.
7.3 Allopurinol
The concurrent administration of allopurinol and amoxicillin substantially increases the
incidence of rashes in patients receiving both drugs as compared to patients receiving
amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to
allopurinol or the hyperuricemia present in these patients. In controlled clinical trials of
AUGMENTIN XR, 25 patients received concomitant allopurinol and AUGMENTIN XR.
No rashes were reported in these patients. However, this sample size is too small to allow for
any conclusions to be drawn regarding the risk of rashes with concomitant
AUGMENTIN XR and allopurinol use.
7.4 Oral Contraceptives
AUGMENTIN XR may affect intestinal flora, leading to lower estrogen reabsorption and
reduced efficacy of combined oral estrogen/progesterone contraceptives.
7.5 Effects on Laboratory Tests
High urine concentrations of amoxicillin may result in false-positive reactions when
testing for the presence of glucose in urine using CLINITEST®, Benedict’s Solution, or
Fehling’s Solution. Since this effect may also occur with AUGMENTIN XR, it is
recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Following administration of amoxicillin to pregnant women, a transient decrease in plasma
concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol
has been noted.
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8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data from published epidemiologic studies and pharmacovigilance case reports over
several decades of use with amoxicillin and clavulanate during pregnancy have not established a
drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. A study
in women with preterm prelabor rupture of membranes (PPROM) reported that prophylactic
treatment with amoxicillin and clavulanate may be associated with an increased risk of
necrotizing enterocolitis in neonates (see Data). Reproduction studies performed in pregnant
rodents, given oral doses up to approximately 1.6 times the amount of amoxicillin and 13 times
the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) of
AUGMENTIN XR, revealed no evidence of harm to the fetus (see Data).
The background risk of major birth defects and miscarriage for the indicated populations is
unknown. All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
One randomized, controlled trial included 4,826 pregnant women with premature rupture of fetal
membranes who were randomly assigned to 250 mg erythromycin (n=1,197), 250 mg amoxicillin
and 125 mg clavulanic acid (amoxicillin and clavulanate, n=1,212), amoxicillin and clavulanate
and erythromycin (n=1,192), or placebo (n=1,225) four times daily for 10 days or until delivery.
Amoxicillin and clavulanate was associated with a significantly increased rate of proven neonatal
necrotizing enterocolitis: 1.9% (n = 24) in the amoxicillin and clavulanate only group versus
0.5% (n = 6) in the placebo group (p = 0.001), and 1.8% (n = 44) in the any amoxicillin and
clavulanate group versus 0.7% (n =17) in the no amoxicillin and clavulanate group (p = 0.0005).
Animal Data
Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate (2:1
ratio formulation) at oral doses up to 1,200 mg/kg/day revealed no evidence of harm to the fetus
due to amoxicillin and clavulanate. In terms of body surface area, the doses in rats were 1.6
times the Maximum Human Recommended Dose (MHRD) of amoxicillin and 13 times the
MHRD for clavulanate in AUGMENTIN XR. For mice, these doses were 0.9 and 7.4 times the
MHRD of amoxicillin and clavulanate, respectively.
8.2 Lactation
Risk Summary
Data from a published clinical lactation study report that amoxicillin is present in human milk.
There are reports of diarrhea, irritability, and rash in infants exposed to amoxicillin and
clavulanate through breast milk; therefore, infants exposed to AUGMENTIN XR should be
monitored for these symptoms. There are no data on the effects of amoxicillin and clavulanate on
milk production. The developmental and health benefits of breastfeeding should be considered
along with the mother’s clinical need for AUGMENTIN XR and any potential adverse effects on
the breastfed child from AUGMENTIN XR or from the underlying maternal condition.
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8.4 Pediatric Use
The safety and effectiveness of AUGMENTIN XR have been established for pediatric patients
weighing greater than or equal to 40 kg who are able to swallow tablets. Use of
AUGMENTIN XR in these pediatric patients is supported by evidence from adequate and well-
controlled trials of adults with acute bacterial sinusitis and community-acquired pneumonia with
additional data from a pediatric pharmacokinetic study.
A pharmacokinetic study in pediatric patients (7 to 15 years of age and weighing greater than or
equal to 40 kg) was conducted [see Clinical Pharmacology (12.3)]. The adverse event profile in
44 pediatric patients who received at least one dose of AUGMENTIN XR was consistent with
the established adverse event profile for the product in adults.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of AUGMENTIN XR, 18% were 65 years or
older and 7% were 75 years or older. No overall differences in safety and effectiveness were
observed between these subjects and younger subjects, and other clinical experience has not
reported differences in responses between the elderly and younger patients, but a greater
sensitivity of some older individuals cannot be ruled out.
AUGMENTIN XR is known to be substantially excreted by the kidney, and the risk of dose
dependent toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, it may be useful to
monitor renal function.
8.6 Renal Impairment
The pharmacokinetics of AUGMENTIN XR have not been studied in patients with renal
impairment. AUGMENTIN XR is contraindicated in patients with a creatinine clearance of less
than 30 mL/min and in hemodialysis patients [see Contraindications (4.3)].
8.7 Hepatic Impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at
regular intervals [see Contraindications (4.2), Warnings and Precautions (5.4)].
10 OVERDOSAGE
Following overdosage, patients have experienced primarily gastrointestinal symptoms including
stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have
also been observed in a small number of patients.
In the case of overdosage, discontinue AUGMENTIN XR, treat symptomatically, and institute
supportive measures as required. If the overdosage is very recent and there is no
contraindication, an attempt at emesis or other means of removal of drug from the stomach may
be performed. A prospective study of 51 pediatric patients at a poison control center suggested
that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant
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clinical symptoms and do not require gastric emptying.1
Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of
patients after overdosage with amoxicillin.
Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin
overdosage in adult and pediatric patients. In the case of overdosage, adequate fluid intake and
diuresis should be maintained to reduce the risk of amoxicillin crystalluria.
Renal impairment appears to be reversible with cessation of drug administration. High blood
levels may occur more readily in patients with impaired renal function because of decreased
renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are
removed from the circulation by hemodialysis.
11 DESCRIPTION
AUGMENTIN XR is an oral antibacterial combination consisting of the semisynthetic
antibacterial amoxicillin (present as amoxicillin sodium and amoxicillin trihydrate) and the beta-
lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is
an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The
amoxicillin trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is
419.45.
Chemically, amoxicillin trihydrate is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-
hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic
acid trihydrate and may be represented structurally as:
The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is
387.39. Chemically, amoxicillin sodium is [2 -[2α,5α,6β(S*)]]-6-[[Amino (4-
hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-
carboxylic acid monosodium salt and may be represented structurally as:
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Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam
structurally related to the penicillins and possesses the ability to inactivate a wide variety of
beta-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly
active against the clinically important plasmid-mediated beta-lactamases frequently responsible
for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium
molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate
potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-
heptane-2-carboxylate, and may be represented structurally as:
Each tablet of AUGMENTIN XR contains 1,000 mg of amoxicillin (437.5 mg of amoxicillin
equivalent to 463.8 mg of amoxicillin sodium and 562.5 mg of amoxicillin in the form of
amoxicillin trihydrate), and 62.5 mg of clavulanic acid (equivalent to 74.5 mg of clavulanate
potassium).
Inactive Ingredients: Citric acid, colloidal silicon dioxide, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and
xanthan gum.
Each tablet of AUGMENTIN XR contains approximately 13 mg of potassium and 30 mg of
sodium.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
AUGMENTIN XR is an antibacterial drug [see Microbiology (12.4)].
12.3 Pharmacokinetics
Reference ID: 5500276
12
AUGMENTIN XR is an extended-release formulation which provides sustained plasma
concentrations of amoxicillin. Amoxicillin systemic exposure achieved with AUGMENTIN XR
is similar to that produced by the oral administration of equivalent doses of amoxicillin alone.
Absorption
Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after
oral administration of AUGMENTIN XR.
In a study of healthy adult volunteers, the pharmacokinetics of AUGMENTIN XR were
compared when administered in a fasted state, at the start of a standardized meal (612 kcal, 89.3
g carb, 24.9 g fat, and 14 g protein), or 30 minutes after a high‑fat meal.
When the systemic exposure to both amoxicillin and clavulanate is taken into consideration,
AUGMENTIN XR is optimally administered at the start of a standardized meal. Absorption of
amoxicillin is decreased in the fasted state. AUGMENTIN XR is not recommended to be taken
with a high‑fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the
components of AUGMENTIN XR following administration of two AUGMENTIN XR tablets at
the start of a standardized meal are presented in Table 2.
Table 2: Mean (SD) Pharmacokinetic Parameter for Amoxicillin and Clavulanate
Following Oral Administration of Two AUGMENTIN XR Tablets (2,000 mg/125 mg) to
Healthy Adult Volunteers (n = 55) Fed a Standardized Meal
a Median (range)
The half-life of amoxicillin after the oral administration of AUGMENTIN XR is approximately
1.3 hours, and that of clavulanate is approximately 1.0 hour.
Distribution
Neither component in AUGMENTIN XR is highly protein‑bound; clavulanate has been found to
be approximately 25% bound to human serum and amoxicillin approximately 18% bound.
Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain
and spinal fluid. The results of experiments involving the administration of clavulanic acid to
animals suggest that this compound, like amoxicillin, is well distributed in body tissues.
Excretion
Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose
being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to
Parameter (units)
Amoxicillin
Clavulanate
AUC(0‑inf) (mcg•hr/mL)
71.6 (16.5)
5.29 (1.55)
Cmax (mcg/mL)
17.0 (4.0)
2.05 (0.80)
Tmax (hours)a
1.50 (1.00 to 6.00)
1.03 (0.75 to 3.00)
T1/2 (hours)
1.27 (0.20)
1.03 (0.17)
Reference ID: 5500276
13
50%) and a non‑renal component.
Specific Populations
Pediatric Patients
In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing
at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following
administration of AUGMENTIN XR 2,000 mg/125 mg (as two 1,000 mg/62.5 mg tablets) every
12 hours with food (Table 3).
Table 3: Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate
Following Oral Administration of Two AUGMENTIN XR Tablets (2,000 mg/125 mg)
Every 12 Hours with Food to Pediatric Patients (7 to 15 Years of Age and Weighing greater
than or equal to 40 kg) With Acute Bacterial Sinusitis
Parameter (units)
Amoxicillin
(n = 24)
Clavulanate
(n = 23)
AUC(0‑τ) (mcg•hr/mL)
57.8 (15.6)
3.18 (1.37)
Cmax (mcg/mL)
11.0 (3.34)
1.17 (0.67)
Tmax (hours)a
2.0 (1.0 to 5.0)
2.0 (1.0 to 4.0)
T1/2(hours)
3.32 (2.21)b
0.94 (0.13)c
a Median (range).
b n equals 18.
c n equals 17.
Drug Interaction Studies
Clinical Studies
Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal
excretion of clavulanate [see Drug Interactions (7.1)].
In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were not affected by
administration of an antacid (MAALOX®), either simultaneously with or 2 hours after
AUGMENTIN XR.
12.4 Microbiology
Mechanism of Action
Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits
bacterial cell wall synthesis.
Clavulanic acid is a beta-lactam, structurally related to penicillin, that may inactivate certain
beta‑lactamase enzymes.
Resistance
Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-
lactamase, altered affinity of penicillin for target, or decreased penetration of the antibacterial
drug to reach the target site. Amoxicillin alone is susceptible to degradation by beta‑lactamases,
and therefore its spectrum of activity does not include bacteria that produce these enzymes.
Reference ID: 5500276
14
Antimicrobial Activity
Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following
microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria:
Staphylococcus aureus (methicillin-susceptible)
Streptococcus pneumoniae
Gram-negative bacteria:
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
The following in vitro data are available, but their clinical significance is unknown. At least 90
percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC)
less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid against
isolates of similar genus or organism group. However, the efficacy of amoxicillin and clavulanic
acid in treating clinical infections caused by these bacteria have not been established in adequate
and well‑controlled clinical trials.
Gram-positive bacteria:
Streptococcus pyogenes
Susceptibility Testing:
For specific information regarding susceptibility test interpretive criteria and associated test
methods and quality control standards recognized by FDA for this drug, please see:
https://www.fda.gov/STIC.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Amoxicillin and clavulanate (4:1 ratio formulation of amoxicillin:clavulanate) was non-
mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay.
Amoxicillin and clavulanate was weakly positive in the mouse lymphoma assay, but the trend
toward increased mutation frequencies in this assay occurred at concentrations that were also
associated with decreased cell survival. Amoxicillin and clavulanate was negative in the mouse
micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was
tested in the Ames bacterial mutation assay and in the mouse micronucleus test and was negative
in each of these assays.
Amoxicillin and clavulanate (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up
to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats.
Reference ID: 5500276
15
Based on body surface area, this dose of amoxicillin is approximately 1.6 times the Maximum
Human Recommended Dose (MHRD) in AUGMENTIN XR and the clavulanate dose multiple is
approximately 13 times higher than the MHRD.
14 CLINICAL STUDIES
14.1 Acute Bacterial Sinusitis
Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In
one study, 363 patients were randomized to receive either AUGMENTIN XR 2,000 mg/125 mg
orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double‑blind,
multicenter, prospective trial. These patients were clinically and radiologically evaluated at the
test of cure (day 17 to 28) visit. The combined clinical and radiological responses were 84% for
AUGMENTIN XR and 84% for levofloxacin at the test of cure visit in clinically evaluable
patients (95% CI for the treatment difference equals ‑9.4, 8.3). The clinical response rates at the
test of cure were 87% and 89%, respectively.
The other 2 trials were non‑comparative, multicenter studies designed to assess the
bacteriological and clinical efficacy of AUGMENTIN XR (2,000 mg/125 mg orally every 12
hours for 10 days) in the treatment of 2,288 patients with ABS. Evaluation timepoints were the
same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to
receiving study medication. Patients with acute bacterial sinusitis due to S. pneumoniae with
reduced susceptibility to penicillin were accrued through enrollment in these 2 open‑label
non‑comparative clinical trials. Microbiologic eradication rates for key pathogens in these
studies are shown in Table 4.
Table 4: Clinical Outcome for ABS
Penicillin MICs of S. pneumoniae
Isolates
Intent-To-Treat
Clinically Evaluable
n/Na
% 95% CIb
n/Na
% 95% CIb
All S. pneumoniae
344/370 93
—
318/326 98
—
MIC greater than or equal to
2.0 mcg/mLc
35/36
97 85.5, 99.9
30/31
96 83.3, 99.9
MIC equal to 2.0 mcg/mL
23/24
96 78.9, 99.9
19/20
95 75.1, 99.9
MIC greater than or equal to
4.0 mcg/mLd
12/12 100 73.5, 100
11/11 100 71.5, 100
H. influenzae
265/305 87
—
242/259 93
—
M. catarrhalis
94/105 90
—
86/90
96
—
a n/N equals patients with pathogen eradicated or presumed eradicated/total number of patients.
b Confidence limits calculated using exact probabilities.
c S. pneumoniae strains with penicillin MICs of greater than or equal to 2 mcg/mL are considered resistant to
penicillin.
d Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL.
14.2 Community-Acquired Pneumonia
Four randomized, controlled, double‑blind clinical studies and one non‑comparative study were
conducted in adults with community-acquired pneumonia (CAP). In comparative
Reference ID: 5500276
16
studies, 904 patients received AUGMENTIN XR at a dose of 2,000 mg/125 mg orally every 12
hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological
efficacy, 1,122 patients received AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours for
7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged
from 86% to 95% in clinically evaluable patients who received AUGMENTIN XR.
Data on the efficacy of AUGMENTIN XR in the treatment of community‑acquired pneumonia
due to S. pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled
clinical studies and the 1 non‑comparative study. The majority of these cases were accrued from
the non‑comparative study. Results are shown in Table 5.
Table 5: Clinical Outcome for CAP due to S. pneumoniae
Penicillin MICs of S.
pneumoniae Isolates
Intent-To-Treat
Clinically Evaluable
n/Na
%
95% CIb
n/Na
%
95% CIb
All S. pneumoniae
318/367
87
—
275/297
93
—
MIC greater than or equal to
2.0 mcg/mLc
30/35
86
69.7, 95.2
24/25
96
79.6, 99.9
MIC equal to 2.0 mcg/mL
22/24
92
73.0, 99.0
18/18
100
81.5, 100
MIC greater than or equal to
4.0 mcg/mLd
8/11
73
39.0, 94.0
6/7
86
42.1, 99.6
a n/N equals patients with pathogen eradicated or presumed eradicated/total number of patients.
b Confidence limits calculated using exact probabilities.
c S. pneumoniae strains with penicillin MICs of greater than or equal to 2 mcg/mL are considered resistant to
penicillin.
d Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent‑To‑Treat group only.
15 REFERENCES
1.
Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and
cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;
30:66-67.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
AUGMENTIN XR (amoxicillin and clavulanate potassium) extended-release tablets are white,
oval film‑coated bilayer scored tablets and debossed with “AUGMENTIN XR”. Each tablet
contains 1,000 mg of amoxicillin (as amoxicillin sodium and amoxicillin trihydrate) and 62.5 mg
clavulanic acid as the potassium salt.
AUGMENTIN XR is supplied as follows:
• NDC 81964‑020‑28 Bottles of 28 (7-day XR pack)
• NDC 81964‑020‑40 Bottles of 40 (10-day XR pack)
Storage
Store tablets at or below 25°C (77°F). Dispense in original container.
Reference ID: 5500276
17
17 PATIENT COUNSELING INFORMATION
Administration Instructions
Counsel patients to take AUGMENTIN XR every 12 hours with a low fat meal or snack to
reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more
than 2 or 3 days, they should call their doctor [see Dosage and Administration (2.1), Warnings
and Precautions (5.5)].
Allergic Reactions
Counsel patients that AUGMENTIN XR contains a penicillin class drug product that can cause
allergic reactions in some individuals [see Warnings and Precautions (5.1, 5.3)].
Severe Cutaneous Adverse Reactions (SCAR)
Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to
stop taking AUGMENTIN XR immediately and promptly report the first signs or symptoms of
skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions
(5.2)].
Diarrhea
Counsel patients that diarrhea is a common problem caused by antibacterial drugs, including
AUGMENTIN XR, which usually ends when the antibacterial drug is discontinued. Sometimes
after starting treatment with antibacterial drugs, patients can develop watery and bloody stools
(with or without stomach cramps and fever) even as late as 2 or more months after having taken
their last dose of the antibacterial drug. If diarrhea is severe or lasts more than 2 or 3 days,
patients should contact their physician as soon as possible [see Warnings and Precautions
(5.5)].
Antibacterial Resistance
Patients should be counseled that antibacterial drugs, including AUGMENTIN XR, should only
be used to treat bacterial infections. Antibacterial drugs do not treat viral infections (e.g., the
common cold). When AUGMENTIN XR is prescribed to treat a bacterial infection, patients
should be told that although it is common to feel better early in the course of therapy, the
medication should be taken exactly as directed. Skipping doses or not completing the full course
of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the
likelihood that bacteria will develop resistance and will not be treatable by AUGMENTIN XR
or other antibacterial drugs in the future [see Warnings and Precautions (5.8)].
Manufactured by:
USAntibiotics, LLC
Bristol, TN 37620 (USA)
AUGMENTIN XR and AUGMENTIN are registered trademarks of GlaxoSmithKline and are
licensed to USAntibiotics, LLC
MAALOX is a registered trademark of Novartis Consumer Health, Inc.
Reference ID: 5500276
18
CLINITEST is a registered trademark of Miles, Inc.
Reference ID: 5500276
| custom-source | 2025-02-12T15:48:11.606549 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/050785s019lbl.pdf', 'application_number': 50785, 'submission_type': 'SUPPL ', 'submission_number': 19} |
80,735 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PYZCHIVA safely and effectively. See full prescribing information for
PYZCHIVA.
PYZCHIVA® (ustekinumab-ttwe) injection, for subcutaneous or
intravenous use
Initial U.S. Approval: 2024
PYZCHIVA (ustekinumab-ttwe) is biosimilar* to STELARA (ustekinumab)
-----------------------------INDICATIONS AND USAGE-------------------------
PYZCHIVA is a human interleukin-12 and -23 antagonist indicated for the
treatment of:
Adult patients with:
•
moderate to severe plaque psoriasis (PsO) who are candidates for
phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
•
moderately to severely active Crohn's disease (CD). (1.3)
•
moderately to severely active ulcerative colitis. (1.4)
Pediatric patients 6 years and older with:
•
moderate to severe plaque psoriasis, who are candidates for
phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
------------------------DOSAGE AND ADMINISTRATION---------------------
Psoriasis Adult Subcutaneous Recommended Dosage (2.1):
Weight Range (kilograms)
Recommended Dosage
less than or equal to 100 kg
45 mg administered subcutaneously
initially and 4 weeks later,
followed by 45 mg administered
subcutaneously every 12 weeks
greater than 100 kg
90 mg administered subcutaneously
initially and 4 weeks later,
followed by 90 mg administered
subcutaneously every 12 weeks
Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended
Dosage (2.1):
Weight-based dosing is recommended at the initial dose, 4 weeks later, then
every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
greater than 100 kg
90 mg
Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):
•
The recommended dosage is 45 mg administered subcutaneously
initially and 4 weeks later, followed by 45 mg administered
subcutaneously every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis
weighing greater than 100 kg, the recommended dosage is 90 mg
administered subcutaneously initially and 4 weeks later, followed by 90
mg administered subcutaneously every 12 weeks.
Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended
Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4
weeks later, then every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co
existent moderate-to-severe plaque
psoriasis
90 mg
Crohn's Disease and Ulcerative Colitis Initial Adult Intravenous
Recommended Dosage (2.3): A single intravenous infusion using weight-
based dosing:
Weight Range (kilograms)
Dose
up to 55 kg
260 mg (2 vials)
greater than 55 kg to 85 kg
390 mg (3 vials)
greater than 85 kg
520 mg (4 vials)
Crohn's Disease and Ulcerative Colitis Maintenance Adult Subcutaneous
Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the
initial intravenous dose, then every 8 weeks thereafter.
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Subcutaneous Injection (3)
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled
syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
Intravenous Infusion (3)
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
-------------------------------CONTRAINDICATIONS-----------------------------
•
Clinically significant hypersensitivity to ustekinumab products or to any
of the excipients in PYZCHIVA. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
•
Infections: Serious infections have occurred. Avoid starting
PYZCHIVA during any clinically important active infection. If a
serious infection or clinically significant infection develops, discontinue
PYZCHIVA until the infection resolves. (5.1)
•
Theoretical Risk for Particular Infections: Serious infections from
mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG)
vaccinations have been reported in patients genetically deficient in IL
12/IL-23. Consider diagnostic tests for these infections as dictated by
clinical circumstances. (5.2)
•
Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment
with PYZCHIVA. Initiate treatment of latent TB before administering
PYZCHIVA. (5.3)
•
Malignancies: Ustekinumab products may increase risk of malignancy.
The safety of ustekinumab products in patients with a history of or a
known malignancy has not been evaluated. (5.4)
•
Hypersensitivity Reactions: If an anaphylactic or other clinically
significant hypersensitivity reaction occurs, institute appropriate therapy
and discontinue PYZCHIVA. (5.5)
•
Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is
suspected, treat promptly and discontinue PYZCHIVA. (5.6)
•
Immunizations: Avoid use of live vaccines in patients during treatment
with PYZCHIVA. (5.7)
•
Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic
pneumonia and cryptogenic organizing pneumonia have been reported
during post-approval use of ustekinumab products. If diagnosis is
confirmed, discontinue PYZCHIVA and institute appropriate treatment.
(5.8)
-------------------------------ADVERSE REACTIONS-----------------------------
Most common adverse reactions are:
•
Psoriasis QDVRSKDU\QJLWLVXSSHUUHVSLUDWRU\WUDFWLQIHFWLRQ
headache, and fatigue. (6.1)
•
Crohn's Disease, induction YRPLWLQJ
•
Crohn's Disease, maintenance QDVRSKDU\QJLWLVLQMHFWLRQVLWH
erythema, vulvovaginal candidiasis/mycotic infection, bronchitis,
pruritus, urinary tract infection, and sinusitis. (6.1)
•
Ulcerative colitis, induction QDVRSKDU\QJLWLV
•
Ulcerative colitis, maintenance QDVRSKDU\QJLWLVKHDGDFKH
abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at
1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
*Biosimilar means that the biological product is approved based on data
demonstrating that it is highly similar to an FDA-approved biological product,
known as a reference product, and that there are no clinically meaningful
differences between the biosimilar product and the reference product.
Biosimilarity of PYZCHIVA has been demonstrated for the condition(s) of
use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and
route(s) of administration described in its Full Prescribing Information
Revised: 12/2024
Reference ID: 5500909
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Plaque Psoriasis (PsO)
1.2 Psoriatic Arthritis (PsA)
1.3 Crohn's Disease (CD)
1.4 Ulcerative Colitis
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage in Plaque Psoriasis
2.2 Recommended Dosage in Psoriatic Arthritis
2.3 Recommended Dosage in Crohn's Disease and Ulcerative Colitis
2.4 General Considerations for Administration
2.5 Instructions for Administration of PYZCHIVA Prefilled Syringes
Equipped with Needle Safety Guard
2.6 Preparation and Administration of PYZCHIVA 130 mg/26 mL (5
mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative
Colitis)
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Infections
5.2 Theoretical Risk for Vulnerability to Particular Infections
5.3 Pre-treatment Evaluation for Tuberculosis
5.4 Malignancies
5.5 Hypersensitivity Reactions
5.6 Posterior Reversible Encephalopathy Syndrome (PRES)
5.7 Immunizations
5.8 Noninfectious Pneumonia
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Concomitant Therapies
7.2 CYP450 Substrates
7.3 Allergen Immunotherapy
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Adult Plaque Psoriasis
14.2 Pediatric Plaque Psoriasis
14.3 Psoriatic Arthritis
14.4 Crohn's Disease
14.5 Ulcerative Colitis
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5500909
1
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Plaque Psoriasis (PsO)
PYZCHIVA is indicated for the treatment of adults and pediatric patients 6 years of age and older with
moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
1.2
Psoriatic Arthritis (PsA)
PYZCHIVA is indicated for the treatment of adults and pediatric patients 6 years of age and older with
active psoriatic arthritis.
1.3
Crohn's Disease (CD)
PYZCHIVA is indicated for the treatment of adult patients with moderately to severely active Crohn's
disease.
1.4
Ulcerative Colitis
PYZCHIVA is indicated for the treatment of adult patients with moderately to severely active ulcerative
colitis.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage in Plaque Psoriasis
Subcutaneous Adult Dosage Regimen
•
For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks
later, followed by 45 mg every 12 weeks.
•
For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks
later, followed by 90 mg every 12 weeks.
In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg
resulted in greater efficacy in these subjects [see Clinical Studies (14)].
Subcutaneous Pediatric Dosage Regimen
Administer PYZCHIVA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of PYZCHIVA for pediatric patients (6–17 years old) with plaque psoriasis
based on body weight is shown below (Table 1).
Reference ID: 5500909
Table 1:
Recommended Dose of PYZCHIVA for Subcutaneous Injection in Pediatric Patients (6–17 years old)
with Plaque Psoriasis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
more than 100 kg
90 mg
For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose
(0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the single-dose vial.
Table 2:
Injection volumes of PYZCHIVA45 mg/0.5 mL single-dose vials for pediatric patients (6–17 years
old) with plaque psoriasis and pediatric patients (6-17 years old) with psoriatic arthritis
* weighing less
than 60 kg
Body Weight (kg) at the time of
dosing
Dose (mg)
Volume of injection (mL)
15
11.3
0.12
16
12
0.13
17
12.8
0.14
18
13.5
0.15
19
14.3
0.16
20
15
0.17
21
15.8
0.17
22
16.5
0.18
23
17.3
0.19
24
18
0.20
25
18.8
0.21
26
19.5
0.22
27
20.3
0.22
28
21
0.23
29
21.8
0.24
30
22.5
0.25
31
23.3
0.26
32
24
0.27
33
24.8
0.27
34
25.5
0.28
35
26.3
0.29
36
27
0.30
37
27.8
0.31
38
28.5
0.32
39
29.3
0.32
40
30
0.33
41
30.8
0.34
42
31.5
0.35
43
32.3
0.36
44
33
0.37
45
33.8
0.37
46
34.5
0.38
47
35.3
0.39
48
36
0.40
49
36.8
0.41
50
37.5
0.42
51
38.3
0.42
52
39
0.43
53
39.8
0.44
54
40.5
0.45
55
41.3
0.46
Reference ID: 5500909
56
42
0.46
57
42.8
0.47
58
43.5
0.48
59
44.3
0.49
* Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen.
2.2
Recommended Dosage in Psoriatic Arthritis
Subcutaneous Adult Dosage Regimen
•
The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the
recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
Subcutaneous Pediatric Dosage Regimen
Administer PYZCHIVA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of PYZCHIVA for pediatric patients (6 to 17 years old) with psoriatic arthritis,
based on body weight, is shown below (Table 3).
Table 3:
Recommended Dose of PYZCHIVA for Subcutaneous Injection in Pediatric Patients (6 to 17 years
old) with Psoriatic Arthritis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg*
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co-existent moderate-to-severe plaque
90 mg
psoriasis
* For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the
appropriate volume from the single-dose vial.
2.3
Recommended Dosage in Crohn's Disease and Ulcerative Colitis
Intravenous Induction Adult Dosage Regimen
A single intravenous infusion dose of PYZCHIVA using the weight-based dosage regimen specified in
Table 4 [see Dosage and Administration (2.6)].
Reference ID: 5500909
Table 4:
Initial Intravenous Dosage of PYZCHIVA
Body Weight of Patient at the time of dosing
Dose
Number of 130 mg/26 mL
(5 mg/mL) PYZCHIVA vials
55 kg or less
260 mg
2
more than 55 kg to 85 kg
390 mg
3
more than 85 kg
520 mg
4
Subcutaneous Maintenance Adult Dosage Regimen
The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the
initial intravenous dose, then every 8 weeks thereafter.
2.4
General Considerations for Administration
•
PYZCHIVA is intended for use under the guidance and supervision of a healthcare provider.
PYZCHIVA should only be administered to patients who will be closely monitored and have
regular follow-up visits with a healthcare provider. The appropriate dose should be determined by
a healthcare provider using the patient's current weight at the time of dosing. In pediatric patients,
it is recommended that PYZCHIVA be administered by a healthcare provider. If a healthcare
provider determines that it is appropriate, a patient may self-inject or a caregiver may inject
PYZCHIVA after proper training in subcutaneous injection technique. Instruct patients to follow
the directions provided in the Medication Guide [see Medication Guide].
•
It is recommended that each injection be administered at a different anatomic location (such as
upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and
not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-
dose vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended.
•
Prior to administration, visually inspect PYZCHIVA for particulate matter and discoloration.
PYZCHIVA is a clear, colorless to light yellow, sterile and preservative-free solution. Do not use
PYZCHIVA if it is discolored or cloudy, or if other particulate matter is present. PYZCHIVA does
not contain preservatives; therefore, discard any unused product remaining in the vial and/or
syringe.
Reference ID: 5500909
Viewing window
Body
Needle guard wings
Plunger
Needle cover
Needle
Label
Plunger head
2.5
Instructions for Administration of PYZCHIVA Prefilled Syringes Equipped with Needle
Safety Guard
Refer to the diagram below for the provided instructions.
•
Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER
HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the
prefilled syringe if it is dropped without the NEEDLE COVER in place.
•
Inject PYZCHIVA subcutaneously as recommended [see Dosage and Administration (2.1, 2.2,
2.3)].
•
Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is
completely between the needle guard wings. Injection of the entire prefilled syringe contents is
necessary to activate the needle guard.
•
After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the
skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up
until the entire needle is covered by the needle guard, as shown by the illustration below:
Reference ID: 5500909
•
Used syringes should be placed in a puncture-resistant container.
2.6
Preparation and Administration of PYZCHIVA 130 mg/26 mL (5 mg/mL) Vial for
Intravenous Infusion (Crohn's Disease and Ulcerative Colitis)
PYZCHIVA solution for intravenous infusion must be diluted, prepared and infused by a healthcare
professional using aseptic technique.
1.
Calculate the dose and the number of PYZCHIVA vials needed based on patient weight (Table 4).
Each 26 mL vial of PYZCHIVA contains 130 mg of ustekinumab-ttwe.
2.
:LWKGUDZDQGWKHQGLVFDUGDYROXPHRIWKH 6RGLXP&KORULGH,QMHFWLRQ863IURPWKH
250 mL infusion bag equal to the volume of PYZCHIVA to be added (discard 26 mL sodium
chloride for each vial of PYZCHIVA needed, for 2 vials- discard 52 mL, for 3 vials- discard 78
mL, 4 vials- GLVFDUGP/ $OWHUQDWLYHO\DP/LQIXVLRQEDJFRQWDLQLQJ6RGLXP
Chloride Injection, USP may be used.
3.
Withdraw 26 mL of PYZCHIVA from each vial needed and add it to the 250 mL infusion bag.
The final volume in the infusion bag should be 250 mL. Gently mix. Protect from light.
4.
Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles,
discoloration or foreign particles are observed.
5.
Infuse the diluted solution over a period of at least one hour. Once diluted in the infusion bag, the
infusion should be completely administered within 36 hours at room temperature up to 30°C
(86°F) .
6.
Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore
size 0.2 micrometer).
7.
Do not infuse PYZCHIVA concomitantly in the same intravenous line with other agents.
8.
PYZCHIVA does not contain preservatives. Each vial is for one-time use in only one patient.
Discard any remaining solution. Dispose any unused medicinal product in accordance with local
requirements.
Reference ID: 5500909
Storage
•
The diluted infusion solution may be kept at room temperature up to 30°C (86°F) for up to 36
hours including infusion period.
•
If necessary, the diluted infusion solution may be stored refrigerated at 2ºC to 8ºC (36ºF to
46ºF) for up to 15 days. After removal from refrigeration, the diluted solution may be stored at
room temperature at up to 30°C (86°F) for an additional 24 hours including infusion period.
Storage time at refrigerated or room temperature begins once the diluted solution has been
prepared. Do not freeze. Protect from light. Discard any unused portion of the infusion solution.
3
DOSAGE FORMS AND STRENGTHS
PYZCHIVA (ustekinumab-ttwe) is a clear, colorless to light yellow, sterile and preservative-free
solution.
Subcutaneous Injection
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
Intravenous Infusion
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
4
CONTRAINDICATIONS
PYZCHIVA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab
products or to any of the excipients in PYZCHIVA [see Warnings and Precautions (5.5)].
5
WARNINGS AND PRECAUTIONS
5.1
Infections
Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious
bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab
products [see Adverse Reactions (6.1, 6.3)].
Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in
clinical trials included the following:
•
Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis,
osteomyelitis, viral infections, gastroenteritis and urinary tract infections.
•
Psoriatic arthritis: cholecystitis.
•
Crohn's disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria
meningitis.
•
Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.
Reference ID: 5500909
Avoid initiating treatment with PYZCHIVA in patients with any clinically important active infection
until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to
initiating use of PYZCHIVA in patients with a chronic infection or a history of recurrent infection.
Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on
treatment with PYZCHIVA and discontinue PYZCHIVA for serious or clinically significant infections
until the infection resolves or is adequately treated.
5.2
Theoretical Risk for Vulnerability to Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections
from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including
nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal
outcomes have been reported in such patients.
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with
ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic
testing (e.g., tissue culture, stool culture, as dictated by clinical circumstances).
5.3
Pre-treatment Evaluation for Tuberculosis
Evaluate patients for tuberculosis infection prior to initiating treatment with PYZCHIVA.
Avoid administering PYZCHIVA to patients with active tuberculosis infection. Initiate treatment of
latent tuberculosis prior to administering PYZCHIVA. Consider anti-tuberculosis therapy prior to
initiation of PYZCHIVA in patients with a past history of latent or active tuberculosis in whom an
adequate course of treatment cannot be confirmed. Closely monitor patients receiving PYZCHIVA for
signs and symptoms of active tuberculosis during and after treatment.
5.4
Malignancies
Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies
were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)].
In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical
Toxicology (13)].
The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy
or who have a known malignancy.
There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell
carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing
non-melanoma skin cancer. Monitor all patients receiving PYZCHIVA for the appearance of non-
melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history
of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse
Reactions (6.1)].
Reference ID: 5500909
5.5
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with
ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically
significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue PYZCHIVA.
5.6
Posterior Reversible Encephalopathy Syndrome (PRES)
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior
Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported
in postmarketing experience in patients with psoriasis, psoriatic arthritis and Crohn's disease. Clinical
presentation included headaches, seizures, confusion, visual disturbances, and imaging changes
consistent with PRES a few days to several months after ustekinumab product initiation. A few cases
reported latency of a year or longer. Patients recovered with supportive care following withdrawal of
ustekinumab products.
Monitor all patients treated with PYZCHIVA for signs and symptoms of PRES. If PRES is suspected,
promptly administer appropriate treatment and discontinue PYZCHIVA.
5.7
Immunizations
Prior to initiating therapy with PYZCHIVA, patients should receive all age-appropriate immunizations
as recommended by current immunization guidelines. Patients being treated with PYZCHIVA should
avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with PYZCHIVA or
for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is
advised when administering live vaccines to household contacts of patients receiving PYZCHIVA
because of the potential risk for shedding from the household contact and transmission to patient.
Non-live vaccinations received during a course of PYZCHIVA may not elicit an immune response
sufficient to prevent disease.
5.8
Noninfectious Pneumonia
Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have
been reported during post-approval use of ustekinumab products. Clinical presentations included cough,
dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included
respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and
in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue PYZCHIVA and
institute appropriate treatment [see Adverse Reactions (6.3)].
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the label:
•
Infections [see Warnings and Precautions (5.1)]
•
Malignancies [see Warnings and Precautions (5.4)]
Reference ID: 5500909
•
Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
•
Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]
•
Noninfectious Pneumonia [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Adult Subjects with Plaque Psoriasis
The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including
2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two
years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at
least five years.
Table 5 VXPPDUL]HVWKHDGYHUVHUHDFWLRQVWKDWRFFXUUHGDWDUDWHRIDWOHDVWwith higher rates in the
ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see
Clinical Studies (14)].
Table 5:
$GYHUVH5HDFWLRQV5HSRUWHGE\RI6XEMHFWV with Plaque Psoriasis and at Higher Rates in the
Ustekinumab Groups through Week 12 in Ps STUDY 1 and Ps STUDY 2
Ustekinumab
Placebo
45 mg
90 mg
Subjects treated
665
664
666
Nasopharyngitis
Upper respiratory tract infection
Headache
Fatigue
Back pain
Dizziness
Pharyngolaryngeal pain
Pruritus
Injection site erythema
Myalgia
8
Depression
$GYHUVHUHDFWLRQVWKDWRFFXUUHGDWUDWHVOHVVWKDQLQWKHcontrolled period of Ps STUDIES 1 and 2
through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions
(pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).
One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions
(5.6)].
Reference ID: 5500909
Infections
In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of
12.6 weeks for placebo-treated subjects and 13.4 weeks for ustekinumab-WUHDWHGVXEMHFWV RI
ustekinumab-treated subjects reported infections (1.39 per subject-year of follow-up) compared with
RISODFHER-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in
RIustekinumab-treated subjects (0.01 per subject-year of follow-XS DQGLQRISODFHER
treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)].
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2
years), representing 8998 subject-\HDUVRIH[SRVXUHRIustekinumab-treated subjects reported
infections (0.87 per subject-years of follow-XS 6HULRXVLQIHFWLRQVZHUHUHSRUWHGLQRIVXEMHFWV
(0.01 per subject-years of follow-up).
Malignancies
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2
years, representing 8998 subject-\HDUVRIH[SRVXUH RIustekinumab-treated subjects reported
malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non
PHODQRPDVNLQFDQFHUZDVUHSRUWHGLQRIustekinumab-treated subjects (0.52 per hundred subject-
years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies
other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and
breast. Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the
controlled and uncontrolled portions of trials were similar in type and number to what would be
expected in the general U.S. population according to the SEER database (adjusted for age, gender and
race).1
Pediatric Subjects with Plaque Psoriasis
The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe
plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17
years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old.
The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque
psoriasis.
Psoriatic Arthritis
The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-
controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab
in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher
incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects
when compared with placebo- WUHDWHGVXEMHFWV YVIRUDUWKUDOJLDDQGYVIRUQDXVHD
YVIRUGHQWDOLQIHFWLRQV LQWKHSODFHER-controlled portions of the PsA clinical trials.
Crohn's Disease
Reference ID: 5500909
The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn's
disease (Crohn's Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to
450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials. These
1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab
formulation but were not included in the efficacy analyses. In trials CD-1 and CD-2 there were 470
subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and
466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in
either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90
mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may
have received other concomitant therapies including aminosalicylates, immunomodulatory agents
[azathioprine (AZA), 6- mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone
or budesonide), and/or antibiotics for their Crohn's disease [see Clinical Studies (14.4)].
The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult
psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in
trial CD-3 are listed in Table 6 and Table 7, respectively.
Table 6:
Common adverse reactions through Week 8 in Trials CD-1 and CD-2 occurring in RI
ustekinumab-treated subjects and higher than placebo
Ustekinumab
6 mg/kg single intravenous
Placebo
induction dose
N=466
N=470
Vomiting
Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia
YV DFQH YV DQGSUXULWXV YV
Table 7:
Common adverse reactions through Week 44 in Trial CD-RFFXUULQJLQRIustekinumab
treated subjects and higher than placebo
Ustekinumab
90 mg subcutaneous maintenance
Placebo
dose every 8 weeks
N=133
N=131
Nasopharyngitis
Injection site erythema
0
Vulvovaginal candidiasis/mycotic
infection
Bronchitis
Pruritus
Urinary tract infection
Sinusitis
Infections
In subjects with Crohn's disease, serious or other clinically significant infections included anal abscess,
gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were
reported in one patient each [see Warnings and Precautions (5.1)].
Reference ID: 5500909
Malignancies
With up to one year of treatment in the Crohn's disease clinical trialsRIustekinumab-treated
subjects (0.36 events per hundred patient-\HDUV DQGRISODFHER-treated subjects (0.58 events per
hundred patient-years) developed non- melanoma skin cancer. Malignancies other than non-melanoma
VNLQFDQFHUVRFFXUUHGLQRIustekinumab-treated subjects (0.27 events per hundred patient-years)
and in none of the placebo-treated subjects.
Hypersensitivity Reactions Including Anaphylaxis
In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One
patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness
RIEUHDWKDQGIOXVKLQJ DIWHUDVLQJOHVXEFXWDQHRXVDGPLQLVWUDWLRQ RIsubjects receiving
subcutaneous ustekinumab). In addition, one subject experienced signs and symptoms consistent with or
related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body
temperature) after the initial intravenous ustekinumab GRVH RIsubjects receiving intravenous
ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases
symptoms resolved within an hour.
Ulcerative Colitis
The safety of ustekinumab was evaluated in two randomized, double-blind, placebo- controlled clinical
trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to
severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of ustekinumab
in subjects with ulcerative colitis was consistent with the safety profile seen across all approved
LQGLFDWLRQV$GYHUVHUHDFWLRQVUHSRUWHGLQDWOHDVWRIustekinumab-treated subjects and at a higher
rate than placebo were:
•
Induction (UC- QDVRSKDU\QJLWLV YV
•
Maintenance (UC-2): QDVRSKDU\QJLWLV YV KHDGDFKH YV DEGRPLQDOSDLQ
YV LQIOXHQ]D YV IHYHU YV GLDUUKHD YV VLQXVLWLV YV
IDWLJXH YV DQGQDXVHD YV
Infections
In subjects with ulcerative colitis, serious or other clinically significant infections included
gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one
subject each [see Warnings and Precautions (5.1)].
Malignancies
With up to one year of treatment in the ulcerative colitis clinical trialsRIustekinumab-treated
subjects (0.48 events per hundred patient-\HDUV DQGRISODFHER-treated subjects (0.00 events per
hundred patient-years) developed non- melanoma skin cancer. Malignancies other than non-melanoma
Reference ID: 5500909
VNLQFDQFHUVRFFXUUHGLQRIustekinumab-treated subjects (0.64 events per hundred patient-years)
DQGRISODFHER-treated subjects (0.40 events per hundred patient-years).
6.2
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of
the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug
antibodies in the studies described below with the incidence of anti-drug antibodies in other studies,
including those of ustekinumab or of other ustekinumab products.
$SSUR[LPDWHO\WRRIVXEMHFWVWUHDWHGZLWKustekinumab in plaque psoriasis and psoriatic
arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In plaque
psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum
ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who
were positive for antibodies to ustekinumab had neutralizing antibodies.
In Crohn's disease and ulcerative colitis clinical trials DQGRIVXEMHFWVUHVSHFWLYHO\
developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No
apparent association between the development of antibodies to ustekinumab and the development of
injection site reactions was seen.
6.3
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of ustekinumab products.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product
exposure.
Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema),
other hypersensitivity reactions (including rash and urticaria).
Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections
and tuberculosis).
Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and
cryptogenic organizing pneumonia.
Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.
7
DRUG INTERACTIONS
7.1
Concomitant Therapies
Reference ID: 5500909
In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive
agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not
appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis
induction trials, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately
RIVXEMHFWVDQGFRUWLFRVWHURLGVZHUHXVHGFRQFRPLWDQWO\LQDSSUR[LPDWHO\DQGRI&URKQ
V
disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to
influence the overall safety or efficacy of ustekinumab.
7.2
CYP450 Substrates
The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL
1, IL-71)Į,)1 GXULQJFKURQLFLQIODPPDWLRQ7KXVuse of ustekinumab products, antagonists of IL
12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of
PYZCHIVA in patients who are receiving concomitant CYP450 substrates, particularly those with a
narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the
individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP
substrates.
A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical
Pharmacology (12.3)].
7.3
Allergen Immunotherapy
Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy.
Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease
tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy.
Therefore, caution should be exercised in patients receiving or who have received allergen
immunotherapy, particularly for anaphylaxis.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Limited data from observational studies, published case reports, and postmarketing surveillance on the
use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major
birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody
across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore,
ustekinumab products may be transferred to the developing fetus (see Clinical Considerations). In
animal reproductive and developmental toxicity studies, no adverse developmental effects were
observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than
100 times the maximum recommended human dose (MRHD).
The background risk of major birth defects and miscarriage for the indicated population(s) are unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.
Reference ID: 5500909
general population, the estimated background risk of major birth defects and miscarriage of clinically
UHFRJQL]HGSUHJQDQFLHVLVWRDQGWRUHVSHFWLYHO\
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Because ustekinumab products may theoretically interfere with immune response to infections, consider
risks and benefits prior to administering live vaccines to infants exposed to PYZCHIVA in utero. There
are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the
duration of persistence of ustekinumab products in infant serum after birth. Although a specific
timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown,
consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance
of the product.
Data
Animal Data
Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No
teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that
were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period
of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100
times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for
4 weeks.
In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant
cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures
greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery.
Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and
one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or
immunological development were observed in the neonates from birth through six months of age.
8.2
Lactation
Risk Summary
Limited data from published literature suggests that ustekinumab is present in human breast milk. There
are no available data on the effects of ustekinumab products on milk production. The effects of local
gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products
are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products have
been identified in the published literature or postmarketing experience.
The developmental and health benefits of breastfeeding should be considered along with the mother's
clinical need for PYZCHIVA and any potential adverse effects on the breastfed child from PYZCHIVA
or from the underlying maternal condition.
Reference ID: 5500909
8.4
Pediatric Use
Plaque Psoriasis
The safety and effectiveness of PYZCHIVA have been established for the treatment of moderate to
severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or
systemic therapy.
Use of PYZCHIVA in pediatric patients 12 to less than 17 years of age is supported by evidence from a
multicenter, randomized, 60 week trial (Ps STUDY 3) of ustekinumab that included a 12 week, double-
blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older [see
Adverse Reactions (6.1), Clinical Studies (14.2)].
Use of PYZCHIVA in pediatric patients 6 to 11 years of age is supported by evidence from an open-
label, single-arm, efficacy, safety and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44
subjects [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
The safety and effectiveness of PYZCHIVA have not been established in pediatric patients less than 6
years of age with plaque psoriasis.
Psoriatic Arthritis
The safety and effectiveness of PYZCHIVA have been established for treatment of psoriatic arthritis in
pediatric patients 6 to 17 years old.
Use of PYZCHIVA in these age groups is supported by evidence from adequate and well controlled
trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with
psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab
from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects
12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally
comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with
psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with
PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2,
14.3)].
The safety and effectiveness of PYZCHIVA have not been established in pediatric patients less than 6
years old with psoriatic arthritis.
Crohn's Disease and Ulcerative Colitis
The safety and effectiveness of PYZCHIVA have not been established in pediatric patients with Crohn's
disease or ulcerative colitis.
8.5
Geriatric Use
Reference ID: 5500909
Of the 6709 subjects exposed to ustekinumab, a total of 340 were 65 years of age or older (183 subjects
with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn's disease and 34
subjects with ulcerative colitis), and 40 subjects were 75 years of age or older. Clinical trials of
ustekinumab did not include sufficient numbers of subjects 65 years of age and older to determine
whether they respond differently from younger adult subjects.
10
OVERDOSAGE
Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting
toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or
effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison
Help line (1-800-222-1222) or a medical toxicologist for additional overdose management
recommendations.
11
DESCRIPTION
Ustekinumab-ttweDKXPDQ,J*țPRQRFORQDODQWLERG\LVDKXPDQLQWHUOHXNLQ-12 and -23 antagonist.
Using DNA recombinant technology, ustekinumab-ttwe is produced in a Chinese hamster ovary cell
line. The manufacturing process contains steps for the clearance of viruses. Ustekinumab-ttwe is
comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to
149,690 Daltons.
PYZCHIVA (ustekinumab-ttwe) injection is a clear, colorless to light yellow, sterile and preservative-
free solution with pH of 5.7– 6.3.
PYZCHIVA for Subcutaneous Use
Available as 45 mg of ustekinumab-ttwe in 0.5 mL and 90 mg of ustekinumab-ttwe in 1 mL, supplied as
a sterile solution in a single-dose prefilled syringe with a 29 gauge fixed ½ inch needle and as 45 mg of
ustekinumab-ttwe in 0.5 mL in a single-dose Type I glass vial with a coated stopper. The syringe is
fitted with a passive needle guard and a needle cover.
Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab-ttwe, histidine (0.095 mg), histidine
hydrochloride monohydrate (0.405 mg), polysorbate 80 (0.02 mg), and sucrose (42.5 mg).
Each 1 mL prefilled syringe delivers 90 mg ustekinumab-ttwe, histidine (0.19 mg), histidine
hydrochloride monohydrate (0.81 mg), polysorbate 80 (0.04 mg), and sucrose (85 mg).
PYZCHIVA for Intravenous Infusion
Available as 130 mg of ustekinumab-ttwe in 26 mL, supplied as a single-dose Type I glass vial with a
coated stopper.
Reference ID: 5500909
Each 26 mL vial delivers 130 mg ustekinumab-ttwe, edetate disodium (0.52 mg), histidine (20 mg),
histidine hydrochloride monohydrate (27 mg), methionine (10.4 mg), polysorbate 80 (10.4 mg) and
sucrose (2,210 mg).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ustekinumab products are KXPDQ,J*ԕPRQRFORQDODQWLERGies that bind with specificity to the p40
protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring
cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation
and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab products were shown to
disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these
cytokines with a shared cell- surface receptor chain, IL-5ȕ7KHF\WRNLQHV,/-12 and IL-23 have
been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's
disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the
p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective.
12.2
Pharmacodynamics
Plaque Psoriasis
In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets
IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in
subjects with plaque psoriasis.
Ulcerative Colitis
In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed
between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The
response rate approached a plateau at the ustekinumab exposures associated with the recommended
dosing regimen for maintenance treatment [see Clinical Studies (14.5)].
12.3
Pharmacokinetics
Absorption
In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration
(Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg
(N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days)
following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that
observed in subjects with plaque psoriasis.
Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-
state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state
trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to
Reference ID: 5500909
100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90
mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when
given subcutaneously every 12 weeks.
Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab
concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn's disease, and 129.1 ± 27.6 mcg/mL in
subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing
of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was
achieved by the start of the second maintenance dose. There was no apparent accumulation in
ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ± SD steady-
state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn's disease, and 3.3 ± 2.3 mcg/mL
in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks.
Distribution
Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the
FHQWUDOFRPSDUWPHQWZDV/ &, LQsubjects ZLWK&URKQ
VGLVHDVHDQG/ &,
2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady-state was 4.6 L
in subjects with Crohn's disease and 4.4 L in subjects with ulcerative colitis.
Elimination
The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials
following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance
RIXVWHNLQXPDEZDV /GD\ &, LQsubjects with Crohn's disease and 0.19 L/day
&, LQsubjects with ulcerative colitis with an estimated median terminal half-life of
approximately 19 days for both IBD (Crohn's disease and ulcerative colitis) populations.
These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn's
disease and ulcerative colitis.
Metabolism
The metabolic pathway of ustekinumab products has QRWEHHQFKDUDFWHUL]HG$VDKXPDQ,J*ț
monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino
acids via catabolic pathways in the same manner as endogenous IgG.
Specific Populations
Weight
When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100
kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg
or less. The median trough serum concentrations of ustekinumab in subjects of higher weight (greater
than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less)
in the 45 mg group.
Reference ID: 5500909
Age: Geriatric Population
A population pharmacokinetic analysis (N=106/1937 subjects with plaque psoriasis greater than or equal
to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab.
There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution)
in subjects older than 65 years old.
Age: Pediatric Population
Following multiple recommended doses of ustekinumab in pediatric subjects 6 to 17 years of age with
plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At
Week 28, the mean ±SD steady-state trough serum ustekinumab concentrations were 0.36 ± 0.26
mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric subjects 6 to 11 years of age and pediatric
subjects 12 to 17 years of age.
Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque
psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult
subjects with PsA after administration of ustekinumab.
Drug Interaction Studies
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study
using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter
human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).
No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9
substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam
(CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved
recommended dosage in subjects with Crohn’s disease [see Drug Interactions (7.2)].
Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by
concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects
with psoriatic arthritis.
In subjects with Crohn's disease and ulcerative colitis, population pharmacokinetic analyses did not
indicate changes in ustekinumab clearance with concomitant use of corticosteroids or
immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted
by concomitant use of these medications.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of
ustekinumab products. Published literature showed that administration of murine IL-12 caused an anti-
Reference ID: 5500909
tumor effect in mice that contained transplanted tumors and IL-12/IL- 23p40 knockout mice or mice
treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically
manipulated to be deficient in both IL-12 and IL- 23 or IL-12 alone developed UV-induced skin cancers
earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in
mouse models for malignancy risk in humans is unknown.
No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab
at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and
during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated
females.
No effects on fertility were observed in female mice that were administered an analogous IL-12/IL
23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and
during early pregnancy.
13.2
Animal Toxicology and/or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg
ustekinumab twice weekly for 26 weeks had a bacterial infection.
14
CLINICAL STUDIES
14.1
Adult Plaque Psoriasis
Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2)
enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum
ERG\VXUIDFHDUHDLQYROYHPHQWRIDQG3VRULDVLV$UHDDQG6HYHULW\,QGH[ 3$6, VFRUHDQG
who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or
pustular psoriasis were excluded from the trials.
Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same
design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg
or 90 mg of ustekinumab. Subjects randomized to ustekinumab received 45 mg or 90 mg doses,
regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4
crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16.
In both trials, subjects in all treatment groups had a median baseline PASI score ranging from
DSSUR[LPDWHO\WR%DVHOLQH3*$VFRUHZDVPDUNHGRUVHYHUHLQRIVXEMHFWVLQ3V678'<
DQGRIVXEMHFWVLQ3V678'<$SSUR[LPDWHO\WZR-thirds of all subjects had received prior
SKRWRWKHUDS\ KDGUHFHLYHGHLWKHUSULRUFRQYHQWLRQDOV\VWHPLFRUELRORJLFWKHUDS\IRUWKHWUHDWPHQW
RISVRULDVLVZLWKUHFHLYLQJSULRUFRQYHQWLRQDOV\VWHPLFWKHUDS\DQGUHFHLYLQJSULRUELRORJLF
therapy. A total of RIVXEMHFWVKDGDKLVWRU\RISVRULDWLFDUWKULWLV
,QERWKWULDOVWKHHQGSRLQWVZHUHWKHSURSRUWLRQRIVXEMHFWVZKRDFKLHYHGDWOHDVWDUHGXFWLRQLQ
PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the
Physician's Global Assessment (PGA). The PGA is a 6- category scale ranging from 0 (cleared) to 5
Reference ID: 5500909
(severe) that indicates the physician's overall assessment of psoriasis focusing on plaque
thickness/induration, erythema, and scaling.
Clinical Response
The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.
Table 8:
Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
Ustekinumab
Ustekinumab
Placebo
45 mg
90 mg
Placebo
45 mg
90 mg
Subjects randomized
255
255
256
410
409
411
PASI 75 response
171
170
273
311
PGA of Cleared or Minimal
151
156
277
300
Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab
among these subgroups.
In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg
doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90
mg dosing compared with 45 mg dosing (Table 9 below).
Table 9:
Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and
Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
Ustekinumab
Ustekinumab
Placebo
45 mg
90 mg
Placebo
45 mg
90 mg
Subjects
255
255
256
410
409
411
randomized
PASI 75 response*
kg
6/166
124/168
107/164
12/290
218/297
225/289
>100 kg
2/89
47/87
63/92
3/120
55/112
86/121
PGA of Cleared or Minimal *
kg
7/166
108/168
103/164
14/290
220/297
216/289
>100 kg
3/89
43/87
53/92
4/120
57/112
84/121
* Subjects were dosed with trial medication at Weeks 0 and 4.
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at
Week 40 to either continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of
WKHUDS\ SODFHERDW:HHN $W:HHN RIVXEMHFWVUH-randomized to ustekinumab
WUHDWPHQWZHUH3$6,UHVSRQGHUVFRPSDUHGZLWK RIVXEMHFWVUH-randomized to placebo
(treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the
subjects randomized to treatment withdrawal was 16 weeks.
14.2
Pediatric Plaque Psoriasis
Reference ID: 5500909
A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric
VXEMHFWVWR\HDUVRIDJHZLWKDPLQLPXP%6$LQYROYHPHQWRID3$6,VFRUHJUHDWHUWKDQRU
equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or
systemic therapy and whose disease was inadequately controlled by topical therapy.
Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36),
or one-half the recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4
followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for
subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects
weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive
ustekinumab at the recommended dose or one-half the recommended dose.
Of the pediatric VXEMHFWVDSSUR[LPDWHO\KDGSULRUH[SRVXUHWRSKRWRWKHUDS\RUFRQYHQWLRQDO
V\VWHPLFWKHUDS\DQGDSSUR[LPDWHO\KDGSULRUH[SRVXUHWRELRORJLFV
The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1),
PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first
administration of trial agent.
Clinical Response
The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10.
Table 10:
Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3
Ps STUDY 3
Placebo
Ustekinumab*
Q
Q
N
37
36
PGA
PGA of cleared (0) or minimal (1)
PASI
PASI 75 responders
4
PASI 90 responders
* Using the weight-based dosage regimen specified in Table 1 and Table 2.
14.3
Psoriatic Arthritis
The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA
STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 18 years
RIDJHDQGROGHUZLWKDFWLYH3V$ VZRllen joints and WHQGHUMRLQWV GHVSLWHQRQVWHURLGDODQWL
inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Subjects in these trials
had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA were enrolled, including
polyartLFXODUDUWKULWLVZLWKWKHDEVHQFHRIUKHXPDWRLGQRGXOHV VSRQG\OLWLVZLWKSHULSKHUDODUWKULWLV
DV\PPHWULFSHULSKHUDODUWKULWLV GLVWDOLQWHUSKDODQJHDOLQYROYHPHQW DQGDUWKULWLV
PXWLODQV 2YHUDQGRIWKHsubjects, respectively, had enthesitis and dactylitis at
baseline.
Reference ID: 5500909
Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo
subcutaneously at Weeks 0 and 4 followed E\HYHU\ZHHNV TZ GRVLQJ$SSUR[LPDWHO\RI
subjects FRQWLQXHGRQVWDEOHGRVHVRI07; PJZHHN 7KHSULPDU\HQGSRLQt was the percentage of
subjects achieving ACR 20 response at Week 24.
,Q3V$678'<DQG3V$678'<DQGRIWKHsubjects, respectively, had been previously
treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-Į
agent was not allowed,Q3V$678'< Q RIWKHsubjects had been previously treated with
71)EORFNHURIZKRPRYHUKDGGLVFRQWLQXHGWKHLU71)EORFNHUWUHDWPHQWIRUODFNRIHIILFDF\RU
intolerance at any time.
Clinical Response
In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the
ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70
responses were also higher in the ustekinumab 45 mg and 90 mg groups, although the difference was
only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with ustekinumab
alone or in combination with methotrexate. Responses were similar in subjects UHJDUGOHVVRISULRU71)Į
exposure.
Table 11:
ACR 20, ACR 50, ACR 70 an
Placebo
d PASI 75 responses in PsA S
PsA STUDY 1
Ustekinumab
45 mg
90 mg
TUDY 1 and
Placebo
PsA STUDY 2 at Week 24
PsA STUDY 2
Ustekinumab
45 mg
90 mg
Number of subjects
Randomized
206
205
204
104
103
105
ACR 20 UHVSRQVH1
101
ACR 50 UHVSRQVH1
18
ACR 70 UHVSRQVH1
Number of subjects with
%6$
146
145
149
80
80
81
PASI 75 UHVSRQVH1
*Number of subjects ZLWK%6$SVRULDVLVVNLQLQYROYHPHQWDWEDVHOLQH
The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1.
Reference ID: 5500909
~
'o'
~
V, .... s
·=
(II
(l.,
60
40
20
0
PsASTUDY I
Weeks~
-o- Placebo•(n=206)
_.,_ Ustekinumab•45mg•(n=205),I
-
Ustekinumab•90mg•(n=204)
Figure 1: Percent of subjects achieving ACR 20 response through Week 24
The results of the components of the ACR response criteria are shown in Table 12.
Table 12:
Mean change from baseline in ACR components at Week 24
PsA STUDY 1
Ustekinumab
Placebo
45 mg
90 mg
(N = 206)
(N = 205)
(N = 204)
Number of swollen jointsa
Baseline
15
12
13
Mean Change at Week 24
-3
-5
-6
Number of tender jointsb
Baseline
25
22
23
Mean Change at Week 24
-4
-8
-9
Subject's assessment of painc
Baseline
6.1
6.2
6.6
Mean Change at Week 24
-0.5
-2.0
-2.6
Subject global assessmentc
Baseline
6.1
6.3
6.4
Mean Change at Week 24
-0.5
-2.0
-2.5
Physician global assessmentc
Baseline
5.8
5.7
6.1
Reference ID: 5500909
Mean Change at Week 24
-1.4
-2.6
-3.1
Disability index (HAQ)d
Baseline
1.2
1.2
1.2
Mean Change at Week 24
-0.1
-0.3
-0.4
CRP (mg/dL)e
Baseline
1.6
1.7
1.8
Mean Change at Week 24
0.01
-0.5
-0.8
a
Number of swollen joints counted (0–66)
b
Number of tender joints counted (0–68)
c
Visual analogue scale; 0= best, 10=worst.
d
Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to perform the
following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
e
CRP: (Normal Range 0.0–1.0 mg/dL)
An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared
with placebo at Week 24.
Physical Function
Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated
with placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ-DI responders
LPSURYHPHQWLQ+$4-DI score) was greater in the ustekinumab 45 mg and 90 mg groups
compared to placebo at Week 24.
14.4
Crohn's Disease
Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult
subjects with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI]
score of 220 to 450). There were two 8-week intravenous induction trials (CD-1 and CD-2) followed by
a 44-week subcutaneous randomized withdrawal maintenance trial (CD-3) representing 52 weeks of
therapy. Subjects in CD- 1 had failed or were intolerant to treatment with one or more TNF blockers,
while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or
corticosteroids, but never failed treatment with a TNF blocker.
Trials CD-1 and CD-2
In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627)
were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in
CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and
clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials,
subjects were randomized to receive a single intravenous administration of ustekinumab at either
approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended).
In trial CD-1, subjects KDGIDLOHGRUZHUHLQWROHUDQWWRSULRUWUHDWPHQWZLWKD71)EORFNHU subjects
had an inadequate initial response (primary non-UHVSRQGHUV UHVSRQGHGEXWVXEVHTXHQWO\ORVW
response (secondary non-UHVSRQGHUV DQGZHUHLQWROHUDQWWRD71)EORFNHU2IWKHVHsubjects
IDLOHGRUZHUHLQWROHUDQWWRRQH71)EORFNHUDQGKDGIDLOHGRUSULRU71)EORFNHUV$WEDVHOLQH
Reference ID: 5500909
and throughout the trialDSSUR[LPDWHO\RIWKHsubjects ZHUHUHFHLYLQJFRUWLFRVWHURLGVDQGRI
the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score
was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group.
In trial CD-2, subjects KDGIDLOHGRUZHUHLQWROHUDQWWRSULRUWUHDWPHQWZLWKFRUWLFRVWHURLGV RI
subjects), at least one immunomodulator (6-MP, AZA, MTX; 68 of subjects), or both (49 of
subjects). Additionall\ QHYHUUHFHLYHGD71)EORFNHUDQGSUHYLRXVO\UHFHLYHGEXWKDGQRW
failed a TNF blocker. At baseline, and throughout the trialDSSUR[LPDWHO\ RIWKHsubjects were
UHFHLYLQJFRUWLFRVWHURLGVDQGRIWKHsubjects were receiving immunomodulators (AZA, 6-MP,
MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group.
In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended
dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at
Week 8 compared to placebo (see Table 13 for clinical response and remission rates). Clinical response
and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to
improve through Week 8.
Reference ID: 5500909
Table 13:
Induction of Clinical Response and Remission in CD-1* and CD-2**
CD-1
CD-2
n = 741
n = 627
Treatment
Treatment
Placebo
Ustekinumab†
difference
Placebo
Ustekinumab†
difference
N = 247
N = 249
DQG Cl
N = 209
N = 209
DQG Cl
Clinical Response
53
a
b
(100 point), Week 6
Clinical Remission,
b
b
Week 8
Clinical Response
b
121 b
(100 point), Week 8
70 Point Response,
a
b
Week 6
70 Point Response,
a
b
Week 3
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being
in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points
*
Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy
**
Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA,
MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker.
†
Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
a
S
b
p < 0.001
Trial CD-3
The maintenance trial (CD-3), evaluated 388 subjects ZKRDFKLHYHGFOLQLFDOUHVSRQVH 100 point
reduction in CDAI score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2.
Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab
every 8 weeks or placebo for 44 weeks (see Table 14).
Table 14:
Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)
Placebo*
N = 131**
90 mg ustekinumab
every 8 weeks
N = 128**
Treatment
difference
DQG &,
Clinical Remission
†
Clinical Response
Clinical Remission in subjects in remission at
the start of maintenance therapyb
a
52/78 †
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in
clinical remission
*
The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start
of maintenance therapy.
**
Subjects who achieved clinical response to ustekinumab at the end of the induction trial.
†
p < 0.01
a
S
b
Subjects in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not
account for any other time point during maintenance therapy.
$W:HHNRI subjects who received ustekinumab were corticosteroid-free and in clinical
UHPLVVLRQFRPSDUHGWRRIsubjects in the placebo group.
Reference ID: 5500909
At Week 0 of trial CD- ustekinumab-treated subjects who previously failed or were
LQWROHUDQWWR71)EORFNHUWKHUDSLHVZHUHLQFOLQLFDOUHPLVVLRQDQG RI these subjects were in
FOLQLFDOUHPLVVLRQDW:HHN,QWKHSODFHERDUP subjects were in clinical remission at
:HHNZKLOH RIWKHVHsubjects were in remission at Week 44.
At Week 0 of trial CD- ustekinumab-treated subjects who had previously failed
immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and
RIWKHVHsubjects were in clinical remission at Week ,QWKHSODFHERDUP RI
these subjects ZHUHLQFOLQLFDOUHPLVVLRQDW:HHNZKLOH ZHUHLQUHPLVVLRQDW:HHN,Q
the subset of these subjects ZKRZHUHDOVRQDwYHWR71)EORFNHUV RIustekinumab-treated
subjects ZHUHLQFOLQLFDOUHPLVVLRQDW:HHNDVFRPSDUHGWR LQWKHSODFHERDUP
Subjects who were not in clinical response 8 weeks after ustekinumab induction were not included in the
primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg
subcutaneous injection of ustekinumab upon entry into trial CD-3. Of these subjects
achieved clinical response eight weeks later and were followed for the duration of the trial.
14.5
Ulcerative Colitis
Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1
and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who
had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab),
corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was
followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of
52 weeks of therapy.
Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores
that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on
centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active
ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo
HQGRVFRS\VXEVFRUH$QHQGRVFRS\VFRUHRIZDVGHILQHGE\PDUNHGHU\WKHPDDEVHQWYDVFXODU
pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At
baseline, subjects KDGDPHGLDQ0D\RVFRUHRI ZLWKRIsubjects having moderate disease (Mayo
score 6– DQGKDYLQJVHYHUHGLVHDVH 0D\RVFRUH–12).
Subjects in these trials may have received other concomitant therapies including aminosalicylates,
immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).
Reference ID: 5500909
Trial UC-1
In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab
of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in
UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. A total
RIKDGIDLOHGDWOHDVWRQHELRORJLFDQGKDGIDLOHGERWKD71)EORFNHUDQGDQLQWHJULQUHFHSWRU
EORFNHU2IWKHWRWDOSRSXODWLRQKDGIDiled corticosteroids or immunomodulators but were
biologic-QDwYHDQGDQDGGLWLRQDOKDGSUHYLRXVO\UHFHLYHGEXWKDGQRWIDLOHGDELRORJLF$WLQGXFWLRQ
baseline and throughout the trialDSSUR[LPDWHO\subjects ZHUHUHFHLYLQJRUDOFRUWLFRVWHURLGV
subjects were receiving immunomodulators (AZA, 6-03RU07; DQG subjects were receiving
aminosalicylates.
The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo
stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo
endoscopy subscore of 0 or 1 (Mayo endoscopy subscore of 0 defined as normal or inactive disease and
Mayo subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability) is
provided in Table 15.
The secondary endpoints were clinical response, endoscopic improvement, and histologic-endoscopic
PXFRVDOLPSURYHPHQW&OLQLFDOUHVSRQVHZLWKDGHILQLWLRQRI SRLQWVDQGGHFUHDVHLQ
modified Mayo score, defined as 3-component Mayo score without the Physician's Global Assessment,
ZLWKHLWKHUDGHFUHDVHIURPEDVHOLQHLQWKHUHFWDOEOHHGLQJVXEVFRUHRUDUHFWDOEOHHGLQJVXEVFRUHRI
or 1), endoscopic improvement with a definition of Mayo endoscopy subscore of 0 or 1, and histologic-
endoscopic mucosal improvement with a definition of combined endoscopic improvement and
histologic improvement of the colon tissue [neutrophil infiltration in RIFU\SWVQRFU\SW
destruction, and no erosions, ulcerations, or granulation tissue]) are provided in Table 15.
In UC-1, a significantly greater proportion of subjects treated with ustekinumab (at the recommended
dose of approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic
improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 15).
Table 15:
Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1
Endpoint
Placebo
N = 319
Ustekinumab†
N = 322
Treatment
difference and
97.&,a
N
N
Clinical Remission*
22
62
b
Bio-naïveᄾ
14/151
36/147
Prior biologic failure
7/161
24/166
Endoscopic Improvement§
40
80
b
Bio-naïveᄾ
28/151
43/147
Prior biologic failure
11/161
34/166
Clinical Response¶
99
186
b
Bio-naïveᄾ
55/151
94/147
Prior biologic failure
42/161
86/166
Histologic-Endoscopic
Mucosal
26
54
b
Reference ID: 5500909
Endpoint
Placebo
N = 319
Ustekinumab†
N = 322
Treatment
difference and
97.&,a
N
N
Improvement‡
Bio-naïveᄾ
19/151
30/147
Prior biologic failure
6/161
21/166
†
Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
ᄾ
An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics.
*
Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo
endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
§
Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
¶
Clinical response was defined as a decrease from baseline in the modified Mayo score by DQGSRLQWVZLWKHLWKHUD
decrease from baseline in the rectal bleeding subscore RUDUHFWDOEOHHGLQJVXEVFRUHRIRU
‡
Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0
RU DQGKLVWRORJLFLPSURYHPHQWRIWKHFRORQWLVVXH QHXWURSKLOLQILOWUDWLRQLQ RIFU\SWVQRFU\SWGHVWUXFWLRQDQGQR
erosions, ulcerations, or granulation tissue).
a
$GMXVWHGWUHDWPHQWGLIIHUHQFH &,
b
p < 0.001
The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to
disease progression and long-term outcomes was not evaluated during UC-1.
Rectal Bleeding and Stool Frequency Subscores
Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in
ustekinumab-treated subjects.
Trial UC-2
The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following
the intravenous administration of either induction dose of ustekinumab in UC-1. These subjects were
randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8
weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks.
The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary
endpoints included the proportion of subjects maintaining clinical response at Week 44, the proportion
of subjects with endoscopic improvement at Week 44, the proportion of subjects with corticosteroid-free
clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44
among subjects who achieved clinical remission 8 weeks after induction.
Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the
recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16.
Reference ID: 5500909
Table 16:
Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction
Dose)
Endpoint
Placebo*
N = 175†
90 mg ustekinumab
every 8 weeks N = 176
Treatment
GLIIHUHQFHDQG
CI
N
N
Clinical Remission**
46
79
a
Bio-naïveᄾ
30/84
39/79
Prior biologic failure
16/88
37/91
Maintenance of Clinical
Response at Week 44†
84
130
a
Bio-naïveᄾ
49/84
62/79
Prior biologic failure
35/88
64/91
Endoscopic Improvement§
47
83
a
Bio-naïveᄾ
29/84
42/79
Prior biologic failure
18/88
38/91
Corticosteroid-free Clinical
Remission‡
45
76
a
Bio-naïveᄾ
30/84
38/79
Prior biologic failure
15/88
35/91
Maintenance of Clinical
Remission at Week 44 in
subjects who achieved clinical
remission 8 weeks after
induction
18/50
27/41
b
Bio-naïveᄾ
12/27
14/20
Prior biologic failure
6/23
12/18
ᄾ
An additional 3 subjects on placebo and 6 subjects on ustekinumab had been exposed to, but had not failed, biologics.
*
The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the
start of maintenance therapy.
**
Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo
endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
‡
Clinical response was defined as a decrease from baseline in the modified Mayo score by DQGSRLQWVZLWKHLWKHUD
decrease from baseline in the rectal bleeding subscore RUDUHFWDOEOHHGLQJVXEVFRUHRIRU
§
Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
‡
Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44.
a
p =<0.001
b
p=0.004
Reference ID: 5500909
Other Endpoints
Week 16 Responders to Ustekinumab Induction
Subjects who were not in clinical response 8 weeks after induction with ustekinumab in UC- 1 were not
included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive
a 90 mg subcutaneous injection of ustekinumab at Week 8. Of these subjects DFKLHYHG
clinical response eight weeks later (Week 16) and received ustekinumab 90 mg subcutaneously every 8
weeks during the UC-WULDO$W:HHNWKHUHZHUH subjects who maintained clinical
UHVSRQVHDQGWKHUHZHUH ZKRDFKLHYHGFOLQLFDOUHPLVVLRQ
Histologic-Endoscopic Mucosal Improvement at Week 44
The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance
treatment in UC-ZDV DPRQJsubjects on ustekinumab DQG LQsubjects on
placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC
2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2.
Endoscopic Normalization
Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of
0. At Week 8 in UC-HQGRVFRSLFQRUPDOL]DWLRQZDVDFKLHYHGLQ RIsubjects treated with
ustekinumab DQG RIsubjects in the placebo group. At Week 44 of UC-2, endoscopic
QRUPDOL]DWLRQZDVDFKLHYHGLQ RIsubjects treated with ustekinumab DQGLQ
of subjects in placebo group.
15
REFERENCES
1
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov)
SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973–2007) -
Linked To County Attributes - Total U.S., 1969– 2007 Counties, National Cancer Institute,
DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010,
based on the November 2009 submission.
16
HOW SUPPLIED/STORAGE AND HANDLING
PYZCHIVA (ustekinumab-ttwe) injection is a clear, colorless to light yellow, sterile and preservative-
free solution. It is supplied as individually packaged, single-dose prefilled syringe or single-dose vial.
For Subcutaneous Use
Prefilled Syringes
•
45 mg/0.5 mL (NDC 61314-651-01)
•
90 mg/mL (NDC 61314-652-01)
Reference ID: 5500909
Each prefilled syringe is equipped with a 29 gauge fixed ½ inch needle, a needle safety guard, and a
needle cover that is not made with natural rubber latex.
Single-dose Vial
•
45 mg/0.5 mL (NDC 61314-651-94)
For Intravenous Infusion
Single-dose Vial
•
130 mg/26 mL (5 mg/mL) (NDC 61314-654-94)
Storage and Stability
Store PYZCHIVA vials, and prefilled syringes refrigerated between 2°C to 8°C (36°F to 46°F). Store
PYZCHIVA vials upright. Keep the product in the original carton to protect from light until the time of
use. Do not freeze. Do not shake.
If needed, individual prefilled syringes may be stored at room temperature up to 30°C (86°F) for a
maximum single period of up to 35 days in the original carton to protect from light. If not used within 35
days of room temperature storage, discard the prefilled syringe. The prefilled syringe may be returned to
the refrigerator one time only for a maximum of 60 days. If not used within 60 days, discard the
prefilled syringe. Record the date when the prefilled syringe is removed from and returned to the
refrigerator on the carton in the space provided.
Do not use PYZCHIVA after the expiration date on the carton or on the prefilled syringe.
17
PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and
Instructions for Use).
Infections
Inform patients that PYZCHIVA may lower the ability of their immune system to fight infections and
to contact their healthcare provider immediately if they develop any signs or symptoms of infection [see
Warnings and Precautions (5.1)].
Malignancies
Inform patients of the risk of developing malignancies while receiving PYZCHIVA [see Warnings and
Precautions (5.4)].
Hypersensitivity Reactions
Reference ID: 5500909
•
Advise patients to seek immediate medical attention if they experience any signs or symptoms
of serious hypersensitivity reactions and discontinue PYZCHIVA [see Warnings and
Precautions (5.5)].
Posterior Reversible Encephalopathy Syndrome (PRES)
Inform patients to immediately contact their healthcare provider if they experience signs and symptoms
of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and
Precautions (5.6)].
Immunizations
Inform patients that PYZCHIVA can interfere with the usual response to immunizations and that they
should avoid live vaccines [see Warnings and Precautions (5.7)].
Administration
Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.
Manufactured by:
Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for:
Sandoz Inc.
Princeton, NJ 08540
Reference ID: 5500909
MEDICATION GUIDE
PYZCHIVA® (Piz-chi-va)
(ustekinumab-ttwe)
injection, for subcutaneous or intravenous use
What is the most important information I should know about PYZCHIVA?
PYZCHIVA is a medicine that affects your immune system. PYZCHIVA can increase your risk of having serious side
effects, including:
Serious infections: PYZCHIVA may lower the ability of your immune system to fight infections and may increase your
risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB),
and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their
infection.
•
Your doctor should check you for TB before starting PYZCHIVA.
•
If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment
with PYZCHIVA and during treatment with PYZCHIVA.
•
Your doctor should watch you closely for signs and symptoms of TB while you are being treated with PYZCHIVA.
You should not start taking PYZCHIVA if you have any kind of infection unless your doctor says it is okay.
Before starting PYZCHIVA, tell your doctor if you:
•
think you have an infection or have symptoms of an infection such as:
o
fever, sweat, or chills
o
weight loss
o
muscle aches
o
warm, red, or painful skin or sores on your body
o
cough
o
diarrhea or stomach pain
o
shortness of breath
o
burning when you urinate or urinate more often than normal
o
blood in phlegm
o
feel very tired
•
are being treated for an infection or have any open cuts.
•
get a lot of infections or have infections that keep coming back.
•
have TB, or have been in close contact with someone with TB.
After starting PYZCHIVA, call your doctor right away if you have any symptoms of an infection (see above). These
may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications.
PYZCHIVA can make you more likely to get infections or make an infection that you have worse. People who have a
genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are
at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People
who take PYZCHIVA may also be more likely to get these infections.
Cancers. PYZCHIVA may decrease the activity of your immune system and increase your risk for certain types of
cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab
products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with
PYZCHIVA, tell your doctor if you develop any new skin growths.
Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain and can
cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your
doctor right away if you have any new or worsening medical problems including:
o
headache
o
confusion
o
seizures
o
vision problems
What is PYZCHIVA?
PYZCHIVA is a prescription medicine used to treat:
•
adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or
pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).
•
adults and children 6 years and older with active psoriatic arthritis.
•
adults 18 years and older with moderately to severely active Crohn's disease.
•
adults 18 years and older with moderately to severely active ulcerative colitis.
It is not known if PYZCHIVA is safe and effective in children less than 6 years of age.
Do not take PYZCHIVA if you are allergic to ustekinumab products or any of the ingredients in PYZCHIVA. See the
end of this Medication Guide for a complete list of ingredients in PYZCHIVA.
Before you receive PYZCHIVA, tell your doctor about all of your medical conditions, including if you:
•
have any of the conditions or symptoms listed in the section "What is the most important information I should
know about PYZCHIVA?"
•
ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.
•
have recently received or are scheduled to receive an immunization (vaccine). People who take PYZCHIVA should
not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some
types of live vaccines can spread to people with a weakened immune system, and can cause serious problems.
Reference ID: 5500909
You should not receive the BCG vaccine during the one year before receiving PYZCHIVA or one year after
you stop receiving PYZCHIVA.
•
have any new or changing lesions within psoriasis areas or on normal skin.
•
are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as
well for you during treatment with PYZCHIVA. PYZCHIVA may also increase your risk of having an allergic
reaction to an allergy shot.
•
receive or have received phototherapy for your psoriasis.
•
are pregnant or plan to become pregnant. It is not known if PYZCHIVA can harm your unborn baby. You and your
doctor should decide if you will receive PYZCHIVA. See “What should I avoid while using PYZCHIVA?”
•
received PYZCHIVA while you were pregnant. It is important that you tell your baby’s healthcare provider before
any vaccinations are given to your baby.
•
are breastfeeding or plan to breastfeed. PYZCHIVA can pass into your breast milk.
•
Talk to your doctor about the best way to feed your baby if you receive PYZCHIVA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins,
and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I use PYZCHIVA?
•
Use PYZCHIVA exactly as your doctor tells you to.
•
Adults with Crohn's disease and ulcerative colitis will receive the first dose of PYZCHIVA through a vein in the arm
(intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full
dose of medicine. You will then receive PYZCHIVA as an injection under the skin (subcutaneous injection) 8
weeks after the first dose of PYZCHIVA, as described below.
•
Adults with psoriasis or psoriatic arthritis and children 6 years and older with psoriasis or psoriatic arthritis will
receive PYZCHIVA as an injection under the skin (subcutaneous injection) as described below.
•
Injecting PYZCHIVA under your skin
o
PYZCHIVA is intended for use under the guidance and supervision of your doctor. In children 6 years and
older, it is recommended that PYZCHIVA be administered by a healthcare provider. If your doctor decides that
you or a caregiver may give your injections of PYZCHIVA at home, you should receive training on the right
way to prepare and inject PYZCHIVA. Your doctor will determine the right dose of PYZCHIVA for you, the
amount for each injection, and how often you should receive it. Do not try to inject PYZCHIVA yourself until
you or your caregiver have been shown how to inject PYZCHIVA by your doctor or nurse.
o
Inject PYZCHIVA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or
stomach area (abdomen).
o
Do not give an injection in an area of the skin that is tender, bruised, red or hard.
o
Use a different injection site each time you use PYZCHIVA.
o
If you inject more PYZCHIVA than prescribed, call your doctor right away.
o
Be sure to keep all of your scheduled follow-up appointments.
Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to
prepare and inject a dose of PYZCHIVA, and how to properly throw away (dispose of) used needles, and
syringes. The syringe, needle, and vial must never be re-used. After the rubber stopper is punctured,
PYZCHIVA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore,
throw away any unused portion of PYZCHIVA.
What should I avoid while using PYZCHIVA?
You should not receive a live vaccine while taking PYZCHIVA. See "Before you receive PYZCHIVA, tell your doctor
about all of your medical conditions, including if you:"
What are the possible side effects of PYZCHIVA?
PYZCHIVA may cause serious side effects, including:
y
See "What is the most important information I should know about PYZCHIVA?"
•
Serious allergic reactions. Serious allergic reactions can occur with PYZCHIVA. Stop using PYZCHIVA and get
medical help right away if you have any of the following symptoms of a serious allergic reaction:
o
feeling faint
o
chest tightness
o
swelling of your face, eyelids, tongue, or throat
o
skin rash
•
Lung inflammation. Cases of lung inflammation have happened in some people who receive ustekinumab
products, and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right
away if you develop shortness of breath or a cough that doesn't go away during treatment with PYZCHIVA.
Common side effects of PYZCHIVA include:
Reference ID: 5500909
•
nasal congestion, sore throat, and runny nose
•
redness at the injection site
y
upper respiratory infections
y
vaginal yeast infections
y
fever
y
urinary tract infections
y
headache
y
sinus infection
y
tiredness
y
bronchitis
y
itching
y
diarrhea
•
nausea and vomiting
y
stomach pain
These are not all of the possible side effects of PYZCHIVA. Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to Sandoz Inc. at 1-800-525-8747.
How should I store PYZCHIVA?
•
Store PYZCHIVA vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Store PYZCHIVA vials standing up straight.
•
Store PYZCHIVA in the original carton to protect it from light until time to use it.
•
Do not freeze PYZCHIVA.
•
Do not shake PYZCHIVA.
•
If needed, individual PYZCHIVA prefilled syringes may be stored at room temperature up to 86ºF (30°C) for a
maximum single period of up to 35 days in the original carton to protect from light.
•
Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space
provided.
•
You may return the prefilled syringe to the refrigerator 1 time only for a maximum of 60 days, either during the 35
day period or at the end of the 35-day period.
•
Record the date when the prefilled syringe is returned to the refrigerator on the carton.
•
Discard the prefilled syringe if not used within 35 days of room temperature storage and you did not return it to the
refrigerator, or if it has been returned to the refrigerator and is not used within 60 days.
•
Do not use PYZCHIVA after the expiration date on the carton or on the prefilled syringe.
Keep PYZCHIVA and all medicines out of the reach of children.
General information about the safe and effective use of PYZCHIVA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PYZCHIVA
for a condition for which it was not prescribed. Do not give PYZCHIVA to other people, even if they have the same
symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about PYZCHIVA
that was written for health professionals.
What are the ingredients in PYZCHIVA?
Active ingredient: ustekinumab-ttwe
Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains histidine, histidine hydrochloride
monohydrate, polysorbate 80, and sucrose. Single-dose vial for subcutaneous use contains histidine, histidine
hydrochloride monohydrate, polysorbate 80, and sucrose. Single-dose vial for intravenous infusion contains edetate
disodium, histidine, histidine hydrochloride monohydrate, methionine, polysorbate 80, and sucrose.
Manufactured by: Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for: Sandoz Inc.
Princeton, NJ 08540
For more information, call 1-800-525-8747.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
Reference ID: 5500909
INSTRUCTIONS FOR USE
PYZCHIVA® (Piz-chi-va)
(ustekinumab-ttwe)
injection, for subcutaneous use
Instructions for injecting PYZCHIVA using a prefilled syringe.
Read this Instructions for Use before you start using PYZCHIVA. Your doctor or nurse
should show you how to prepare and give your injection of PYZCHIVA the right way.
If you cannot give yourself the injection:
•
ask your doctor or nurse to help you, or
•
ask someone who has been trained by a doctor or nurse to give your injections.
Do not try to inject PYZCHIVA yourself until you have been shown how to inject PYZCHIVA by
your doctor, nurse or health professional.
Important information:
•
Before you start, check the carton to make sure that it is the right dose. You will have
either 45 mg or 90 mg as prescribed by your doctor.
ƕ
If your dose is 45 mg, you will receive one 45 mg prefilled syringe.
ƕ
If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg
prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you
will need to give yourself two injections, one right after the other.
•
Children 12 years of age and older with psoriasis who weigh 132 pounds (60 kg) or more may
use a prefilled syringe.
•
Check the expiration date on the prefilled syringe and carton. Do not use PYZCHIVA after
the expiration date has passed. If the expiration date has passed or if the prefilled syringe
has been stored above 86ºF (30ºC), call your doctor or pharmacist, or call Sandoz Inc. at
1-800-525-8747 for help.
•
Make sure the syringe is not damaged. Do not use the prefilled syringe if it is damaged.
•
Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should
look clear and colorless to light yellow.
•
Do not use if it is frozen, discolored, cloudy or has particles. Get a new prefilled syringe.
•
Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may
damage your PYZCHIVA medicine. If your prefilled syringe has been shaken, do not use it.
Get a new prefilled syringe.
•
To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard
that is automatically activated to cover the needle after you have given your injection. Do
not pull back on the plunger at any time.
Storage information
•
Store PYZCHIVA in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Store PYZCHIVA in the original carton to protect from light until the time of use.
•
Do not freeze PYZCHIVA.
•
If needed, individual prefilled syringes may be stored at room temperature up to 86ºF (30ºC)
for a maximum single period of up to 35 days in the original carton to protect from light.
•
Record the date when the prefilled syringe is removed from the refrigerator on the carton in
the space provided.
•
You may return the prefilled syringe to the refrigerator 1 time only for a maximum of 60 days,
either during the 35-day period or at the end of the 35-day period.
•
Record the date when the prefilled syringe is returned to the refrigerator on the carton.
•
Discard the prefilled syringe if not used within 35 days of room temperature storage and you
Reference ID: 5500909
PYZCHIVA prefilled syringe
Viewing window
Needle cover
Needle
Adhesive
bandage
Body
Label
Antiseptic
Cotton ball
FDA-cleared sharps
wipes
or gauze pads
disposal container
Needle guard wings
Plunger
Plunger head
did not return it to the refrigerator, or if it has been returned to the refrigerator and is not used
within 60 days.
Gather the supplies you will need to prepare and to give your injection. (See Figure A)
You will need:
•
antiseptic wipes
•
cotton balls or gauze pads
•
adhesive bandage
•
your prescribed dose of PYZCHIVA (See Figure B)
•
FDA-cleared sharps disposal container. See "Step 4: Dispose of the syringe."
Figure A
Figure B
Step 1: Prepare the injection
•
Choose a well-lit, clean, flat work surface.
•
Leave PYZCHIVA prefilled syringe at room temperature for about 30 minutes before injecting.
Do not warm the prefilled syringe in any other way (for example, do not warm it in a
microwave or in hot water).
•
Wash your hands well with soap and warm water.
•
Hold the prefilled syringe with the covered needle pointing upward.
Step 2: Prepare your injection site
•
Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs).
If a caregiver is giving you the injection, the outer area of the upper arms may also be used.
(See Figure C)
Reference ID: 5500909
~
•
Use a different injection site for each injection. Do not give an injection in an area of
the skin that is tender, bruised, red or hard.
•
Clean the skin with an antiseptic wipe where you plan to give your injection.
•
Do not touch this area again before giving the injection. Let your skin dry before injecting.
•
Do not fan or blow on the clean area.
Figure C
*Areas in gray are recommended injection sites.
Step 3: Inject PYZCHIVA
•
Remove the needle cover when you are ready to inject your PYZCHIVA.
•
Do not touch the plunger or plunger head while removing the needle cover.
•
Hold the body of the prefilled syringe with one hand, and pull the needle cover straight off.
(See Figure D)
•
Put the needle cover in the trash.
•
You may also see a drop of liquid at the end of the needle. This is normal.
•
Do not touch the needle or let it touch anything.
•
Do not use the prefilled syringe if it is dropped without the needle cover in place. Call your
doctor, nurse or health professional for instructions.
Figure D
•
Hold the body of the prefilled syringe in one hand between the thumb and index fingers. (See
Reference ID: 5500909
45°
Figure E)
Figure E
•
Do not pull back on the plunger at any time.
•
Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
•
Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree
angle. (See Figure F)
Figure F
•
Inject all of the liquid by using your thumb to push in the plunger until the plunger head is
completely between the needle guard wings. (See Figure G)
Reference ID: 5500909
Needle guard wings
Figure G
•
When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take
the needle out of the skin and let go of the skin.
•
Slowly take your thumb off the plunger head. This will let the empty syringe move up until the
entire needle is covered by the needle guard. (See Figure H)
Figure H
•
When the needle is pulled out of your skin, there may be a little bleeding at the injection
site. This is normal. You can press a cotton ball or gauze pad to the injection site if
needed. Do not rub the injection site. You may cover the injection site with a small adhesive
bandage, if necessary.
If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg
prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need
Reference ID: 5500909
to give yourself a second injection right after the first. Repeat Steps 1 to 3 for the second
injection using a new syringe. Choose a different site for the second injection.
Step 4: Dispose of the syringe.
•
Put the syringe in an FDA-cleared sharps disposal container right away after use. Do not
throw away (dispose of) loose syringes in your household trash.
•
If you do not have an FDA-cleared sharps disposal container, you may use a household
container that is:
ƕ
made of heavy-duty plastic,
ƕ
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come
out,
ƕ
upright and stable during use,
ƕ
leak-resistant,
ƕ
and properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be local
or state laws about how to throw away syringes and needles. For more information about safe
sharps disposal, and for specific information about sharps disposal in the state that you live
in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your sharps disposal container.
•
If you have any questions, talk to your doctor or pharmacist.
Keep PYZCHIVA and all medicines out of the reach of children.
Manufactured by:
Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for:
Sandoz Inc.
Princeton, NJ 08540
This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised 12/2024
Reference ID: 5500909
INSTRUCTIONS FOR USE
PYZCHIVA® (Piz-chi-va)
(ustekinumab-ttwe)
injection, for subcutaneous use
Instructions for injecting PYZCHIVA from a vial.
Read this Instructions for Use before you start using PYZCHIVA. Your doctor or nurse
should show you how to prepare, measure your dose, and give your injection of
PYZCHIVA the right way.
If you cannot give yourself the injection:
•
ask your doctor or nurse to help you, or
•
ask someone who has been trained by a doctor or nurse to give your injections.
Do not try to inject PYZCHIVA yourself until you have been shown how to inject PYZCHIVA by
your doctor, nurse or health professional.
Important information:
•
Before you start, check the carton to make sure that it is the right dose. You will have
either 45 mg or 90 mg as prescribed by your doctor.
ƕ
If your dose is 45 mg or less you will receive one 45 mg vial.
ƕ
If your dose is 90 mg, you will receive two 45 mg vials and you will need to give
yourself two injections, one right after the other.
•
Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45
mg.
•
Check the expiration date on the vial and carton. If the expiration date has passed, do not use it.
If the expiration date has passed, call your doctor or pharmacist, or call Sandoz Inc. at 1-800
525-8747 for help.
•
Check the vial for any particles or discoloration. Your vial should look clear and colorless to light
yellow.
•
Do not use if it is frozen, discolored, cloudy or has particles. Get a new vial.
•
Do not shake the vial at any time. Shaking your vial may damage your PYZCHIVA medicine. If
your vial has been shaken, do not use it. Get a new vial.
•
Do not use a PYZCHIVA vial more than one time, even if there is medicine left in the vial. After
the rubber stopper is punctured, PYZCHIVA can become contaminated by harmful bacteria
which could cause an infection if re-used. Therefore, throw away any unused PYZCHIVA after
you give your injection.
•
Safely throw away (dispose of) PYZCHIVA vials after use.
•
Do not re-use syringes or needles. See "Step 6: Dispose of needles and syringes."
•
To avoid needle-stick injuries, do not recap needles.
Storage information
•
Store PYZCHIVA in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Store PYZCHIVA vials standing up straight.
•
Store PYZCHIVA in the original carton to protect from light until the time of use.
•
Do not freeze PYZCHIVA.
Gather the supplies you will need to prepare PYZCHIVA and to give your injection. (See
Figure A)
You will need:
•
a syringe with the needle attached, you will need a prescription from your healthcare provider to
get syringes with the needles attached from your pharmacy.
Reference ID: 5500909
g
,
□ (5) 0
tr
Adhesive
Antiseptic
Cotton ball
PYZCHIVA
Syringe and Attached Needle
FDA-cleared sharps
bandage
wipes
or gauze pads
Vial
disposal container
) \
•
antiseptic wipes
•
cotton balls or gauze pads
•
adhesive bandage
•
your prescribed dose of PYZCHIVA
•
FDA-cleared sharps disposal container. See "Step 6: Dispose of needles and syringes."
Figure A
Step 1: Prepare the injection.
•
Choose a well-lit, clean, flat work surface.
•
Wash your hands well with soap and warm water.
Step 2: Prepare your injection site
•
Choose an injection site around your stomach area (abdomen), buttocks, and upper legs
(thighs).
•
If a caregiver is giving you the injection, the outer area of the upper arms may also be used.
(See Figure B)
•
Use a different injection site for each injection. Do not give an injection in an area of the skin
that is tender, bruised, red or hard.
•
Clean the skin with an antiseptic wipe where you plan to give your injection.
•
Do not touch this area again before giving the injection. Let your skin dry before injecting.
•
Do not fan or blow on the clean area.
Figure B
*Areas in gray are recommended injection sites.
Reference ID: 5500909
g
Step 3: Prepare the vial.
•
Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber
stopper. (See Figure C)
Figure C
•
Clean the rubber stopper with an antiseptic swab. (See Figure D)
Figure D
•
Do not touch the rubber stopper after you clean it.
•
Put the vial on a flat surface.
Step 4: Prepare the syringe
•
Pick up the syringe with the needle attached.
•
Remove the cap that covers the needle. (See Figure E)
•
Throw the needle cap away. Do not touch the needle or allow the needle to touch anything.
Figure E
Reference ID: 5500909
•
Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor.
•
Hold the vial between your thumb and index (pointer) finger.
•
Use your other hand to push the syringe needle through the center of the rubber
stopper. (See Figure F)
Figure F
•
Push down on the plunger until all of the air has gone from the syringe into the vial.
•
Turn the vial and the syringe upside down. (See Figure G)
•
Hold the PYZCHIVA vial with one hand.
•
It is important that the needle is always in the liquid in order to prevent air bubbles forming in the
syringe.
•
Pull back on the syringe plunger with your other hand.
•
Fill the syringe until the black tip of the plunger lines up with the mark that matches your
prescribed dose.
Figure G
Reference ID: 5500909
I~))
•
Do not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it
has any air bubbles inside.
•
If there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the
top. (See Figure H)
•
Slowly press the plunger up until all of the air bubbles are out of the syringe (but none of the
liquid is out).
•
Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch
anything.
Figure H
Step 5: Inject PYZCHIVA
•
Hold the barrel of the syringe in one hand, between the thumb and index fingers.
•
Do not pull back on the plunger at any time.
Reference ID: 5500909
g
•
Use the other hand to gently pinch the cleaned area of skin. Hold firmly.
•
Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree
angle. (See Figure I)
Figure I
•
Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and
evenly, keeping the skin gently pinched.
•
When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J)
Figure J
•
When the needle is pulled out of your skin, there may be a little bleeding at the injection site.
This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not
Reference ID: 5500909
rub the injection site. You may cover the injection site with a small adhesive bandage, if
necessary.
If your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a
second injection right after the first. Repeat Steps 1 to 5 using a new syringe. Choose a
different site for the second injection.
Step 6: Dispose of the needles and syringes.
•
Do not re-use a syringe or needle.
•
To avoid needle-stick injuries, do not recap a needle.
•
Put your needles and syringes in an FDA-cleared sharps disposal container right away after use.
Do not throw away (dispose of) loose needles and syringes in your household trash.
•
If you do not have an FDA-cleared sharps disposal container, you may use a household
container that is:
ƕ
made of heavy-duty plastic
ƕ
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come
out
ƕ
upright and stable during use
ƕ
leak-resistant,
ƕ
and properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be local or
state laws about how to throw away syringes and needles. For more information about safe
sharps disposal, and for specific information about sharps disposal in the state that you live in,
go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your sharps disposal container.
•
Throw away the vial into the container where you put the syringes and needles.
•
If you have any questions, talk to your doctor or pharmacist.
Keep PYZCHIVA and all medicines out of reach IURP children.
Manufactured by:
Samsung Bioepis Co., Ltd.,
76, Songdogyoyuk-ro, Yeonsu-gu, Incheon, 21987, Republic of Korea
U.S. License No. 2046
Manufactured for:
Sandoz Inc.
Princeton, NJ 08540
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued 12/2024
Reference ID: 5500909
| custom-source | 2025-02-12T15:48:11.807206 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761373s002,761425s002lbl.pdf', 'application_number': 761425, 'submission_type': 'SUPPL ', 'submission_number': 2} |
80,746 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IBRANCE safely and effectively. See full prescribing information for
IBRANCE.
IBRANCE® (palbociclib) capsules, for oral use
Initial U.S. Approval: 2015
--------------------------- INDICATIONS AND USAGE ----------------------------
IBRANCE is a kinase inhibitor indicated for the treatment of adult patients
with hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer in
combination with:
•
an aromatase inhibitor as initial endocrine-based therapy (1); or
•
fulvestrant in patients with disease progression following
endocrine therapy. (1)
----------------------- DOSAGE AND ADMINISTRATION -----------------------
IBRANCE capsules are taken orally with food in combination with an
aromatase inhibitor or fulvestrant. (2)
•
Recommended starting dose: 125 mg once daily taken with food for
21 days followed by 7 days off treatment. (2.1)
•
Dosing interruption and/or dose reductions are recommended based on
individual safety and tolerability. (2.2)
--------------------- DOSAGE FORMS AND STRENGTHS ----------------------
Capsules: 125 mg, 100 mg, and 75 mg. (3)
------------------------------ CONTRAINDICATIONS ------------------------------
None. (4)
----------------------- WARNINGS AND PRECAUTIONS -----------------------
•
Neutropenia: Monitor complete blood count prior to start of IBRANCE
therapy and at the beginning of each cycle, as well as on Day 15 of the
first 2 cycles, and as clinically indicated. (2.2, 5.1)
•
Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of
ILD/pneumonitis have been reported. Monitor for pulmonary symptoms
of ILD/pneumonitis. Interrupt IBRANCE immediately in patients with
suspected ILD/pneumonitis. Permanently discontinue IBRANCE if
severe ILD/pneumonitis occurs. (5.2)
•
Embryo-Fetal Toxicity: IBRANCE can cause fetal harm. Advise
patients of potential risk to a fetus and to use effective contraception.
(5.3, 8.1, 8.3)
------------------------------ ADVERSE REACTIONS ------------------------------
Most common adverse reactions (incidence ≥10%) were neutropenia,
infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea,
thrombocytopenia, rash, vomiting, decreased appetite, asthenia, and
pyrexia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS-------------------------------
•
CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong
CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the
IBRANCE dose. (2.2, 7.1)
•
CYP3A Inducers: Avoid concurrent use of IBRANCE with strong
CYP3A inducers. (7.2)
•
CYP3A Substrates: The dose of sensitive CYP3A4 substrates with
narrow therapeutic indices may need to be reduced when given
concurrently with IBRANCE. (7.3)
----------------------------USE IN SPECIFIC POPULATIONS-------------------
•
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dose and Schedule
2.2 Dose Modification
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Neutropenia
5.2 Interstitial Lung Disease (ILD)/Pneumonitis
5.3 Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Agents That May Increase Palbociclib Plasma Concentrations
7.2 Agents That May Decrease Palbociclib Plasma Concentrations
7.3 Drugs That May Have Their Plasma Concentrations Altered by
Palbociclib
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed
_______________________________________________________________________________________________________________________________________
Reference ID: 5501310
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
IBRANCE is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human
epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:
• an aromatase inhibitor as initial endocrine-based therapy; or
• fulvestrant in patients with disease progression following endocrine therapy.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dose and Schedule
The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days
followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with
food [see Clinical Pharmacology (12.3)].
Administer the recommended dose of an aromatase inhibitor when given with IBRANCE. Please refer to the
Full Prescribing Information for the aromatase inhibitor being used.
When given with IBRANCE, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29,
and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant.
Patients should be encouraged to take their dose of IBRANCE at approximately the same time each day.
If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should
be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush, or open them
prior to swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact.
Pre/perimenopausal women treated with the combination IBRANCE plus an aromatase inhibitor or fulvestrant
therapy should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to
current clinical practice standards.
For men treated with combination IBRANCE plus aromatase inhibitor therapy, consider treatment with an
LHRH agonist according to current clinical practice standards.
2.2
Dose Modification
The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3.
Table 1. Recommended Dose Modification for Adverse Reactions
Dose Level
Dose
Recommended starting dose
125 mg/day
First dose reduction
100 mg/day
Second dose reduction
75 mg/day*
*If further dose reduction below 75 mg/day is required, discontinue.
Reference ID: 5501310
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Table 2. Dose Modification and Management – Hematologic Toxicitiesa
Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of
each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.
For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles,
monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a
cycle and as clinically indicated.
CTCAE Grade
Dose Modifications
Grade 1 or 2
No dose adjustment is required.
Grade 3
Day 1 of cycle:
Withhold IBRANCE, repeat complete blood count monitoring within
1 week. When recovered to Grade ≤2, start the next cycle at the same
dose.
Day 15 of first 2 cycles:
If Grade 3 on Day 15, continue IBRANCE at current dose to complete
cycle and repeat complete blood count on Day 22.
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below.
Consider dose reduction in cases of prolonged (>1 week) recovery from
Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of
subsequent cycles.
Grade 3
neutropeniab with
fever ≥38.5 ºC
and/or infection
At any time:
Withhold IBRANCE until recovery to Grade ≤2.
Resume at the next lower dose.
Grade 4
At any time:
Withhold IBRANCE until recovery to Grade ≤2.
Resume at the next lower dose.
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal.
a
Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events,
e.g., opportunistic infections).
b
Absolute neutrophil count (ANC): Grade 1: ANC < LLN - 1500/mm3; Grade 2: ANC 1000 - <1500/mm3;
Grade 3: ANC 500 - <1000/mm3; Grade 4: ANC <500/mm3.
Table 3. Dose Modification and Management – Non-Hematologic Toxicities
CTCAE Grade
Dose Modifications
Grade 1 or 2
No dose adjustment is required.
Grade ≥3 non-hematologic toxicity (if
persisting despite optimal medical
treatment)
Withhold until symptoms resolve to:
• Grade ≤1;
• Grade ≤2 (if not considered a safety risk
for the patient)
Resume at the next lower dose.
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events.
Reference ID: 5501310
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Permanently discontinue IBRANCE in patients with severe interstitial lung disease (ILD)/pneumonitis.
Refer to the Full Prescribing Information for coadministered endocrine therapy dose adjustment guidelines in
the event of toxicity and other relevant safety information or contraindications.
Dose Modifications for Use With Strong CYP3A Inhibitors
Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no
or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the
IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose
(after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see
Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Dose Modifications for Hepatic Impairment
No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A
and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of
IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a
complete cycle of 28 days [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
125 mg capsules: opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with white ink
“Pfizer” on the cap, “PBC 125” on the body.
100 mg capsules: opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, printed with
white ink “Pfizer” on the cap, “PBC 100” on the body.
75 mg capsules: opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with white ink
“Pfizer” on the cap, “PBC 75” on the body.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Neutropenia
Neutropenia was the most frequently reported adverse reaction in PALOMA-2 with an incidence of 80% and
PALOMA-3 with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in 66% of
patients receiving IBRANCE plus letrozole in PALOMA-2 and 66% of patients receiving IBRANCE plus
fulvestrant in PALOMA-3. In PALOMA-2 and PALOMA-3, the median time to first episode of any grade
neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days [see Adverse
Reactions (6.1)].
Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, as well
as on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in
starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and
Administration (2.2)].
Reference ID: 5501310
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Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and
PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Physicians should inform
patients to promptly report any episodes of fever [see Patient Counseling Information (17)].
5.2
Interstitial Lung Disease (ILD)/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated
with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in combination with
endocrine therapy.
Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had
ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4 and no fatal cases were reported. Additional cases of
ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Adverse
Reactions (6.2)].
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In
patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis,
interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with
severe ILD or pneumonitis [see Dosage and Administration (2.2)].
5.3
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when
administered to a pregnant woman. In animal reproduction studies, administration of palbociclib to pregnant
rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times
the human clinical exposure based on area under the curve (AUC). Advise pregnant women of the potential
risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with
IBRANCE and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1 and 8.3) and
Clinical Pharmacology (12.1)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Neutropenia [see Warnings and Precautions (5.1)]
• ILD/Pneumonitis [see Warnings and Precautions (5.2)]
Reference ID: 5501310
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6.1
Clinical Studies Experience
Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be
directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
PALOMA-2: IBRANCE plus Letrozole
Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for
initial endocrine based therapy
The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was evaluated
in PALOMA-2. The data described below reflect exposure to IBRANCE in 444 out of 666 patients with
ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of IBRANCE plus letrozole in
PALOMA-2. The median duration of treatment for IBRANCE plus letrozole was 19.8 months while the
median duration of treatment for placebo plus letrozole arm was 13.8 months.
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus
letrozole. No dose reduction was allowed for letrozole in PALOMA-2.
Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients receiving
IBRANCE plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole. Adverse reactions
leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included
neutropenia (1.1%) and alanine aminotransferase increase (0.7%).
The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole
arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis,
diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and
dysgeusia.
The most frequently reported Grade >3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole
by descending frequency were neutropenia, leukopenia, infections, and anemia.
Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole
in PALOMA-2 are listed in Table 4.
Reference ID: 5501310
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Table 4. Adverse Reactions (≥10%) in PALOMA-2
IBRANCE plus Letrozole
(N=444)
Placebo plus Letrozole
(N=222)
Adverse Reaction
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Infections and infestations
Infectionsa
60b
6
1
42
3
0
Blood and lymphatic system disorders
Neutropenia
Leukopenia
Anemia
Thrombocytopenia
80
39
24
16
56
24
5
1
10
1
<1
<1
6
2
9
1
1
0
2
0
1
0
0
0
Metabolism and nutrition disorders
Decreased appetite
15
1
0
9
0
0
Nervous system disorders
Dysgeusia
10
0
0
5
0
0
Gastrointestinal disorders
Stomatitisc
Nausea
Diarrhea
Vomiting
30
35
26
16
1
<1
1
1
0
0
0
0
14
26
19
17
0
2
1
1
0
0
0
0
Skin and subcutaneous tissue disorders
Alopecia
Rashf
Dry skin
33d
18
12
N/A
1
0
N/A
0
0
16e
12
6
N/A
1
0
N/A
0
0
General disorders and administration site conditions
Fatigue
Asthenia
Pyrexia
37
17
12
2
2
0
0
0
0
28
12
9
1
0
0
0
0
0
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable;
a Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and
infestations.
b Most common infections (>1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection,
oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster,
pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection,
gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis.
c
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation,
oral pain, oral discomfort, oropharyngeal pain, and stomatitis.
d
Grade 1 events – 30%; Grade 2 events – 3%.
e
Grade 1 events – 15%; Grade 2 events – 1%.
f
Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular,
dermatitis, dermatitis acneiform, and toxic skin eruption.
Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus
letrozole in PALOMA-2 included alanine aminotransferase increased (9.9%), aspartate aminotransferase
increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%), vision blurred (3.6%), and
febrile neutropenia (2.5%).
Reference ID: 5501310
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Table 5. Laboratory Abnormalities in PALOMA-2
IBRANCE plus Letrozole
(N=444)
Placebo plus Letrozole
(N=222)
Laboratory Abnormality
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
WBC decreased
97
35
1
25
1
0
Neutrophils decreased
95
56
12
20
1
1
Anemia
78
6
0
42
2
0
Platelets decreased
63
1
1
14
0
0
Aspartate aminotransferase
increased
52
3
0
34
1
0
Alanine aminotransferase
increased
43
2
<1
30
0
0
N=number of patients; WBC=white blood cells.
PALOMA-3: IBRANCE plus Fulvestrant
Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease
progression on or after prior adjuvant or metastatic endocrine therapy
The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated
in PALOMA-3. The data described below reflect exposure to IBRANCE in 345 out of 517 patients with
HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of IBRANCE
plus fulvestrant in PALOMA-3. The median duration of treatment for IBRANCE plus fulvestrant was
10.8 months while the median duration of treatment for placebo plus fulvestrant arm was 4.8 months.
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus
fulvestrant. No dose reduction was allowed for fulvestrant in PALOMA-3.
Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving
IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions
leading to discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%),
infections (0.6%), and thrombocytopenia (0.6%).
The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus fulvestrant
arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis,
diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.
The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus
fulvestrant in descending frequency were neutropenia and leukopenia.
Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus
fulvestrant in PALOMA-3 are listed in Table 6.
Reference ID: 5501310
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Table 6. Adverse Reactions (≥10%) in PALOMA-3
Adverse Reaction
IBRANCE plus Fulvestrant
(N=345)
Placebo plus Fulvestrant
(N=172)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
%
%
%
%
%
%
Infections and infestations
Infectionsa
47b
3
1
31
3
0
Blood and lymphatic system disorders
Neutropenia
83
55
11
4
1
0
Leukopenia
53
30
1
5
1
1
Anemia
30
4
0
13
2
0
Thrombocytopenia
23
2
1
0
0
0
Metabolism and nutrition disorders
Decreased appetite
16
1
0
8
1
0
Gastrointestinal disorders
Nausea
34
0
0
28
1
0
Stomatitisc
28
1
0
13
0
0
Diarrhea
24
0
0
19
1
0
Vomiting
19
1
0
15
1
0
Skin and subcutaneous tissue disorders
Alopecia
18d
N/A
N/A
6e
N/A
N/A
Rashf
17
1
0
6
0
0
General disorders and administration site conditions
Fatigue
41
2
0
29
1
0
Pyrexia
13
<1
0
5
0
0
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
a
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections
and infestations.
b Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract
infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes,
respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and
paronychia.
c
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal
inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
d Grade 1 events – 17%; Grade 2 events – 1%.
e
Grade 1 events – 6%.
f
Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis,
dermatitis acneiform, toxic skin eruption.
Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus
fulvestrant in PALOMA-3 included asthenia (7.5%), aspartate aminotransferase increased (7.5%),
dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine aminotransferase
increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).
Reference ID: 5501310
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Table 7. Laboratory Abnormalities in PALOMA-3
Laboratory Abnormality
IBRANCE plus Fulvestrant
(N=345)
Placebo plus Fulvestrant
(N=172)
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
WBC decreased
99
45
1
26
0
1
Neutrophils decreased
96
56
11
14
0
1
Anemia
78
3
0
40
2
0
Platelets decreased
62
2
1
10
0
0
Aspartate aminotransferase
increased
43
4
0
48
4
0
Alanine aminotransferase
increased
36
2
0
34
0
0
N=number of patients; WBC=white blood cells.
Other Clinical Trials Experience
The following adverse reaction has been reported following administration of IBRANCE: venous
thromboembolism.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of IBRANCE. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Respiratory Disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis
Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES)
Male patients with HR-positive, HER2-negative advanced or metastatic breast cancer
Based on limited data from postmarketing reports and electronic health records, the safety profile for men
treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.
7
DRUG INTERACTIONS
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo,
palbociclib is a time-dependent inhibitor of CYP3A.
7.1
Agents That May Increase Palbociclib Plasma Concentrations
Effect of CYP3A Inhibitors
Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in
healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir,
itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
telaprevir, telithromycin, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment.
If coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of
IBRANCE [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Reference ID: 5501310
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7.2
Agents That May Decrease Palbociclib Plasma Concentrations
Effect of CYP3A Inducers
Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in
healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin,
carbamazepine, enzalutamide, and St John’s Wort) [see Clinical Pharmacology (12.3)].
7.3
Drugs That May Have Their Plasma Concentrations Altered by Palbociclib
Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by
61%, in healthy subjects, compared to administration of midazolam alone. The dose of the sensitive CYP3A
substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine,
everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced, as IBRANCE
may increase its exposure [see Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when
administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant
women to inform the drug-associated risk. In animal reproduction studies, administration of palbociclib to
pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were
≥4 times the human clinical exposure based on AUC [see Data]. Advise pregnant women of the potential risk
to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data
Animal Data
In a fertility and early embryonic development study in female rats, palbociclib was administered orally for
15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses up
to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the
recommended dose.
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of palbociclib up
to 300 mg/kg/day and 20 mg/kg/day, respectively, during the period of organogenesis. The maternally toxic
dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. At doses ≥100 mg/kg/day
in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the
seventh cervical vertebra). At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased
incidence of skeletal variations, including small phalanges in the forelimb. At 300 mg/kg/day in rats and
20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human
exposure (AUC) at the recommended dose, respectively.
Reference ID: 5501310
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CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5
until birth) due to severe anemia. However, knockout mouse data may not be predictive of effects in humans
due to differences in degree of target inhibition.
8.2
Lactation
Risk Summary
There is no information regarding the presence of palbociclib in human milk, its effects on milk production, or
the breastfed infant. Because of the potential for serious adverse reactions in breastfed infants from IBRANCE,
advise a lactating woman not to breastfeed during treatment with IBRANCE and for 3 weeks after the last dose.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Based on animal studies, IBRANCE can cause fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting
treatment with IBRANCE.
Contraception
Females
IBRANCE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations
(8.1)]. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE
and for at least 3 weeks after the last dose.
Males
Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to
use effective contraception during treatment with IBRANCE and for 3 months after the last dose [see
Nonclinical Toxicology (13.1)].
Infertility
Males
Based on animal studies, IBRANCE may impair fertility in males of reproductive potential [see Nonclinical
Toxicology (13.1)].
8.4
Pediatric Use
The safety and efficacy of IBRANCE in pediatric patients have not been studied.
Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the
pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, chronic
progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose toxicology
study in rats that were immature at the beginning of the studies and were most prevalent in males at oral
palbociclib doses ≥30 mg/kg/day (approximately 11 times the adult human exposure [AUC] at the
recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and
Reference ID: 5501310
13
kidney tubule vacuolation) were present with lower incidence and severity in a 15 week repeat-dose toxicology
study in immature rats. Altered glucose metabolism or associated changes in the pancreas, eye, kidney and
adipose tissue were not identified in a 27-week repeat-dose toxicology study in rats that were mature at the
beginning of the study and in dogs in repeat-dose toxicology studies up to 39 weeks duration.
Toxicities in teeth independent of altered glucose metabolism were observed in rats. Administration of
100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the
recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast
degeneration/necrosis, mononuclear cell infiltrate). Other toxicities of potential concern to pediatric patients
have not been evaluated in juvenile animals.
8.5
Geriatric Use
Of 444 patients who received IBRANCE in PALOMA-2, 181 patients (41%) were ≥65 years of age and
48 patients (11%) were ≥75 years of age. Of 347 patients who received IBRANCE in PALOMA-3, 86 patients
(25%) were ≥65 years of age and 27 patients (8%) were ≥75 years of age. No overall differences in safety or
effectiveness of IBRANCE were observed between these patients and younger patients.
8.6
Hepatic Impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh classes A and
B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is
75 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of
28 days [see Dosage and Administration (2.2)]. Based on a pharmacokinetic trial in subjects with varying
degrees of hepatic function, the palbociclib unbound exposure (unbound AUCINF) decreased by 17% in subjects
with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate
(Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, relative to subjects with
normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax) increased by 7%, 38% and 72%
for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic
function [see Clinical Pharmacology (12.3)].
Review the Full Prescribing Information for the aromatase inhibitor or fulvestrant for dose modifications related
to hepatic impairment.
8.7
Renal Impairment
No dose adjustment is required in patients with mild, moderate, or severe renal impairment (CrCl >15 mL/min).
Based on a pharmacokinetic trial in subjects with varying degrees of renal function, the total palbociclib
exposure (AUCINF) increased by 39%, 42%, and 31% with mild (60 mL/min ≤ CrCl <90 mL/min), moderate
(30 mL/min ≤ CrCl <60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, relative to
subjects with normal renal function. Peak palbociclib exposure (Cmax) increased by 17%, 12%, and 15% for
mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. The
pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis [see Clinical
Pharmacology (12.3)].
10
OVERDOSAGE
There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general
supportive measures.
Reference ID: 5501310
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11
DESCRIPTION
IBRANCE capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor.
The molecular formula for palbociclib is C24H29N7O2. The molecular weight is 447.54 daltons. The chemical
name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-
7(8H)-one, and its structural formula is:
NN
NN
NN
M
Mee
O
O
NNHH
NN
NN
HHNN
O
O
M
Mee
Palbociclib is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the
pyridine nitrogen). At or below pH 4, palbociclib behaves as a high-solubility compound. Above pH 4, the
solubility of the drug substance reduces significantly.
Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon
dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light orange/caramel, and
caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, and titanium dioxide; the
printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol, and simethicone.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream
of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of
estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase
of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens
leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and
signaling, and increased growth arrest compared to treatment with each drug alone. In vitro treatment of
ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens led to increased cell
senescence compared to each drug alone, which was sustained for up to 6 days following palbociclib removal
and was greater if antiestrogen treatment was continued. In vivo studies using a patient-derived ER-positive
breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the
inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone.
Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti-estrogen
in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.
12.2
Pharmacodynamics
Cardiac Electrophysiology
The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched
electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in
77 patients with breast cancer. Palbociclib had no large effect on QTc (i.e., >20 ms) at 125 mg once daily for
21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.
Reference ID: 5501310
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12.3
Pharmacokinetics
The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including advanced
breast cancer and in healthy subjects.
Absorption
The mean maximum observed concentration (Cmax) of palbociclib is generally observed between 6 to 12 hours
(time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability
of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax
increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once
daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation
ratio of 2.4 (range 1.5 to 4.2).
Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under
the fasted condition. Food intake increased the palbociclib exposure in this small subset of the population, but
did not alter palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food
intake reduced the intersubject variability of palbociclib exposure, which supports administration of IBRANCE
with food. Compared to IBRANCE given under overnight fasted conditions, the population average area under
the concentration-time curve from zero to infinity (AUCINF) and Cmax of palbociclib increased by 21% and 38%,
respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250,
and 500 to 600 calories from protein, carbohydrate, and fat, respectively), by 12% and 27%, respectively, when
given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories
from protein, carbohydrate, and fat, respectively), and by 13% and 24%, respectively, when moderate-fat,
standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories
from protein, carbohydrate, and fat, respectively) was given 1 hour before and 2 hours after IBRANCE dosing.
Distribution
Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration
dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction unbound (fu) of
palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There was no
obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function. The geometric
mean apparent volume of distribution (Vz/F) was 2583 L with a coefficient of variation (CV) of 26%.
Metabolism
In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral
administration of a single 125 mg dose of [14C]palbociclib to humans, the primary metabolic pathways for
palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor
pathways. Palbociclib was the major circulating drug-derived entity in plasma (23%). The major circulating
metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered
dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and
6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was
the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human
hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and
SULT2A1 are mainly involved in the metabolism of palbociclib.
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Elimination
The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean
(± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer.
In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total
administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of
excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites.
Age, Gender, and Body Weight
Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients,
age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender had no effect on the
exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of
palbociclib.
Pediatric Population
Pharmacokinetics of IBRANCE have not been evaluated in patients <18 years of age.
Hepatic Impairment
Data from a pharmacokinetic trial in subjects with varying degrees of hepatic impairment indicate that
palbociclib unbound AUCINF decreased 17% in subjects with mild hepatic impairment (Child-Pugh class A),
and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh class C)
hepatic impairment, respectively, relative to subjects with normal hepatic function. Palbociclib unbound Cmax
increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to
subjects with normal hepatic function. In addition, based on a population pharmacokinetic analysis that
included 183 patients, where 40 patients had mild hepatic impairment based on National Cancer Institute (NCI)
classification (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild
hepatic impairment had no effect on the exposure of palbociclib, further supporting the findings from the
dedicated hepatic impairment study.
Renal Impairment
Data from a pharmacokinetic trial in subjects with varying degrees of renal impairment indicate that palbociclib
AUCINF increased by 39%, 42%, and 31% with mild (60 mL/min ≤ CrCl < 90 mL/min), moderate
(30 mL/min ≤ CrCl <60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, relative to
subjects with normal renal function. Peak palbociclib exposure (Cmax) increased by 17%, 12%, and 15% for
mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. In
addition, based on a population pharmacokinetic analysis that included 183 patients where 73 patients had mild
renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no
effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients
requiring hemodialysis.
Drug Interactions
In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism of
palbociclib. Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady
state in humans. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and
is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.
Reference ID: 5501310
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CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate that coadministration
of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose increased palbociclib
AUCINF and the Cmax by approximately 87% and 34%, respectively, relative to a single 125 mg IBRANCE dose
given alone [see Drug Interactions (7.1)].
CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=15) indicate that coadministration of
multiple 600 mg daily doses of rifampin, a strong CYP3A inducer, with a single 125 mg IBRANCE dose
decreased palbociclib AUCINF and Cmax by 85% and 70%, respectively, relative to a single 125 mg IBRANCE
dose given alone. Data from a drug interaction trial in healthy subjects (N=14) indicate that coadministration of
multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose
decreased palbociclib AUCINF and Cmax by 32% and 11%, respectively, relative to a single 125 mg IBRANCE
dose given alone [see Drug Interactions (7.2)].
CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to
steady state in humans. In a drug interaction trial in healthy subjects (N=26), coadministration of midazolam
with multiple doses of IBRANCE increased the midazolam AUCINF and the Cmax values by 61% and 37%,
respectively, as compared to administration of midazolam alone [see Drug Interactions (7.3)].
Gastric pH Elevating Medications: In a drug interaction trial in healthy subjects, coadministration of a single
125 mg dose of IBRANCE with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed
conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCINF (13% decrease), when
compared to a single dose of IBRANCE administered alone. Given the reduced effect on gastric pH of
H2-receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents
on palbociclib exposure under fed conditions is expected to be minimal. Under fed conditions there is no
clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure. In another
healthy subject study, coadministration of a single dose of IBRANCE with multiple doses of the PPI
rabeprazole under fasted conditions decreased palbociclib AUCINF and Cmax by 62% and 80%, respectively,
when compared to a single dose of IBRANCE administered alone.
Letrozole: Data from a clinical trial in patients with breast cancer showed that there was no drug interaction
between palbociclib and letrozole when the 2 drugs were coadministered.
Fulvestrant: Data from a clinical trial in patients with breast cancer showed that there was no clinically relevant
drug interaction between palbociclib and fulvestrant when the 2 drugs were coadministered.
Goserelin: Data from a clinical trial in patients with breast cancer showed that there was no clinically relevant
drug interaction between palbociclib and goserelin when the 2 drugs were coadministered.
Anastrozole or Exemestane: No clinical data are available to evaluate drug interactions between anastrozole or
exemestane and palbociclib. A clinically significant drug interaction between anastrozole or exemestane and
palbociclib is not expected based on analyses of the effects of anastrozole, exemestane and palbociclib on or by
metabolic pathways or transporter systems.
Effect of Palbociclib on Transporters: In vitro evaluations indicated that palbociclib has a low potential to
inhibit the activities of drug transporters organic anion transporter (OAT)1, OAT3, organic cation transporter
(OCT)2, and organic anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically relevant
concentrations. In vitro, palbociclib has the potential to inhibit OCT1 at clinically relevant concentrations, as
well as the potential to inhibit P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in the
gastrointestinal tract at the proposed dose.
Reference ID: 5501310
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Effect of Transporters on Palbociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to
affect the extent of oral absorption of palbociclib at therapeutic doses.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat study.
Oral administration of palbociclib for 2 years resulted in an increased incidence of microglial cell tumors in the
central nervous system of male rats at a dose of 30 mg/kg/day (approximately 8 times the human clinical
exposure based on AUC). There were no neoplastic findings in female rats at doses up to 200 mg/kg/day
(approximately 5 times the human clinical exposure based on AUC). Oral administration of palbociclib to male
and female rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to
60 mg/kg/day.
Palbociclib was aneugenic in Chinese Hamster Ovary cells in vitro and in the bone marrow of male rats at doses
≥100 mg/kg/day for 3 weeks. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames)
assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay.
In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day
(approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the
female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the
dog (approximately 6 times and similar to human exposure [AUC], at the recommended dose, respectively).
The adverse effects of palbociclib on male reproductive function and fertility were observed in the repeat-dose
toxicology studies in rats and dogs and a male fertility study in rats. In repeat-dose toxicology studies,
palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle at ≥30 mg/kg/day in rats and
≥0.2 mg/kg/day in dogs included decreased organ weight, atrophy or degeneration, hypospermia, intratubular
cellular debris, and decreased secretion. Partial reversibility of male reproductive organ effects was observed in
the rat and dog following a 4- and 12-week non-dosing period, respectively. These doses in rats and dogs
resulted in approximately ≥10 and 0.1 times, respectively, the exposure [AUC] in humans at the recommended
dose. In the fertility and early embryonic development study in male rats, palbociclib caused no effects on
mating but resulted in a slight decrease in fertility in association with lower sperm motility and density at
100 mg/kg/day with projected exposure levels [AUC] of 20 times the exposure in humans at the recommended
dose.
14
CLINICAL STUDIES
PALOMA-2: IBRANCE plus Letrozole
Patients with ER-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine
based therapy
PALOMA-2 was an international, randomized, double-blind, parallel-group, multicenter study of IBRANCE
plus letrozole versus placebo plus letrozole conducted in postmenopausal women with ER-positive,
HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced
disease. A total of 666 patients were randomized 2:1 to IBRANCE plus letrozole or placebo plus letrozole.
Randomization was stratified by disease site (visceral versus non-visceral), disease-free interval (de novo
metastatic versus ≤12 months from the end of adjuvant treatment to disease recurrence versus >12 months from
the end of adjuvant treatment to disease recurrence), and nature of prior (neo)adjuvant anticancer therapies
(prior hormonal therapies versus no prior hormonal therapy). IBRANCE was given orally at a dose of 125 mg
Reference ID: 5501310
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daily for 21 consecutive days followed by 7 days off treatment. Patients received study treatment until
objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of
consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed
progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors
Version 1.1 (RECIST). Additional efficacy outcome measures were confirmed overall response rate (ORR) as
assessed by the investigator according to RECIST Version 1.1 and overall survival (OS).
Patients enrolled in this study had a median age of 62 years (range 28 to 89). The majority of patients were
White (78%), and most patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS)
of 0 or 1 (98%). Forty-eight percent of patients had received chemotherapy and 56% had received antihormonal
therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Thirty-seven
percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of
patients (97%) had metastatic disease. Twenty-three percent of patients had bone only disease, and 49% of
patients had visceral disease.
Major efficacy results from PALOMA-2 are summarized in Table 8 and Figure 1. Consistent results were
observed across patient subgroups of disease-free interval (DFI), disease site, and prior therapy. The treatment
effect of the combination on PFS was also supported by an independent review of radiographs. Based on the
prespecified final OS analysis conducted after 435 events, OS was not statistically significant.
Table 8. Efficacy Results – PALOMA-2
IBRANCE
plus Letrozole
Placebo
plus Letrozole
Progression-free survival for ITT
(investigator assessment)
N=444
N=222
Number of PFS events (%)
194 (43.7)
137 (61.7)
Median progression-free survival
(months, 95% CI)
24.8 (22.1, NE)
14.5 (12.9, 17.1)
Hazard ratio (95% CI) and p-value
0.576 (0.463, 0.718)†, p<0.0001‡
Objective Response for patients with
measurable disease (investigator assessment)
N=338
N=171
Objective response rate* (%, 95% CI)
55.3 (49.9, 60.7)
44.4 (36.9, 52.2)
Overall survival for ITT
N=444
N=222
Number of OS events (%)
287 (64.6)
148 (66.7)
Median OS (months, 95% CI)
53.8 (49.8, 59.2)
49.8 (42.3, 56.4)
Hazard ratio (95% CI) and p-value
0.921 (0.755, 1.124)†, p=0.2087‡
CI=confidence interval; ITT=Intent-to-Treat; N=number of patients; NE=not estimable; OS=overall survival; PFS=progression-free
survival.
* Response is based on confirmed responses.
† Cox proportional hazards model stratified by disease site (visceral vs. non-visceral) per randomization.
‡ Stratified log-rank test one-sided p-value.
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Figure 1. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-2 (Investigator Assessment,
Intent-to-Treat Population)
LET=letrozole; PAL=palbociclib; PBO=placebo.
PALOMA-3: IBRANCE plus Fulvestrant
Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease
progression on or after prior adjuvant or metastatic endocrine therapy
PALOMA-3 was an international, randomized, double-blind, parallel group, multicenter study of IBRANCE
plus fulvestrant versus placebo plus fulvestrant conducted in women with HR-positive, HER2-negative
advanced breast cancer, regardless of their menopausal status, whose disease progressed on or after prior
endocrine therapy. A total of 521 pre/postmenopausal women were randomized 2:1 to IBRANCE plus
fulvestrant or placebo plus fulvestrant and stratified by documented sensitivity to prior hormonal therapy,
menopausal status at study entry (pre/peri versus postmenopausal), and presence of visceral metastases.
IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment.
Pre/perimenopausal women were enrolled in the study and received the LHRH agonist goserelin for at least
4 weeks prior to and for the duration of PALOMA-3. Patients continued to receive assigned treatment until
objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of
consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed PFS
evaluated according to RECIST 1.1.
Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients on study
were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were postmenopausal. All patients had
received prior systemic therapy, and 75% of patients had received a previous chemotherapy regimen.
Twenty-five percent of patients had received no prior therapy in the metastatic disease setting, 60% had visceral
metastases, and 23% had bone only disease.
The results from the investigator-assessed PFS and final OS from PALOMA-3 are summarized in Table 9. The
relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively. Consistent PFS results were observed
across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. After a
median follow-up time of 45 months, the final OS results were not statistically significant.
0
3
6
9
12
15
18
21
24
27
30
33
Time (Month)
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival Probability (%)
palbociclib+letrozole
placebo+letrozole
444
395
360
328
295
263
238
154
69
29
10
2
PAL+LET
222
171
148
131
116
98
81
54
22
12
4
2
PBO+LET
Number of patients at risk
Reference ID: 5501310
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Table 9. Efficacy Results – PALOMA-3
IBRANCE
plus Fulvestrant
Placebo
plus Fulvestrant
Progression-free survival for ITT
(investigator assessment)
N=347
N=174
Number of PFS events (%)
145 (41.8)
114 (65.5)
Median PFS (months, 95% CI)
9.5 (9.2, 11.0)
4.6 (3.5, 5.6)
Hazard ratio (95% CI) and p-value
0.461 (0.360, 0.591), p<0.0001
Objective Response for patients with
measurable disease
(investigator assessment)
N=267
N=138
Objective response rate* (%, 95% CI)
24.6 (19.6, 30.2)
10.9 (6.2, 17.3)
Overall survival for ITT
N=347
N=174
Number of OS events (%)
201 (57.9)
109 (62.6)
Median OS (months, 95% CI)
34.9 (28.8, 40.0)
28.0 (23.6, 34.6)
Hazard ratio (95% CI) and p-value
0.814 (0.644, 1.029), p=0.0857†‡
CI=confidence interval; ITT=Intent-to-Treat; N=number of patients; OS=overall survival; PFS=progression-free survival.
* Responses are based on confirmed responses.
† Not statistically significant at the pre-specified 2-sided alpha level of 0.047.
‡ 2-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior endocrine therapy
per randomization.
Figure 2. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-3 (Investigator Assessment,
Intent-to-Treat Population)
FUL=fulvestrant; PAL=palbociclib; PBO=placebo.
0
2
4
6
8
10
12
14
Time (Month)
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival Probability (%)
palbociclib+fulvestrant
placebo+fulvestrant
347
281
247
202
91
32
7
1
PAL+FUL
174
112
83
59
22
13
2
PBO+FUL
Number of patients at risk
0
Reference ID: 5501310
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Figure 3. Kaplan-Meier Plot of Overall Survival (Intent-to-Treat Population) – PALOMA-3
FUL=fulvestrant; PAL=palbociclib; PBO=placebo.
16
HOW SUPPLIED/STORAGE AND HANDLING
IBRANCE is supplied in the following strengths and package configurations:
IBRANCE Capsules
Package
Configuration
Capsule
Strength (mg)
NDC
Capsule Description
Bottles of 21
capsules
125
NDC 0069-0189-21 opaque, hard gelatin capsules, size 0,
with caramel cap and body, printed with
white ink “Pfizer” on the cap,
“PBC 125” on the body
Bottles of 21
capsules
100
NDC 0069-0188-21 opaque, hard gelatin capsules, size 1,
with caramel cap and light orange body,
printed with white ink “Pfizer” on the
cap, “PBC 100” on the body
Bottles of 21
capsules
75
NDC 0069-0187-21 opaque, hard gelatin capsules, size 2,
with light orange cap and body, printed
with white ink “Pfizer” on the cap,
“PBC 75” on the body
Store at 20 oC to 25 oC (68 oF to 77 oF); excursions permitted between 15 oC to 30 oC (59 oF to 86 oF) [see USP
Controlled Room Temperature].
0
6
12
18
24
30
36
42
48
54
Time (Month)
0
10
20
30
40
50
60
70
80
90
100
Overall Survival Probability (%)
palbociclib+fulvestrant
placebo+fulvestrant
347
321
286
247
209
165
148
126
17
PAL+FUL
174
155
135
115
86
68
57
43
7
PBO+FUL
Number of patients at risk
0
0
Reference ID: 5501310
23
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Myelosuppression/Infection
• Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as
fever, chills, dizziness, shortness of breath, weakness, or any increased tendency to bleed and/or to
bruise [see Warnings and Precautions (5.1)].
Interstitial Lung Disease/Pneumonitis
• Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and
Precautions (5.2)].
Drug Interactions
• Grapefruit may interact with IBRANCE. Patients should not consume grapefruit products while on
treatment with IBRANCE.
• Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers.
• Advise patients to inform their healthcare providers of all concomitant medications, including
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug
Interactions (7)].
Dosing and Administration
• Advise patients to take IBRANCE with food.
• If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose
should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush,
or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise
not intact.
• Pre/perimenopausal women treated with IBRANCE should also be treated with LHRH agonists [see
Dosage and Administration (2.1)].
Pregnancy, Lactation, and Infertility
• Embryo-Fetal Toxicity
o Advise females of reproductive potential of the potential risk to a fetus and to use effective
contraception during treatment with IBRANCE therapy and for at least 3 weeks after the last
dose. Advise females to inform their healthcare provider of a known or suspected pregnancy
[see Warnings and Precautions (5.3) and Use in Specific Populations (8.1 and 8.3)].
o Advise male patients with female partners of reproductive potential to use effective
contraception during treatment with IBRANCE and for at least 3 months after the last dose [see
Use in Specific Populations (8.3)].
• Lactation: Advise women not to breastfeed during treatment with IBRANCE and for 3 weeks after the
last dose [see Use in Specific Populations (8.2)].
• Infertility: Inform males of reproductive potential that IBRANCE may cause infertility and to consider
sperm preservation before taking IBRANCE [see Use in Specific Populations (8.3)].
Reference ID: 5501310
24
This product’s labeling may have been updated. For full prescribing information, please visit
www.pfizer.com.For medical information about IBRANCE, please visit www.pfizermedinfo.com or call 1-800-
438-1985.
LAB-0723-10.2b
Reference ID: 5501310
1
PATIENT INFORMATION
IBRANCE® (EYE-brans)
(palbociclib)
Capsules
What is the most important information I should know about IBRANCE?
IBRANCE may cause serious side effects, including:
Low white blood cell counts (neutropenia). Low white blood cell counts are very common when taking IBRANCE
and may cause serious infections that can lead to death. Your healthcare provider should check your white blood cell
counts before and during treatment.
If you develop low white blood cell counts during treatment with IBRANCE, your healthcare provider may stop your
treatment, decrease your dose, or may tell you to wait to begin your treatment cycle. Tell your healthcare provider right
away if you have signs and symptoms of low white blood cell counts or infections such as fever and chills.
Lung problems (pneumonitis). IBRANCE may cause severe or life-threatening inflammation of the lungs during
treatment that can lead to death. Tell your healthcare provider right away if you have any new or worsening symptoms,
including:
•
chest pain
•
cough with or without mucus
•
trouble breathing or shortness of breath
Your healthcare provider may interrupt or stop treatment with IBRANCE completely if your symptoms are severe.
See “What are the possible side effects of IBRANCE?” for more information about side effects.
What is IBRANCE?
IBRANCE is a prescription medicine used in adults to treat hormone receptor (HR)-positive, human epidermal growth
factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic) in combination
with:
•
an aromatase inhibitor as the first hormonal based therapy, or
•
fulvestrant in people with disease progression following hormonal therapy.
It is not known if IBRANCE is safe and effective in children.
What should I tell my healthcare provider before taking IBRANCE?
Before taking IBRANCE, tell your healthcare provider about all of your medical conditions, including if you:
•
have fever, chills, or any other signs or symptoms of infection.
•
have liver or kidney problems.
•
have any other medical conditions.
•
are pregnant, or plan to become pregnant. IBRANCE can harm your unborn baby.
o
Females who are able to become pregnant should use effective birth control during treatment and for at least 3
weeks after the last dose of IBRANCE. Your healthcare provider may ask you to take a pregnancy test before
you start treatment with IBRANCE.
o
Males with female partners who can become pregnant should use effective birth control during treatment with
IBRANCE for at least 3 months after the last dose of IBRANCE.
o
Talk to your healthcare provider about birth control methods that may be right for you during this time.
o
If you become pregnant or think you are pregnant, tell your healthcare provider right away.
•
are breastfeeding or plan to breastfeed. It is not known if IBRANCE passes into your breast milk. Do not
breastfeed during treatment with IBRANCE and for 3 weeks after the last dose.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. IBRANCE and other medicines may affect each other causing side
effects.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new
medicine.
Reference ID: 5501310
2
How should I take IBRANCE?
•
Take IBRANCE exactly as your healthcare provider tells you.
•
Take IBRANCE with food.
•
IBRANCE should be taken at about the same time each day.
•
Swallow IBRANCE capsules whole. Do not chew, crush or open IBRANCE capsules before swallowing them.
•
Do not take any IBRANCE capsules that are broken, cracked, or that look damaged.
•
Avoid grapefruit and grapefruit products during treatment with IBRANCE. Grapefruit may increase the amount of
IBRANCE in your blood.
•
Do not change your dose or stop taking IBRANCE unless your healthcare provider tells you.
•
If you miss a dose of IBRANCE or vomit after taking a dose of IBRANCE, do not take another dose on that day.
Take your next dose at your regular time.
•
If you take too much IBRANCE, call your healthcare provider right away or go to the nearest hospital emergency
room.
What are the possible side effects of IBRANCE?
IBRANCE may cause serious side effects. See “What is the most important information I should know about
IBRANCE?”
The most common side effects of IBRANCE when used with either letrozole or fulvestrant include:
•
Low red blood cell counts and low platelet counts are common with IBRANCE. Call your healthcare provider right
away if you develop any of these symptoms during treatment:
o
dizziness
o
bleeding or bruising more easily
o
shortness of breath
o
weakness
o
nosebleeds
•
infections (see “What is the most important
information I should know about IBRANCE?”)
•
tiredness
•
diarrhea
•
hair thinning or hair loss
•
vomiting
•
nausea
•
sore mouth
•
abnormalities in liver blood tests
•
rash
•
loss of appetite
IBRANCE may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare
provider about family planning options before starting IBRANCE if this is a concern for you.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of IBRANCE.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store IBRANCE?
•
Store IBRANCE at 68 °F to 77 °F (20 °C to 25 °C).
Keep IBRANCE and all medicines out of the reach of children.
General information about the safe and effective use of IBRANCE
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
IBRANCE for a condition for which it was not prescribed. Do not give IBRANCE to other people, even if they have the
same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more
information about IBRANCE that is written for health professionals.
What are the ingredients in IBRANCE?
Active ingredient: palbociclib
Inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide,
magnesium stearate, and hard gelatin capsule shells.
The light orange, light orange/caramel and caramel opaque capsule shells contain: gelatin, red iron oxide, yellow iron
oxide, and titanium dioxide.
The printing ink contains: shellac, titanium dioxide, ammonium hydroxide, propylene glycol, and simethicone.
Reference ID: 5501310
3
This product’s labeling may have been updated. For the most recent prescribing information, please visit
www.pfizer.com.
LAB-0724-7.2b
For more information, go to www.pfizer.com or call 1-800-438-1985.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: December 2024
Reference ID: 5501310
| custom-source | 2025-02-12T15:48:11.840679 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/207103s022lbl.pdf', 'application_number': 207103, 'submission_type': 'SUPPL ', 'submission_number': 22} |
80,747 |
_______________________________________________________________________________________________________________________________________
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
•
Embryo-Fetal Toxicity: IBRANCE can cause fetal harm. Advise
These highlights do not include all the information needed to use
patients of potential risk to a fetus and to use effective contraception.
IBRANCE safely and effectively. See full prescribing information for
(5.3, 8.1, 8.3)
IBRANCE.
------------------------------ ADVERSE REACTIONS -----------------------------
IBRANCE® (palbociclib) tablets, for oral use
Most common adverse reactions (incidence ≥10%) were neutropenia,
Initial U.S. Approval: 2015
infections, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, diarrhea,
thrombocytopenia, rash, vomiting, decreased appetite, asthenia, and
--------------------------- INDICATIONS AND USAGE----------------------------
pyrexia. (6)
IBRANCE is a kinase inhibitor indicated for the treatment of adult patients
with hormone receptor (HR)-positive, human epidermal growth factor
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at
receptor 2 (HER2)-negative advanced or metastatic breast cancer in
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
combination with:
•
an aromatase inhibitor as initial endocrine-based therapy (1); or
------------------------------ DRUG INTERACTIONS------------------------------
•
fulvestrant in patients with disease progression following
•
CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong
endocrine therapy. (1)
CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the
IBRANCE dose. (2.2, 7.1)
-----------------------DOSAGE AND ADMINISTRATION -----------------------
•
CYP3A Inducers: Avoid concurrent use of IBRANCE with strong
IBRANCE tablets are taken orally with or without food in combination with
CYP3A inducers. (7.2)
an aromatase inhibitor or fulvestrant. (2)
•
CYP3A Substrates: The dose of sensitive CYP3A4 substrates with
•
Recommended starting dose: 125 mg once daily taken with or without
narrow therapeutic indices may need to be reduced when given
food for 21 days followed by 7 days off treatment. (2.1)
concurrently with IBRANCE. (7.3)
•
Dosing interruption and/or dose reductions are recommended based on
individual safety and tolerability. (2.2)
----------------------------USE IN SPECIFIC POPULATIONS------------------
•
Lactation: Advise not to breastfeed. (8.2)
--------------------- DOSAGE FORMS AND STRENGTHS---------------------
Tablets: 125 mg, 100 mg, and 75 mg. (3)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
------------------------------ CONTRAINDICATIONS -----------------------------
None. (4)
Revised: 12/2024
----------------------- WARNINGS AND PRECAUTIONS-----------------------
•
Neutropenia: Monitor complete blood count prior to start of IBRANCE
therapy and at the beginning of each cycle, as well as on Day 15 of the
first 2 cycles, and as clinically indicated. (2.2, 5.1)
•
Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of
ILD/pneumonitis have been reported. Monitor for pulmonary symptoms
of ILD/pneumonitis. Interrupt IBRANCE immediately in patients with
suspected ILD/pneumonitis. Permanently discontinue IBRANCE if
severe ILD/pneumonitis occurs. (5.2)
FULL PRESCRIBING INFORMATION: CONTENTS*
8.2 Lactation
8.3 Females and Males of Reproductive Potential
1
INDICATIONS AND USAGE
8.4 Pediatric Use
2
DOSAGE AND ADMINISTRATION
8.5 Geriatric Use
2.1 Recommended Dose and Schedule
8.6 Hepatic Impairment
2.2 Dose Modification
8.7 Renal Impairment
3
DOSAGE FORMS AND STRENGTHS
10
OVERDOSAGE
4
CONTRAINDICATIONS
11
DESCRIPTION
5
WARNINGS AND PRECAUTIONS
12
CLINICAL PHARMACOLOGY
5.1 Neutropenia
12.1 Mechanism of Action
5.2 Interstitial Lung Disease (ILD)/Pneumonitis
12.2 Pharmacodynamics
5.3 Embryo-Fetal Toxicity
12.3 Pharmacokinetics
6
ADVERSE REACTIONS
13
NONCLINICAL TOXICOLOGY
6.1 Clinical Studies Experience
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
6.2 Postmarketing Experience
14
CLINICAL STUDIES
7
DRUG INTERACTIONS
16
HOW SUPPLIED/STORAGE AND HANDLING
7.1 Agents That May Increase Palbociclib Plasma Concentrations
17
PATIENT COUNSELING INFORMATION
7.2 Agents That May Decrease Palbociclib Plasma Concentrations
7.3 Drugs That May Have Their Plasma Concentrations Altered by
* Sections or subsections omitted from the full prescribing information are not
Palbociclib
listed.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
1
Reference ID: 5501319
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
IBRANCE is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human
epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in
combination with:
• an aromatase inhibitor as initial endocrine-based therapy; or
• fulvestrant in patients with disease progression following endocrine therapy.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dose and Schedule
The recommended dose of IBRANCE is a 125 mg tablet taken orally once daily for 21 consecutive days
followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE tablet may be
taken with or without food [see Clinical Pharmacology (12.3)].
Administer the recommended dose of an aromatase inhibitor when given with IBRANCE. Please refer
to the Full Prescribing Information for the aromatase inhibitor being used.
When given with IBRANCE, the recommended dose of fulvestrant is 500 mg administered on Days 1,
15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant.
Patients should be encouraged to take their dose of IBRANCE at approximately the same time each day.
If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose
should be taken at the usual time. IBRANCE tablets should be swallowed whole (do not chew, crush, or
split them prior to swallowing). Tablets should not be ingested if they are broken, cracked, or otherwise
not intact.
Pre/perimenopausal women treated with the combination IBRANCE plus an aromatase inhibitor or
fulvestrant therapy should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists
according to current clinical practice standards.
For men treated with combination IBRANCE plus aromatase inhibitor therapy, consider treatment with
an LHRH agonist according to current clinical practice standards.
2.2
Dose Modification
The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3.
Table 1. Recommended Dose Modification for Adverse Reactions
Dose Level
Dose
Recommended starting dose
125 mg/day
First dose reduction
100 mg/day
Second dose reduction
75 mg/day*
*If further dose reduction below 75 mg/day is required, discontinue.
2
Reference ID: 5501319
Table 2. Dose Modification and Management – Hematologic Toxicitiesa
Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of
each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.
For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles,
monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a
cycle and as clinically indicated.
CTCAE Grade
Dose Modifications
Grade 1 or 2
No dose adjustment is required.
Grade 3
Day 1 of cycle:
Withhold IBRANCE, repeat complete blood count monitoring within
1 week. When recovered to Grade ≤2, start the next cycle at the same
dose.
Day 15 of first 2 cycles:
If Grade 3 on Day 15, continue IBRANCE at current dose to complete
cycle and repeat complete blood count on Day 22.
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below.
Consider dose reduction in cases of prolonged (>1 week) recovery from
Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of
subsequent cycles.
Grade 3
neutropeniab with
fever ≥38.5 ºC
and/or infection
At any time:
Withhold IBRANCE until recovery to Grade ≤2.
Resume at the next lower dose.
Grade 4
At any time:
Withhold IBRANCE until recovery to Grade ≤2.
Resume at the next lower dose.
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal.
a
Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events,
e.g., opportunistic infections).
b
Absolute neutrophil count (ANC): Grade 1: ANC < LLN - 1500/mm3; Grade 2: ANC 1000 - <1500/mm3;
Grade 3: ANC 500 - <1000/mm3; Grade 4: ANC <500/mm3.
Table 3. Dose Modification and Management – Non-Hematologic Toxicities
CTCAE Grade
Dose Modifications
Grade 1 or 2
No dose adjustment is required.
Grade ≥3 non-hematologic toxicity (if
persisting despite optimal medical
treatment)
Withhold until symptoms resolve to:
• Grade ≤1;
• Grade ≤2 (if not considered a safety risk
for the patient)
Resume at the next lower dose.
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events.
Permanently discontinue IBRANCE in patients with severe interstitial lung disease (ILD)/pneumonitis.
3
Reference ID: 5501319
Refer to the Full Prescribing Information for coadministered endocrine therapy dose adjustment
guidelines in the event of toxicity and other relevant safety information or contraindications.
Dose Modifications for Use With Strong CYP3A Inhibitors
Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication
with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor,
reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the
IBRANCE dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the
strong CYP3A inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Dose Modifications for Hepatic Impairment
No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh
classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended
dose of IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to
comprise a complete cycle of 28 days [see Use in Specific Populations (8.6) and Clinical Pharmacology
(12.3)].
3
DOSAGE FORMS AND STRENGTHS
125 mg tablets: Oval, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC
125” on the other side.
100 mg tablets: Oval, green, film-coated tablets debossed with “Pfizer” on one side and “PBC 100” on
the other side.
75 mg tablets: Round, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC 75”
on the other side.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Neutropenia
Neutropenia was the most frequently reported adverse reaction in PALOMA-2 with an incidence of 80%
and PALOMA-3 with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in
66% of patients receiving IBRANCE plus letrozole in PALOMA-2 and 66% of patients receiving
IBRANCE plus fulvestrant in PALOMA-3. In PALOMA-2 and PALOMA-3, the median time to first
episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was
7 days [see Adverse Reactions (6.1)].
Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle,
as well as on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction,
or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia
[see Dosage and Administration (2.2)].
4
Reference ID: 5501319
Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and
PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Physicians should
inform patients to promptly report any episodes of fever [see Patient Counseling Information (17)].
5.2
Interstitial Lung Disease (ILD)/Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients
treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in
combination with endocrine therapy.
Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients had
ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4 and no fatal cases were reported. Additional
cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported [see
Adverse Reactions (6.2)].
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough,
dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have
developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently
discontinue IBRANCE in patients with severe ILD or pneumonitis [see Dosage and Administration
(2.2)].
5.3
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm
when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib
to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures
that were ≥4 times the human clinical exposure based on area under the curve (AUC). Advise pregnant
women of the potential risk to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with IBRANCE and for at least 3 weeks after the last dose [see Use in
Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Neutropenia [see Warnings and Precautions (5.1)]
• ILD/Pneumonitis [see Warnings and Precautions (5.2)]
6.1
Clinical Studies Experience
Because clinical trials are conducted under varying conditions, the adverse reaction rates observed
cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical
practice.
PALOMA-2: IBRANCE plus Letrozole
Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast
cancer for initial endocrine based therapy
The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was
evaluated in PALOMA-2. The data described below reflect exposure to IBRANCE in 444 out of
666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of
5
Reference ID: 5501319
-
IBRANCE plus letrozole in PALOMA-2. The median duration of treatment for IBRANCE plus
letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was
13.8 months.
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving
IBRANCE plus letrozole. No dose reduction was allowed for letrozole in PALOMA-2.
Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients
receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole.
Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole
included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).
The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus
letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea,
alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite,
dry skin, pyrexia, and dysgeusia.
The most frequently reported Grade >3 adverse reactions (≥5%) in patients receiving IBRANCE plus
letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.
Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus
letrozole in PALOMA-2 are listed in Table 4.
6
Reference ID: 5501319
Table 4. Adverse Reactions (≥10%) in PALOMA-2
IBRANCE plus Letrozole
(N=444)
Placebo plus Letrozole
(N=222)
Adverse Reaction
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
Infections and infestations
Infectionsa
60b
6
1
42
3
0
Blood and lymphatic system disorders
Neutropenia
Leukopenia
Anemia
Thrombocytopenia
80
39
24
16
56
24
5
1
10
1
<1
<1
6
2
9
1
1
0
2
0
1
0
0
0
Metabolism and nutrition disorders
Decreased appetite
15
1
0
9
0
0
Nervous system disorders
Dysgeusia
10
0
0
5
0
0
Gastrointestinal disorders
Stomatitisc
Nausea
Diarrhea
Vomiting
30
35
26
16
1
<1
1
1
0
0
0
0
14
26
19
17
0
2
1
1
0
0
0
0
Skin and subcutaneous tissue disorders
Alopecia
Rashf
Dry skin
33d
18
12
N/A
1
0
N/A
0
0
16e
12
6
N/A
1
0
N/A
0
0
General disorders and administration site conditions
Fatigue
Asthenia
Pyrexia
37
17
12
2
2
0
0
0
0
28
12
9
1
0
0
0
0
0
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable;
a
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and
infestations.
b
Most common infections (>1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection,
oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster,
pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection,
gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis.
c
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation,
oral pain, oral discomfort, oropharyngeal pain, and stomatitis.
d
Grade 1 events – 30%; Grade 2 events – 3%.
e
Grade 1 events – 15%; Grade 2 events – 1%.
f
Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular,
dermatitis, dermatitis acneiform, and toxic skin eruption.
Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving
IBRANCE plus letrozole in PALOMA-2 included alanine aminotransferase increased (9.9%), aspartate
aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%),
vision blurred (3.6%), and febrile neutropenia (2.5%).
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Table 5. Laboratory Abnormalities in PALOMA-2
IBRANCE plus Letrozole
(N=444)
Placebo plus Letrozole
(N=222)
Laboratory Abnormality
All
Grades
%
Grade
3
%
Grade 4
%
All
Grades
%
Grade 3
%
Grade 4
%
WBC decreased
97
35
1
25
1
0
Neutrophils decreased
95
56
12
20
1
1
Anemia
78
6
0
42
2
0
Platelets decreased
63
1
1
14
0
0
Aspartate
aminotransferase
increased
52
3
0
34
1
0
Alanine aminotransferase
increased
43
2
<1
30
0
0
N=number of patients; WBC=white blood cells.
PALOMA-3: IBRANCE plus Fulvestrant
Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had
disease progression on or after prior adjuvant or metastatic endocrine therapy
The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was
evaluated in PALOMA-3. The data described below reflect exposure to IBRANCE in 345 out of
517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at
least 1 dose of IBRANCE plus fulvestrant in PALOMA-3. The median duration of treatment for
IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus
fulvestrant arm was 4.8 months.
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving
IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in PALOMA-3.
Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients
receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant.
Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant
included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).
The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus
fulvestrant arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea,
anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and
pyrexia.
The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus
fulvestrant in descending frequency were neutropenia and leukopenia.
Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus
fulvestrant in PALOMA-3 are listed in Table 6.
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Table 6. Adverse Reactions (≥10%) in PALOMA-3
Adverse Reaction
IBRANCE plus Fulvestrant
(N=345)
Placebo plus Fulvestrant
(N=172)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
%
%
%
%
%
%
Infections and infestations
Infectionsa
47b
3
1
31
3
0
Blood and lymphatic system disorders
Neutropenia
83
55
11
4
1
0
Leukopenia
53
30
1
5
1
1
Anemia
30
4
0
13
2
0
Thrombocytopenia
23
2
1
0
0
0
Metabolism and nutrition disorders
Decreased appetite
16
1
0
8
1
0
Gastrointestinal disorders
Nausea
34
0
0
28
1
0
Stomatitisc
28
1
0
13
0
0
Diarrhea
24
0
0
19
1
0
Vomiting
19
1
0
15
1
0
Skin and subcutaneous tissue disorders
Alopecia
18d
N/A
N/A
6e
N/A
N/A
Rashf
17
1
0
6
0
0
General disorders and administration site conditions
Fatigue
41
2
0
29
1
0
Pyrexia
13
<1
0
5
0
0
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.
a
Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections
and infestations.
b
Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract
infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes,
respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and
paronychia.
c
Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal
inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.
d
Grade 1 events – 17%; Grade 2 events – 1%.
e
Grade 1 events – 6%.
f
Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis,
dermatitis acneiform, toxic skin eruption.
Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving
IBRANCE plus fulvestrant in PALOMA-3 included asthenia (7.5%), aspartate aminotransferase
increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%),
alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile
neutropenia (0.9%).
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Table 7. Laboratory Abnormalities in PALOMA-3
Laboratory Abnormality
IBRANCE plus Fulvestrant
(N=345)
Placebo plus Fulvestrant
(N=172)
All Grades
%
Grade 3
%
Grade 4
%
All Grades
%
Grade 3
%
Grade 4
%
WBC decreased
99
45
1
26
0
1
Neutrophils decreased
96
56
11
14
0
1
Anemia
78
3
0
40
2
0
Platelets decreased
62
2
1
10
0
0
Aspartate aminotransferase
increased
43
4
0
48
4
0
Alanine aminotransferase
increased
36
2
0
34
0
0
N=number of patients; WBC=white blood cells.
Other Clinical Trials Experience
The following adverse reaction has been reported following administration of IBRANCE: venous
thromboembolism.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of IBRANCE. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
Respiratory Disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis
Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES)
Male patients with HR-positive, HER2-negative advanced or metastatic breast cancer
Based on limited data from postmarketing reports and electronic health records, the safety profile for
men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.
7
DRUG INTERACTIONS
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1.
In vivo, palbociclib is a time-dependent inhibitor of CYP3A.
7.1
Agents That May Increase Palbociclib Plasma Concentrations
Effect of CYP3A Inhibitors
Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of
palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors
(e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir,
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole). Avoid grapefruit or
grapefruit juice during IBRANCE treatment. If coadministration of IBRANCE with a strong CYP3A
inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration (2.2) and
Clinical Pharmacology (12.3)].
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7.2
Agents That May Decrease Palbociclib Plasma Concentrations
Effect of CYP3A Inducers
Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of
palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g.,
phenytoin, rifampin, carbamazepine, enzalutamide, and St John’s Wort) [see Clinical
Pharmacology (12.3)].
7.3
Drugs That May Have Their Plasma Concentrations Altered by Palbociclib
Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma
exposure by 61%, in healthy subjects, compared to administration of midazolam alone. The dose of the
sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine,
dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus)
may need to be reduced, as IBRANCE may increase its exposure [see Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm
when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available
data in pregnant women to inform the drug-associated risk. In animal reproduction studies,
administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal
toxicity at maternal exposures that were ≥4 times the human clinical exposure based on AUC
(see Data). Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data
Animal Data
In a fertility and early embryonic development study in female rats, palbociclib was administered orally
for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses
up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure
(AUC) at the recommended dose.
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of
palbociclib up to 300 mg/kg/day and 20 mg/kg/day, respectively, during the period of organogenesis.
The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body
weights. At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation
(increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of
20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small
phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic
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Reference ID: 5501319
exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose,
respectively.
CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation
Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be predictive of
effects in humans due to differences in degree of target inhibition.
8.2
Lactation
Risk Summary
There is no information regarding the presence of palbociclib in human milk, its effects on milk
production, or the breastfed infant. Because of the potential for serious adverse reactions in breastfed
infants from IBRANCE, advise a lactating woman not to breastfeed during treatment with IBRANCE
and for 3 weeks after the last dose.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Based on animal studies, IBRANCE can cause fetal harm when administered to a pregnant woman [see
Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior
to starting treatment with IBRANCE.
Contraception
Females
IBRANCE can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during
treatment with IBRANCE and for at least 3 weeks after the last dose.
Males
Because of the potential for genotoxicity, advise male patients with female partners of reproductive
potential to use effective contraception during treatment with IBRANCE and for 3 months after the last
dose [see Nonclinical Toxicology (13.1)].
Infertility
Males
Based on animal studies, IBRANCE may impair fertility in males of reproductive potential [see
Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
The safety and efficacy of IBRANCE in pediatric patients have not been studied.
Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in
the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation,
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Reference ID: 5501319
chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose
toxicology study in rats that were immature at the beginning of the studies and were most prevalent in
males at oral palbociclib doses ≥30 mg/kg/day (approximately 11 times the adult human exposure
[AUC] at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet
cell vacuolation, and kidney tubule vacuolation) were present with lower incidence and severity in a
15 week repeat-dose toxicology study in immature rats. Altered glucose metabolism or associated
changes in the pancreas, eye, kidney and adipose tissue were not identified in a 27-week repeat-dose
toxicology study in rats that were mature at the beginning of the study and in dogs in repeat-dose
toxicology studies up to 39 weeks duration.
Toxicities in teeth independent of altered glucose metabolism were observed in rats. Administration of
100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the
recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast
degeneration/necrosis, mononuclear cell infiltrate). Other toxicities of potential concern to pediatric
patients have not been evaluated in juvenile animals.
8.5
Geriatric Use
Of 444 patients who received IBRANCE in PALOMA-2, 181 patients (41%) were ≥65 years of age and
48 patients (11%) were ≥75 years of age. Of 347 patients who received IBRANCE in PALOMA-3,
86 patients (25%) were ≥65 years of age and 27 patients (8%) were ≥75 years of age. No overall
differences in safety or effectiveness of IBRANCE were observed between these patients and younger
patients.
8.6
Hepatic Impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh
classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended
dose of IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to
comprise a complete cycle of 28 days [see Dosage and Administration (2.2)]. Based on a
pharmacokinetic trial in subjects with varying degrees of hepatic function, the palbociclib unbound
exposure (unbound AUCINF) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh
class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe
(Child-Pugh class C) hepatic impairment, respectively, relative to subjects with normal hepatic function.
Peak palbociclib unbound exposure (unbound Cmax) increased by 7%, 38% and 72% for mild, moderate
and severe hepatic impairment, respectively, relative to subjects with normal hepatic function [see
Clinical Pharmacology (12.3)].
Review the Full Prescribing Information for the aromatase inhibitor or fulvestrant for dose modifications
related to hepatic impairment.
8.7
Renal Impairment
No dose adjustment is required in patients with mild, moderate, or severe renal impairment
(CrCl >15 mL/min).
Based on a pharmacokinetic trial in subjects with varying degrees of renal function, the total palbociclib
exposure (AUCINF) increased by 39%, 42%, and 31% with mild (60 mL/min ≤ CrCl <90 mL/min),
moderate (30 mL/min ≤ CrCl <60 mL/min), and severe (CrCl <30 mL/min) renal impairment,
respectively, relative to subjects with normal renal function. Peak palbociclib exposure (Cmax) increased
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Reference ID: 5501319
by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to
subjects with normal renal function.
The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis [see
Clinical Pharmacology (12.3)].
10
OVERDOSAGE
There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of
general supportive measures.
11
DESCRIPTION
IBRANCE tablets for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase
inhibitor. The molecular formula for palbociclib is C24H29N7O2. The molecular weight is
447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2
yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, and its structural formula is:
Palbociclib is a yellow to orange powder. At or below pH 4, palbociclib behaves as a high-solubility
compound. Above pH 4, the solubility of the drug substance reduces significantly.
Inactive Ingredients: Microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium
stearate, succinic acid, HPMC 2910/hypromellose, titanium dioxide, triacetin, and FD&C Blue
#2/Indigo Carmine Aluminum Lake. In addition, the 75 mg and 125 mg tablets contain red iron oxide
and the 100 mg tablets contain yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are
downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced
cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression
of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the
combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein
phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest
compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines
with the combination of palbociclib and antiestrogens led to increased cell senescence compared to each
drug alone, which was sustained for up to 6 days following palbociclib removal and was greater if
antiestrogen treatment was continued. In vivo studies using a patient-derived ER-positive breast cancer
xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition
of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone.
14
Reference ID: 5501319
Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an
anti-estrogen in vitro did not become senescent and resumed proliferation following palbociclib
withdrawal.
12.2
Pharmacodynamics
Cardiac Electrophysiology
The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using
time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding
pharmacokinetic data in 77 patients with breast cancer. Palbociclib had no large effect on QTc
(i.e., >20 ms) at 125 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise
a complete cycle of 28 days.
12.3
Pharmacokinetics
The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including
advanced breast cancer and in healthy subjects.
Absorption
The maximum observed concentration (Cmax) of palbociclib is generally observed between 4 to 12 hours
(time to reach maximum concentration, Tmax) following oral administration of IBRANCE tablets. The
mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of
25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was
achieved within 8 days following repeated once daily dosing. With repeated once daily administration,
palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2).
Food Effect: The area under the concentration-time curve from zero to infinity (AUCINF) and Cmax of
palbociclib increased by 22% and 26%, respectively, when IBRANCE tablets were given with a
high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories
from protein, carbohydrate, and fat, respectively), and by 9% and 10%, respectively, when IBRANCE
tablets were given with a moderate-fat, standard-calorie meal (approximately 500 to 700 calories with
75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate, and fat, respectively),
compared to IBRANCE tablets given under overnight fasted conditions.
Distribution
Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration
dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction unbound (fu)
of palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There
was no obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function.
The geometric mean apparent volume of distribution (Vz/F) was 2583 L with a coefficient of variation
(CV) of 26%.
Metabolism
In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans.
Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the primary
metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and
glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived
15
Reference ID: 5501319
entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib,
although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively
metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine,
respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component,
accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic
and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly
involved in the metabolism of palbociclib.
Elimination
The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the
mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced
breast cancer. In 6 healthy male subjects given a single oral dose of [14C] palbociclib, a median of
91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was
the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material
was excreted as metabolites.
Age, Gender, and Body Weight
Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female
patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender had no
effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the
exposure of palbociclib.
Pediatric Population
Pharmacokinetics of IBRANCE have not been evaluated in patients <18 years of age.
Hepatic Impairment
Data from a pharmacokinetic trial in subjects with varying degrees of hepatic impairment indicate that
palbociclib unbound AUCINF decreased 17% in subjects with mild hepatic impairment (Child-Pugh
class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe
(Child-Pugh class C) hepatic impairment, respectively, relative to subjects with normal hepatic function.
Palbociclib unbound Cmax increased by 7%, 38% and 72% for mild, moderate and severe hepatic
impairment, respectively, relative to subjects with normal hepatic function. In addition, based on a
population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic
impairment based on National Cancer Institute (NCI) classification (total bilirubin ≤ ULN and
AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect
on the exposure of palbociclib, further supporting the findings from the dedicated hepatic impairment
study.
Renal Impairment
Data from a pharmacokinetic trial in subjects with varying degrees of renal impairment indicate that
palbociclib AUCINF increased by 39%, 42%, and 31% with mild (60 mL/min ≤ CrCl < 90 mL/min),
moderate (30 mL/min ≤ CrCl <60 mL/min), and severe (CrCl <30 mL/min) renal impairment,
respectively, relative to subjects with normal renal function. Peak palbociclib exposure (Cmax) increased
by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to
subjects with normal renal function. In addition, based on a population pharmacokinetic analysis that
included 183 patients where 73 patients had mild renal impairment and 29 patients had moderate renal
16
Reference ID: 5501319
impairment, mild and moderate renal impairment had no effect on the exposure of palbociclib. The
pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis.
Drug Interactions
In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism
of palbociclib. Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing
to steady state in humans. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9,
2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant
concentrations.
CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate that
coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose
increased palbociclib AUCINF and the Cmax by approximately 87% and 34%, respectively, relative to a
single 125 mg IBRANCE dose given alone [see Drug Interactions (7.1)].
CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=15) indicate that
coadministration of multiple 600 mg daily doses of rifampin, a strong CYP3A inducer, with a single
125 mg IBRANCE dose decreased palbociclib AUCINF and Cmax by 85% and 70%, respectively, relative
to a single 125 mg IBRANCE dose given alone. Data from a drug interaction trial in healthy subjects
(N=14) indicate that coadministration of multiple 400 mg daily doses of modafinil, a moderate
CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCINF and Cmax by 32%
and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone [see Drug Interactions
(7.2)].
CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg
dosing to steady state in humans. In a drug interaction trial in healthy subjects (N=26),
coadministration of midazolam with multiple doses of IBRANCE increased the midazolam AUCINF and
the Cmax values by 61% and 37%, respectively, as compared to administration of midazolam alone
[see Drug Interactions (7.3)].
Gastric pH Elevating Medications: In a drug interaction trial in healthy subjects, coadministration of a
single 125 mg IBRANCE tablet with multiple doses of the proton pump inhibitor (PPI) rabeprazole
under overnight fasted conditions had no effect on the rate and extent of absorption of palbociclib when
compared to a single 125 mg IBRANCE tablet administered alone. Given the reduced effect on
gastric pH of H2-receptor antagonists and local antacids compared to PPIs, an effect of these classes of
acid reducing agents on palbociclib exposure is not expected.
Letrozole: Data from a clinical trial in patients with breast cancer showed that there was no drug
interaction between palbociclib and letrozole when the 2 drugs were coadministered.
Fulvestrant: Data from a clinical trial in patients with breast cancer showed that there was no clinically
relevant drug interaction between palbociclib and fulvestrant when the 2 drugs were coadministered.
Goserelin: Data from a clinical trial in patients with breast cancer showed that there was no clinically
relevant drug interaction between palbociclib and goserelin when the 2 drugs were coadministered.
Anastrozole or Exemestane: No clinical data are available to evaluate drug interactions between
anastrozole or exemestane and palbociclib. A clinically significant drug interaction between anastrozole
or exemestane and palbociclib is not expected based on analyses of the effects of anastrozole,
exemestane and palbociclib on or by metabolic pathways or transporter systems.
17
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Effect of Palbociclib on Transporters: In vitro evaluations indicated that palbociclib has a low potential
to inhibit the activities of drug transporters organic anion transporter (OAT)1, OAT3, organic cation
transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically
relevant concentrations. In vitro, palbociclib has the potential to inhibit OCT1 at clinically relevant
concentrations, as well as the potential to inhibit P-glycoprotein (P-gp) or breast cancer resistance
protein (BCRP) in the gastrointestinal tract at the proposed dose.
Effect of Transporters on Palbociclib: Based on in vitro data, P-gp and BCRP mediated transport are
unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat
study. Oral administration of palbociclib for 2 years resulted in an increased incidence of microglial cell
tumors in the central nervous system of male rats at a dose of 30 mg/kg/day (approximately 8 times the
human clinical exposure based on AUC). There were no neoplastic findings in female rats at doses up
to 200 mg/kg/day (approximately 5 times the human clinical exposure based on AUC). Oral
administration of palbociclib to male and female rasH2 transgenic mice for 6 months did not result in
increased incidence of neoplasms at doses up to 60 mg/kg/day.
Palbociclib was aneugenic in Chinese Hamster Ovary cells in vitro and in the bone marrow of male rats
at doses ≥100 mg/kg/day for 3 weeks. Palbociclib was not mutagenic in an in vitro bacterial reverse
mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome
aberration assay.
In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to
300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects
were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in
the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure [AUC], at the
recommended dose, respectively).
The adverse effects of palbociclib on male reproductive function and fertility were observed in the
repeat-dose toxicology studies in rats and dogs and a male fertility study in rats. In repeat-dose
toxicology studies, palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle at
≥30 mg/kg/day in rats and ≥0.2 mg/kg/day in dogs included decreased organ weight, atrophy or
degeneration, hypospermia, intratubular cellular debris, and decreased secretion. Partial reversibility of
male reproductive organ effects was observed in the rat and dog following a 4- and 12-week non-dosing
period, respectively. These doses in rats and dogs resulted in approximately ≥10 and 0.1 times,
respectively, the exposure [AUC] in humans at the recommended dose. In the fertility and early
embryonic development study in male rats, palbociclib caused no effects on mating but resulted in a
slight decrease in fertility in association with lower sperm motility and density at 100 mg/kg/day with
projected exposure levels [AUC] of 20 times the exposure in humans at the recommended dose.
18
Reference ID: 5501319
14
CLINICAL STUDIES
PALOMA-2: IBRANCE plus Letrozole
Patients with ER-positive, HER2-negative advanced or metastatic breast cancer for initial
endocrine based therapy
PALOMA-2 was an international, randomized, double-blind, parallel-group, multicenter study of
IBRANCE plus letrozole versus placebo plus letrozole conducted in postmenopausal women with
ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment
for their advanced disease. A total of 666 patients were randomized 2:1 to IBRANCE plus letrozole or
placebo plus letrozole. Randomization was stratified by disease site (visceral versus non-visceral),
disease-free interval (de novo metastatic versus ≤12 months from the end of adjuvant treatment to
disease recurrence versus >12 months from the end of adjuvant treatment to disease recurrence), and
nature of prior (neo)adjuvant anticancer therapies (prior hormonal therapies versus no prior hormonal
therapy). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by
7 days off treatment. Patients received study treatment until objective disease progression, symptomatic
deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The
major efficacy outcome of the study was investigator-assessed progression-free survival (PFS) evaluated
according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST). Additional efficacy
outcome measures were confirmed overall response rate (ORR) as assessed by the investigator
according to RECIST Version 1.1 and overall survival (OS).
Patients enrolled in this study had a median age of 62 years (range 28 to 89). The majority of patients
were White (78%), and most patients had an Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of 0 or 1 (98%). Forty-eight percent of patients had received chemotherapy and
56% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of
advanced breast cancer. Thirty-seven percent of patients had no prior systemic therapy in the
neoadjuvant or adjuvant setting. The majority of patients (97%) had metastatic disease. Twenty-three
percent of patients had bone only disease, and 49% of patients had visceral disease.
Major efficacy results from PALOMA-2 are summarized in Table 8 and Figure 1. Consistent results
were observed across patient subgroups of disease-free interval (DFI), disease site, and prior therapy.
The treatment effect of the combination on PFS was also supported by an independent review of
radiographs. Based on the prespecified final OS analysis conducted after 435 events, OS was not
statistically significant.
19
Reference ID: 5501319
Table 8. Efficacy Results – PALOMA-2
IBRANCE
plus Letrozole
Placebo
plus Letrozole
Progression-free survival for ITT
(investigator assessment)
N=444
N=222
Number of PFS events (%)
194 (43.7)
137 (61.7)
Median progression-free survival
(months, 95% CI)
24.8 (22.1, NE)
14.5 (12.9, 17.1)
Hazard ratio (95% CI) and p-value
0.576 (0.463, 0.718)†, p<0.0001‡
Objective Response for patients with
measurable disease (investigator assessment)
N=338
N=171
Objective response rate* (%, 95% CI)
55.3 (49.9, 60.7)
44.4 (36.9, 52.2)
Overall survival for ITT
N=444
N=222
Number of OS events (%)
287 (64.6)
148 (66.7)
Median OS (months, 95% CI)
53.8 (49.8, 59.2)
49.8 (42.3, 56.4)
Hazard ratio (95% CI) and p-value
0.921 (0.755, 1.124)†, p=0.2087‡
CI=confidence interval; ITT=Intent-to-Treat; N=number of patients; NE=not estimable; OS=Overall survival;
PFS=Progression-free survival.
* Response is based on confirmed responses.
† Cox proportional hazards model stratified by disease site (visceral vs. non-visceral) per randomization.
‡ Stratified log-rank test one-sided p-value.
Figure 1. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-2 (Investigator
Assessment, Intent-to-Treat Population)
100
90
80
70
60
50
40
30
20
10
0
Number of patients at risk
PAL+LET 444
395
360
328
295
263
238
154
69
29
10
2
PBO+LET 222
171
148
131
116
98
81
54
22
12
4
2
LET=letrozole; PAL=palbociclib; PBO=placebo.
Progression-Free Survival Probability (%)
palbociclib+letrozole
placebo+letrozole
0
3
6
9
12
15
18
21
24
27
30
33
Time (Month)
20
Reference ID: 5501319
PALOMA-3: IBRANCE plus Fulvestrant
Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had
disease progression on or after prior adjuvant or metastatic endocrine therapy
PALOMA-3 was an international, randomized, double-blind, parallel group, multicenter study of
IBRANCE plus fulvestrant versus placebo plus fulvestrant conducted in women with HR-positive,
HER2-negative advanced breast cancer, regardless of their menopausal status, whose disease progressed
on or after prior endocrine therapy. A total of 521 pre/postmenopausal women were randomized 2:1 to
IBRANCE plus fulvestrant or placebo plus fulvestrant and stratified by documented sensitivity to prior
hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal), and presence of
visceral metastases. IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days
followed by 7 days off treatment. Pre/perimenopausal women were enrolled in the study and received
the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of PALOMA-3. Patients
continued to receive assigned treatment until objective disease progression, symptomatic deterioration,
unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The major efficacy
outcome of the study was investigator-assessed PFS evaluated according to RECIST 1.1.
Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients
on study were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were postmenopausal. All
patients had received prior systemic therapy, and 75% of patients had received a previous chemotherapy
regimen. Twenty-five percent of patients had received no prior therapy in the metastatic disease setting,
60% had visceral metastases, and 23% had bone only disease.
The results from the investigator-assessed PFS and final OS from PALOMA-3 are summarized in
Table 9. The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively. Consistent PFS
results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy, and
menopausal status. After a median follow-up time of 45 months, the final OS results were not
statistically significant.
Table 9. Efficacy Results – PALOMA-3
IBRANCE
plus Fulvestrant
Placebo
plus Fulvestrant
Progression-free survival for ITT
(investigator assessment)
N=347
N=174
Number of PFS events (%)
145 (41.8)
114 (65.5)
Median PFS (months, 95% CI)
9.5 (9.2, 11.0)
4.6 (3.5, 5.6)
Hazard ratio (95% CI) and p-value
0.461 (0.360, 0.591), p<0.0001
Objective Response for patients with
measurable disease
(investigator assessment)
N=267
N=138
Objective response rate* (%, 95% CI)
24.6 (19.6, 30.2)
10.9 (6.2, 17.3)
Overall survival for ITT
N=347
N=174
Number of OS events (%)
201 (57.9)
109 (62.6)
Median OS (months, 95% CI)
34.9 (28.8, 40.0)
28.0 (23.6, 34.6)
Hazard ratio (95% CI) and p-value
0.814 (0.644, 1.029), p=0.0857†‡
CI=confidence interval; ITT=Intent-to-Treat; N=number of patients; OS=overall survival; PFS=progression-free survival.
* Responses are based on confirmed responses.
† Not statistically significant at the pre-specified 2-sided alpha level of 0.047.
‡ 2-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior endocrine
therapy per randomization.
21
Reference ID: 5501319
Figure 2. Kaplan-Meier Plot of Progression-Free Survival – PALOMA-3 (Investigator
Assessment, Intent-to-Treat Population)
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival Probability (%)
palbociclib+fulvestrant
placebo+fulvestrant
0
2
4
6
8
10
12
14
Time (Month)
Number of patients at risk
PAL+FUL 347
281
247
202
91
32
7
1
PBO+FUL 174
112
83
59
22
13
2
0
FUL=fulvestrant; PAL=palbociclib; PBO=placebo.
Figure 3. Kaplan-Meier Plot of Overall Survival (Intent-to-Treat Population) - PALOMA-3
0
10
20
30
40
50
60
70
80
90
100
Overall Survival Probability (%)
palbociclib+fulvestrant
placebo+fulvestrant
0
6
12
18
24
30
36
42
48
54
Number of patients at risk
PAL+FUL 347
321
286
247
Time (Month)
209
165
148
126
17
0
PBO+FUL 174
155
135
115
86
68
57
43
7
0
FUL=fulvestrant; PAL=palbociclib; PBO=placebo.
22
Reference ID: 5501319
16
HOW SUPPLIED/STORAGE AND HANDLING
IBRANCE is supplied in the following strengths and package configurations:
IBRANCE Tablets
Package
Configuration
Tablet
Strength (mg)
NDC
Tablet Description
Monthly box
containing 3
weekly blister
packs of 7 tablets
each (21 tablets
total)
125
NDC 0069-0688-03 Oval, light purple, film-coated tablets
debossed with “Pfizer” on one side and
“PBC 125” on the other side.
Monthly box
containing 3
weekly blister
packs of 7 tablets
each (21 tablets
total)
100
NDC 0069-0486-03 Oval, green, film-coated tablets
debossed with “Pfizer” on one side and
“PBC 100” on the other side.
Monthly box
containing 3
weekly blister
packs of 7 tablets
each (21 tablets
total)
75
NDC 0069-0284-03 Round, light purple, film-coated tablets
debossed with “Pfizer” on one side and
“PBC 75” on the other side.
Store at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC to 30oC (59oF to 86oF) [see
USP Controlled Room Temperature]. Store in the original blister pack.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Myelosuppression/Infection
• Advise patients to immediately report any signs or symptoms of myelosuppression or infection,
such as fever, chills, dizziness, shortness of breath, weakness, or any increased tendency to bleed
and/or to bruise [see Warnings and Precautions (5.1)].
Interstitial Lung Disease/Pneumonitis
• Advise patients to immediately report new or worsening respiratory symptoms [see Warnings
and Precautions (5.2)].
Drug Interactions
• Grapefruit may interact with IBRANCE. Patients should not consume grapefruit products while
on treatment with IBRANCE.
• Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers.
• Advise patients to inform their healthcare providers of all concomitant medications, including
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug
Interactions (7)].
23
Reference ID: 5501319
&Pfizer
Distributed by
Pfizer Labs
Division of Pfizer Inc.
New York, NY 10001
Dosing and Administration
• Inform patients that IBRANCE tablets may be taken with or without food.
• If the patient vomits or misses a dose, an additional dose should not be taken. The next
prescribed dose should be taken at the usual time. IBRANCE tablets should be swallowed whole
(do not chew, crush, or split them prior to swallowing). No tablet should be ingested if it is
broken, cracked, or otherwise not intact.
• Pre/perimenopausal women treated with IBRANCE should also be treated with LHRH agonists
[see Dosage and Administration (2.1)].
Pregnancy, Lactation, and Infertility
• Embryo-Fetal Toxicity
o Advise females of reproductive potential of the potential risk to a fetus and to use
effective contraception during treatment with IBRANCE therapy and for at least 3 weeks
after the last dose. Advise females to inform their healthcare provider of a known or
suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific
Populations (8.1 and 8.3)].
o Advise male patients with female partners of reproductive potential to use effective
contraception during treatment with IBRANCE and for at least 3 months after the last
dose [see Use in Specific Populations (8.3)].
• Lactation: Advise women not to breastfeed during treatment with IBRANCE and for 3 weeks
after the last dose [see Use in Specific Populations (8.2)].
• Infertility: Inform males of reproductive potential that IBRANCE may cause infertility and to
consider sperm preservation before taking IBRANCE [see Use in Specific Populations (8.3)].
This product’s labeling may have been updated. For full prescribing information, please visit
www.pfizer.com. For medical information about IBRANCE, please visit www.pfizermedinfo.com or
call 1-800-438-1985.
LAB-1371-3.2b
24
Reference ID: 5501319
PATIENT INFORMATION
IBRANCE® (EYE-brans)
(palbociclib)
Tablets
What is the most important information I should know about IBRANCE?
IBRANCE may cause serious side effects, including:
Low white blood cell counts (neutropenia). Low white blood cell counts are very common when taking IBRANCE
and may cause serious infections that can lead to death. Your healthcare provider should check your white blood cell
counts before and during treatment.
If you develop low white blood cell counts during treatment with IBRANCE, your healthcare provider may stop your
treatment, decrease your dose, or may tell you to wait to begin your treatment cycle. Tell your healthcare provider right
away if you have signs and symptoms of low white blood cell counts or infections such as fever and chills.
Lung problems (pneumonitis). IBRANCE may cause severe or life-threatening inflammation of the lungs during
treatment that can lead to death. Tell your healthcare provider right away if you have any new or worsening symptoms,
including:
•
chest pain
•
cough with or without mucus
•
trouble breathing or shortness of breath
Your healthcare provider may interrupt or stop treatment with IBRANCE completely if your symptoms are severe.
See “What are the possible side effects of IBRANCE?” for more information about side effects.
What is IBRANCE?
IBRANCE is a prescription medicine used in adults to treat hormone receptor (HR)-positive, human epidermal growth
factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic) in combination
with:
•
an aromatase inhibitor as the first hormonal based therapy, or
•
fulvestrant in people with disease progression following hormonal therapy.
It is not known if IBRANCE is safe and effective in children.
What should I tell my healthcare provider before taking IBRANCE?
Before taking IBRANCE, tell your healthcare provider about all of your medical conditions, including if you:
•
have fever, chills, or any other signs or symptoms of infection.
•
have liver or kidney problems.
•
are pregnant, or plan to become pregnant. IBRANCE can harm your unborn baby.
o
Females who are able to become pregnant should use effective birth control during treatment and for at least 3
weeks after the last dose of IBRANCE. Your healthcare provider may ask you to take a pregnancy test before
you start treatment with IBRANCE.
o
Males with female partners who can become pregnant should use effective birth control during treatment with
IBRANCE for at least 3 months after the last dose of IBRANCE.
o
Talk to your healthcare provider about birth control methods that may be right for you during this time.
o
If you become pregnant or think you are pregnant, tell your healthcare provider right away.
•
are breastfeeding or plan to breastfeed. It is not known if IBRANCE passes into your breast milk. Do not
breastfeed during treatment with IBRANCE and for 3 weeks after the last dose.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. IBRANCE and other medicines may affect each other causing side
effects.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new
medicine.
Reference ID: 5501319
How should I take IBRANCE?
•
Take IBRANCE exactly as your healthcare provider tells you.
•
IBRANCE tablets may be taken with or without food.
•
IBRANCE should be taken at about the same time each day.
•
Swallow IBRANCE tablets whole. Do not chew, crush or split IBRANCE tablets before swallowing them.
•
Do not take any IBRANCE tablets that are broken, cracked, or that look damaged.
•
Avoid grapefruit and grapefruit products during treatment with IBRANCE. Grapefruit may increase the amount of
IBRANCE in your blood.
•
Do not change your dose or stop taking IBRANCE unless your healthcare provider tells you.
•
If you miss a dose of IBRANCE or vomit after taking a dose of IBRANCE, do not take another dose on that day.
Take your next dose at your regular time.
•
If you take too much IBRANCE, call your healthcare provider right away or go to the nearest hospital emergency
room.
What are the possible side effects of IBRANCE?
IBRANCE may cause serious side effects. See “What is the most important information I should know about
IBRANCE?”
The most common side effects of IBRANCE when used with either letrozole or fulvestrant include:
•
Low red blood cell counts and low platelet counts are common with IBRANCE. Call your healthcare provider right
away if you develop any of these symptoms during treatment:
o
dizziness
o
bleeding or bruising more easily
o
shortness of breath
o
nosebleeds
o
weakness
•
infections (see “What is the most important
•
diarrhea
information I should know about IBRANCE?”)
•
hair thinning or hair loss
•
tiredness
•
vomiting
•
nausea
•
rash
•
sore mouth
•
loss of appetite
•
abnormalities in liver blood tests
IBRANCE may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare
provider about family planning options before starting IBRANCE if this is a concern for you.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of IBRANCE.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store IBRANCE?
•
Store IBRANCE at 68 °F to 77 °F (20 °C to 25 °C) in the original blister pack.
Keep IBRANCE and all medicines out of the reach of children.
General information about the safe and effective use of IBRANCE
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
IBRANCE for a condition for which it was not prescribed. Do not give IBRANCE to other people, even if they have the
same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more
information about IBRANCE that is written for health professionals.
What are the ingredients in IBRANCE?
Active ingredient: palbociclib
Inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, succinic
acid, HPMC 2910/hypromellose, titanium dioxide, triacetin, and FD&C Blue #2/Indigo Carmine Aluminum Lake. In
addition, the 75 mg and 125 mg tablets contain red iron oxide and the 100 mg tablets contain yellow iron oxide.
This product’s labeling may have been updated. For the most recent prescribing information, please visit
www.pfizer.com.
Reference ID: 5501319
~Pfizer
Distributed by
Pfizer Labs
Division of Pfizer Inc.
New York, NY 10001
LAB-1372-3.2b
For more information, go to www.pfizer.com or call 1-800-438-1985.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: December 2024
Reference ID: 5501319
| custom-source | 2025-02-12T15:48:12.361853 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212436s010lbl.pdf', 'application_number': 212436, 'submission_type': 'SUPPL ', 'submission_number': 10} |
80,748 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
XENPOZYME safely and effectively. See full prescribing information for
XENPOZYME.
XENPOZYME® (olipudase alfa-rpcp) for injection, for intravenous use
Initial U.S. Approval: 2022
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING
ANAPHYLAXIS
See full prescribing information for complete boxed warning.
Appropriate medical monitoring and support measures, including
cardiopulmonary resuscitation equipment, should be readily available. If
a severe hypersensitivity reaction occurs, discontinue XENPOZYME
immediately and initiate appropriate medical treatment. (5.1)
----------------------------RECENT MAJOR CHANGES-------------------------
Dosage and Administration, Missed Doses (2.4)
12/2024
Dosage and Administration, Administration Instructions (2.7)
12/2024
----------------------------INDICATIONS AND USAGE--------------------------
XENPOZYME is a hydrolytic lysosomal sphingomyelin-specific enzyme
indicated for treatment of non–central nervous system manifestations of acid
sphingomyelinase deficiency (ASMD) in adult and pediatric patients. (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
• See Full Prescribing Information for important recommendations prior to
XENPOZYME treatment initiation. (2.1)
• Adults: Recommended starting dose is 0.1 mg/kg administered as an
intravenous infusion. (2.2)
• Pediatrics: Recommended starting dose is 0.03 mg/kg administered as an
intravenous infusion. (2.3)
• See Full Prescribing Information for the recommended dose escalation and
maintenance dosage, dosage modifications to reduce the risk of adverse
reactions, and preparation and administration instructions. (2.2, 2.3, 2.5,
2.6, 2.7)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
For injection: 4 mg or 20 mg of olipudase alfa-rpcp as a lyophilized powder in
a single-dose vial for reconstitution. (3)
---------------------------CONTRAINDICATIONS---------------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
• Infusion-Associated Reactions (IARs): If severe IARs occur, discontinue
XENPOZYME and initiate appropriate medical treatment. (5.2)
• Elevated Transaminases: Assess ALT and AST within one month prior to
initiation of XENPOZYME, within 72 hours prior to any infusion during
dose escalation, or prior to the next scheduled XENPOZYME infusion
upon resuming treatment following a missed dose. (5.3)
• Risk of Fetal Malformations During Dosage Initiation or Escalation in
Pregnancy: XENPOZYME dosage initiation or escalation, at any time
during pregnancy, is not recommended as it may lead to elevated
sphingomyelin metabolite levels that may increase the risk of fetal
malformations. Advise females of reproductive potential to use effective
contraception during treatment and for 14 days after the last dose if
XENPOZYME is discontinued. (5.4, 8.1, 8.3)
------------------------------ADVERSE REACTIONS------------------------------
• Most common adverse reactions in adult patients (incidence ≥10%) are
headache, cough, diarrhea, hypotension, and ocular hyperemia. (6.1)
• Most common adverse reactions in pediatric patients (incidence ≥20%) are
pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache,
urticaria, nausea, rash, arthralgia, pruritus, fatigue, and pharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme
Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING
ANAPHYLAXIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Recommendations Prior to XENPOZYME Treatment
Initiation
2.2
Recommended Dosage in Adult Patients
2.3
Recommended Dosage in Pediatric Patients
2.4
Missed Doses
2.5
Dosage and Administration Modifications and Monitoring
2.6
Preparation Instructions
2.7
Administration Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions Including Anaphylaxis
5.2
Infusion-Associated Reactions
5.3
Elevated Transaminase Levels
5.4
Risk of Fetal Malformations During Dosage Initiation or Escalation
in Pregnancy
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 Immunogenicity
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Overview of Clinical Trials
14.2 Clinical Trial in Adult Patients with ASMD
14.3 Clinical Trial in Pediatric Patients with ASMD
14.4 Extension Trial in ASMD Pediatric Patients
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5497359
1
FULL PRESCRIBING INFORMATION
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS
Patients treated with XENPOZYME have experienced life-threatening hypersensitivity
reactions, including anaphylaxis. Appropriate medical monitoring and support measures,
including cardiopulmonary resuscitation equipment, should be readily available during
XENPOZYME administration. If a severe hypersensitivity reaction (e.g., anaphylaxis)
occurs, discontinue XENPOZYME immediately and initiate appropriate medical
treatment. In patients with severe hypersensitivity reactions, a desensitization procedure to
XENPOZYME may be considered [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
XENPOZYME is indicated for treatment of non–central nervous system manifestations of acid
sphingomyelinase deficiency (ASMD) in adult and pediatric patients.
2 DOSAGE AND ADMINISTRATION
2.1
Important Recommendations Prior to XENPOZYME Treatment Initiation
Therapy with XENPOZYME should be directed in consultation with physicians knowledgeable
in the management of ASMD. In order to avoid dosing errors including overdosage [see
Overdosage (10)], follow all instructions for dosage and administration.
Laboratory Testing
Before initiating XENPOZYME:
• Obtain baseline transaminase (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST]) levels in all patients within 1 month prior to treatment initiation
[see Warnings and Precautions (5.3)].
• Verify pregnancy status in females of reproductive potential [see Use in Specific
Populations (8.1, 8.3)].
Premedication
Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics,
and/or corticosteroids [see Warnings and Precautions (5.1, 5.2)].
Medical Support
Appropriate medical support measures including cardiopulmonary resuscitation equipment
should be readily available during XENPOZYME administration [see Warnings and Precautions
(5.1)].
Weight-Based Dosing Information
The recommended adult and pediatric dosages of XENPOZYME for the dose escalation and
maintenance phases [see Dosage and Administration (2.2, 2.3)] are based on body weight as
follows for patients with a body mass index (BMI):
• Less than or equal to 30, the dosage is based on actual body weight (kg)
• Greater than 30, the dosage is based on adjusted body weight (kg). Calculate an adjusted
body weight (kg) based on height in meters as described below:
Adjusted body weight (kg) = (actual height in m)2 x 30
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2.2
Recommended Dosage in Adult Patients
Dose Escalation Phase
The recommended starting dose of XENPOZYME in adults is 0.1 mg/kg.
In order to reduce the risk of infusion-associated reactions or elevated transaminase levels,
follow the dose escalation regimen in Table 1 [see Warnings and Precautions (5.1, 5.2, 5.3)].
Administer XENPOZYME via intravenous infusion every 2 weeks.
Table 1: XENPOZYME Dose Escalation Regimen for Adult Patients*
Adult Patients (18 years and older)
First dose (Day 1/Week 0)
0.1 mg/kg
Second dose (Week 2)
0.3 mg/kg
Third dose (Week 4)
0.3 mg/kg
Fourth dose (Week 6)
0.6 mg/kg
Fifth dose (Week 8)
0.6 mg/kg
Sixth dose (Week 10)
1 mg/kg
Seventh dose (Week 12)
2 mg/kg
Eighth dose (Week 14)†
3 mg/kg (recommended maintenance dose)
* Use actual body weight for patients with a BMI less than or equal to 30. For patients with a BMI greater than 30,
calculate adjusted body weight (kg) = (actual height in m)2 x 30 [see Dosage and Administration (2.1)].
† The dose escalation phase includes the first 3 mg/kg dose.
Maintenance Phase
The recommended maintenance dosage of XENPOZYME in adults is 3 mg/kg via intravenous
infusion every 2 weeks.
2.3
Recommended Dosage in Pediatric Patients
Dose Escalation Phase
The recommended starting dose of XENPOZYME in pediatric patients is 0.03 mg/kg.
In order to reduce the risk of infusion-associated reactions or elevated transaminase levels,
follow the dose escalation regimen in Table 2 [see Warnings and Precautions (5.2, 5.3)].
Administer XENPOZYME via intravenous infusion every 2 weeks.
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Table 2: XENPOZYME Dose Escalation Regimen for Pediatric Patients*
Pediatric Patients (0 to 17 years)
First dose (Day 1/Week 0)
0.03 mg/kg
Second dose (Week 2)
0.1 mg/kg
Third dose (Week 4)
0.3 mg/kg
Fourth dose (Week 6)
0.3 mg/kg
Fifth dose (Week 8)
0.6 mg/kg
Sixth dose (Week 10)
0.6 mg/kg
Seventh dose (Week 12)
1 mg/kg
Eighth dose (Week 14)
2 mg/kg
Ninth dose (Week 16)†
3 mg/kg (recommended maintenance dose)
* Use actual body weight for patients with a BMI less than or equal to 30. For patients with a BMI greater than 30, calculate
adjusted body weight (kg) = (actual height in m)2 x 30 [see Dosage and Administration (2.1)].
† The dose escalation phase includes the first 3 mg/kg dose.
Maintenance Phase
The recommended maintenance dosage of XENPOZYME in pediatric patients is 3 mg/kg via
intravenous infusion every 2 weeks.
2.4
Missed Doses
A dose is considered missed when it is not administered within 3 days of the scheduled date.
When a dose of XENPOZYME is missed, refer to Table 3. Follow the instructions in the “Dose
Escalation Phase” or “Maintenance Phase” depending on which phase the patient misses the
dose.
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Table 3: Dosing Recommendations for XENPOZYME Missed Doses*
Consecutive
Missed Doses In:
Dose Escalation Phase
Maintenance Phase
1 missed dose
• First dose after a missed dose:
Administer last tolerated dose
• Second and subsequent doses after
missed dose: Resume dose escalation at
next infusion according to Table 1 for
adult patients or Table 2 for pediatric
patients
First and subsequent doses after
missed dose: Administer maintenance
dose
2 consecutive
• First dose after missed doses:
• First dose after missed doses:
missed doses
Administer 1 dose below last tolerated
Administer 1 dose below the
dose
maintenance dose
• Second and subsequent doses after
• Second and subsequent doses after
missed doses: Resume dose escalation
missed doses: Resume the
according to Table 1 for adults or Table
maintenance dose
2 for pediatric patients
3 or more
First and subsequent doses after
consecutive
missed doses
• For adult patients who have not
completed the dose escalation phase:
Reinitiate dose escalation regimen
starting at 0.1 mg/kg and follow Table
1.
• For pediatric patients who have not
completed the dose escalation phase:
Reinitiate dose escalation regimen
starting at 0.03 mg/kg and follow Table
2.
missed doses: Restart dosing at
0.3 mg/kg and follow Table 1 for adult
patients or Table 2 for pediatric
patients.
• For adult patients who have missed 3
or more consecutive doses in the
maintenance phase during which
sphingomyelin could have
reaccumulated: The treating
physician may consider resuming the
dosing at 0.1 mg/kg and dose
escalate according to Table 1.
• For pediatric patients who have
missed 3 or more consecutive doses
in the maintenance phase during
which sphingomyelin could have
reaccumulated: The treating
physician may consider resuming the
dosing at 0.03 mg/kg and dose
escalate according to Table 2.
*At scheduled infusion after a missed dose, if the dose administered is 0.3 or 0.6 mg/kg, administer that dose twice as per Table 1 and 2.
2.5
Dosage and Administration Modifications and Monitoring
• In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe infusion-
associated reaction (IAR), immediately discontinue XENPOZYME administration and
initiate appropriate medical treatment [see Warnings and Precautions (5.1, 5.2)].
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• In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR,
consider temporarily holding or slowing the infusion rate, and/or reducing the
XENPOZYME dose. If dose is reduced, re-escalate following dose escalation described in
Tables 1 and 2 for adult and pediatric patients, respectively [see Warnings and Precautions
(5.1, 5.2)].
• If transaminase levels are elevated above baseline and >2 times the ULN prior to the next
scheduled administration, the XENPOZYME dose can be adjusted (prior dose repeated or
reduced) or treatment can be temporarily withheld until the liver transaminases return to the
patient’s baseline value [see Warnings and Precautions (5.3)].
2.6
Preparation Instructions
Use aseptic technique during preparation. Reconstitute and dilute XENPOZYME in the
following manner:
Reconstitution and Dilution Instructions
1. Determine the number of XENPOZYME vials to be reconstituted based on the calculated
dose [see Dosage and Administration (2.2, 2.3)].
2. Remove XENPOZYME vials from refrigeration and set aside for approximately 20 to
30 minutes to allow vials to reach room temperature.
3. Reconstitute each vial with:
• 1.1 mL of Sterile Water for Injection, USP into the 4 mg vial
• 5.1 mL of Sterile Water for Injection, USP into the 20 mg vial
by directing the diluent flow to the inside wall of the vial to avoid foaming.
4. Gently roll and tilt vial(s) to reconstitute XENPOZYME and avoid foaming. Each
reconstituted vial will yield a 4 mg/mL clear, colorless solution.
5. Visually inspect the reconstituted solution in the vials for particulate matter and
discoloration. The solution should be clear and colorless. Discard if the solution is discolored
or if visible particulate matter is present.
6. Withdraw the required volume of XENPOZYME from the vial(s) and dilute the
XENPOZYME solution for infusion with 0.9% Sodium Chloride Injection, USP in a syringe
or infusion bag depending on the volume of infusion (see Table 4).
• For patients who weigh less than 10 kg receiving 0.03 mg/kg and 0.1 mg/kg and patients
who weigh between 10 to 20 kg receiving 0.03 mg/kg dose, the volume of infusion will
vary to achieve a fixed final concentration of 0.1 mg/mL (see Table 4). Prepare the
required dose diluted to a final concentration of 0.1 mg/mL in a syringe for infusion.
• For all other patient weights and doses, the final concentration will vary to achieve a
fixed total volume (see Table 4).
-
For total volume less than or equal to 20 mL prepare a syringe for infusion:
o Inject the required volume of the reconstituted XENPOZYME solution (4 mg/mL)
from step 3 slowly down the inside wall of the syringe.
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o Add slowly the quantity sufficient of 0.9% Sodium Chloride Injection, USP to obtain
the required total infusion volume (avoid foaming within the syringe).
-
For a total volume of greater than or equal to 50 mL prepare an infusion bag:
Add slowly the required volume of the reconstituted XENPOZYME solution
(4 mg/mL) from step 3 into the appropriate size 0.9% Sodium Chloride Injection,
USP infusion bag (avoid foaming within the bag) to achieve a fixed total volume per
Table 4.
7. Gently invert the syringe or the infusion bag to mix. Do not shake. Because this is a protein
solution, slight flocculation (described as thin translucent fibers) occurs occasionally after
dilution.
8. Vials are for single dose only. Discard any unused solution.
Storage and Handling of the Reconstituted and Diluted Solutions
• If the reconstituted XENPOZYME vials are not used immediately, store refrigerated at 2°C
to 8°C (36°F to 46°F) for up to 24 hours or at controlled room temperature at 20°C to 25°C
(68°F to 77°F) for up to 6 hours. Discard the unused XENPOZYME reconstituted solution
after 24 hours if stored refrigerated or 6 hours if stored at controlled room temperature.
• If the diluted solution is not used immediately, refrigerate the diluted solution at 2°C to 8°C
(36°F to 46°F) for up to 24 hours or store at room temperature at 20°C to 25°C (68°F to
77°F) for up to 12 hours (inclusive of infusion time), or discard.
• Do not freeze.
Table 4: XENPOZYME Infusion Volumes for Pediatric and Adult Patients Based on Body
Weight*
Pediatric Patients (0 to 17 years)
Adult patients (18 years
and older)
Body Weight
≥2 kg and <10 kg
Body Weight
≥10 kg and <20 kg
Body Weight
≥20 kg
Body Weight
≥20 kg
XENPOZYME
Dose
Total Infusion Volume
0.03 mg/kg
Actual volume will vary†
(0.6 mL to 3 mL)
Actual volume will vary†
(3 mL to 6 mL)
5 mL
NA
0.1 mg/kg
Actual volume will vary†
(2 mL to 10 mL)
5 mL
10 mL
20 mL
0.3 mg/kg
5 mL
10 mL
20 mL
100 mL
0.6 mg/kg
10 mL
20 mL
50 mL
100 mL
1 mg/kg
20 mL
50 mL
100 mL
100 mL
2 mg/kg
50 mL
75 mL
200 mL
100 mL
3 mg/kg
50 mL
100 mL
250 mL
100 mL
* Use actual or adjusted body weight per patient BMI. Refer to section 2. [see Dosage and Administration (2.2, 2.3)].
† Volume will vary to achieve a final concentration of 0.1 mg/mL
2.7
Administration Instructions
1.
Prior to administration, inspect the syringe or infusion bag for foaming. If foaming is present,
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let foam dissipate before administering XENPOZYME.
2.
Use a low-protein binding, 0.2 micron, in-line filter during administration. The following
materials can be used: polyolefin or polyvinylchloride (PVC) with DEHP for infusion bags,
polypropylene for syringes, polyurethane or PVC DEHP-free for infusion sets and
polyethersulfone or polytetrafluoroethylene for in-line filters.
3.
Infuse XENPOZYME using the infusion rates described in Table 5 and Table 6. In absence
of infusion-associated reactions, increase infusion rate per the steps of infusion as indicated
(+/- 5 minutes). Each step of infusion will last for 20 minutes with the exception of the final
step which should last until completion of the infusion volume.
4.
At the end of the infusion, flush the infusion line with 0.9% Sodium Chloride Injection, USP
using the same infusion rate as the one used for the last part of the infusion.
5.
Do not infuse XENPOZYME in the same intravenous line with other products.
Table 5: XENPOZYME Infusion Rates for Adult Patients
Dose
Infusion Rate
step 1
step 2
step 3
step 4
0.1 mg/kg
20 mL/hour
60 mL/hour
NA
NA
0.3 to 3 mg/kg
3.33 mL/hour
10 mL/hour
20 mL/hour
33.33 mL/hour
NA: Not applicable.
Start infusion at step 1 and in absence of infusion-associated reaction increase infusion rate sequentially per the
steps of infusion.
Table 6: XENPOZYME Infusion Rates for Pediatric Patients
Dose
Infusion rate
step 1
step 2
step 3
step 4
0.03 mg/kg
0.1 mg/kg/hour
for the full length
of the infusion
NA
NA
NA
0.1 mg/kg
0.1 mg/kg/hour
0.3 mg/kg/hour
NA
NA
0.3 mg/kg
0.1 mg/kg/hour
0.3 mg/kg/hour 0.6 mg/kg/hour
NA
0.6 mg/kg
0.1 mg/kg/hour
0.3 mg/kg/hour 0.6 mg/kg/hour 1 mg/kg/hour
1 mg/kg
2 mg/kg
3 mg/kg
NA: Not applicable.
Start infusion at step 1 and in absence of infusion-associated reactions increase infusion rate sequentially per the
steps of infusion.
Home Infusion
Home administration under the supervision of a healthcare provider may be considered for
patients on maintenance dose [see Dosage and Administration (2.2, 2.3)] and who are tolerating
their infusion well. The decision to have patients moved to home infusion should be made after
evaluation and recommendation by a physician.
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The dose and infusion rate used in the home setting should remain the same as were used in the
supervised clinical setting and should not be changed without supervision of a physician. In case
of missed dose(s) or delayed infusion, contact a physician as subsequent infusions may occur in a
supervised clinical setting.
3 DOSAGE FORMS AND STRENGTHS
For injection: 4 mg or 20 mg of olipudase alfa-rpcp as a sterile, white to off white lyophilized
powder in a single-dose vial for reconstitution.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions Including Anaphylaxis
Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in
olipudase alfa-treated patients. One 18-month-old XENPOZYME-treated patient experienced an
anaphylactic reaction during the sixth infusion in the dose escalation period in Trial 2 [see
Adverse Reactions (6.1)]. Additionally, a 16-month-old patient with ASMD type A, treated with
a version of olipudase alfa manufactured from a different process, experienced two anaphylactic
reactions during the fifth and sixth infusions in the dose escalation period; the patient received an
immune tolerance induction therapy prior to treatment. In both of these pediatric patients with
anaphylaxis, anti-olipudase alfa-rpcp IgE (IgE ADA) and IgG (IgG ADA) antibodies were
detected [see Adverse Reactions (6.1) and Clinical Pharmacology (12.6)].
Hypersensitivity reactions that were mild to moderate in severity occurred in 10 (33%)
XENPOZYME-treated adult patients and 4 (50%) XENPOZYME-treated pediatric patients in
clinical trials. Hypersensitivity reactions in adults included urticaria, pruritus, erythema, rash,
rash erythematous, eczema, angioedema, and erythema nodosum. Hypersensitivity reactions in
pediatric patients included urticaria, pruritus, rash, erythema, and localized edema [see Adverse
Reactions (6)].
Prior to XENPOZYME administration, consider premedicating with antihistamines, antipyretics,
and/or corticosteroids. Appropriate medical monitoring and support measures, including
cardiopulmonary resuscitation equipment, should be readily available during XENPOZYME
administration.
• If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue
XENPOZYME immediately and initiate appropriate medical treatment. Consider the
risks and benefits of re-administering XENPOZYME following a severe hypersensitivity
reaction (including anaphylaxis). One patient has been rechallenged using slower infusion
rates at a dosage lower than the recommended dosage. In patients with a severe
hypersensitivity reaction, a tailored desensitization procedure to XENPOZYME may be
considered. If the decision is made to readminister XENPOZYME, ensure the patient
tolerates the infusion. If the patient tolerates the infusion, the dosage (dose and/or the
rate) may be increased to reach the recommended dosage.
o Consider testing for IgE ADA in XENPOZYME-treated patients who
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experienced severe hypersensitivity reactions, including anaphylaxis [see
Adverse Reactions (6.1)]. Testing for antibodies against olipudase alfa-rpcp
are available through Genzyme Corporation (at 1-800-745-4447). Consider
other clinical laboratory testing such as serum tryptase and complement
activation in patients who experience anaphylaxis.
• If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding the
infusion, slowing the infusion rate, and/or reducing the XENPOZYME dose [see Dosage
and Administration (2.5)].
5.2
Infusion-Associated Reactions
IARs occurred in approximately 75% of pediatric and 50% of adult XENPOZYME-treated
patients in the clinical trials; a severe IAR occurred in one (12.5%) of the pediatric patients. The
most frequent IARs in:
• ≥10% of adult patients were headache, pruritus, vomiting, and urticaria
• >20% of pediatric patients were urticaria, erythema, headache, nausea, pyrexia, and
vomiting
Acute phase reaction (APR), an acute inflammatory response accompanied by elevations in
inflammatory serum protein concentrations, was observed in one XENPOZYME-treated adult
and one XENPOZYME-treated pediatric patient. Most of the APRs occurred at 48 hours post
infusion during the dose escalation period. Elevations of C-reactive protein, calcitonin, and IL-6,
and reduction of serum iron were observed. The most common clinical symptoms associated
with APRs were pyrexia, vomiting, and diarrhea. Acute phase reactions were managed similar to
other IARs. In the postmarketing setting, 24 hours after receiving XENPOZYME at a higher than
recommended initial dose, a 2-year-old male patient with ASMD, experienced fever, respiratory
distress, hypotension, and death [see Overdosage (10)].
Prior to XENPOZYME administration, consider pre-medicating with antihistamines,
antipyretics, and/or corticosteroids to reduce the risk of infusion-associated reactions (IARs).
However, IARs may still occur in patients after receiving pre-treatment. Follow the dose
escalation regimen to minimize IARs [see Dosage & Administration (2.2, 2.3)].
• If a severe IAR occurs, discontinue XENPOZYME immediately and initiate appropriate
medical treatment. Consider the risks and benefits of re-administering XENPOZYME
following a severe IAR. One patient has been rechallenged using slower infusion rates at
a dosage lower than the recommended dosage. If the patient tolerates the infusion, the
dosage (dose and/or the rate) may be increased to reach the recommended dosage.
• If a mild or moderate IAR occurs, consider temporarily holding the infusion, slowing the
infusion rate, and/or reducing the XENPOZYME dosage [see Dosage and Administration
(2.5)].
5.3
Elevated Transaminase Levels
XENPOZYME may be associated with elevated transaminases (ALT, AST, or both) within 24 to
48 hours after infusion. Elevated transaminase levels were reported in 4 (13%) XENPOZYME-
treated adults and 1 (13%) XENPOZYME-treated pediatric patient during the dose escalation
phase in clinical trials. At the time of the next scheduled infusion, these elevated transaminase
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levels generally returned to levels observed prior to the XENPOZYME infusion [see Adverse
Reactions (6.1)].
To manage the risk of elevated transaminase levels, assess ALT and AST within one month prior
to initiation of XENPOZYME, within 72 hours prior to any infusion during dose escalation,
which includes the first 3 mg/kg dose outlined in Tables 1 and 2, or prior to the next scheduled
XENPOZYME infusion upon resuming treatment following a missed dose.
If either the baseline or pre-infusion transaminase level (during the dose escalation phase) is
>2 times the ULN, repeat transaminase levels within 72 hours after the end of the infusion. If the
pre-infusion transaminase levels are elevated above baseline and >2 times the ULN prior to the
next scheduled administration, the XENPOZYME dose can be reduced (repeat prior lower dose
or reduce the dose) or XENPOZYME can be temporarily withheld until the liver transaminases
return to the patient’s baseline value.
Upon reaching the recommended maintenance dose, transaminase testing is recommended to be
continued as part of routine clinical management of ASMD.
5.4
Risk of Fetal Malformations During Dosage Initiation or Escalation in
Pregnancy
There is no evidence that olipudase alfa-rpcp crosses the human placenta. However, published
literature reports that early embryonic exposure to a metabolite of sphingomyelin (ceramide) or
the S1P receptor modulator fingolimod can produce exencephaly in chicks and mice,
respectively. In animal reproduction studies, exencephaly, a neural tube defect occurring in the
first trimester of pregnancy, was observed in mouse fetuses at exposures less than the exposure at
the maximum recommended human dose of olipudase alfa-rpcp.
XENPOZYME dosage initiation or escalation, at any time during pregnancy, is not
recommended as it may lead to elevated sphingomyelin metabolite levels that may increase the
risk of fetal malformations [see Use in Specific Population (8.1), Clinical Pharmacology (12.2)].
The decision to continue or discontinue XENPOZYME maintenance dosing in pregnancy should
consider the female’s need for XENPOZYME, the potential drug-related risks to the fetus, and
the potential adverse outcomes from untreated maternal ASMD disease.
Verify the pregnancy status in females of reproductive potential prior to initiating
XENPOZYME treatment. Advise females of reproductive potential to use effective
contraception during treatment and for 14 days after the last dose if XENPOZYME is
discontinued [see Use in Specific Populations (8.3)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•
Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1)]
•
Infusion-Associated Reactions (IARs) [see Warnings and Precautions (5.2)]
•
Elevated Transaminase Levels [see Warnings and Precautions (5.3)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
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of another drug and may not reflect the rates observed in practice.
The pooled safety analysis from 3 clinical trials included a total of 38 XENPOZYME-treated
patients (30 adult and 8 pediatric patients) with age range from 1.5 to 59 years old receiving
intravenous doses up to 3 mg/kg every 2 weeks [see Clinical Studies (14)]. The median exposure
duration was 2.5 years (range: 0.4 to 3.7 years) in adult patients and 2.7 years (range: 2.5 to
3.2 years) in pediatric patients.
Serious adverse reactions of anaphylactic reaction were reported in 2 (25%) XENPOZYME-
treated pediatric patients.
Most frequently reported adverse drug reactions in adults (incidence ≥10%) were headache,
cough, diarrhea, hypotension, and ocular hyperemia.
Most frequently reported adverse drug reactions in pediatric patients (incidence ≥20%) were
pyrexia, cough, diarrhea, rhinitis, abdominal pain, vomiting, headache, urticaria, nausea, rash,
arthralgia, pruritus, fatigue, and pharyngitis.
Adult patients with ASMD type B and type A/B (Trial 1)
In Trial 1, 13 adult patients received XENPOZYME once every 2 weeks for 52 weeks (primary
analysis period (PAP)) at dosages escalating from 0.1 mg/kg to a target dose of 3 mg/kg [see
Clinical Studies (14.2)].
Adverse reactions that occurred in at least 7% of XENPOZYME-treated adult patients during the
PAP are described in Table 7.
Table 7: Adverse Reactions Occurring at >7% in Adult Patients with ASMD During the
52-Week Primary Analysis Period in Trial 1
Adverse Reaction
XENPOZYME
N=13
Placebo
N=18
Headache
7 (54%)
8 (44%)
Cough
4 (31%)
2 (11%)
Diarrhea
2 (15%)
2 (11%)
Hypotension
2 (15%)
2 (11%)
Ocular hyperemia
2 (15%)
1 (6%)
Erythema
1 (8%)
1 (6%)
Asthenia
1 (8%)
1 (6%)
Pharyngitis
1 (8%)
1 (6%)
Dyspnea
1 (8%)
0
Urticaria
1 (8%)
0
Papule
1 (8%)
0
Myalgia
1 (8%)
0
Throat irritation
1 (8%)
0
C-reactive protein abnormal
1 (8%)
0
Pediatric Patients with ASMD type B and type A/B (Trial 2 and Trial 3)
In Trial 2, 8 pediatric patients less than or equal to 17 years of age received XENPOZYME
intravenously once every 2 weeks for 64 weeks [see Clinical Studies (14.3)]. After 64 weeks, all
pediatric patients entered into Trial 3.
Adverse reactions that occurred in at least 13% of pediatric patients are described in Table 8.
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Table 8: Adverse Reactions Occurring at ≥13% in XENPOZYME-Treated Pediatric
Patients with ASMD in Trial 2* and Trial 3 for an Overall Observation Period of 2.5 to 3.2
Years
Adverse Reactions
XENPOZYME
N=8
Pyrexia
8 (100%)
Cough
6 (75%)
Diarrhea
6 (75%)
Rhinitis
6 (75%)
Abdominal pain
5 (63%)
Vomiting
4 (50%)
Headache
4 (50%)
Urticaria
4 (50%)
Nausea
3 (38%)
Rash
3 (38%)
Arthralgia
3 (38%)
Pruritus
2 (25%)
Fatigue
2 (25%)
Pharyngitis
2 (25%)
C-reactive protein increased
1 (13%)
Hypotension
1 (13%)
Anaphylactic reaction
1 (13%)
Hypersensitivity
1 (13%)
Infusion site swelling
1 (13%)
Tachycardia
1 (13%)
Pharyngeal swelling
1 (13%)
Abdominal pain includes abdominal pain and abdominal pain upper
Fatigue includes fatigue and asthenia
Rash includes rash and erythema
*Duration of treatment in Trial 2 was 64 weeks. All patients continued into Trial 3.
Treatment related serious adverse reactions, hypersensitivity reactions including anaphylaxis,
and IARs occurred within 24 hours of infusion and were observed in a higher percentage of
pediatric patients than in adult patients.
Laboratory Adverse Reaction
Elevated transaminase levels ranging from 3 times to 14 times the upper limit of normal (ULN)
were reported in 4 (13%) adults and 1 (13%) pediatric patient during the XENPOZYME dose
escalation phase in clinical trials.
Immunogenicity: Antidrug Antibody-Associated Adverse Reactions
In Trial 1, infusion-associated reactions (including hypersensitivity reactions) occurred in a
higher percentage in XENPOZYME-treated patients who developed IgG ADA compared to
those who did not develop IgG ADA (73% versus 44%) [see Clinical Pharmacology (12.6) and
Clinical Studies (14.2)].
In Trial 2, one XENPOZYME-treated pediatric patient (18-months old) experienced an
anaphylactic reaction during the sixth infusion and developed IgE ADA and the highest IgG
ADA titers (ADA peak titer 1,600) of the patients in this trial. After treatment discontinuation,
XENPOZYME was resumed four months later using a diluted drug solution and a
desensitization procedure.
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One pediatric patient (16-months old) with ASMD type A, treated with a version of olipudase
alfa manufactured from a different process, experienced anaphylactic reactions (both during the
fifth and sixth infusions) and developed IgG ADA (highest titer 1,600) and IgE ADA [see
Warnings and Precautions (5.1)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on findings from animal reproduction studies, XENPOZYME may cause embryo-fetal
harm when administered to a pregnant female. XENPOZYME dosage initiation or escalation, at
any time during pregnancy, is not recommended as it may lead to elevated sphingomyelin
metabolite levels that may increase the risk of fetal malformations (see Data), [see Clinical
Pharmacology (12.2)]. However, the decision to continue or discontinue XENPOZYME
maintenance dosing in pregnancy should consider the female’s need for XENPOZYME, the
potential drug-related risks to the fetus, and the potential adverse outcomes from untreated
maternal ASMD disease.
In an embryo-fetal toxicity study in pregnant mice, a rare malformation (exencephaly) was
observed in offspring at an exposure less than the exposure at the maximum recommended
human dose (MRHD) of olipudase alfa-rpcp (see Data).
There are no available data on XENPOZYME use in pregnant females to evaluate for a drug
associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
Advise the pregnant female of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is
unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In an embryo-fetal development study in pregnant mice, olipudase alfa-rpcp was administered
intravenously at doses of 3, 10, or 30 mg/kg daily from gestation day (GD) 6 through GD 15.
Exencephaly was observed in 1 litter at each of the 10 and 30 mg/kg dose groups (2 and
3 fetuses, respectively). These data are consistent with published literature reports that brief
embryonic exposures to sphingomyelin metabolites or a sphingosine-1-phosphate (S1P) receptor
modulator produced neural tube defects, including exencephaly, in chicks and mice.
The developmental No Observed Adverse Effect Level (NOAEL) is 3 mg/kg. The AUC
associated with this dose is 0.14-fold the clinical exposure at the MRHD. The developmental
Lowest-Observed-Adverse-Effect Level (LOAEL), 10 mg/kg, is also associated with an
exposure that is less than the clinical exposure at the MRHD.
In an embryo-fetal development study in pregnant rabbits, olipudase alfa-rpcp was administered
intravenously at doses of 3, 10, or 30 mg/kg daily from GD 6 through GD 19. There was no
maternal or developmental toxicity. The developmental NOAEL was 30 mg/kg; the AUC0-24 at
this dose is approximately 10.5-fold the exposure at the MRHD.
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In a study of pre- and postnatal development in mice, olipudase alfa-rpcp was administered
intravenously every other day from GD 6 through GD 18; then resumed every other day after
parturition, from Lactation Day (LD) 1 through LD 19. Olipudase alfa-rpcp did not induce any
effect on maternal reproductive function or on developmental and reproductive parameters of
male and female offspring. Therefore, the maternal and developmental NOAELs are 30 mg/kg.
Exposures at this dose, based on the embryo-fetal development study, were estimated to be
approximately 1.5-fold the MRHD of olipudase alfa-rpcp.
8.2
Lactation
Risk Summary
There are no data on the presence of olipudase alfa-rpcp in human milk, the effects on the
breastfed infant, or the effects on milk production. Olipudase alfa-rpcp is present in animal milk.
(see Data). When a drug is present in animal milk, it is likely that the drug will be present in
human milk. The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for XENPOZYME and any potential adverse effects on the
breastfed infant from XENPOZYME or from the underlying maternal condition.
Data
Olipudase alfa-rpcp was administered as a single intravenous dose (3 mg/kg) to lactating CD1
mice on post-partum day 7. Milk was not evaluated until post-partum day 9, at which time
concentrations of olipudase alfa-rpcp detected were approximately 1.3% the estimated maximal
maternal plasma concentration.
8.3
Females and Males of Reproductive Potential
XENPOZYME may cause embryo-fetal harm when administered during the first trimester of
pregnancy [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status in females of reproductive potential prior to initiating
XENPOZYME.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment and for
14 days after the last dose if XENPOZYME is discontinued.
8.4
Pediatric Use
The safety and effectiveness of XENPOZYME for the treatment of non-central nervous system
manifestations of acid sphingomyelinase deficiency (ASMD) have been established in pediatric
patients down to birth.
Use of XENPOZYME for this indication is supported by evidence from an adequate, and well-
controlled trial (Trial 1) in adults with supportive efficacy, safety, and tolerability data in
pediatric patients (Trial 2 and Trial 3) [see Adverse Reactions (6.1) and Clinical Studies (14.2,
14.3, 14.4)].
Compared to adults, a higher percentage of pediatric patients experienced treatment related
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serious adverse reactions, anaphylaxis, hypersensitivity reactions, and IARs that occurred within
24 hours of infusion [see Adverse Reactions (6.1)]. Two pediatric patients, an 18 month old
receiving XENPOZYME and a 16 month old with ASMD type A that received a version of
olipudase alfa manufactured from a different process developed anaphylaxis [see Warnings and
Precautions (5.1)].
8.5
Geriatric Use
Of the total number of XENPOZYME-treated adult patients in these trials, 1 (3%) was 65 to
74 years of age, and none were 75 years of age and older [see Clinical Studies (14)].
Clinical trials of XENPOZYME did not include sufficient numbers of patients 65 years of age
and older to determine whether they respond differently from younger adult patients.
10
OVERDOSAGE
Cases of overdosage with XENPOZYME have been reported in pediatric patients during dose
escalation. Some patients experienced serious adverse reactions including death within 24 hours
of initial dose [see Warnings and Precautions (5.2)]. The clinical findings included fever,
hypotension, gastrointestinal bleeding, marked elevation in liver tests, metabolic acidosis,
respiratory failure, and vomiting.
There is no known specific antidote for XENPOZYME overdosage. In the event of overdosage,
immediately stop the infusion, and monitor the patient closely in a hospital setting for the
development of hypersensitivity reactions and IARs including acute phase reactions. For the
management of adverse reactions, see Warnings and Precautions (5.1, 5.2, 5.3) and Adverse
Reactions (6.1).
11
DESCRIPTION
Olipudase alfa-rpcp is a hydrolytic lysosomal sphingomyelin-specific enzyme consisting of
570 amino acids produced in a Chinese hamster ovary cell line by recombinant DNA technology.
The molecular weight of olipudase alfa-rpcp is approximately 76 kDa.
XENPOZYME (olipudase alfa-rpcp) for injection is supplied as a sterile, preservative-free, white
to off-white lyophilized powder for reconstitution and dilution to be administered via intravenous
infusion. XENPOZYME is supplied in single-dose vials.
Each 4 mg vial contains 4 mg olipudase alfa-rpcp, dibasic sodium phosphate (0.89 mg),
methionine (14.92 mg), monobasic sodium phosphate (1.63 mg), and sucrose (50 mg). After
reconstitution with 1.1 mL of Sterile Water for Injection, USP, the final concentration is
4 mg/mL [see Dosage and Administration (2.6)].
Each 20 mg vial contains 20 mg olipudase alfa-rpcp, dibasic sodium phosphate (4.47 mg),
methionine (74.6 mg), monobasic sodium phosphate (8.17 mg), and sucrose (250 mg). After
reconstitution with 5.1 mL of Sterile Water for Injection, USP, the final concentration is
4 mg/mL [see Dosage and Administration (2.6)].
The pH is 6.5 after reconstitution.
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12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ASMD is a lysosomal storage disease that results from reduced activity of the enzyme acid
sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin
phosphodiesterase 1 gene. ASM degrades sphingomyelin to ceramide and phosphocholine. The
deficiency of ASM causes an intra-lysosomal accumulation of sphingomyelin (as well as
cholesterol and other cell membrane lipids) in various tissues. XENPOZYME provides an
exogenous source of ASM.
XENPOZYME is not expected to cross the blood-brain barrier or modulate the CNS
manifestations of ASMD.
12.2 Pharmacodynamics
Plasma Ceramide Levels
Ceramide is elevated in plasma of adult and pediatric patients with ASMD. Plasma ceramide
levels showed a transient increase after each administration (post infusion) of XENPOZYME. In
the dose escalation phase, plasma ceramide levels were substantially increased compared to the
baseline level. Plasma ceramide levels gradually decreased following repeated administration of
XENPOZYME and the pre-infusion levels were generally lower than the baseline level during
the maintenance phase of treatment.
• In adult patients with ASMD in Trial 1 [see Clinical Studies (14.2)], the mean (standard
deviation, SD) pre-infusion plasma ceramide concentration was 3.7 (1.4) mg/L at
baseline and decreased to 2.2 (0.6) mg/L at Week 52 following treatment with
XENPOZYME.
• In pediatric patients with ASMD in Trial 2 [see Clinical Studies (14.3)], the mean (SD)
pre-infusion plasma ceramide concentration was 4.7 (0.9) mg/L at baseline and decreased
to 1.8 (0.3) mg/L at Week 52 following treatment with XENPOZYME.
Plasma Lysosphingomyelin Levels
Lysosphingomyelin is substantially elevated in plasma of adult and pediatric patients with
ASMD. Plasma lysosphingomyelin levels decreased after repeated administration of
XENPOZYME.
• In adult patients with ASMD in Trial 1 [see Clinical Studies (14.2)], the mean (SD) pre
infusion plasma lysosphingomyelin concentration was 379 (204) mcg/L at baseline and
decreased to 99 (118) mcg/L at Week 52 following treatment with XENPOZYME.
• In pediatric patients with ASMD in Trial 2 [see Clinical Studies (14.3)], the mean (SD)
pre-infusion plasma lysosphingomyelin concentration was 625 (339) mcg/L at baseline
and decreased to 80 (47) mcg/L at Week 52 following treatment with XENPOZYME.
Liver Sphingomyelin Content
In adult patients, the liver sphingomyelin content, as assessed by histopathology, decreased from
baseline to Week 52 in the XENPOZYME treatment group compared to an increase in the
placebo group.
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12.3 Pharmacokinetics
In adult patients with ASMD, the mean (SD) maximum plasma olipudase alfa-rpcp concentration
(Cmax) and area under the concentration-time curve (AUC) at steady state were 30 (5) mcg/mL
and 607 (120) mcg∙h/mL, respectively, at the recommended maintenance dose of 3 mg/kg
administered once every 2 weeks. Olipudase alfa-rpcp Cmax and AUC increase proportionally
over a dose range of 0.1 to 3 mg/kg (0.03 to 1 times the approved recommended maintenance
dose).
Distribution
The mean (SD) volume of distribution of olipudase alfa-rpcp was 13 (2) L in adult patients with
ASMD.
Elimination
The mean (SD) clearance of olipudase alfa-rpcp was 0.33 (0.07) L/h and the mean half-life (t1/2)
ranged from 32 to 38 hours in adult patients with ASMD.
Metabolism
The metabolic pathway of olipudase alfa-rpcp has not been characterized. Olipudase alfa-rpcp is
expected to be metabolized into small peptides and amino acids via catabolic pathways.
Specific Populations
Pediatric Patients
In pediatric patients (1.5 to 17.5 years of age) with ASMD, the mean (SD) Cmax was
24.3 (2.8) mcg/mL and the mean (SD) AUC was 449 (70) mcg∙h/mL at the recommended
maintenance dose of 3 mg/kg administered once every 2 weeks.
12.6 Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug
antibodies in other studies, including those of olipudase alfa-rpcp or of other olipudase alfa
products.
Following 0.4 to 3.7 years of XENPOZYME treatment in Trial 1 [see Clinical Studies (14.2)],
9 out of 30 (30%) XENPOZYME-treated adult patients with ASMD developed anti-olipudase
alfa-rpcp IgG antibodies (referred to as IgG ADA). The median time to seroconversion from first
XENPOZYME infusion was approximately 8 weeks. One out of these 9 (11%) adult patients had
neutralizing antibodies (NAb) that inhibited the olipudase alfa-rpcp enzyme activity. None of
these 9 patients had NAb that inhibit the cellular uptake of olipudase alfa-rpcp.
Following 2.5 to 3.2 years of XENPOZYME treatment in Trial 2 and 3 [see Clinical Studies
(14.3)], 6 out of 8 (75%) XENPOZYME-treated pediatric patients with ASMD developed IgG
ADA. The median time to seroconversion from first XENPOZYME infusion was 10 weeks. One
out of the 6 (17%) pediatric patients developed NAb that inhibited olipudase alfa-rpcp enzyme
activity. None of these 6 patients had NAb that inhibited the cellular uptake of olipudase alfa
rpcp.
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Infusion-associated reactions (including hypersensitivity reactions) occurred in a higher
percentage in XENPOZYME-treated patients who developed ADA compared to those who did
not develop ADA [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
There was no identified clinically significant effect of ADA on pharmacokinetics of
XENPOZYME.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Studies to evaluate the carcinogenic potential of olipudase alfa-rpcp have not been conducted.
Mutagenesis
Studies to evaluate the mutagenic potential of olipudase alfa-rpcp have not been conducted.
Impairment of Fertility
Intravenous administration of olipudase alfa-rpcp every other day at doses up to 30 mg/kg had no
adverse effects in a combined study of fertility in male and female mice. Exposures at this dose,
based on the embryo-fetal development study, were estimated to be approximately 1.5-fold those
of the MRHD of olipudase alfa-rpcp.
13.2 Animal Toxicology and/or Pharmacology
In acid sphingomyelinase knockout (ASMKO) mice (a disease model of ASMD), mortality was
observed after a single dose ≥10 mg/kg administered as an IV bolus injection. Observations
(lethargy, coolness to touch, and unwillingness to move), combined with the adrenal
hemorrhage, suggested that hypotensive shock may be the cause of death. These findings were
accompanied by necrosis and apoptosis in the liver and adrenal gland, elevations of ceramide,
sphingosine and sphingosine 1-phosphate in the serum, catabolites of accumulated
sphingomyelin as well as elevations in the serum concentrations of inflammatory mediators, such
as cytokines and acute phase proteins.
In ASMKO mice, a dose-dependent reduction in heart rate accompanied by a decrease in motor
activity and followed by a slow decline in blood pressure was noted after a single IV
administration at 3, 10, and 20 mg/kg. After 2 doses of olipudase alfa-rpcp at 3 and 10 mg/kg to
ASMKO mice, a slight decline in heart rate was noted following the second administration.
Repeated dose studies in adult ASMKO mice show that administration of olipudase alfa-rpcp via
a dose escalation regimen, (3 mg/kg administered IV every other day, followed by a single IV
dose of 20 mg/kg 3 days later) did not result in toxicity. The lack of adverse findings in BALB/c,
C57BL/6 mice, rats, dogs, and monkeys at comparable olipudase alfa-rpcp doses suggested that
the dose-related toxicity observed in ASMKO mice may be due to the rate and amount of
substrate degradation.
14 CLINICAL STUDIES
14.1 Overview of Clinical Trials
The efficacy of XENPOZYME for the treatment of non–central nervous system manifestations
of acid sphingomyelinase deficiency (ASMD) has been evaluated in 3 clinical trials involving a
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total of 61 patients with ASMD:
• Trial 1 in adult patients (NCT02004691),
• Trial 2 in pediatric patients (NCT02292654), and
• Trial 3 a long-term trial in pediatric patients (NCT02004704).
14.2 Clinical Trial in Adult Patients with ASMD
Trial 1 was a multicenter, randomized, double-blinded, placebo-controlled, repeat-dose phase
II/III trial in adult patients with ASMD (clinical diagnosis consistent with ASMD type B and
A/B). In this trial, patients received either XENPOZYME or placebo. Treatment was
administered in both groups as an intravenous infusion once every 2 weeks. XENPOZYME was
dosed as follows: 0.1 mg/kg (Day 1, Week 0), 0.3 mg/kg (Weeks 2 and 4), 0.6 mg/kg (Weeks 6
and 8), 1 mg/kg (Week 10), 2 mg/kg (Week 12), and then a maintenance dose of 3 mg/kg (Week
14 onwards). The trial was divided into 2 consecutive periods: a randomized placebo-controlled,
double-blinded primary analysis period (PAP) which lasted to Week 52, followed by an
extension treatment period (ETP) for up to 4 years. Patients randomized to the placebo arm in the
PAP crossed over to receive XENPOZYME treatment in the ETP to reach the targeted dose of
3 mg/kg, while patients in the original XENPOZYME arm continued treatment.
Patients enrolled in the trial had a diffusion capacity of the lungs for carbon monoxide (DLco)
≤70% of the predicted normal value and a spleen volume ≥6 multiples of normal (MN) measured
by magnetic resonance imaging (MRI). The trial population included 87% White, 7% Asian, and
7% other; for ethnicity, 32% identified as Hispanic/Latino, 65% as non-Hispanic/Latino, and 3%
were not reported.
Five males and 13 females with a median age of 34 years (range: 18 to 66) were included in the
placebo arm and 8 males and 5 females with a median age of 34 years (range: 20 to 59) were
included in the XENPOZYME arm. The XENPOZYME and placebo groups included 1 patient
(8%) and 2 patients (11%) with mild renal impairment (60 mL/minute ≤ creatinine clearance
<90 mL/minute), respectively. There were no patients with moderate or severe renal impairment.
Key efficacy endpoints included assessment of % predicted DLco, spleen volume, liver volume,
and platelet count.
At Week 52 during the PAP, an increase of 21% in the mean percent change in % predicted
DLco was observed in the XENPOZYME-treated patients compared to the placebo-treated
patients (Table 9). A reduction in spleen volume of 39% was observed in the XENPOZYME-
treated patients compared to the placebo-treated patients. The changes in % predicted DLco and
spleen volume were noted at Week 26 of treatment, the first post-dose endpoint assessment
(Figures 1 and 2).
A decrease in mean liver volume and an increase in mean platelet count were noted in the
XENPOZYME-treated patients compared to the placebo-treated patients at Week 52 (Table 9).
Reference ID: 5497359
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Table 9: Observed Value and Percentage Change from Baseline to Week 52 in Key
Endpoints in Adult Patients with ASMD Type B, A/B on XENPOZYME or Placebo (Trial
1)
Placebo
XENPOZYME
Difference
[95% CI]
DLco
n
18
13
Mean % predicted DLco at baseline (SD)
48.5 (10.8)
49.1 (9.7)
NA
n
17
12
Mean % predicted DLco at Week 52 (SD)
49.9 (11.1)
59.4 (9.6)
NA
n
17
12
LS Mean Percent change in % predicted DLco at
Week 52 (SE)
3.0 (3.3)
23.9 (3.8)
20.9 (5.0)*
[10.6, 31.2]
Spleen volume
n
18
13
Mean Spleen Volume (MN) at baseline (SD)
11.2 (3.8)
11.5 (4.7)
NA
n
17
13
Mean Spleen Volume (MN) at Week 52 (SD)
11.2 (4.2)
7.2 (3.9)
NA
n
17
13
LS Mean Percent change in Spleen Volume (in MN)
at Week 52 (SE)
0.5 (2.62)
-38.9 (3.0)
-39.4 (4.0)†
[-47.6, -31.2]
Liver volume
n
18
13
Mean Liver Volume (MN) at baseline (SD)
1.6 (0.5)
1.4 (0.3)
NA
n
17
12
Mean Liver Volume (MN) at Week 52 (SD)
1.6 (0.5)
1.0 (0.2)
NA
n
17
12
LS Mean Percent change in Liver Volume from
baseline to Week 52 (SE)
-1.8 (2.7)
-26.5 (3.2)
-24.7 (4.2)†
[-33.4, -16.1]
Platelet count
n
18
13
Mean Platelet Count (109/L) at baseline (SD)
115.6 (36.3)
109.3 (30.6)
NA
n
16
13
Mean Platelet Count (109/L) at Week 52 (SD)
120.2 (43.2)
126.4 (29.0)
NA
n
16
13
LS Mean Percent change in Platelet Count from
baseline to Week 52 (SE)
2.7 (4.5)
18.3 (5.0)
+15.6 (6.7) ‡
[1.8, 29.4]
Nominal p value: *p value = 0.0003; † p value <0.0001; ‡ p value= 0.0280
Seventeen of 18 patients previously receiving placebo and 13 of 13 patients previously treated
with XENPOZYME for 52 weeks (in the PAP) started or continued treatment with
XENPOZYME, respectively, for up to 4 years. At Week 104, patients initially randomized to
placebo had received XENPOZYME for 52 weeks and demonstrated the following LS mean
(SE) percent changes in clinical parameters from baseline (before first administration of
XENPOZYME): increase in % predicted DLco was 26.8% (6.2) (Figure 1); reduction in spleen
volume (MN) was 36.5% (2.5) (Figure 2); reduction in liver volume (MN) was 29.5 (2.6); and
increase in platelet count was 19.5 (6.7).
Patients in the previous XENPOZYME group demonstrated improvement from baseline to Week
104 in the following parameters: LS mean (SE) percent increase in % predicted DLco was 34.1%
Reference ID: 5497359
21
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Baseline
Week 26
Week 52
Week SO
Week 104
Analysis visit (week)
1--- Placebo - - - • XENPOZYME I
Number of Patients
Placebo/XENPOZYME
18
17
17
15
10
XENPOZYME/XENPOZYME
13
12
12
11
5
(7.9) (Figure 1); LS mean (SE) percent reduction in spleen volume (MN) was 48.3 (2.9) (Figure
2); LS mean (SE) percent reduction in liver volume (MN) was 31.7 (2.9); LS mean (SE) percent
increase in platelet count was 24.0 (8.2).
Figure 1: Plot of the LS Means (95% CI) of the Percentage Change in DLco (% predicted)
from Baseline to Week 104 in Adult Patients with ASMD (Trial 1)
The vertical bars represent the 95% CIs for the LS means.
The LS means and 95% CIs are based on a mixed model for repeated measures approach, using data up to Week
104. Patients in placebo/XENPOZYME group received placebo by Week 52 and switched to XENPOZYME
thereafter.
Reference ID: 5497359
22
10
0
-10
-20
-30
-40
-50
-60
Number of Patients
Placebo/XENPOZYME
XENPOZYME/XENPOZYME
~---.:f--l,
'
'
'
'
Baseline
Week 26
Week 52
Week 80
Week 104
Analysis visit (week)
1-- Placebo - - - • XENPOZYME I
18
13
17
13
17
13
16
13
11
9
Figure 2: Plot of the LS Means (95% CI) of the Percentage Change in Spleen Volume (MN)
from Baseline to Week 104 in Patients with ASMD (Trial 1)
The vertical bars represent the 95% CIs for the LS means.
The LS means and 95% CIs are based on a mixed model for repeated measures approach, using data up to Week
104. Patients in placebo/XENPOZYME group received placebo by Week 52 and switched to XENPOZYME
thereafter.
14.3 Clinical Trial in Pediatric Patients with ASMD
Trial 2 was a multi-center, open-label, repeated-dose trial of XENPOZYME administered
intravenously once every 2 weeks (via infusion) for 64 weeks in pediatric patients aged
<18 years with a clinical diagnosis consistent with ASMD type B and A/B. Exploratory efficacy
endpoints related to organomegaly, pulmonary and liver functions, and linear growth were
evaluated at Week 52. XENPOZYME was dosed as follows: 0.03 mg/kg (Day 1, Week 0),
0.1 mg/kg (Weeks 2), 0.3 mg/kg (Weeks 4 and 6), 0.6 mg/kg (Week 8 and 10), 1 mg/kg (Week
12), 2 mg/kg (Week 14), and then a maintenance dose of 3 mg/kg (Week 16 onwards).
In Trial 2, 8 patients (7 patients from 2 to <12 years old, and 1 patient <2 years old) received an
initial dose of 0.03 mg/kg XENPOZYME and all but one completed the dose escalation up to the
maintenance dose of 3 mg/kg within 22 weeks. All patients were White and of non-
Hispanic/Latino ethnicity.
Patients enrolled in the trial had a spleen volume ≥5 MN measured by MRI. Age of patients
treated with XENPOZYME ranged from 1 to 10 years old, with both sexes equally represented.
Treatment with XENPOZYME resulted in improvements in mean percent change in % predicted
DLco, spleen and liver volumes, platelet counts, and linear growth progression (as measured by
height Z-scores) at Week 52 as compared to baseline (Table 10).
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Table 10: Efficacy Results in XENPOZYME-Treated Pediatric Patients with ASMD (Trial
2)
Baseline Values
Week 52 Values
Mean % predicted DLco (SD)
LS Mean Percent change in % predicted DLco* (SE)
95% CI
(n=3)
48.5 (8.1)
(n=3)
70.9 (13.7)
45.9 (22.7)
-12.5, 104.3
Mean Spleen Volume (MN) (SD)
LS Mean Percent change in Spleen Volume (in MN) (SE)
95% CI
(n=8)
18.3 (5.6)
(n=8)
9.50 (2.4)
-46.7 (3.6)
-55.5, -37.9
Mean Liver Volume (MN) (SD)
LS Mean Percent change in Liver Volume (in MN) (SE)
95% CI
(n=8)
2.5 (0.5)
(n=8)
1.6 (0.3)
-38.1 (2.9)
-44.1, -32.0
Mean Platelet Count (109/L) (SD)
LS Mean Percent change in Platelet Count (SE)
95% CI
(n=8)
136.7 (33.2)
(n=7)
184.5 (54.2)
37.6 (13.7)
8.5, 66.7
Mean height Z-scores (SD)
LS Mean Change in height Z-scores (SE)
95% CI
(n=8)
-1.9 (0.8)
(n=7)
-1.5 (1.0)
0.5 (0.1)
0.2, 0.8
14.4 Extension Trial in ASMD Pediatric Patients
The 8 pediatric patients 2 to <12 years of age from Trial 2 continued treatment in an open label
long term trial (Trial 3) and were treated with XENPOZYME for 2.5 to 3.2 years.
Efficacy analyses showed continued improvements in the 3 patients evaluated for % predicted
DLco, 6 patients evaluated for platelet counts, and all 8 patients evaluated for spleen and liver
volumes, compared to baseline, during the additional 6 months extension. In addition, the height
Z-score increased by 1.3 from baseline when evaluated through 24 months of XENPOZYME
treatment. Bone age, as assessed by hand x-ray, was delayed by a mean of 26.4 months at
baseline in the 7 pediatric patients enrolled in Trial 2 with a bone age measured at Month 24 in
Trial 3. The bone age improved to within a mean of 12 months of the chronological age when
assessed at Month 24 in these 7 patients.
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
XENPOZYME (olipudase alfa-rpcp) for injection is supplied as a sterile white to off-white
lyophilized powder for reconstitution in a single-dose vial. XENPOZYME does not contain any
preservatives.
XENPOZYME is supplied as:
Reference ID: 5497359
24
• Carton containing one 20 mg single-dose vial (NDC 58468-0050-1)
• Carton containing one 4 mg single-dose vial (NDC 58468-0051-1)
Storage and Handling
Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze.
For storage of reconstituted and diluted solution [see Dosage and Administration (2.6)].
17
PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions (Including Anaphylaxis) and Infusion-Associated Reactions (IARs)
Advise the patient and caregiver that reactions related to the infusion may occur during and after
XENPOZYME treatment, including life-threatening hypersensitivity reactions, anaphylaxis, and
IARs. Inform the patient and/or caregiver of the signs and symptoms of hypersensitivity
reactions and IARs and to seek immediate medical care should signs and symptoms occur [see
Warnings and Precautions (5.1, 5.2)].
Embryo-Fetal Toxicity
XENPOZYME may cause embryo-fetal harm. Advise the pregnant female and females of
reproductive potential of the potential risk to the fetus. Advise a female patient and caregiver to
inform their healthcare provider of a known or suspected pregnancy [see Use in Specific
Populations (8.1)].
Advise a female of reproductive potential to use effective contraception during treatment and for
14 days after the last dose if XENPOZYME is discontinued [see Use in Specific Populations
(8.1, 8.3)].
Manufactured by:
Genzyme Corporation
450 Water Street
Cambridge, MA 02141
U.S. License Number: 1596
©2024 Sanofi. All rights reserved. XENPOZYME is a registered trademark of Genzyme Corporation.
Reference ID: 5497359
25
| custom-source | 2025-02-12T15:48:12.970276 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761261s004lbl.pdf', 'application_number': 761261, 'submission_type': 'SUPPL ', 'submission_number': 4} |
80,749 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SOVALDI safely and effectively. See full prescribing information
for SOVALDI.
SOVALDI® (sofosbuvir) tablets, for oral use
SOVALDI® (sofosbuvir) oral pellets
Initial U.S. Approval: 2013
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
See full prescribing information for complete boxed warning.
Hepatitis B virus (HBV) reactivation has been reported, in some
cases resulting in fulminant hepatitis, hepatic failure, and death.
(5.1)
------------------------------INDICATIONS AND USAGE-------------------------
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B
polymerase inhibitor indicated for the treatment of:
• Adult patients with genotype 1, 2, 3 or 4 chronic HCV infection
without cirrhosis or with compensated cirrhosis as a component of a
combination antiviral treatment regimen. (1)
• Pediatric patients 3 years of age and older with genotype 2 or 3
chronic HCV infection without cirrhosis or with compensated
cirrhosis in combination with ribavirin. (1)
------------------------DOSAGE AND ADMINISTRATION---------------------
• Testing Prior to the Initiation of Therapy: Test all patients for HBV
infection by measuring HBsAg and anti-HBc. (2.1)
• Recommended dosage in adults: One 400 mg tablet taken once
daily with or without food. (2.2)
• Recommended dosage in pediatric patients 3 years of age and
older: Recommended dosage of SOVALDI in pediatric patients 3
years of age and older with genotype 2 or 3 HCV using SOVALDI
tablets or oral pellets is based on weight. Refer to Table 3 of the full
prescribing information for specific dosing guidelines based on body
weight. (2.3)
• HCV/HIV-1 coinfection: For adult and pediatric patients with
HCV/HIV-1 coinfection, follow the dosage recommendations in the
tables below, respectively. (2.2, 2.3)
• Recommended adult treatment regimen and duration: (2.2)
Adult Patient Population
Regimen
and
Duration
Genotype
1 or 4
Treatment-naïve without cirrhosis
or with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
peginterferon
alfa + ribavirin
12 weeks
Genotype
2
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
12 weeks
Genotype
3
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
24 weeks
• SOVALDI in combination with ribavirin for 24 weeks can be
considered for adult patients with genotype 1 infection who are
interferon ineligible. (2.2)
• Should be used in combination with ribavirin for treatment of HCV in
adult patients with hepatocellular carcinoma awaiting liver
transplantation for up to 48 weeks or until liver transplantation,
whichever occurs first. (2.2)
• Recommended treatment regimen and duration for pediatric patients
3 years of age and older: (2.3, 2.4)
Pediatric Patient Population
3 Years of Age and Older
Regimen
and
Duration
Genotype
2
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
12 weeks
Genotype
3
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
24 weeks
• A dosage recommendation cannot be made for patients with severe
renal impairment or end stage renal disease. (2.7, 8.6)
• Instructions for Use should be followed for preparation and
administration of SOVALDI oral pellets. (2.4)
-----------------------DOSAGE FORMS AND STRENGTHS-------------------
• Tablets: 400 mg and 200 mg of sofosbuvir. (3)
• Oral Pellets: 200 mg and 150 mg of sofosbuvir. (3)
--------------------------------CONTRAINDICATIONS-----------------------------
• When used in combination with peginterferon alfa/ribavirin or ribavirin
alone, all contraindications to peginterferon alfa and/or ribavirin also
apply to SOVALDI combination therapy. (4)
-------------------------WARNINGS AND PRECAUTIONS---------------------
• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of
current or prior HBV infection before initiation of HCV treatment.
Monitor HCV/HBV coinfected patients for HBV reactivation and
hepatitis flare during HCV treatment and post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically
indicated. (5.1)
• Bradycardia with amiodarone coadministration: Serious symptomatic
bradycardia may occur in patients taking amiodarone with a
sofosbuvir-containing regimen, particularly in patients also receiving
beta blockers, or those with underlying cardiac comorbidities and/or
advanced liver disease. Coadministration of amiodarone with
SOVALDI is not recommended. In patients without alternative, viable
treatment options, cardiac monitoring is recommended. (5.2, 6.2, 7.1)
--------------------------------ADVERSE REACTIONS----------------------------
• The most common adverse events (incidence greater than or equal to
20%, all grades) observed with SOVALDI in combination with ribavirin
were fatigue and headache. The most common adverse events
observed with SOVALDI in combination with peginterferon alfa and
ribavirin were fatigue, headache, nausea, insomnia and anemia.
(6.1). The most common adverse events observed with SOVALDI in
combination with ribavirin oral solution in pediatric patients was
decreased appetite. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
---------------------------------DRUG INTERACTIONS----------------------------
• Coadministration of amiodarone with a sofosbuvir-containing regimen
may result in serious symptomatic bradycardia. (5.2, 6.2, 7.1)
• Drugs that are intestinal P-gp inducers (e.g., rifampin, St. John’s wort)
may alter the concentrations of sofosbuvir. (5.3, 7, 12.3)
• Consult the full prescribing information prior to use for potential drug-
drug interactions. (5.2, 5.3, 7, 12.3)
• Clearance of HCV infection with direct acting antivirals may lead to
changes in hepatic function, which may impact safe and effective use
of concomitant medications. Frequent monitoring of relevant
laboratory parameters (INR or blood glucose) and dose adjustments
of certain concomitant medications may be necessary. (7.1)
---------------------------USE IN SPECIFIC POPULATIONS-------------------
• Patients with HCV/HIV-1 coinfection: Safety and efficacy have been
studied. (14.4)
• Patients with hepatocellular carcinoma awaiting liver transplantation:
Safety and efficacy have been studied. (8.8)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
Reference ID: 5501595
1
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
2.2 Recommended Dosage in Adults
2.3 Recommended Dosage in Pediatric Patients 3 Years of
Age and Older with Genotype 2 or 3 HCV
2.4 Preparation and Administration of Oral Pellets
2.5 Dosage Modification
2.6 Discontinuation of Dosing
2.7 Severe Renal Impairment and End Stage Renal Disease
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Hepatitis B Virus Reactivation in Patients
Coinfected with HCV and HBV
5.2 Serious Symptomatic Bradycardia When Coadministered
with Amiodarone
5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp
Inducers
5.4 Risks Associated with Combination Treatment
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Potentially Significant Drug Interactions
7.2 Drugs without Clinically Significant Interactions with
SOVALDI
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
8.8 Patients with Hepatocellular Carcinoma Awaiting Liver
Transplantation
8.9 Post-Liver Transplant Patients
8.10 Patients with Genotype 5 or 6 HCV Infection
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV
14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV
14.4 Clinical Trials in Adult Subjects Coinfected with HCV and
HIV-1 – Photon-1 (Study 0123)
14.5 Clinical Trial in Pediatrics (Study 1112)
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5501595
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FULL PRESCRIBING INFORMATION
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
COINFECTED WITH HCV AND HBV
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection
before initiating treatment with SOVALDI. HBV reactivation has been reported in
HCV/HBV coinfected patients who were undergoing or had completed treatment
with HCV direct acting antivirals and were not receiving HBV antiviral therapy.
Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation
during HCV treatment and post-treatment follow-up. Initiate appropriate patient
management for HBV infection as clinically indicated [see Warnings and
Precautions (5.1)].
1
INDICATIONS AND USAGE
Adult Patients:
SOVALDI is indicated for the treatment of adult patients with chronic hepatitis C virus
(HCV) infection as a component of a combination antiviral treatment regimen [see
Dosage and Administration (2.2), and Clinical Studies (14)]:
• genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis for use
in combination with pegylated interferon and ribavirin
• genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use
in combination with ribavirin.
Pediatric Patients:
SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in
pediatric patients 3 years of age and older without cirrhosis or with compensated
cirrhosis for use in combination with ribavirin [see Dosage and Administration (2.3) and
Clinical Studies (14.5)].
2
DOSAGE AND ADMINISTRATION
2.1
Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV
treatment with SOVALDI [see Warnings and Precautions (5.1)].
2.2
Recommended Dosage in Adults
The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily
with or without food [see Clinical Pharmacology (12.3)].
Reference ID: 5501595
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Administer SOVALDI in combination with ribavirin or in combination with pegylated
interferon and ribavirin for the treatment of HCV. The recommended treatment regimen
and duration for SOVALDI combination therapy is provided in Table 1.
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table
1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1
antiviral drugs.
Table 1
Recommended Treatment Regimen and Duration in Adult Patients
with Genotype 1, 2, 3, or 4 HCV
Patient Population
Treatment Regimen and
Duration
Genotype 1 or 4
Treatment-naïve without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
SOVALDI + peginterferon alfaa
+ ribavirinb 12 weeks
Genotype 2
Treatment-naïve and treatment-experiencedc
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 12 weeks
Genotype 3
Treatment-naïve and treatment-experiencedc
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 24 weeks
a. See peginterferon alfa prescribing information for dosage recommendation for patients with genotype 1 or 4 HCV.
b. Dosage of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dosage of ribavirin is
administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require
ribavirin dosage reduction; refer to ribavirin tablet prescribing information.
c. Treatment-experienced patients have failed an interferon-based regimen with or without ribavirin.
Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based
Regimen
SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic
option for patients with genotype 1 infection who are ineligible to receive an interferon-
based regimen [see Clinical Studies (14.4)]. Treatment decision should be guided by an
assessment of the potential benefits and risks for the individual patient.
Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
Administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of
liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection
[see Use in Specific Populations (8.8)].
2.3
Recommended Dosage in Pediatric Patients 3 Years of Age and Older with
Genotype 2 or 3 HCV
The recommended treatment regimen, duration, and recommended dosage for
SOVALDI combination therapy is provided in Table 2 and Table 3. Table 4 provides the
weight-based dosage of ribavirin when used in combination with SOVALDI for pediatric
patients. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations
in Table 3 and Table 4. Refer to Drug Interactions (7) for dosage recommendations for
concomitant HIV-1 antiviral drugs. In pediatric patients with hepatocellular carcinoma
Reference ID: 5501595
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awaiting liver transplantation, administer SOVALDI in combination with ribavirin for up to
48 weeks or until the time of liver transplantation, whichever occurs first, to prevent
post-transplant HCV reinfection [see Use in Specific Populations (8.8)].
Table 2
Recommended Treatment Regimen and Duration in Pediatric
Patients 3 Years and Older with Genotype 2 or 3 HCV
Patient Population
Treatment Regimen and
Duration
Genotype 2
Treatment-naïve and treatment-experienceda
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 12 weeks
Genotype 3
Treatment-naïve and treatment-experienceda
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 24 weeks
a. Treatment-experienced patients have failed an interferon based regimen with or without ribavirin.
b. See Table 4 for weight-based ribavirin dosing recommendations.
The recommended dosage of SOVALDI in pediatric patients 3 years and older with
genotype 2 or 3 HCV using SOVALDI tablets or oral pellets (with or without food) is
based on weight (Table 3), and is to be taken orally once daily in combination with
ribavirin [see Dosage and Administration (2.4), Use in Specific Populations (8.4),
Clinical Pharmacology (12.3), and Clinical Studies (14.5)]. SOVALDI pellets can be
taken by pediatric patients who cannot swallow the tablet formulation [see Dosage and
Administration (2.4)].
Table 3
Dosing for Pediatric Patients 3 Years and Older Using SOVALDI
Tablets or Oral Pellets
Body Weight (kg)
Dosing of SOVALDI Tablets or Oral Pellets
SOVALDI Daily Dose
at least 35
one 400 mg tablet once daily
or
two 200 mg tablets once daily
or
two 200 mg packets of pellets once daily
400 mg per day
17 to less than 35
one 200 mg tablet once daily
or
one 200 mg packet of pellets once daily
200 mg per day
less than 17
one 150 mg packet of pellets once daily
150 mg per day
Reference ID: 5501595
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Table 4
Recommended Dosing for Ribavirin in Combination Therapy with
SOVALDI for Pediatric Patients 3 Years and Older
Body Weight (kg)
Oral Ribavirin Daily Dosagea
less than 47
15 mg per kg per day
(divided dose AM and PM)
47–49
600 mg per day
(1 x 200 mg AM, 2 x 200 mg PM)
50–65
800 mg per day
(2 x 200 mg AM, 2 x 200 mg PM)
66–80
1000 mg per day
(2 x 200 mg AM, 3 x 200 mg PM)
greater than 80
1200 mg per day
(3 x 200 mg AM, 3 x 200 mg PM)
a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
2.4
Preparation and Administration of Oral Pellets
See the SOVALDI oral pellets full Instructions for Use for details on the preparation and
administration of SOVALDI pellets.
Do not chew SOVALDI pellets. If SOVALDI pellets are administered with food, sprinkle
the pellets on one or more spoonfuls of non-acidic soft food at or below room
temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed
potato, and ice cream. Take SOVALDI pellets within 30 minutes of gently mixing with
food and swallow the entire contents without chewing to avoid a bitter aftertaste.
2.5
Dosage Modification
Dosage reduction of SOVALDI is not recommended.
If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or
ribavirin, the peginterferon alfa and/or ribavirin dosage should be reduced or
discontinued, if appropriate, until the adverse reaction abates or decreases in severity.
Refer to the peginterferon alfa and ribavirin prescribing information for additional
information about how to reduce and/or discontinue the peginterferon alfa and/or
ribavirin dosage.
2.6
Discontinuation of Dosing
If the other agents used in combination with SOVALDI are permanently discontinued,
SOVALDI should also be discontinued.
2.7
Severe Renal Impairment and End Stage Renal Disease
No dosage recommendation can be given for patients with severe renal impairment
(estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m2) or with end
stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant
sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology
(12.3)].
Reference ID: 5501595
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3
DOSAGE FORMS AND STRENGTHS
SOVALDI is available as tablets or pellets for oral use. Each dosage form is available in
two dose strengths.
• 400 mg Tablets: 400 mg sofosbuvir: yellow, capsule-shaped, film-coated tablet
debossed with “GSI” on one side and “7977” on the other side.
• 200 mg Tablets: 200 mg sofosbuvir: yellow, oval-shaped, film-coated tablet
debossed with “GSI” on one side and “200” on the other side.
• 200 mg Pellets: 200 mg sofosbuvir: white to off-white pellets in unit-dose
packets.
• 150 mg Pellets: 150 mg sofosbuvir: white to off-white pellets in unit-dose
packets.
4
CONTRAINDICATIONS
When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the
contraindications applicable to those agents are applicable to combination therapies.
Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their
contraindications.
5
WARNINGS AND PRECAUTIONS
5.1
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and
HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients
who were undergoing or had completed treatment with HCV direct acting antivirals, and
who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Cases have been reported in patients who are
HBsAg positive and also in patients with serologic evidence of resolved HBV infection
(i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported
in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of
HBV reactivation associated with treatment with HCV direct-acting antivirals may be
increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting
as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection,
reappearance of HBsAg can occur. Reactivation of HBV replication may be
accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe
cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and
anti-HBc before initiating HCV treatment with SOVALDI. In patients with serologic
evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or
HBV reactivation during HCV treatment with SOVALDI and during post-treatment follow
up. Initiate appropriate patient management for HBV infection as clinically indicated.
Reference ID: 5501595
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5.2
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker
intervention have been reported when amiodarone is coadministered with a sofosbuvir
containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone
who was coadministered a sofosbuvir-containing regimen (HARVONI
[ledipasvir/sofosbuvir]). Bradycardia has generally occurred within hours to days, but
cases have been observed up to 2 weeks after initiating HCV treatment. Patients also
taking beta blockers, or those with underlying cardiac comorbidities and/or advanced
liver disease may be at increased risk for symptomatic bradycardia with
coadministration of amiodarone. Bradycardia generally resolved after discontinuation of
HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with SOVALDI is not recommended. For patients taking
amiodarone who have no other alternative, viable treatment options and who will be
coadministered SOVALDI:
• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of
coadministration is recommended, after which outpatient or self-monitoring of the
heart rate should occur on a daily basis through at least the first 2 weeks of
treatment.
Patients who are taking SOVALDI who need to start amiodarone therapy due to no
other alternative, viable treatment options should undergo similar cardiac monitoring as
outlined above.
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to
starting SOVALDI should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation
immediately. Symptoms may include near-fainting or fainting, dizziness or
lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest
pains, confusion or memory problems [see Adverse Reactions (6.2), Drug Interactions
(7.1)].
5.3
Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
Drugs that are P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may
significantly decrease sofosbuvir plasma concentrations and may lead to a reduced
therapeutic effect of SOVALDI. The use of rifampin and St. John’s wort with SOVALDI is
not recommended [see Drug Interactions (7.1)].
5.4
Risks Associated with Combination Treatment
Because SOVALDI is used in combination with other antiviral drugs for treatment of
HCV infection, consult the prescribing information for these drugs used in combination
with SOVALDI. Warnings and Precautions related to these drugs also apply to their use
in SOVALDI combination treatment.
Reference ID: 5501595
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6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the
labeling:
• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see
Warnings and Precautions (5.2)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the
respective prescribing information for a description of adverse reactions associated with
their use.
Adverse Reactions in Adult Subjects
The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data
(both controlled and uncontrolled) including:
• 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for
12 weeks,
• 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks,
• 250 subjects who received SOVALDI + ribavirin combination therapy for
24 weeks,
• 327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin
combination therapy for 12 weeks,
• 243 subjects who received peginterferon alfa + ribavirin for 24 weeks, and
• 71 subjects who received placebo (PBO) for 12 weeks [see Clinical Studies (14)].
The proportion of subjects who permanently discontinued treatment due to adverse
events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI +
ribavirin for 12 weeks, less than 1% for subjects receiving SOVALDI + ribavirin for 24
weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for
subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks.
Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials
outlined above are provided in Table 5. A side-by-side tabulation is displayed to simplify
presentation; direct comparison across trials should not be made due to differing trial
designs.
The most common adverse events (at least 20%) for SOVALDI + ribavirin combination
therapy were fatigue and headache. The most common adverse events (at least 20%)
for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue,
headache, nausea, insomnia and anemia.
Reference ID: 5501595
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Table 5
Adverse Events (All Grades and without Regard to Causality)
Reported in ≥15% of Subjects with HCV in Any Treatment Arm
Interferon-free Regimens
Interferon-containing Regimens
PBO
12 weeks
SOVALDI
+ RBVa
12 weeks
SOVALDI
+ RBVa
24 weeks
Peg-IFN alfa +
RBVb
24 weeks
SOVALDI
+ Peg-IFN alfa
+ RBVa
12 weeks
N=71
N=650
N=250
N=243
N=327
Fatigue
24%
38%
30%
55%
59%
Headache
20%
24%
30%
44%
36%
Nausea
18%
22%
13%
29%
34%
Insomnia
4%
15%
16%
29%
25%
Pruritus
8%
11%
27%
17%
17%
Anemia
0%
10%
6%
12%
21%
Asthenia
3%
6%
21%
3%
5%
Rash
8%
8%
9%
18%
18%
Decreased
Appetite
10%
6%
6%
18%
18%
Chills
1%
2%
2%
18%
17%
Influenza
Like Illness
3%
3%
6%
18%
16%
Pyrexia
0%
4%
4%
14%
18%
Diarrhea
6%
9%
12%
17%
12%
Neutropenia
0%
<1%
<1%
12%
17%
Myalgia
0%
6%
9%
16%
14%
Irritability
1%
10%
10%
16%
13%
a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
≥75 kg).
b. Subjects received 800 mg ribavirin per day regardless of weight.
With the exception of anemia and neutropenia, the majority of events presented in
Table 5 occurred at severity of grade 1 in SOVALDI-containing regimens.
Less Common Adverse Reactions Reported in Clinical Trials (less than 1%): The
following adverse reactions occurred in less than 1% of subjects receiving SOVALDI in
a combination regimen in any one trial. These events have been included because of
their seriousness or assessment of potential causal relationship.
Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant
pegylated interferon).
Reference ID: 5501595
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Psychiatric Disorders: severe depression (particularly in subjects with pre-existing
history of psychiatric illness), including suicidal ideation and suicide.
Laboratory Abnormalities:
Changes in selected hematological parameters are described in Table 6. A side-by-side
tabulation is displayed to simplify presentation; direct comparison across trials should
not be made due to differing trial designs.
Table 6
Percentage of Subjects Reporting Selected Hematological
Parameters
Hematological
Parameters
Interferon-free Regimens
Interferon-containing Regimens
PBO
12 weeks
SOVALDI +
RBVa
12 weeks
SOVALDI +
RBVa
24 weeks
Peg-IFN
+ RBVb
24 weeks
SOVALDI
+ Peg-IFN + RBVa
12 weeks
N=71
N=647
N=250
N=242
N=327
Hemoglobin (g/dL)
<10
0
8%
6%
14%
23%
<8.5
0
1%
<1%
2%
2%
Neutrophils (x109/L)
≥0.5 – <0.75
1%
<1%
0
12%
15%
<0.5
0
<1%
0
2%
5%
Platelets (x109/L)
≥25 – <50
3%
<1%
1%
7%
<1%
<25
0
0
0
0
0
a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
≥75 kg).
b. Subjects received 800 mg ribavirin per day regardless of weight.
Bilirubin Elevations
Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in
the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of
subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks
and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during
the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline
levels by post-treatment Week 4. These bilirubin elevations were not associated with
transaminase elevations.
Creatine Kinase Elevations
Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated,
asymptomatic creatine kinase elevation of greater than or equal to 10xULN was
observed in less than 1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin
24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin
12 weeks groups, respectively.
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Lipase Elevations
Isolated, asymptomatic lipase elevation of greater than 3xULN was observed in less
than 1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12
weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and
peginterferon alfa + ribavirin 24 weeks groups, respectively.
Patients with HCV/HIV-1 Coinfection
SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 coinfected
subjects [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 coinfected
subjects was similar to that observed in HCV mono-infected subjects. Elevated total
bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as
part of the antiretroviral regimen. None of the subjects had concomitant transaminase
increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin
was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected
subjects receiving SOVALDI + ribavirin in Phase 3 trials.
Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
The safety assessment of SOVALDI in pediatric subjects 3 years of age and older is
based on data from 106 subjects who were treated with SOVALDI plus ribavirin for
12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open-
label clinical trial. The adverse reactions observed were consistent with those observed
in clinical studies of SOVALDI plus ribavirin in adults. Among pediatric subjects 3 years
to < 12 years of age taking SOVALDI in combination with ribavirin oral solution,
decreased appetite was observed in 13% (7/54) of subjects [see Clinical Studies 14.5)].
In a 5-year follow-up study, 88 of the 106 subjects from the Phase 2 open-label clinical
trial (Study 1112) were followed for a median (Q1, Q3) duration of 239 (179, 244)
weeks. No notable effects on growth as assessed by changes from baseline through
end of study were observed for height, weight, BMI percentiles, and Z-scores for any
age group. No notable effects were observed on the development of secondary sexual
characteristics of subjects as assessed by changes from baseline through end of study
in Tanner pubertal stages [see Use in Specific Populations (8.4)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of
SOVALDI. Because postmarketing reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Cardiac Disorders
Serious symptomatic bradycardia has been reported in patients taking amiodarone who
initiate treatment with a sofosbuvir-containing regimen [see Warnings and Precautions
(5.2), Drug Interactions (7.1)].
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Skin and Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling
Angioedema
7
DRUG INTERACTIONS
7.1
Potentially Significant Drug Interactions
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein
(BCRP) while the predominant circulating metabolite GS-331007 is not. Drugs that are
P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease
sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI,
and thus concomitant use with SOVALDI is not recommended [see Warnings and
Precautions (5.3)].
Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic
function, which may impact the safe and effective use of concomitant medications. For
example, altered blood glucose control resulting in serious symptomatic hypoglycemia
has been reported in diabetic patients in postmarketing case reports and published
epidemiological studies. Management of hypoglycemia in these cases required either
discontinuation or dose modification of concomitant medications used for diabetes
treatment.
Frequent monitoring of relevant laboratory parameters (e.g. International Normalized
Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug
concentrations of concomitant medications such as cytochrome P450 substrates with a
narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure
safe and effective use. Dose adjustments of concomitant medications may be
necessary.
Information on potential drug interactions with SOVALDI is summarized in Table 7. The
table is not all-inclusive [see Warnings and Precautions (5.2, 5.3) and Clinical
Pharmacology (12.3)].
Table 7
Potentially Significant Drug Interactions: Alteration in Dosage or
Regimen May Be Recommended Based on Drug Interaction Studies
or Predicted Interactiona
Concomitant Drug
Class: Drug Name
Effect on
Concentrationb
Clinical Comment
Antiarrhythmics:
amiodarone
Effect on
amiodarone and
sofosbuvir
concentrations
unknown
Coadministration of amiodarone with a sofosbuvir
containing regimen may result in serious symptomatic
bradycardia. The mechanism of this effect is unknown.
Coadministration of amiodarone with SOVALDI is not
recommended; if coadministration is required, cardiac
monitoring is recommended [see Warnings and
Precautions (5.2), Adverse Reactions (6.2)].
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Anticonvulsants:
↓ sofosbuvir
Coadministration of SOVALDI with carbamazepine,
Carbamazepine
phenytoin
↓ GS-331007
phenytoin, phenobarbital or oxcarbazepine is expected
to decrease the concentration of sofosbuvir, leading to
phenobarbital
reduced therapeutic effect of SOVALDI.
oxcarbazepine
Coadministration is not recommended.
Antimycobacterials:
↓ sofosbuvir
Coadministration of SOVALDI with rifabutin or
Rifabutin
↓ GS-331007
rifapentine is expected to decrease the concentration of
sofosbuvir, leading to reduced therapeutic effect of
rifampin
SOVALDI. Coadministration is not recommended.
rifapentine
Coadministration of SOVALDI with rifampin, an
intestinal P-gp inducer, is not recommended [see
Warnings and Precautions (5.3)].
Herbal Supplements:
St. John’s wort
(Hypericum
perforatum)
↓ sofosbuvir
↓ GS-331007
Coadministration of SOVALDI with St. John’s wort, an
intestinal P-gp inducer, is not recommended [see
Warnings and Precautions (5.3)].
HIV Protease
Inhibitors:
tipranavir/ritonavir
↓ sofosbuvir
↓ GS-331007
Coadministration of SOVALDI with tipranavir/ritonavir is
expected to decrease the concentration of sofosbuvir,
leading to reduced therapeutic effect of SOVALDI.
Coadministration is not recommended.
a. This table is not all-inclusive.
b. ↓ = decrease.
7.2
Drugs without Clinically Significant Interactions with SOVALDI
Based on drug interaction studies conducted with SOVALDI, no clinically significant
drug interactions have been either observed or are expected when SOVALDI is
combined with the following drugs [see Clinical Pharmacology (12.3)]: cyclosporine,
darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir,
rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
If SOVALDI is administered with ribavirin or peginterferon alfa and ribavirin, the
combination regimen is contraindicated in pregnant women and in men whose female
partners are pregnant. Refer to the ribavirin and/or peginterferon alfa prescribing
information for more information on ribavirin- and peginterferon alfa-associated risks of
use during pregnancy.
No adequate human data are available to establish whether or not SOVALDI poses a
risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse
developmental outcomes was observed with sofosbuvir at exposures greater than those
in humans at the recommended human dose (RHD) [see Data]. During organogenesis
in the rat and rabbit, systemic exposures (AUC) to the predominant circulating
metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and 12 (rabbits) times the
exposure in humans at the RHD. In the rat pre/postnatal development study, maternal
Reference ID: 5501595
14
systemic exposure (AUC) to GS-331007 was ≥6 times the exposure in humans at the
RHD.
The background risk of major birth defects and miscarriage for the indicated population
is unknown. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
respectively.
Data
Animal Data
Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits
(up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to
rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum
day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats)
development were observed at the highest doses tested. Systemic exposures (AUC) to
the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and
12 (rabbits) times the exposure in humans at the RHD, with exposures increasing
during gestation from approximately 5 to 10 (rats) and 12 to 28 (rabbits) times the
exposure in humans at the RHD.
8.2
Lactation
Risk Summary
It is not known whether sofosbuvir or its metabolites are present in human breast milk,
affect human milk production or have effects on the breastfed infant. The predominant
circulating metabolite of sofosbuvir (GS-331007) was the primary component observed
in the milk of lactating rats, without effect on nursing pups [see Data].
The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for SOVALDI and any potential adverse effects on the
breastfed child from SOVALDI or from the underlying maternal condition.
If SOVALDI is administered with ribavirin, the nursing mother’s information for ribavirin
also applies to this combination regimen. Refer to the ribavirin prescribing information
for more information on use during lactation.
Data
Animal Data
No effects of sofosbuvir on growth and postnatal development were observed in nursing
pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the
predominant circulating metabolite of sofosbuvir (GS-331007) was approximately
12 times the exposure in humans at the RHD, with exposure of approximately 2% that
of maternal exposure observed in nursing pups on lactation day 10. In a lactation study,
sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating
rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation
day 2, with milk concentrations of approximately 10% that of maternal plasma
concentrations observed 1 hour post-dose.
Reference ID: 5501595
15
8.3
Females and Males of Reproductive Potential
If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the information
for ribavirin and peginterferon with regard to pregnancy testing, contraception, and
infertility also applies to these combination regimens. Refer to ribavirin and/or
peginterferon prescribing information for additional information.
8.4
Pediatric Use
The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 3 years of
age and older with genotype 2 and 3 infection have been established. SOVALDI was
evaluated in an open-label clinical trial (Study 1112), which included 106 subjects (31
genotype 2; 75 genotype 3) 3 years of age and older. The safety, pharmacokinetics,
and efficacy were comparable to that observed in adults [see Dosage and
Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and
Clinical Studies (14.5)].
The safety and efficacy of SOVALDI in pediatric patients 3 years of age and older with
compensated cirrhosis is supported by comparable sofosbuvir and GS-331007
exposures between: 1) adults and pediatric patients without cirrhosis and 2) adults
without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be
expected for pediatric patients with compensated cirrhosis as adults with compensated
cirrhosis.
The safety and efficacy of SOVALDI have not been established in pediatric patients less
than 3 years of age with HCV genotype 2 or 3. The safety and efficacy of SOVALDI
have not been established in pediatric patients with HCV genotype 1 or 4.
In a 5-year follow-up study, the long-term effects of SOVALDI on pediatric growth were
assessed in 88 pediatric subjects 3 years of age and older treated with SOVALDI in
Study 1112. No notable effects on growth from baseline through end of study were
observed [see Adverse Reactions (6.1)]. All subjects who had achieved SVR12
maintained SVR through end of study.
8.5
Geriatric Use
SOVALDI was administered to 90 subjects aged 65 and over. The response rates
observed for subjects over 65 years of age were similar to that of younger subjects
across treatment groups. No dosage adjustment of SOVALDI is warranted in geriatric
patients [see Clinical Pharmacology (12.3)].
8.6
Renal Impairment
No dosage adjustment of SOVALDI is required for patients with mild or moderate renal
impairment. The safety and efficacy of SOVALDI have not been established in patients
with severe renal impairment (eGFR less than 30 mL/min/1.73m2) or ESRD requiring
hemodialysis. No dosage recommendation can be given for patients with severe renal
impairment or ESRD [see Dosage and Administration (2.7) and Clinical Pharmacology
(12.3)]. Refer also to ribavirin and peginterferon alfa prescribing information for patients
with CrCl less than 50 mL/min.
Reference ID: 5501595
16
8.7
Hepatic Impairment
No dosage adjustment of SOVALDI is required for patients with mild, moderate or
severe hepatic impairment (Child-Pugh Class A, B or C) [see Clinical Pharmacology
(12.3)]. Safety and efficacy of SOVALDI have not been established in patients with
decompensated cirrhosis. See peginterferon alfa prescribing information for
contraindication in hepatic decompensation.
8.8
Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
SOVALDI was studied in HCV-infected adult subjects with hepatocellular carcinoma
prior to undergoing liver transplantation in an open-label clinical trial evaluating the
safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent
post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant
virologic response (pTVR) defined as HCV RNA less than lower limit of quantification
(LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype,
with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the
presence of a tumor 5 cm or less in diameter in patients with single hepatocellular
carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in
patients with multiple tumors and no extrahepatic manifestations of the cancer or
evidence of vascular invasion of tumor) received 400 mg SOVALDI and weight-based
1000-1200 mg ribavirin daily for 24-48 weeks or until the time of liver transplantation,
whichever occurred first. An interim analysis was conducted on 61 subjects who
received SOVALDI and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a
baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score
up to 14. Of these 61 subjects, 41 subjects underwent liver transplantation following up
to 48 weeks of treatment with SOVALDI and ribavirin; 37 had HCV RNA less than LLOQ
at the time of transplantation. Of the 37 subjects, the post-transplant virologic response
(pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week
post-transplant time point. The safety profile of SOVALDI and ribavirin in HCV-infected
subjects prior to liver transplantation was comparable to that observed in subjects
treated with SOVALDI and ribavirin in Phase 3 clinical trials.
8.9
Post-Liver Transplant Patients
The safety and efficacy of SOVALDI have not been established in post-liver transplant
patients.
8.10 Patients with Genotype 5 or 6 HCV Infection
Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing
recommendations.
10
OVERDOSAGE
The highest documented dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg
(three times the recommended dosage) administered to 59 healthy subjects. In that trial,
there were no untoward effects observed at this dosage level, and adverse events were
Reference ID: 5501595
17
y
Q )' .. ,,
... =
I
,,.)
"t--< -f
½
similar in frequency and severity to those reported in the placebo and sofosbuvir
400 mg treatment groups. The effects of higher dosages are not known.
No specific antidote is available for overdose with SOVALDI. If overdose occurs, the
patient must be monitored for evidence of toxicity. Treatment of overdose with
SOVALDI consists of general supportive measures including monitoring of vital signs as
well as observation of the clinical status of the patient. A 4-hour hemodialysis session
removed 18% of the administered dose.
11
DESCRIPTION
SOVALDI (sofosbuvir) is a nucleotide analog inhibitor of HCV NS5B polymerase.
The IUPAC name for sofosbuvir is (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo
3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2
yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
O
N
F
HO
O
H
N
O
O
P
O
HN
O
O
O
Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across
the pH range of 2-7.7 at 37 oC and is slightly soluble in water.
SOVALDI tablets, 200 mg or 400 mg, are for oral administration. Each tablet contains
200 mg or 400 mg of sofosbuvir. The tablets include the following inactive ingredients:
colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing
the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium
dioxide, and yellow iron oxide.
SOVALDI pellets, 150 mg or 200 mg, are for oral administration, supplied as white to
off-white pellets in unit-dose packets. Each unit-dose packet contains 150 mg or 200 mg
of sofosbuvir. The pellets include the following inactive ingredients: amino methacrylate
copolymer, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose,
hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol,
silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, and talc.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [see
Microbiology (12.4)].
Reference ID: 5501595
18
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of sofosbuvir 400 and 1200 mg (three times the recommended dosage) on
QTc interval was evaluated in a randomized, single-dose, placebo- and active-
controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy
subjects. At a dosage three times the maximum recommended dosage, SOVALDI does
not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
Absorption
The pharmacokinetic properties of sofosbuvir and the predominant circulating
metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects
with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was
absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose,
regardless of dose level. Peak plasma concentration of GS-331007 was observed
between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in
subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or
without pegylated interferon), geometric mean steady state AUC0-24 was 969 ng•hr/mL
for sofosbuvir (N=838), and 6790 ng•hr/mL for GS-331007 (N=1695). Relative to
healthy subjects administered sofosbuvir alone (N=272), the sofosbuvir AUC0-24 was
60% higher; and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected
subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose
range of 200 mg to 1200 mg.
Effect of Food
Relative to fasting conditions, the administration of a single dose of SOVALDI with a
standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf.
The exposure of GS-331007 was not altered in the presence of a high-fat meal.
Therefore, SOVALDI can be administered without regard to food.
Distribution
Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding
is independent of drug concentration over the range of 1 microgram/mL to
20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a
single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of
14C-radioactivity was approximately 0.7.
Metabolism
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves
sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A
(CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine
Reference ID: 5501595
19
nucleotide biosynthesis pathway. Dephosphorylation results in the formation of
nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks
anti-HCV activity in vitro.
After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007
accounted for approximately 4% and greater than 90% of drug related material (sum of
molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure,
respectively.
Elimination
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose
was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in
urine, feces, and expired air, respectively. The majority of the sofosbuvir dose
recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir.
These data indicate that renal clearance is the major elimination pathway for
GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and
27 hours, respectively.
Specific Populations
Race
Population pharmacokinetics analysis in HCV-infected subjects indicated that race had
no clinically relevant effect on the exposure of sofosbuvir and GS-331007.
Gender
No clinically relevant pharmacokinetic differences have been observed between men
and women for sofosbuvir and GS-331007.
Pediatric Patients
The pharmacokinetics of sofosbuvir and GS-331007 were determined in HCV genotype
2 or 3 infected pediatric subjects 3 years of age and older receiving a daily dose of
SOVALDI as described in Table 8. Exposures in pediatric subjects were similar to those
observed in adults.
Table 8
Pharmacokinetic Properties of SOVALDI in HCV-infected Pediatric
Subjects 3 Years of Age and Oldera
Geometric Mean (%CV)
Weight Group
Dose
PK Parameter
Sofosbuvir
GS-331007
≥35 kgb
400 mg
AUCtau (ng•hr/mL)
1060 (50.6)
7570 (32.8)
Cmax (ng/mL)
472 (53.0)
572 (40.7)
17 to <35 kgc
200 mg
AUCtau (ng•hr/mL)
891 (36.1)
10400 (31.6)
Cmax (ng/mL)
438 (26.4)
866 (27.1)
<17 kgd
150 mg
AUCtau (ng•hr/mL)
851 (41.7)
9060 (37.6)
Cmax (ng/mL)
418 (26.8)
767 (28.3)
a.
Population PK derived parameters
b.
Sofosbuvir N=28; GS-331007 N=50
c.
Sofosbuvir N=29; GS-331007 N=30
d.
Sofosbuvir N=7; GS-331007 N=7
Reference ID: 5501595
20
The pharmacokinetics of sofosbuvir and GS-331007 have not been established in
pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and
Clinical Studies (14.5)].
Geriatric Patients
Population pharmacokinetic analysis in HCV-infected subjects showed that within the
age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the
exposure to sofosbuvir and GS-331007 [see Use in Specific Populations (8.5)].
Patients with Renal Impairment
The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild
(eGFR between 50 to less than 80 mL/min/1.73m2), moderate (eGFR between 30 to
less than 50 mL/min/1.73m2), severe renal impairment (eGFR less than
30 mL/min/1.73m2) and subjects with end stage renal disease (ESRD) requiring
hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with
normal renal function (eGFR greater than 80 mL/min/1.73m2), the sofosbuvir AUC0-inf
was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while
the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with
ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0
inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis
compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after
hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18%
of administered dose. No dosage adjustment is required for patients with mild or
moderate renal impairment. The safety and efficacy of SOVALDI have not been
established in patients with severe renal impairment or ESRD. No dosage
recommendation can be given for patients with severe renal impairment or ESRD [see
Dosage and Administration (2.6) and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg
sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment
(Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the
sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic
impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively.
Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis
had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No
dosage adjustment of SOVALDI is recommended for patients with mild, moderate or
severe hepatic impairment [see Use in Specific Populations (8.7)].
Assessment of Drug Interactions
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein
(BCRP) while GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g.,
rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to
reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not
recommended [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].
Reference ID: 5501595
21
Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase
sofosbuvir plasma concentration without increasing GS-331007 plasma concentration;
accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors.
Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not
expected to increase exposures of drugs that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low
affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are
unlikely to be affected by concomitant drugs.
The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are
shown in Table 9. The effects of sofosbuvir on the exposure of coadministered drugs
are shown in Table 10 [see Drug Interactions (7.1, 7.2)].
Table 9
Drug Interactions: Changes in Pharmacokinetic Parameters for
Sofosbuvir and the Predominant Circulating Metabolite GS-331007
in the Presence of the Coadministered Druga
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Sofosbuvir
Dose (mg)
N
Mean Ratio (90% CI) of Sofosbuvir and GS
331007 PK With/Without Coadministered Drug
No Effect=1.00
Cmax
AUC
Cmin
Cyclosporine
600 single dose
400 single
dose
19
sofosbuvir
2.54
(1.87, 3.45)
4.53
(3.26, 6.30)
NA
GS-331007
0.60
(0.53, 0.69)
1.04
(0.90, 1.20)
NA
Darunavir
(boosted with
ritonavir)
800/100 once
daily
400 single
dose
18
sofosbuvir
1.45
(1.10, 1.92)
1.34
(1.12, 1.59)
NA
GS-331007
0.97
(0.90, 1.05)
1.24
(1.18, 1.30)
NA
Efavirenzb
600 once daily
400 single
dose
16
sofosbuvir
0.81
(0.60, 1.10)
0.94
(0.76, 1.16)
NA
Emtricitabineb
200 once daily
Tenofovir
disoproxil
fumarateb
300 once daily
GS-331007
0.77
(0.70, 0.84)
0.84
(0.76, 0.92)
NA
Methadone
30 to 130 once
daily
400 once
daily
14
sofosbuvir
0.95c
(0.68, 1.33)
1.30c
(1.00, 1.69)
NA
GS-331007
0.73c
(0.65, 0.83)
1.04c
(0.89, 1.22)
NA
Rilpivirine
25 once daily
400 single
dose
17
sofosbuvir
1.21
(0.90, 1.62)
1.09
(0.94, 1.27)
NA
GS-331007
1.06
(0.99, 1.14)
1.01
(0.97, 1.04)
NA
Tacrolimus
5 single dose
400 single
dose
16
sofosbuvir
0.97
(0.65, 1.43)
1.13
(0.81, 1.57)
NA
GS-331007
0.97
(0.83, 1.14)
1.00
(0.87, 1.13)
NA
NA = not available/not applicable
Reference ID: 5501595
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a. All interaction studies conducted in healthy volunteers
b. Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet
c. Comparison based on historic control
No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was
observed with raltegravir.
Table 10
Drug Interactions: Changes in Pharmacokinetic Parameters for
Coadministered Drug in the Presence of Sofosbuvira
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Sofosbuvir
Dose (mg)
N
Mean Ratio (90% CI) of Coadministered Drug
PK With/Without Sofosbuvir
No Effect=1.00
Cmax
AUC
Cmin
Norelgestromin
norgestimate
0.18/0.215/0.25/
ethinyl estradiol
0.025 once daily
400 once
daily
15
1.07
(0.94, 1.22)
1.06
(0.92, 1.21)
1.07
(0.89, 1.28)
Norgestrel
1.18
(0.99, 1.41)
1.19
(0.98, 1.45)
1.23
(1.00, 1.51)
Ethinyl estradiol
1.15
(0.97, 1.36)
1.09
(0.94, 1.26)
0.99
(0.80, 1.23)
Raltegravir
400 twice daily
400 single
dose
19
0.57
(0.44, 0.75)
0.73
(0.59, 0.91)
0.95
(0.81, 1.12)
Tacrolimus
5 single dose
400 single
dose
16
0.73
(0.59, 0.90)
1.09
(0.84, 1.40)
NA
Tenofovir
disoproxil
fumarateb
300 once daily
400 single
dose
16
1.25
(1.08, 1.45)
0.98
(0.91, 1.05)
0.99
(0.91, 1.07)
NA = not available/not applicable
a. All interaction studies conducted in healthy volunteers
b. Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet
No effect on the pharmacokinetic parameters of the following coadministered drugs was
observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine,
methadone, or rilpivirine.
12.4 Microbiology
Mechanism of Action
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is
essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes
intracellular metabolism to form the pharmacologically active uridine analog
triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B
polymerase and acts as a chain terminator. In a biochemical assay, GS-461203
inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a,
3a and 4a with IC50 values ranging from 0.7 to 2.6 micromolar. GS-461203 is neither an
inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA
polymerase.
Reference ID: 5501595
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Antiviral Activity
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from
genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from
genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median EC50 value of
sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates
was 0.062 micromolar for genotype 1a (range 0.029–0.128 micromolar; N=67),
0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29),
0.029 micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and
0.081 micromolar for genotype 3a (range 0.024–0.181 micromolar; N=106). In infectious
virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and
0.02 micromolar, respectively. The presence of 40% human serum had no effect on the
anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon
alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon
cells.
Resistance
In Cell Culture
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell
culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced
susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in
all replicon genotypes examined. An M289L substitution developed along with the
S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the
S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced
susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99%
compared to the corresponding wild-type. In biochemical assays, recombinant NS5B
polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution
showed reduced susceptibility to GS-461203 compared to respective wild-types.
In Clinical Trials
In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials,
224 subjects had post-baseline NS5B genotypic data from next generation nucleotide
sequencing (assay cutoff of 1%).
Treatment-emergent substitutions L159F (n=6) and V321A (n=5) were detected in post-
baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable
shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or
V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T
was not detected at baseline or in the failure isolates from Phase 3 trials. However, an
S282T substitution was detected in one genotype 2b subject who relapsed at Week 4
post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977
0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced
susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer
detectable at Week 12 post-treatment by next generation sequencing with an assay
cutoff of 1%.
Reference ID: 5501595
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In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation
where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F
substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced
virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions
L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and
relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R
and L320F substitutions were detected on-treatment by next generation sequencing in a
subject infected with GT1a HCV with a partial treatment response.
The clinical significance of these substitutions is not known.
Cross Resistance
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were
susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin
associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir
was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside
inhibitor and NS5A inhibitor resistant variants.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for
ribavirin and/or peginterferon alfa for information on carcinogenesis and mutagenesis.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and
in vivo mouse micronucleus assays.
Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice
were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in
females, while rats were administered doses of up to 750 mg/kg/day in males and
females. No increase in the incidence of drug-related neoplasms were observed at the
highest doses tested in mice and rats, resulting in AUC exposure to the predominant
circulating metabolite GS-331007 of approximately 7 and 30 times (in mice) and 13 and
17 times (in rats), in males and females respectively, the exposure in humans at the
recommended clinical dose.
Impairment of Fertility
Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for
ribavirin and/or peginterferon alfa for information on impairment of fertility.
Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats.
At the highest dose tested, AUC exposure to the predominant circulating metabolite
GS-331007 was approximately 8 times the exposure in humans at the recommended
clinical dose.
Reference ID: 5501595
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14
CLINICAL STUDIES
14.1 Description of Clinical Trials
The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of
1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C virus, one
Phase 3 trial in 223 HCV/HIV-1 coinfected subjects with genotype 1, 2 or 3 HCV, and
one trial in 106 pediatric subjects 3 years of age and older with genotype 2 or 3 HCV, as
summarized in Table 11 [see Clinical Studies (14.2, 14.3, 14.4, and 14.5)].
Table 11
Trials Conducted with SOVALDI with Peginterferon Alfa and/or
Ribavirin in Subjects with Chronic HCV Genotype 1, 2, 3, or 4
Infection
Trial
Population
Study Arms (Number of Subjects Treated)
NEUTRINO a
(NCT01641640)
Treatment naïve (TN) (GT1, 4, 5
or 6)
SOVALDI+Peg-IFN alfa+RBV 12 weeks (327)
FISSION a
(NCT01497366)
TN (GT2 or 3)
SOVALDI+RBV 12 Weeks (256)
Peg-IFN alfa+RBV 24 weeks (243)
POSITRON b
(NCT01542788)
Interferon intolerant, ineligible or
unwilling subjects (GT2 or 3)
SOVALDI+RBV 12 Weeks (207)
Placebo 12 weeks (71)
FUSION b
(NCT01604850)
Previous interferon relapsers or
nonresponders (GT2 or 3)
SOVALDI+RBV 12 Weeks (103)
SOVALDI+RBV 16 Weeks (98)
VALENCE b
(NCT01682720)
TN or previous interferon
relapsers or nonresponders
(GT2 or 3)
SOVALDI+RBV 12 Weeks for GT2 (73)
SOVALDI+RBV 12 Weeks for GT3 (11)
SOVALDI+RBV 24 Weeks for GT3 (250)
Placebo for 12 weeks (85)
PHOTON-1 a
(NCT01667731)
•
HCV/HIV-1 coinfected TN
(GT1)
•
HCV/HIV-1 coinfected TN or
previous interferon relapsers
or nonresponders (GT2 or
3)
SOVALDI+RBV 24 Weeks for GT1 (114)
SOVALDI+RBV 12 Weeks for GT2 or 3 TN (68)
SOVALDI+RBV 24 Weeks for GT2 or 3 previous
interferon relapsers or nonresponders (41)
1112
(NCT02175758)a
GT2 or GT3 pediatric subjects 3
years of age and older
SOVALDI+RBV 12 Weeks for GT2 (31)
SOVALDI+RBV 24 Weeks for GT3 (75)
a. Open label.
b. Double-blind, placebo-controlled.
Subjects in the adult trials did not have cirrhosis or had compensated cirrhosis.
SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dosage
for adult subjects was weight-based at 1000-1200 mg daily administered in two divided
doses when used in combination with SOVALDI, and the peginterferon alfa 2a dosage,
where applicable, was 180 micrograms per week. Treatment duration was fixed in each
trial and was not guided by subjects’ HCV RNA levels (no response guided algorithm).
Plasma HCV RNA values were measured during the clinical trials using the COBAS
TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a
Reference ID: 5501595
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lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response
(SVR12) was the primary endpoint which was defined as HCV RNA less than LLOQ at
12 weeks after the end of treatment.
14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV
Treatment-Naïve Adults ─ NEUTRINO (Study 110)
NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment
with SOVALDI in combination with peginterferon alfa 2a and ribavirin in treatment-naïve
subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical
control.
Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the
subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino;
mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV
RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9%
had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 12 presents the SVR12
for the treatment group of SOVALDI + peginterferon alfa + ribavirin in subjects with
genotype 1 or 4 HCV. Available data on subjects with genotype 5 or 6 HCV treated with
SOVALDI + peginterferon alfa + ribavirin for 12 weeks were insufficient for dosing
recommendations; therefore these results are not presented in Table 12 [see Use in
Specific Populations (8.10)].
Table 12
Study NEUTRINO: SVR12 for Treatment-Naïve Subjects with
Genotype 1 or 4 HCV
SOVALDI + Peg-IFN alfa + RBV 12 weeks
N=320
Overall SVR
90% (289/320)
Genotype 1a
90% (262/292)
Genotype 1a
92% (206/225)
Genotype 1b
83% (55/66)
Genotype 4
96% (27/28)
Outcome for subjects without SVR
On-treatment virologic failure
0/320
Relapseb
9% (28/319)
Otherc
1% (3/320)
a. One subject had genotype 1a/1b mixed infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
SVR12 for selected subgroups are presented in Table 13.
Reference ID: 5501595
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Table 13
SVR12 Rates for Selected Subgroups in NEUTRINO in Subjects with
Genotype 1 or 4 HCV
SOVALDI + Peg-IFN alfa + RBV 12 weeks
Cirrhosis
No
93% (247/267)
Yes
79% (42/53)
Race
Black
87% (47/54)
Non-black
91% (242/266)
Multiple Baseline Factors
Genotype 1, Metavir F3/F4
fibrosis, IL28B non-C/C, HCV
RNA >800,000 IU/mL
71% (37/52)
SVR12 rates were 99% (89/90) in subjects with genotype 1 or 4 HCV and baseline
IL28B C/C allele and 87% (200/230) in subjects with genotype 1 or 4 HCV and baseline
IL28B non-C/C alleles.
It is estimated that the SVR12 in patients who previously failed pegylated interferon and
ribavirin therapy will approximate the observed SVR12 in NEUTRINO subjects with
multiple baseline factors traditionally associated with a lower response to interferon-
based treatment (Table 13).
The SVR12 rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C
alleles, HCV RNA greater than 800,000 IU/mL and Metavir F3/F4 fibrosis was 71%
(37/52).
14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV
Treatment-Naïve Adults ─ FISSION (Study 1231)
FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks
of treatment with SOVALDI and ribavirin compared to 24 weeks of treatment with
peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3
HCV. The ribavirin dosage used in the SOVALDI + ribavirin and peginterferon alfa 2a +
ribavirin arms were weight-based 1000-1200 mg per day and 800 mg per day
regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified
by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA
level (less than 6 log10 IU/mL vs. at least 6 log10 IU/mL). Subjects with genotype 2 or 3
HCV were enrolled in an approximately 1:3 ratio.
Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the
subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV
RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype
3. Table 14 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and
Reference ID: 5501595
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peginterferon alfa + ribavirin in subjects with genotype 2 HCV. SVR12 for genotype 3
subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these
results are not presented in Table 14.
Table 14
Study FISSION: SVR12 in Treatment-Naïve Subjects with Genotype 2
HCV
SOVALDI + RBV 12 weeks
Peg-IFN alfa + RBV 24 weeks
N=73a
N=67a
SVR12
95% (69/73)
78% (52/67)
Outcome for subjects without SVR12
On-treatment virologic failure
0/73
4% (3/67)
Relapseb
5% (4/73)
15% (9/62)
Otherc
0/73
4% (3/67)
a. Including three subjects with recombinant genotype 2/1 HCV infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
SVR12 for genotype 2 HCV-infected subjects with cirrhosis at baseline are presented in
Table 15.
Table 15
SVR12 Rates by Cirrhosis in Study FISSION in Subjects with
Genotype 2 HCV
SOVALDI + RBV
12 weeks
Peg-IFN alfa + RBV
24 weeks
N=73
N=67
Cirrhosis
No
97% (59/61)
81% (44/54)
Yes
83% (10/12)
62% (8/13)
Interferon Intolerant, Ineligible or Unwilling Adults ─ POSITRON (Study 0107)
POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated
12 weeks of treatment with SOVALDI and ribavirin (N=207) compared to placebo
(N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were
randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence).
Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the
subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV
RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype
3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling
were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment
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(81%). Table 16 presents the SVR12 for the treatment groups of SOVALDI + ribavirin
and placebo in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated
with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not
presented in Table 16.
Table 16
Study POSITRON: SVR12 in Interferon Intolerant, Ineligible or
Unwilling Subjects with Genotype 2 HCV
SOVALDI + RBV 12 weeks
Placebo 12 weeks
N=109
N= 34
SVR12
93% (101/109)
0/34
Outcome for subjects without SVR12
On-treatment virologic failure
0/109
97% (33/34)
Relapsea
5% (5/107)
0/0
Otherb
3% (3/109)
3% (1/34)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
Table 17 presents the subgroup analysis for cirrhosis and interferon classification in
subjects with genotype 2 HCV.
Table 17
SVR12 Rates for Selected Subgroups in POSITRON in Subjects with
Genotype 2 HCV
SOVALDI + RBV 12 weeks
N=109
Cirrhosis
No
92% (85/92)
Yes
94% (16/17)
Interferon Classification
Ineligible
88% (36/41)
Intolerant
100% (9/9)
Unwilling
95% (56/59)
Previously Treated Adults ─ FUSION (Study 0108)
FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of
treatment with SOVALDI and ribavirin in subjects who did not achieve SVR with prior
interferon-based treatment (relapsers and nonresponders). Subjects were randomized
in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs.
3).
Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the
subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino;
mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV
Reference ID: 5501595
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RNA levels greater than 6 log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype
3; 75% were prior relapsers. Table 18 presents the SVR12 for the treatment groups of
SOVALDI + ribavirin for 12 weeks in subjects with genotype 2 HCV. Treatment of
16 weeks in subjects with genotype 2 HCV was not shown to increase the SVR12
observed with 12 weeks of treatment. SVR12 for genotype 3 subjects treated with
SOVALDI + ribavirin for 12 or 16 weeks was suboptimal; therefore these results are not
presented in Table 18.
Table 18
Study FUSION: SVR12 in Previous Interferon Relapsers and
Nonresponders with Genotype 2 HCV
SOVALDI + RBV
12 weeks
N=39a
SVR12
82% (32/39)
Outcome for subjects without SVR12
On-treatment virologic failure
0/39
Relapseb
18% (7/39)
Otherc
0/39
a. Including three subjects with recombinant genotype 2/1 HCV infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
Table 19 presents the subgroup analysis for cirrhosis and response to prior HCV
treatment in subjects with genotype 2 HCV.
Table 19
SVR12 Rates for Selected Subgroups in Study FUSION in Subjects
with Genotype 2 HCV
SOVALDI + RBV 12 weeks
N=39
Cirrhosis
No
90% (26/29)
Yes
60% (6/10)
Response to prior HCV treatment
Relapser/ breakthrough
86% (25/29)
Nonresponder
70% (7/10)
Treatment-Naïve and Previously Treated Adults ─ VALENCE (Study 0133)
The VALENCE trial evaluated SOVALDI in combination with weight-based ribavirin for
the treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects
who did not achieve SVR with prior interferon-based treatment, including subjects with
compensated cirrhosis. The original trial design was a 4 to 1 randomization to SOVALDI
+ ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded
Reference ID: 5501595
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and all genotype 2 HCV-infected subjects continued the original planned treatment and
received SOVALDI + ribavirin for 12 weeks, and duration of treatment with SOVALDI +
ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven
genotype 3 subjects had already completed SOVALDI + ribavirin for 12 weeks at the
time of the amendment.
Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the
subjects were male; mean body mass index was 26 kg/m2 (range: 17 to 44 kg/m2); the
mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58%
of the subjects were treatment-experienced and 65% of those subjects experienced
relapse/breakthrough to prior HCV treatment.
Table 20 presents the SVR12 for the treatment groups of SOVALDI + ribavirin for
12 weeks and 24 weeks.
Table 20
Study VALENCEa: SVR12 in Subjects with Genotype 2 or 3 HCV Who
were Treatment-Naïve or Who Did Not Achieve SVR12 with Prior
Interferon-Based Treatment
Genotype 2 SOVALDI
+ RBV 12 weeks
Genotype 3 SOVALDI
+ RBV 24 weeks
N=73
N=250
Overall SVR
93% (68/73)
84% (210/250)
Outcome for subjects without SVR
On-treatment virologic failure
0% (0/73)
<1% (1/250)
Relapseb
7% (5/73)
14% (34/249)
Treatment-naïve
3% (1/32)
5% (5/105)
Treatment-experienced
10% (4/41)
20% (29/144)
Otherc
0% (0/73)
2% (5/250)
a. Placebo subjects (N=85) were not included as none achieved SVR12.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to
follow-up).
Table 21 presents the subgroup analysis by genotype for cirrhosis and prior HCV
treatment experience.
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Table 21
SVR12 Rates for Selected Subgroups by Genotype in Study
VALENCE in Subjects with Genotype 2 or 3 HCV
Genotype 2 SOVALDI +
RBV 12 weeks
Genotype 3 SOVALDI
+ RBV 24 weeks
N=73
N=250
Treatment-naïve
97% (31/32)
93% (98/105)
Non-cirrhotic
97% (29/30)
93% (86/92)
Cirrhotic
100% (2/2)
92% (12/13)
Treatment-experienced
90% (37/41)
77% (112/145)
Non-cirrhotic
91% (30/33)
85% (85/100)
Cirrhotic
88% (7/8)
60% (27/45)
14.4 Clinical Trials in Adult Subjects Coinfected with HCV and HIV-1 ─ Photon-1
(Study 0123)
SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the
safety and efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in adult
subjects with genotype 1, 2 or 3 chronic hepatitis C coinfected with HIV-1. Genotype 2
and 3 subjects were either HCV treatment-naïve or experienced, whereas genotype 1
subjects were all treatment-naïve. Subjects received 400 mg SOVALDI and weight-
based ribavirin (1000 mg for subjects weighing less than 75 kg or 1200 mg for subjects
weighing at least 75 kg) daily for 12 or 24 weeks based on genotype and prior treatment
history. Subjects were either not on antiretroviral therapy with a CD4+ cell count greater
than 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count
greater than 200 cells/mm3. Efficacy data 12 weeks post treatment are available for
210 subjects (see Table 22).
Table 22
Study PHOTON-1a: SVR12 in Treatment-Naïve or Treatment-
Experienced Subjects with Genotype 1, 2, or 3 HCV
HCV genotype 1
HCV genotype 2
HCV genotype 3
SOVALDI + RBV
24 weeks
TN (N=114)
SOVALDI + RBV
12 weeks
TN (N=26)
SOVALDI + RBV
24 weeks
TE (N=13)
Overall
76% (87/114)
88% (23/26)
92% (12/13)
Outcome for subjects without SVR12
On-treatment virologic
failure
1% (1/114)
4% (1/26)
0/13
Relapseb
22% (25/113)
0/25
8% (1/13)
Otherc
1% (1/114)
8% (2/26)
0/13
TN = Treatment-naïve; TE = Treatment-experienced
a. Subjects with genotype 2 HCV treated with SOVALDI + RBV for 24 weeks (N=15) and subjects with genotype 3
HCV treated with SOVALDI + RBV for 12 weeks (N=42) are not included in the table.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to
follow-up).
Reference ID: 5501595
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In subjects with HCV genotype 1 infection, the SVR12 rate was 82% (74/90) in subjects
with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with
relapse accounting for the majority of treatment failures. SVR12 rates in subjects with
HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele
and 75% (62/83) in subjects with baseline IL28B non-C/C alleles.
In the 223 HCV subjects with HIV-1 coinfection, the percentage of CD4+ cells did not
change during treatment. Median CD4+ cell count decreases of 85 cells/mm3 and
84 cells/mm3 were observed at the end of treatment with SOVALDI + ribavirin for 12 or
24 weeks, respectively. HIV-1 rebound during SOVALDI + ribavirin treatment occurred
in 2 subjects (0.9%) on antiretroviral therapy.
14.5 Clinical Trial in Pediatrics (Study 1112)
The efficacy of SOVALDI in HCV-infected pediatric subjects 3 years of age and older
was evaluated in 106 subjects with HCV genotype 2 (N = 31) or genotype 3 (N = 75) in
a Phase 2, open label clinical trial. Subjects with HCV genotype 2 or 3 infection in the
trial were treated with SOVALDI and weight-based ribavirin for 12 or 24 weeks,
respectively [see Dosage and Administration (2.3)].
Subjects 12 Years to <18 Years of Age: SOVALDI was evaluated in 52 subjects12
years to <18 years of age with HCV genotype 2 (N = 13) or genotype 3 (N = 39)
infection. The median age was 15 years (range: 12 to 17); 40% of the subjects were
female; 90% were White, 4% were Black, and 2% were Asian; 4% were
Hispanic/Latino; mean body mass index was 22 kg/m2 (range: 16 to 32 kg/m2);mean
weight was 60 kg (range: 30 to 101 kg); 17% were treatment experienced; 65% had
baseline HCV RNA levels greater than or equal to 800,000 IU/mL; and no subjects had
known cirrhosis. The majority of subjects (71%) had been infected through vertical
transmission.
The SVR12 rate was 100% [13/13] in genotype 2 subjects and 97% [38/39] in genotype
3 subjects. No subject experienced on-treatment virologic failure or relapse.
Subjects 6 Years to <12 Years of Age: SOVALDI was evaluated in 41 subjects 6 years
to <12 years of age with HCV genotype 2 (N = 13) or genotype 3 (N = 28) infection. The
median age was 9 years (range: 6 to 11); 73% of the subjects were female; 71% were
White and 20% were Asian; 15% were Hispanic/Latino; mean body mass index was 19
kg/m2 (range: 13 to 32 kg/m2); mean weight was 34 kg (range 15 to 80 kg); 98% were
treatment naive; 46% had baseline HCV RNA levels greater than or equal to 800,000
IU/mL; and no subjects had known cirrhosis. The majority of subjects (98%) had been
infected through vertical transmission.
The SVR12 rate was 100% (13/13) in genotype 2 and 100% (28/28) in genotype 3
subjects.). No subjects experienced on-treatment virologic failure or relapse.
Subjects 3 Years to <6 Years of Age: SOVALDI was evaluated in 13 subjects 3 years to
<6 years of age with HCV genotype 2 (N = 5) or genotype 3 (N = 8) infection. The
median age was 4 years (range: 3 to 5); 77% of the subjects were female; 69% were
Reference ID: 5501595
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White, 8% were Black, and 8% were Asian; 8% were Hispanic/Latino; mean body mass
index was 15 kg/m2 (range: 13 to 17 kg/m2); mean weight was 17 kg (range 13 to 19
kg); 100% were treatment naive; 23% had baseline HCV RNA levels greater than or
equal to 800,000 IU/mL; and no subjects had known cirrhosis. The majority of subjects
(85%) had been infected through vertical transmission.
The SVR12 rate was 80% (4/5) in genotype 2 subjects and 100% (8/8) in genotype 3
subjects. No subjects experienced on-treatment virologic failure or relapse. One subject
prematurely discontinued study treatment due to an adverse event.
16
HOW SUPPLIED/STORAGE AND HANDLING
Tablets
SOVALDI tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets containing
400 mg sofosbuvir debossed with “GSI” on one side and “7977” on the other side. Each
bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant and polyester coil
with a child-resistant closure.
SOVALDI tablets, 200 mg, are yellow, oval-shaped, film-coated tablets containing 200
mg sofosbuvir debossed with “GSI” on one side and “200” on the other side. Each bottle
contains 28 tablets (NDC 61958-1503-1) and a polyester coil with a child-resistant
closure.
Store below 30 °C (86 °F).
•
Dispense only in original container
•
Do not use if seal over bottle opening is broken or missing
Oral Pellets
SOVALDI pellets, 150 mg, are white to off-white pellets supplied as unit-dose packets in
cartons. Each carton contains 28 packets (NDC 61958-1504-1)
SOVALDI pellets, 200 mg, are white to off-white pellets supplied as unit-dose packets in
cartons. Each carton contains 28 packets (NDC 61958-1505-1)
• Store below 30 °C (86 °F).
• Do not use if carton tamper-evident or packet seal is broken or damaged.
Reference ID: 5501595
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17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during
or after treatment of HCV infection. Advise patients to tell their healthcare provider if
they have a history of HBV infection [see Warnings and Precautions (5.1)].
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Advise patients to seek medical evaluation immediately for symptoms of bradycardia
such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness,
excessive tiredness, shortness of breath, chest pain, confusion or memory problems
[see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions
(7.1)].
Pregnancy
Advise patients to avoid pregnancy during combination treatment with SOVALDI and
ribavirin or SOVALDI and peginterferon and ribavirin. Inform patients to notify their
health care provider immediately in the event of a pregnancy [see Use in Specific
Populations (8.1)].
Drug Interactions
Advise patients that SOVALDI may interact with some drugs; therefore, patients should
be advised to report the use of any prescription, non-prescription medication or herbal
products to their healthcare provider [see Warnings and Precautions (5.3) and Drug
Interactions (7.1)].
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus
during treatment or in the event of treatment failure should be taken.
Administration
Advise patients to take SOVALDI every day at the regularly scheduled time with or
without food. Inform patients that it is important not to miss or skip doses and to take
SOVALDI for the duration that is recommended by the physician.
For SOVALDI oral pellets, advise patients or caregivers to read and follow the
Instructions for Use for preparing the correct dose.
Important Information on Coadministration with Ribavirin or Peginterferon and Ribavirin
Advise patients that the recommended regimen for patients with genotype 1 or 4 HCV
infection is SOVALDI administered in combination with peginterferon alfa and ribavirin
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and the recommended regimen for patients with genotype 2 or 3 HCV infection is
SOVALDI administered in combination with ribavirin. If peginterferon and/or ribavirin are
permanently discontinued, SOVALDI should also be discontinued.
Manufactured and distributed by:
Gilead Sciences, Inc.
Foster City, CA 94404
SOVALDI and HARVONI are trademarks of Gilead Sciences, Inc., or its related
companies. All other trademarks referenced herein are the property of their respective
owners.
©2024 Gilead Sciences, Inc. All rights reserved.
204671-GS-0011
Reference ID: 5501595
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Patient Information
SOVALDI® (soh-VAHL-dee)
SOVALDI® (soh-VAHL-dee)
(sofosbuvir)
(sofosbuvir)
tablets
oral pellets
Important: SOVALDI is used in combination with other antiviral medicines. When taking
SOVALDI with ribavirin or in combination with peginterferon alfa and ribavirin you should also
read those Medication Guides. The information in this Patient Information Leaflet talks about
SOVALDI when it is used with ribavirin and in combination with peginterferon alfa and ribavirin.
What is the most important information I should know about SOVALDI?
SOVALDI can cause serious side effects, including:
•
Hepatitis B virus reactivation: Before starting treatment with SOVALDI, your healthcare provider
will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus
infection, the hepatitis B virus could become active again during or after treatment of hepatitis C
virus with SOVALDI. Hepatitis B virus becoming active again (called reactivation) may cause
serious liver problems including liver failure and death. Your healthcare provider will monitor you if
you are at risk for hepatitis B virus reactivation during treatment and after you stop taking
SOVALDI.
For more information about side effects, see the section “What are the possible side effects of
SOVALDI?”
What is SOVALDI?
SOVALDI is a prescription medicine used with other antiviral medicines to treat adults with chronic
(lasting a long time) hepatitis C virus (HCV):
•
genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with
peginterferon alfa and ribavirin
•
genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with
ribavirin
SOVALDI is used to treat children 3 years of age and older with chronic HCV genotype 2 or 3 infection
without cirrhosis or with compensated cirrhosis in combination with ribavirin.
It is not known if SOVALDI is safe and effective in children under 3 years of age with HCV genotype 2
or 3 infection, or with HCV genotype 1 or 4 infection.
It is not known if SOVALDI is safe and effective in people who have had a liver transplant.
Before taking SOVALDI, tell your healthcare provider about all of your medical conditions,
including if you:
•
have ever had hepatitis B virus infection
•
have liver problems other than hepatitis C infection
•
have had a liver transplant
•
have severe kidney problems or you are on dialysis
•
have HIV infection
•
are pregnant or plan to become pregnant. It is not known if SOVALDI will harm your unborn
baby.
•
Males and females who take SOVALDI in combination with ribavirin should also
read the ribavirin Medication Guide for important pregnancy, contraception, and
infertility information.
•
are breastfeeding or plan to breastfeed. It is not known if SOVALDI passes into your breast
milk. Talk to your healthcare provider about the best way to feed your baby during treatment
with SOVALDI.
Tell your healthcare provider about all the medicines you take, including prescription and over-the
counter medicines, vitamins, and herbal supplements. SOVALDI and other medicines may affect each
Reference ID: 5501595
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other. This can cause you to have too much or not enough SOVALDI or other medicines in your body.
This may affect the way SOVALDI or your other medicines work, or may cause side effects.
Keep a list of your medicines to show your healthcare provider and pharmacist.
•
You can ask your healthcare provider or pharmacist for a list of medicines that interact with
SOVALDI.
•
Do not start taking a new medicine without telling your healthcare provider. Your
healthcare provider can tell you if it is safe to take SOVALDI with other medicines.
How should I take SOVALDI?
•
Take SOVALDI exactly as your healthcare provider tells you to take it. Do not change your
dose unless your healthcare provider tells you to.
•
Do not stop taking SOVALDI without first talking with your healthcare provider.
•
Take SOVALDI tablets or oral pellets by mouth, with or without food.
•
For adults the usual dose of SOVALDI is one 400 mg tablet each day.
•
For children 3 years of age and older, your healthcare provider will prescribe the right dose of
SOVALDI tablets or oral pellets based on your child’s body weight.
o
Tell your healthcare provider if your child has problems with swallowing tablets.
o
If your healthcare provider prescribes SOVALDI pellets for your child, see “How
should I give SOVALDI oral pellets to my child.”
•
Do not miss a dose of SOVALDI. Missing a dose lowers the amount of medicine in your blood.
Refill your SOVALDI prescription before you run out of medicine.
•
If you take too much SOVALDI, call your healthcare provider or go to the nearest hospital
emergency room right away.
How should I give SOVALDI oral pellets to my child?
See the detailed Instructions for Use for information about how to give or take a dose of
SOVALDI oral pellets.
•
Administer SOVALDI oral pellets exactly as instructed by your healthcare provider.
•
Do not open the packet until ready to use.
•
Hold the SOVALDI pellets packet with the cut line on top.
•
Shake the SOVALDI pellets packet gently to settle the pellets.
•
Tear or cut the SOVALDI packet along the cut line.
•
SOVALDI pellets can be taken right in the mouth without chewing, or with food.
•
If SOVALDI pellets are taken with food, sprinkle the pellets on one or more spoonfuls of non-
acidic soft food at or below room temperature. Examples of non-acidic foods include pudding,
chocolate syrup, mashed potato, and ice cream. Take SOVALDI pellets within 30 minutes of
gently mixing with food and swallow the entire contents without chewing to avoid a bitter taste.
•
Do not store any leftover SOVALDI mixture (oral pellets mixed with food) for use at a later time.
Throw away any unused portion.
What are the possible side effects of SOVALDI?
SOVALDI can cause serious side effects, including:
•
Hepatitis B virus reactivation. See “What is the most important information I should know
about SOVALDI?”
•
Slow heart rate (bradycardia). SOVALDI treatment may result in slowing of the heart rate
along with other symptoms when taken with amiodarone (Cordarone®, Nexterone®,
Pacerone®), a medicine used to treat certain heart problems. In some cases bradycardia has
led to death or the need for a heart pacemaker when amiodarone is taken with SOVALDI. Get
medical help right away if you take amiodarone with SOVALDI and get any of the following
symptoms:
•
fainting or near-fainting
•
weakness
•
chest pain
•
dizziness or
•
extreme tiredness
•
confusion
lightheadedness
•
shortness of breath
•
memory problems
•
not feeling well
The most common side effects of SOVALDI when used in combination with ribavirin include:
•
tiredness
• headache
Reference ID: 5501595
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The most common side effects of SOVALDI when used in combination with peginterferon alfa and
ribavirin include:
•
tiredness
•
nausea
• low red blood cell count
•
headache
•
difficulty sleeping
These are not all the possible side effects of SOVALDI. For more information, ask your healthcare
provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store SOVALDI?
•
Store SOVALDI tablets or pellets below 86°F (30°C).
•
Keep SOVALDI tablets in the original container.
•
Do not use SOVALDI tablets if the seal over the bottle opening is broken or missing.
•
Do not use SOVALDI pellets if the carton tamper-evident seal, or the pellets packet seal, is
broken or damaged.
Keep SOVALDI and all medicines out of the reach of children.
General information about the safe and effective use of SOVALDI.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use SOVALDI for a condition for which it was not prescribed. Do not give SOVALDI to
other people, even if they have the same symptoms you have. It may harm them. You can ask your
healthcare provider or pharmacist for information about SOVALDI that is written for health
professionals. For more information, call 1-800-445-3235 or go to www.SOVALDI.com.
What are the ingredients in SOVALDI?
Active ingredient: sofosbuvir
Inactive ingredients, Tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate,
mannitol, and microcrystalline cellulose. The tablet film-coat contains polyethylene glycol, polyvinyl
alcohol, talc, titanium dioxide, and yellow iron oxide.
Inactive ingredients, Oral Pellets: amino methacrylate copolymer, colloidal silicon dioxide,
croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, microcrystalline
cellulose, polyethylene glycol, silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, stearic
acid, and talc.
Gilead Sciences, Inc., Foster City, CA 94404
For more information, call 1-800-445-3235 or go to www.SOVALDI.com.
SOVALDI is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks
referenced herein are the property of their respective owners.
©2024 Gilead Sciences, Inc. All rights reserved.
204671-GS-011
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 03/2020
Reference ID: 5501595
3
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INSTRUCTIONS FOR USE
SOVALDI® (soh-VAHL-dee)
(sofosbuvir)
pellets, for oral use
Read the Patient Information that comes with SOVALDI oral pellets for important information about SOVALDI.
This Instructions for Use contains information on how to take SOVALDI oral pellets. Be sure you understand and follow
the instructions. If you have any questions, ask your healthcare provider or pharmacist.
Important Information You Need to Know Before Taking SOVALDI oral pellets
•
For oral use only (take by mouth with or without food).
•
Do not open the SOVALDI oral pellet packet(s) until ready to use.
•
SOVALDI oral pellets are white to off-white pellets supplied as single-use packets in cartons. Each carton
contains 28 packets.
•
Do not use SOVALDI oral pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or
damaged.
Preparing a dose of SOVALDI oral pellets to be taken with food:
Before you prepare a dose of SOVALDI oral pellets to be taken with food, gather the following supplies:
•
Daily SOVALDI oral pellet packet(s), as prescribed by your healthcare provider
•
One or more spoonfuls of non-acidic soft food such as pudding, chocolate syrup, mashed potato, or ice cream
•
Bowl
•
Spoon
•
Scissors (optional)
Step 1: Add one or more spoonfuls of non-acidic soft food to the bowl first.
Step 2: Hold the SOVALDI oral pellets packet
Step 3: Shake the packet gently to settle the
with the cut line on top (see Figure A).
pellets to the bottom of the packet (see Figure B).
Figure A
Figure B
Reference ID: 5501595
Step 4: Cut the packet along the cut line with scissors (see Figure C), or fold the packet back at the tear line (see
Figure D) and tear open (see Figure E).
OR
Figure C
Figure D
Figure E
Step 5: Carefully pour the entire contents of the prescribed number of SOVALDI oral pellet packet(s) onto the food in the
bowl and gently mix with a spoon (see Figure F). Make sure that no SOVALDI oral pellets remain in the packet(s).
Figure F
Step 6: Take the SOVALDI oral pellets and food mixture within 30 minutes without chewing to avoid a bitter taste. Ensure
all of the SOVALDI oral pellets are taken.
Preparing a dose of SOVALDI oral pellets to be taken without food:
Before you prepare a dose of SOVALDI oral pellets to be taken without food, gather the following supplies:
•
Daily SOVALDI oral pellet packet(s), as prescribed by your healthcare provider
•
Scissors (optional)
•
Water (optional)
Reference ID: 5501595
i
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~
I
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Step 1: Hold the SOVALDI oral pellets packet
Step 2: Shake the packet gently to settle the
with the cut line on top (see Figure G).
pellets to the bottom of the packet (see Figure H).
Figure G
Figure H
Step 3: Cut the packet along the cut line with scissors (see Figure I), or fold the packet back at the tear line (see
Figure J) and tear open (see Figure K).
OR
Figure I
Figure J
Figure K
Reference ID: 5501595
Step 4: Pour the entire contents of the SOVALDI oral pellets packet directly in the mouth and swallow without chewing to
avoid a bitter taste (see Figure L). Water may be taken after swallowing the pellets, if needed. Make sure that no SOVALDI
oral pellets remain in the packet. If your healthcare provider prescribed more than one SOVALDI oral pellets packet, repeat
Steps 1 through 4.
Figure L
Storing SOVALDI oral pellets
•
Store SOVALDI pellets below 86°F (30°C).
•
Keep SOVALDI oral pellets and all medicines out of the reach of children.
Disposing of SOVALDI oral pellets
•
Throw away any unused portion. Do not store and reuse any leftover SOVALDI mixture (pellets mixed with food).
For more information, call 1-800-445-3235 or go to www.SOVALDI.com.
Manufactured for and distributed by: Gilead Sciences, Inc., Foster City, CA 94404
SOVALDI is a trademark of Gilead Sciences, Inc., or its related companies.
© 2024 Gilead Sciences, Inc. All rights reserved.
204671-GS-011
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: March 2020
Reference ID: 5501595
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_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all of the information needed to use
ONIVYDE safely and effectively. See full prescribing information for
ONIVYDE
ONIVYDE® (irinotecan liposome injection), for intravenous use
Initial U.S. Approval: 1996
WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA
See full prescribing information for complete boxed warning
Neutropenia
Severe or life-threatening neutropenia , including fatal
neutropenic sepsis and fatal neutropenic fever, has occurred in
patients receiving ONIVYDE in combination with oxaliplatin,
fluorouracil and leucovorin and in combination with fluorouracil
and leucovorin. Withhold ONIVYDE for absolute neutrophil
count below 1500/mm3 or neutropenic fever. Monitor blood cell
counts periodically during treatment (2.2), (5.1).
Diarrhea
Severe and life-threatening diarrhea has occurred in patients
receiving ONIVYDE in combination with oxaliplatin,
fluorouracil and leucovorin and in combination with fluorouracil
and leucovorin. Do not administer ONIVYDE to patients with
bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2
4 severity. Administer loperamide for late diarrhea of any
severity. Administer atropine, if not contraindicated, for early
diarrhea of any severity (2.2), (5.2).
---------------------RECENT MAJOR CHANGES------------------------------
Indications and Usage (1) __________ ________________________02/2024
Warnings and Precautions (5.1, 5.2) __ ________________________02/2024
Warnings and Precautions (5.3)
12/2024
_________________
__________________ INDICATIONS AND USAGE
ONIVYDE is a topoisomerase inhibitor indicated:
in combination with oxaliplatin, fluorouracil and leucovorin, for the
first-line treatment of adult patients with metastatic pancreatic
adenocarcinoma, (1)
in combination with fluorouracil and leucovorin, for the treatment of
adult patients with metastatic pancreatic adenocarcinoma after disease
progression following gemcitabine-based therapy. (1)
Limitation of Use: ONIVYDE is not indicated as a single agent for the
treatment of patients with metastatic pancreatic adenocarcinoma. (1)
______________
_______________ DOSAGE AND ADMINISTRATION
Do not substitute ONIVYDE for other drugs containing irinotecan
HCl. (2.1)
ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin:
Recommended dose of ONIVYDE is 50 mg/m² intravenous
infusion over 90 minutes every two weeks. (2.2)
Recommended starting dose of ONIVYDE in patients
homozygous for UGT1A1*28 is 50 mg/m2 every two weeks.
(2.2)
There is no recommended dose of ONIVYDE for patients with
serum bilirubin above the upper limit of normal. (2.2)
ONIVYDE in combination with fluorouracil and leucovorin:
Recommended dose of ONIVYDE is 70 mg/m2 intravenous
infusion over 90 minutes every two weeks. (2.2)
Recommended starting dose of ONIVYDE in patients
homozygous for UGT1A1*28 is 50 mg/m2 every two weeks.
(2.2)
There is no recommended dose of ONIVYDE for patients with
serum bilirubin above the upper limit of normal. (2.2)
Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to
ONIVYDE. (2.2)
______________
______________
DOSAGE FORMS AND STRENGTHS
Injection: 43 mg/10 mL (4.3 mg/mL) single dose vial (3)
___________________ CONTRAINDICATIONS____________________
Severe hypersensitivity reaction to ONIVYDE or irinotecan HCl. (4, 5.4)
_______________ WARNINGS AND PRECAUTIONS _______________
Interstitial lung disease (ILD): Fatal ILD has occurred in patients receiving
irinotecan including ONIVYDE. Discontinue ONIVYDE if ILD is
diagnosed. (5.3)
Severe hypersensitivity reaction: Permanently discontinue ONIVYDE for
severe hypersensitivity reactions. (5.4, 4)
Embryo-fetal toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use effective
contraception. (5.5, 8.1, 8.3)
____________________ADVERSE REACTIONS____________________
The most common adverse reactions (reported in ≥ 20% of patients) were for:
ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin:
diarrhea, fatigue, nausea, vomiting, decreased appetite, abdominal pain,
mucosal inflammation, constipation, and decreased weight. The most
common laboratory abnormalities (≥ 10% Grade 3 or 4) were decreased
neutrophils, decreased potassium, decreased lymphocytes, and decreased
hemoglobin. (6.1)
ONIVYDE in combination with fluorouracil and leucovorin: diarrhea,
fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and
pyrexia. The most common laboratory abnormalities (≥ 10% Grade 3 or
4) were lymphopenia and neutropenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Ipsen
Biopharmaceuticals, Inc.at 1-855-463-5127 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
____________________DRUG INTERACTIONS____________________
Strong CYP3A4 Inducers: Avoid the use of strong CYP3A4 inducers if
possible. Substitute non-enzyme inducing therapies at least 2 weeks prior to
initiation of ONIVYDE. (7.1)
Strong CYP3A4 Inhibitors: Avoid the use of strong CYP3A4 or UGT1A1
inhibitors, if possible; discontinue strong CYP3A4 inhibitors at least 1
week prior to starting therapy. (7.2)
_______________ USE IN SPECIFIC POPULATIONS _______________
Lactation: Do not breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION
WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Use Information
2.2
Recommended Dosage
2.3
Dosage Modifications for Adverse Reactions
2.4
Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Severe Neutropenia
5.2
Severe Diarrhea
5.3
Interstitial Lung Disease
5.4
Severe Hypersensitivity Reaction
5.5
Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Strong CYP3A4 Inducers
7.2
Strong CYP3A4 or UGT1A1 Inhibitors
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
12.5
Pharmacogenomics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
Reference ID: 5501873
*Sections or subsections omitted from the full prescribing information are not listed
Reference ID: 5501873
2
FULL PRESCRIBING INFORMATION
WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA
Neutropenia
Severe and life-threatening neutropenia, including fatal neutropenic sepsis and
fatal neutropenic fever, has occurred in patients receiving ONIVYDE in
combination with oxaliplatin, fluorouracil and leucovorin and in combination
with fluorouracil and leucovorin. Withhold ONIVYDE for absolute neutrophil
count below 1500/mm3 or neutropenic fever. Monitor blood cell counts
periodically during treatment [see Dosage and Administration (2.2) and Warnings
and Precautions (5.1)].
Diarrhea
Severe and life-threatening diarrhea has occurred in patients receiving
ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin and in
combination with fluorouracil and leucovorin. Do not administer ONIVYDE to
patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4
severity. Administer loperamide for late diarrhea of any severity. Administer
atropine, if not contraindicated, for early diarrhea of any severity [see Dosage and
Administration (2.2) and Warnings and Precautions (5.2)].
1
INDICATIONS AND USAGE
ONIVYDE is indicated, in combination with oxaliplatin, fluorouracil and leucovorin for
the first-line treatment of adult patients with metastatic pancreatic adenocarcinoma.
ONIVYDE is indicated, in combination with fluorouracil and leucovorin, for the
treatment of adult patients with metastatic pancreatic adenocarcinoma after disease
progression following gemcitabine-based therapy.
Limitations of Use: ONIVYDE is not indicated as a single agent for the treatment of patients
with metastatic pancreatic adenocarcinoma. [see Clinical Studies (14)].
2
DOSAGE AND ADMINISTRATION
2.1
Important Use Information
DO NOT SUBSTITUTE ONIVYDE for other drugs containing irinotecan HCl.
2.2
Recommended Dosage
In combination with oxaliplatin, fluorouracil and leucovorin for the first-line treatment of
patients with metastatic pancreatic adenocarcinoma
Administer ONIVYDE prior to oxaliplatin, fluorouracil and leucovorin [see Clinical Studies
(14)].
The recommended dosage of ONIVYDE regardless of UGT1A1*28 allele genotype is 50
mg/m2 administered by intravenous infusion over 90 minutes every 2 weeks.
3
Reference ID: 5501873
There is no recommended dosage of ONIVYDE for patients with serum bilirubin above
the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14)].
In combination with fluorouracil and leucovorin for the treatment of patients with metastatic
pancreatic adenocarcinoma after disease progression following gemcitabine-based therapy
Administer ONIVYDE prior to fluorouracil and leucovorin [see Clinical Studies (14)].
The recommended dosage of ONIVYDE is 70 mg/m2 administered by intravenous
infusion over 90 minutes every 2 weeks.
The recommended starting dose of ONIVYDE in patients known to be homozygous for
the UGT1A1*28 allele is 50 mg/m2 administered by intravenous infusion over 90
minutes. Increase the dose of ONIVYDE to 70 mg/m2 as tolerated in subsequent cycles.
There is no recommended dosage of ONIVYDE for patients with serum bilirubin above
the upper limit of normal [see Adverse Reactions (6.1) and Clinical Studies (14)].
Premedication
Administer a corticosteroid and an anti-emetic 30 minutes prior to each ONIVYDE infusion.
2.3
Dosage Modifications for Adverse Reactions
Recommended dosage modifications for ONIVYDE are in Table 1 and Table 2.
Table 1
Recommended Dosage Modifications for ONIVYDE in combination with
oxaliplatin, fluorouracil and leucovorin
Toxicitya
Occurrence
ONIVYDE adjustment in patients
receiving 50mg/m2
Withhold ONIVYDE
Upon recovery to ≤ Grade 1c,d,e, resume ONIVYDE at:
Grade 3 or 4 Adverse
reactionsb
First
40 mg/m2
Second
32.5 mg/m2
Third
25 mg/m2
Fourth
Discontinue ONIVYDE
Grade 3 or 4 Hand foot
syndrome
First
Discontinue ONIVYDE
Any grade
neurocerebellar toxicity
First
Discontinue ONIVYDE
Grade ≥ 2 cardiac
toxicity
First
Discontinue ONIVYDE
Interstitial lung disease
First
Discontinue ONIVYDE
Anaphylactic reaction
First
Discontinue ONIVYDE
a Toxicity grading per NCI CTCAE v5.0.
bNo dosage modification is necessary for asthenia, alopecia and Grade 3 anorexia.
cDo not resume until the absolute neutrophil count is ≥2000/mm3 (2x109/L) and the platelet count is ≥100,000/mm3 (100x109/L).
d For Grade ≥3 nausea and vomiting, reduce dose only if occurs despite optimal anti-emetic therapy.
e Refer to the Full Prescribing Information of fluorouracil and oxaliplatin. When ONIVYDE dose is reduced for adverse
reactions, reduce fluorouracil (FU) and oxaliplatin doses: for first occurrence, reduce dose to 80% of original dose; for second
occurrence, reduce dose to 65% of original dose; for third occurrence, reduce dose to 50% of original dose; discontinue therapy
for fourth occurrence. Oxaliplatin may be discontinued if not well tolerated and treatment with ONIVYDE + FU/LV can
continue. Maintain original dose level of leucovorin for first, second and third occurrence of toxicity.
4
Reference ID: 5501873
Table 2
Recommended Dosage Modifications for ONIVYDE in combination with
fluorouracil and leucovorin
Toxicity
NCI CTCAE v4.0†
Occurrence
ONIVYDE adjustment in
patients receiving 70 mg/m2
Patients homozygous for
UGT1A1*28 without previous
increase to 70 mg/m2
Withhold ONIVYDE.
Upon recovery to ≤ Grade 1, resume ONIVYDE at:
Grade 3 or 4
adverse reactions
First
50 mg/m2
43 mg/m2
Second
43 mg/m2
35 mg/m2
Third
Discontinue ONIVYDE
Discontinue ONIVYDE
Interstitial Lung
Disease
First
Discontinue ONIVYDE
Discontinue ONIVYDE
Anaphylactic
Reaction
First
Discontinue ONIVYDE
Discontinue ONIVYDE
† NCI CTCAE v 4.0=National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0
For recommended dose modifications of fluorouracil (FU) or leucovorin (LV), refer to the Full
Prescribing Information; refer to Clinical Studies (14).
2.4
Preparation and Administration
ONIVYDE is a hazardous drug. Follow applicable special handling and disposal procedures.1
Preparation
Withdraw the calculated volume of ONIVYDE from the vial. Dilute ONIVYDE in
500 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP and mix
diluted solution by gentle inversion. Discard vials with any unused portion.
Protect diluted solution from light.
Administer diluted solution within 4 hours of preparation when stored at room
temperature or within 24 hours of preparation when stored under refrigerated conditions
[2ºC to 8ºC (36ºF to 46ºF)]. Allow diluted solution to come to room temperature prior to
administration.
Do NOT freeze.
Administration
Infuse diluted solution intravenously over 90 minutes.
3
DOSAGE FORMS AND STRENGTHS
Injection: 43 mg/10 mL irinotecan free base as a white to slightly yellow, opaque, liposomal
dispersion in a single-dose vial.
5
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4
CONTRAINDICATIONS
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity
reaction or anaphylaxis to ONIVYDE or irinotecan HCl. [see Warnings and Precautions (5.4),
Adverse Reactions (6.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Severe Neutropenia
ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis.
In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving ONIVYDE in
combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic
fever in 0.3% of patients [see Adverse Reactions (6.1)]. In NAPOLI-1, Grade 3 and 4
neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil
and leucovorin (ONIVYDE/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic
sepsis in 0.8% [see Adverse Reactions (6.1)].
In NAPOLI 3, the incidence of Grade 3 or 4 neutropenia was similar among Asian patients [6 of
20 (30%)] compared to White patients [76 of 289 (26%)] receiving ONIVYDE in combination
with oxaliplatin, fluorouracil, and leucovorin. Neutropenic fever was reported in 5% of Asian
patients (1 of 20) compared to 2.3% of White patients (7 of 306). In NAPOLI-1, the incidence of
Grade 3 or 4 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White
patients [13 of 73 (18%)] receiving ONIVYDE/FU/LV. Neutropenic fever/neutropenic sepsis
was reported in 6% of Asian patients compared to 1% of White patients [see Clinical
Pharmacology (12.3)].
Monitor complete blood cell counts on Days 1 and 8 of every cycle and more frequently if
clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below
1500/mm3 or if neutropenic fever occurs. Resume ONIVYDE when the ANC is 1500/mm3 or
above. Reduce ONIVYDE dose for Grade 3-4 neutropenia or neutropenic fever following
recovery in subsequent cycles [see Dosage and Administration (2.2)].
5.2
Severe Diarrhea
ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to
patients with a bowel obstruction. Severe or life-threatening diarrhea can follow one of two
patterns: late onset diarrhea (onset more than 24 hours following chemotherapy) and early onset
diarrhea (onset within 24 hours of chemotherapy, sometimes occurring with other symptoms of
cholinergic reaction) [see Adverse Reactions (6.1)]. An individual patient may experience both
early and late-onset diarrhea.
In NAPOLI 3, Grade 3 and 4 diarrhea (early and late-onset) occurred in 20% receiving
ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX). In
NAPOLI-1, Grade 3 or 4 diarrhea occurred in 13% receiving ONIVYDE/FU/LV. The incidence
of Grade 3 or 4 late onset diarrhea was 9% in patients receiving ONIVYDE/FU/LV. The
incidence of Grade 3 or 4 early onset diarrhea was 3% in patients receiving ONIVYDE/FU/LV.
Of patients receiving ONIVYDE/FU/LV in NAPOLI-1, 34% received loperamide for late-onset
diarrhea and 26% received atropine for early-onset diarrhea.
6
Reference ID: 5501873
To reduce the risk of severe diarrhea, patients should stop lactose-containing products, eat a low-
fat diet and maintain hydration during treatment with ONIVYDE. Withhold ONIVYDE for
Grade 2-4 diarrhea. Administer intravenous or subcutaneous atropine 0.25 to 1 mg (unless
clinically contraindicated) for early onset diarrhea of any severity. Initiate loperamide for late
onset diarrhea of any severity. Local institutional guidelines should be followed for the treatment
of diarrhea that does not improve within 48 hours and may include the addition of diphenoxylate
hydrochloride plus atropine sulfate or octreotide. Following recovery to Grade 1 diarrhea,
resume ONIVYDE at a reduced dose [see Dosage and Administration (2.3)].
5.3
Interstitial Lung Disease
ONIVYDE can cause severe and fatal interstitial lung disease (ILD), including pneumonitis.
Postmarketing cases of severe and fatal ILD have been reported with ONIVYDE. Risk factors
include pre-existing lung disease, use of pneumotoxic medicinal products, colony stimulating
factors or having previously received radiation therapy. Patients with risk factors should be
closely monitored for respiratory symptoms before and during ONIVYDE therapy. Withhold
ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic
evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.
5.4
Severe Hypersensitivity Reaction
Irinotecan including ONIVYDE can cause severe hypersensitivity reactions, including
anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe
hypersensitivity reaction [see Contraindications (4), Adverse reactions (6.2)].
5.5
Embryo-Fetal Toxicity
Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE,
ONIVYDE can cause fetal harm when administered to a pregnant woman. Embryotoxicity and
teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in
irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m2 in humans,
administered to pregnant rats and rabbits during organogenesis. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential to use effective contraception
during treatment with ONIVYDE and for seven months following the last dose [see Use in
Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
6
ADVERSE REACTIONS
The following adverse drug reactions are discussed in greater detail in other sections of the label:
Severe Neutropenia [see Warnings and Precautions (5.1)]
Severe Diarrhea [see Warnings and Precautions (5.2)]
Interstitial Lung Disease [see Warnings and Precautions (5.3)]
Severe Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in clinical trials of ONIVYDE cannot be directly compared to rates in clinical trials of
other drugs and may not reflect the rates observed in practice.
7
Reference ID: 5501873
Pancreatic Adenocarcinoma
In Combination with Oxaliplatin, Fluorouracil and Leucovorin for First-Line Treatment
The safety of ONIVYDE in patients with metastatic pancreatic adenocarcinoma who had not
previously received chemotherapy was evaluated in NAPOLI 3 [see Clinical Studies (14)].
Patients received ONIVYDE 50 mg/m² in combination with oxaliplatin 60 mg/m², leucovorin
400 mg/m² and fluorouracil 2400 mg/m² over 46 hours every 2 weeks (NALIRIFOX; N=383) or
nab-paclitaxel 125 mg/m² over 35 minutes and gemcitabine 1000 mg/m² over 30 minutes on Day
1, 8 and 15 of each 28-day cycle (Gem+NabP; N=387). The median duration of exposure to
ONIVYDE in combination with oxaliplatin, fluorouracil, and leucovorin was 24 weeks (range: 0
to 101 weeks).
Serious adverse reactions occurred in 54% of patients who received ONIVYDE in combination
with oxaliplatin, fluorouracil and leucovorin. Serious adverse reactions in ≥2% of patients
included infections including COVID-19 (14%), diarrhea (9%), vomiting (6%), nausea (4.9%),
fatigue (3.8%), embolism (3.5%), gastrointestinal tract stenosis or obstruction (3.5%),
hemorrhage (3%), abdominal pain (2.7%), cerebrovascular accident (2.7%), dehydration (2.7%),
liver function test abnormalities (2.2%), and pyrexia (2.2%). Fatal adverse reactions occurred in
6% of patients who received ONIVYDE in combination with oxaliplatin, fluorouracil and
leucovorin including cerebrovascular accident (1.1%), hemorrhage (0.5%), pneumonia (0.5%),
sepsis (0.5%) and sudden death (0.5%).
Permanent discontinuation of ONIVYDE due to an adverse reaction occurred in 17% of patients.
Adverse reactions which resulted in permanent discontinuation of ONIVYDE in ≥1% of patients
included neutropenia, thrombocytopenia, diarrhea, fatigue, infections and cerebrovascular
accident.
Dosage reduction of ONIVYDE due to an adverse reaction occurred in 52% of patients. Adverse
reactions which required dosage reduction in ≥1% of patients included anemia, decreased
appetite, diarrhea, fatigue, febrile neutropenia, hypokalemia, liver function test abnormalities,
nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia
and weight decreased.
Dosage interruptions of ONIVYDE due to an adverse reaction occurred in 1.9% of patients.
Adverse reactions which required dosage interruption in ≥0.5% of patients included
hypersensitivity and infusion related reaction.
The most common adverse reactions (≥20% with a difference between arms of ≥ 5% for all
grades or ≥ 2% for Grades 3 or 4 compared to Gem+NabP) of ONIVYDE in combination with
oxaliplatin, fluorouracil, and leucovorin were diarrhea, fatigue, nausea, vomiting, decreased
appetite, abdominal pain, mucosal inflammation, constipation and decreased weight. The most
common laboratory abnormalities (≥10% Grade 3 or 4) were decreased neutrophils, decreased
potassium, decreased lymphocyte and decreased hemoglobin.
Table 3 and 4 summarize the adverse reactions and laboratory abnormalities, respectively, in the
NAPOLI 3 study.
8
Reference ID: 5501873
Table 3
Adverse Reactions* (≥ 20%) in Patients with Metastatic Pancreatic
Adenocarcinoma who Received NALIRIFOX** with a Difference Between Arms of ≥5%
for All Grades or ≥ 2% for Grades 3 and 4 versus Gem+NabP in NAPOLI 3*
Adverse Reaction
NALIRIFOX
N=370
Gem+NabP
N=379
All Grades
(%)
Grade 3 or4
(%)
All Grades
(%)
Grade 3 or4
(%)
Gastrointestinal disorders
Diarrhea1
72
22
37
5
Nausea
59
12
43
2.6
Vomiting1
40
7
27
2.1
Abdominal pain1
35
4.3
25
4.7
Constipation
25
0.8
30
2.1
General disorders and administration site condition
Fatigue1
62
15
63
10
Mucosal inflammation1
28
3.8
17
0.8
Peripheral edema1
16
0.3
34
2.4
Pyrexia1
11
0.8
24
1.6
Investigations
Weight decreased
22
3
9
0.3
Metabolism and nutrition disorders
Decreased appetite
37
9
28
2.6
Dehydration
11
3.2
9
1.1
Skin and subcutaneous tissue disorders
Alopecia
14
0
31
0.5
Rash1
11
0.3
22
1.6
Nail disorder
0.3
0
7
0.3
Vascular disorders
Hemorrhage1
11
2.4
18
3.4
Embolism1
11
7
11
5
Respiratory, thoracic and mediastinal disorders
Dyspnea1
8
0.5
13
2.1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain1
18
1.6
27
1.1
Infections and infestations
Pneumonia
2.4
1.6
6
4
Sepsis1
1.6
1.1
6
3.4
*NCI CTCAE v5.0
**NALIRIFOX=ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel
1 Includes multiple related terms
Table 4
Laboratory Abnormalities in Patients with Metastatic Pancreatic
Adenocarcinoma who Received NALIRIFOX* with a difference between arms of ≥ 5%
versus Gem+NabP in NAPOLI 3 **
Laboratory abnormality
NALIRIFOX
Gem-NabP
All Grades
(%)
Grade 3- or 4
(%)
All Grades
(%)
Grade 3 or4
(%)
Hematology
Hemoglobin decreased
91
10
96
15
Lymphocytes decreased
64
11
76
19
Leukocytes decreased
62
8
77
28
9
Reference ID: 5501873
Laboratory abnormality
NALIRIFOX
Gem-NabP
All Grades
(%)
Grade 3- or 4
(%)
All Grades
(%)
Grade 3 or4
(%)
Neutrophils decreased
56
26
65
37
Platelets decreased
55
1.7
75
7
Hepatic
Alkaline phosphatase increased
45
2.9
35
2.7
Alanine aminotransferase increased
40
2.6
56
4.6
Aspartate aminotransferase increased
38
2
49
2.4
Metabolic
Potassium decreased
62
22
29
8
Sodium increased
11
0
5
0.3
Potassium increased
8
0.6
21
3
*NALIRIFOX=ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin ; Gem+NabP=gemcitabine+nab-paclitaxel
** Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: NALIRIFOX (range: 294 to 351 patients) and Gem+NabP (range: 303 to 373 patients).
In Combination with Fluorouracil and Leucovorin after Progresssion on Gemcitabine or
Gemcitabine-based Therapy
The safety data described below are derived from patients with metastatic pancreatic
adenocarcinoma previously treated with gemcitabine-based therapy who received any part of
protocol-specified therapy in NAPOLI-1, an international, randomized, active-controlled, open-
label trial. Protocol-specified therapy consisted of ONIVYDE 70 mg/m2 with leucovorin 400
mg/m2 and fluorouracil 2400 mg/m2 over 46 hours every 2 weeks (ONIVYDE/FU/LV; N=117),
ONIVYDE 100 mg/m2 every 3 weeks (N=147), or leucovorin 200 mg/m2 and fluorouracil 2000
mg/m2 over 24 hours weekly for 4 weeks followed by 2 week rest (FU/LV; N=134)
[see Clinical Studies (14)]. Serum bilirubin within the institutional normal range, albumin ≥ 3
g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median
duration of exposure was 9 weeks in the ONIVYDE/FU/LV arm, 9 weeks in the ONIVYDE
monotherapy arm, and 6 weeks in the FU/LV arm.
The most common adverse reactions (≥ 20%) of ONIVYDE were diarrhea, fatigue/asthenia,
vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe
laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most
common serious adverse reactions (≥ 2%) of ONIVYDE were diarrhea, vomiting, neutropenic
fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute
renal failure, and thrombocytopenia.
Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving
ONIVYDE/FU/LV; the most frequent adverse reactions resulting in discontinuation of
ONIVYDE were diarrhea, vomiting, and sepsis. Dose reductions of ONIVYDE for adverse
reactions occurred in 33% of patients receiving ONIVYDE/FU/LV; the most frequent adverse
reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia. ONIVYDE
was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/FU/LV;
the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea,
fatigue, vomiting, and thrombocytopenia.
10
Reference ID: 5501873
Table 5 provides the frequency and severity of adverse reactions in NAPOLI-1 that occurred
with higher incidence (≥5% difference for Grades 1-4 or ≥2% difference for Grades 3-4) in
patients who received ONIVYDE/FU/LV compared to patients who received FU/LV.
Table 5 Adverse Reactions with Higher Incidence (≥5% Difference for Grades 1-4* or
≥2% Difference for Grades 3 and 4) in the ONIVYDE/FU/LV Arm
Adverse Reaction
ONIVYDE/FU/LV
N=117
FU/LV
N=134
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Gastrointestinal disorders
Diarrhea
59
13
26
4
Early diarrhea†
30
3
15
0
Late diarrhea‡
43
9
17
4
Vomiting
52
11
26
3
Nausea
51
8
34
4
Stomatitis§
32
4
12
1
Infections and infestations
38
17
15
10
Sepsis
4
3
2
1
Neutropenic fever/neutropenic
sepsis♠
3
3
1
0
Gastroenteritis
3
3
0
0
Intravenous catheter-related
infection
3
3
0
0
General disorders and administration site conditions
Fatigue/asthenia
56
21
43
10
Pyrexia
23
2
11
1
Metabolism and nutrition disorders
Decreased appetite
44
4
32
2
Weight loss
17
2
7
0
Dehydration
8
4
7
2
Skin and subcutaneous tissue disorders
Alopecia
14
1
5
0
* NCI CTCAE v4.0
† Early diarrhea: onset within 24 hours of ONIVYDE administration
‡ Late diarrhea: onset >1 day after ONIVYDE administration
§ Includes stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.
♠ Includes febrile neutropenia
Other Adverse Reactions
Clinically relevant adverse reactions occurring in <5% of patients include:
Cholinergic Reactions: ONIVYDE can cause cholinergic reactions manifesting as rhinitis,
increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal
hyperperistalsis with abdominal cramping and early onset diarrhea. In NAPOLI-1, Grade 1 or 2
cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated
patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was
administered for cholinergic symptoms other than diarrhea.
11
Reference ID: 5501873
Infusion Reactions: Infusion reactions, consisting of rash, urticaria, periorbital edema, or
pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients
receiving ONIVYDE or ONIVYDE/FU/LV.
Laboratory abnormalities that occurred with higher incidence in the ONIVYDE/FU/LV arm
compared to the FU/LV arm (≥5% difference) are summarized in the following table.
Table 6 Laboratory Abnormalities with Higher Incidence (≥5% Difference) in the
ONIVYDE/FU/LV Arm*#
Laboratory abnormality
ONIVYDE/FU/LV
N=117
FU/LV
N=134
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Hematology
Anemia
97
6
86
5
Lymphopenia
81
27
75
17
Neutropenia
52
20
6
2
Thrombocytopenia
41
2
33
0
Hepatic
Increased alanine aminotransferase
(ALT)
51
6
37
1
Hypoalbuminemia
43
2
30
0
Metabolic
Hypomagnesemia
35
0
21
0
Hypokalemia
32
2
19
2
Hypocalcemia
32
1
20
0
Hypophosphatemia
29
4
18
1
Hyponatremia
27
5
12
3
Renal
Increased creatinine
18
0
13
0
* NCI CTCAE v4.0, worst grade shown.
# Percent based on number of patients with a baseline and at least one post-baseline measurement.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of ONIVYDE.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Immune system disorders: Hypersensitivity (including Anaphylactic reaction and Angioedema)
7
DRUG INTERACTIONS
7.1
Strong CYP3A4 Inducers
Following administration of non-liposomal irinotecan (i.e., irinotecan HCl), exposure to
irinotecan or its active metabolite, SN-38, is substantially reduced in adult and pediatric patients
concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin and strong
CYP3A4 inducers. Avoid the use of strong CYP3A4 inducers (e.g., rifampin, phenytoin,
carbamazepine, rifabutin, rifapentine, phenobarbital, St. John's wort) if possible. Substitute non-
enzyme inducing therapies at least 2 weeks prior to initiation of ONIVYDE therapy [see Clinical
Pharmacology (12.3)].
12
Reference ID: 5501873
7.2
Strong CYP3A4 or UGT1A1 Inhibitors
Following administration of non-liposomal irinotecan (i.e., irinotecan HCl), patients receiving
concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to
irinotecan and its active metabolite SN-38. Co-administration of ONIVYDE with other inhibitors
of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g., atazanavir, gemfibrozil,
indinavir) may increase systemic exposure to irinotecan or SN-38. Avoid the use of strong
CYP3A4 or UGT1A1 inhibitors if possible. Discontinue strong CYP3A4 inhibitors at least 1
week prior to starting ONIVYDE therapy [see Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE,
ONIVYDE can cause fetal harm when administered to a pregnant woman [see Clinical
Pharmacology (12.1)]. There are no available data in pregnant women. Embryotoxicity and
teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in
irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m2 in humans,
administered to pregnant rats and rabbits during organogenesis [see Data]. Advise pregnant
women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
No animal studies have been conducted to evaluate the effect of irinotecan liposome on
reproduction and fetal development; however, studies have been conducted with irinotecan HCl.
Irinotecan crosses the placenta of rats following intravenous administration. Intravenous
administration of irinotecan at a dose of 6 mg/kg/day to rats and rabbits during the period of
organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses.
In separate studies in rats, this dose resulted in an irinotecan exposure of approximately 0.002
times the exposure of irinotecan based on area under the curve (AUC) in patients administered
ONIVYDE at the 70 mg/m2 dose. Administration of irinotecan HCl resulted in structural
abnormalities and growth delays in rats at doses greater than 1.2 mg/kg/day (approximately
0.0002 times the clinical exposure to irinotecan in ONIVYDE based on AUC). Teratogenic
effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan HCl
administered to rat dams for the period following organogenesis through weaning at doses of 6
mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.
8.2
Lactation
Risk Summary
13
Reference ID: 5501873
There is no information regarding the presence of irinotecan liposome, irinotecan, or SN-38 (an
active metabolite of irinotecan) in human milk, or the effects on the breastfed infant or on milk
production. Irinotecan is present in rat milk [see Data].
Because of the potential for serious adverse reactions in breastfed infants from ONIVYDE,
advise a nursing woman not to breastfeed during treatment with ONIVYDE and for one month
after the last dose.
Data
Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled
irinotecan HCl and was concentrated up to 65-fold at 4 hours after administration relative to
plasma concentrations.
8.3
Females and Males of Reproductive Potential
Contraception
Females
ONIVYDE can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during
treatment with ONIVYDE and for seven months after the last dose.
Males
Because of the potential for genotoxicity, advise males with female partners of reproductive
potential to use condoms during treatment with ONIVYDE and for four months after the last
dose [see Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
Safety and effectiveness of ONIVYDE have not been established in pediatric patients.
8.5
Geriatric Use
Of the 634 patients who received ONIVYDE as a single agent, in combination with FU and
leucovorin or in combination with oxaliplatin, FU and leucovorin in NAPOLI-1 and NAPOLI 3,
49% were ≥ 65 years old and 10% were ≥ 75 years old. No overall differences in safety and
effectiveness were observed between these patients and younger patients.
10
OVERDOSAGE
There are no treatment interventions known to be effective for management of overdosage of
ONIVYDE.
11
DESCRIPTION
ONIVYDE is formulated with irinotecan hydrochloride trihydrate, a topoisomerase inhibitor,
into a liposomal dispersion for intravenous use. The chemical name of irinotecan hydrochloride
trihydrate is (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3’,4’:6,7]
indolizino[1,2-b]quinolin-9-yl-[1,4’bipiperidine]-1’-carboxylate, monohydrochloride, trihydrate.
14
Reference ID: 5501873
0
0
r
t:J)lO
o)v
The empirical formula is C33H38N4O6∙HCl∙3H2O and the molecular weight is 677.19 g/mole. The
molecular structure is:
ONIVYDE is a sterile, white to slightly yellow opaque isotonic liposomal dispersion. Each 10
mL single-dose vial contains 43 mg irinotecan free base at a concentration of 4.3 mg/mL. The
liposome is a unilamellar lipid bilayer vesicle, approximately 110 nm in diameter, which
encapsulates an aqueous space containing irinotecan in a gelated or precipitated state as the
sucrose octasulfate salt. The vesicle is composed of 1,2-distearoyl-sn-glycero-3-phosphocholine
(DSPC) 6.81 mg/mL, cholesterol 2.22 mg/mL, and methoxy-terminated polyethylene glycol
(MW 2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE) 0.12 mg/mL. Each mL
also contains 2-[4-(2-hydroxyethyl) piperazin-1-yl]ethanesulfonic acid (HEPES) as a buffer
4.05 mg/mL and sodium chloride as an isotonicity reagent 8.42 mg/mL.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer
vesicle or liposome. Topoisomerase 1 relieves torsional strain in DNA by inducing single-strand
breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1-DNA
complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent
double-strand DNA damage and cell death. In mice bearing human tumor xenografts, irinotecan
liposome administered at irinotecan HCl-equivalent doses 5-fold lower than irinotecan HCl
achieved similar intratumoral exposure of SN-38.
12.3
Pharmacokinetics
The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with
cancer who received ONIVYDE, as a single agent or as part of combination chemotherapy, at
doses between 35 mg/m2 and 155 mg/m2 and concentration proportional to dose was observed.
The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration
of ONIVYDE 70 mg/m2 as a single agent or part of combination chemotherapy are presented in
Table 7.
15
Reference ID: 5501873
Table 7
Summary of Geometric Mean (CV) Total Irinotecan and Total SN-38
Dose
(mg/m2)
Descriptive
Statistics
Total Irinotecan
Total SN-38
Cmax
[µg/mL]
AUCSS
[day∙µg/
mL]
t1/2
[day]
V
[L]
Cmax
[ng/mL]
AUCSS
[day∙ng/
mL]
V
[L]
50
Geometric
Mean
25.1
37.8
1.93
3.63
2.09
12.1
3.46
CV (%)
18.5
73.6
14
33.5
42.1
46.6
35.5
70
Geometric
Mean
30.8
50.4
1.87
4.23
2.64
14.7
4.06
CV (%)
19.7
75.3
26.4
28.1
64.5
58
29.4
AUCSS: Area under the plasma concentration curve at steady-state
t1/2: Terminal elimination half-life
V: Volume of distribution
Distribution
Direct measurement of irinotecan liposome showed that 95% of irinotecan remains
liposome -encapsulated, and the ratios between total and encapsulated forms did not change with
time from 0 to 170 hours post-dose. The mean volume of distribution is summarized in Table 7.
Plasma protein binding is <0.44% of the total irinotecan in ONIVYDE.
Elimination
Metabolism
The metabolism of irinotecan liposome has not been evaluated. Irinotecan is subject to extensive
metabolic conversion by various enzyme systems, including carboxylesterases to form the active
metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive
glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative
metabolism to several inactive oxidation products, one of which can be hydrolyzed by
carboxylesterase to release SN-38. In the population PK analysis of irinotecan liposome,
UGT1A1*28 7/7 homozygous status (10.6%) had no effect on SN-38 clearance compared with
patients not homozygous for UGT1A1*28 7/7.
Excretion
The disposition of ONIVYDE has not been elucidated in humans. Following administration of
irinotecan HCl, the urinary excretion of irinotecan is 11 to 20%; SN-38, <1%; and SN-38
glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites
(SN-38 and SN-38 glucuronide), over a period of 48 hours following administration of irinotecan
HCl in two patients, ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).
Specific Populations
Age, Sex, Ethnicity, Renal and Hepatic Impairment:
16
Reference ID: 5501873
The population pharmacokinetic analyses suggest that age (20 to 87 years) and BSA (1.15 to
2.88 m2) had no clinically meaningful effect on the exposure of irinotecan and SN-38.
Irinotecan and SN-38 AUC in female patients were 28% and 32% higher, respectively, than
those in male patients. Irinotecan AUC in patients of Asian ethnicity were 32% lower than that in
non-Asian patients. The exposures of irinotecan and SN-38 in patients with mild or moderate
renal impairment were comparable to patients with normal renal function after adjusting for
BSA. The exposures of irinotecan and SN-38 in patients with mild hepatic impairment (based on
NCI score) were comparable to patients with normal hepatic function. There was insufficient
data in patients with severe renal impairment (CLcr < 30 mL/min) or in patients with moderate
and severe hepatic impairment to assess their effects on the exposures of irinotecan and SN-38.
Increased AST/ALT had no effect on irinotecan clearance; however, increased bilirubin level
was associated with lower SN‑38 clearance. SN-38 AUC was increased by 32% in patients with
bilirubin level of 1.14 mg/dL (95th of the overall population) compared with that of median
bilirubin level of 0.44 mg/dL. No data are available in patients with bilirubin >2.8 mg/dL.
Drug Interactions
In a population pharmacokinetic analysis, the pharmacokinetics of total irinotecan and total SN
38 were not altered by the co-administration of fluorouracil/leucovorin. In Study
MM‑398‑07‑02‑03 and NAPOLI-3, irinotecan AUC was decreased by 33% and SN-38 Cmax
increased by 23% following co-administration with oxaliplatin.
Following administration of irinotecan HCl, dexamethasone (moderate CYP3A4 inducer) does
not alter the pharmacokinetics of irinotecan.
In vitro studies indicate that irinotecan, SN-38 and another metabolite, aminopentane carboxylic
acid (APC), do not inhibit cytochrome P-450 isozymes.
12.5
Pharmacogenomics
Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia
from irinotecan HCl. In NAPOLI-1, patients homozygous for the UGT1A1*28 allele (N=7)
initiated ONIVYDE at a reduced dose of 50 mg/m2 in combination with FU/LV. The frequency
of Grade 3 or 4 neutropenia in these patients [2 of 7 (28.6%)] was similar to the frequency in
patients not homozygous for the UGT1A1*28 allele who received a starting dose of ONIVYDE
of 70 mg/m2 [30 of 110 (27.3%)]. In NAPOLI-3, patients homozygous for the UGT1A1*28
allele (N = 39) initiated ONIVYDE at the same starting dose of 50 mg/m2 as patients not
homozygous for the UGT1A1*28 allele (N = 328). The frequency of Grade 3 or 4 neutropenia
was 23% in patients homozygous for the UGT1A1*28 allele and 13% in patients not
homozygous for the UGT1A1*28 allele. The frequency of dose reduction of ONIVYDE due to
treatment-emergent adverse effects was 59% versus 51% in patients homozygous versus non-
homozygous for the UGT1A1*28 allele.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the potential of irinotecan liposome for
carcinogenicity, genotoxicity or impairment of fertility. Intravenous administration of irinotecan
17
Reference ID: 5501873
hydrochloride to rats once weekly for 13 weeks followed by a 91-week recovery period resulted
in a significant linear trend between irinotecan HCl dosage and the incidence of combined
uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Irinotecan HCl was
clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo
(micronucleus test in mice). Neither irinotecan nor its active metabolite, SN-38, was mutagenic
in the in vitro Ames assay.
Dedicated fertility studies have not been performed with irinotecan liposome injection. Atrophy
of male and female reproductive organs was observed in dogs receiving irinotecan liposome
injection every 3 weeks at doses equal to or greater than 15 mg/kg, (approximately 3 times the
clinical exposure of irinotecan following administration to ONIVYDE dosed at 70 mg/m2) for a
total of 6 doses. No significant adverse effects on fertility and general reproductive performance
were observed after intravenous administration of irinotecan HCl in doses of up to 6 mg/kg/day
to rats; however, atrophy of male reproductive organs was observed after multiple daily
irinotecan HCl doses both in rodents at 20 mg/kg (approximately 0.007 times the clinical
irinotecan exposure following ONIVYDE administration at 70 mg/m2) and in dogs at 0.4 mg/kg
(0.0007 times the clinical exposure to irinotecan following administration of ONIVYDE).
14
CLINICAL STUDIES
Pancreatic Adenocarcinoma
In Combination with Oxaliplatin, Fluorouracil and Leucovorin for First-Line Treatment of
Metastatic Pancreatic Adenocarcinoma
The efficacy of ONIVYDE in combination with oxaliplatin, fluorouracil and leucovorin
(NALIRIFOX) was evaluated in NAPOLI 3 (NCT04083235), a randomized, multicenter, open-
label, active-controlled trial in 770 patients with metastatic pancreatic adenocarcinoma who had
not previously received chemotherapy in the metastatic setting. Randomization was stratified by
region, liver metastases and ECOG performance status. Patients were randomized (1:1) to
receive one of the following treatment arm:
•
NALIRIFOX: ONIVYDE 50 mg/m2 as an intravenous infusion over 90 minutes, followed
by oxaliplatin 60 mg/m2 as an intravenous infusion over 120 minutes, followed by
leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2
intravenously over 46 hours, every 2 weeks.
•
Gem+NabP: Nab-paclitaxel 125 mg/m2 as an intravenous infusion over 35 minutes,
followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes on days 1, 8 and 15
of each 28-day cycle.
Patients homozygous for the UGT1A1*28 allele initiated ONIVYDE at the same dose (50
mg/m2 ONIVYDE). Treatment continued until RECIST v1.1 defined disease progression or
unacceptable toxicity. Tumor status assessments were conducted at baseline and every 8 weeks
thereafter as assessed by the investigator according to RECIST v1.1.
The main efficacy outcome measure was overall survival (OS). Additional efficacy measures
were investigator-assessed progression-free survival (PFS) and objective response rate (ORR).
18
Reference ID: 5501873
Baseline demographic and patient characteristics were: median age of 65 years (range: 20-85);
50% age 65 or older; 56% male; 83% White, 4.9% Asian, 2.5% Black or African American,
0.4% multiple race, 0.3% American Indian or Alaska Native; 0.1% Native Hawaiian or other
Pacific Islander, 1.7% other, 7% not reported; and 82% non-Hispanic, 10% Hispanic, 8% not
reported. ECOG performance status was 0 or 1 in 44% and 56% of patients, respectively; 80%
had liver metastases.
NAPOLI 3 demonstrated a statistically significant improvement in OS and PFS for the
NALIRIFOX arm over Gem+NabP arm as summarized in Table 8 and Figure 1.
Table 8
Efficacy Results of All Randomized Patients in NAPOLI 3
NALIRIFOX*
(N=383)
Gem+NabP
(N=387)
Overall Survival
Number of Deaths, n (%)
259 (68)
285 (74)
Median Overall Survival (months)
11.1
9.2
(95% CI)
(10.0, 12.1)
(8.3, 10.6)
Hazard Ratio (95% CI) *
0.84 (0.71, 0.99)
p-value †
0.0403
Progression-Free Survival
Death or Progression, n (%)
249 (65)
259 (67)
Median Progression-Free Survival (months)
7.4
5.6
(95% CI)
(6.0, 7.7)
(5.3, 5.8)
Hazard Ratio (95% CI) *
0.70 (0.59, 0.85)
P-value †
0.0001
Objective Response Rate #
ORR (95% CI)
41.8 (36.8, 46.9)
36.2 (31.4, 41.2)
CR, n (%)
1 (0.3)
1 (0.3)
PR, n (%)
159 (41.5)
139 (35.9)
* NALIRIFOX= ONIVYDE+oxaliplatin/5-fluorouracil/leucovorin; Gem+NabP=gemcitabine+nab-paclitaxel; CI=confidence
interval
** Based on the stratified Cox proportional hazard model; stratified by ECOG PS (0 vs. 1), region (North America vs. East
Asia vs. Rest of the world), and liver metastases (yes vs. no) per interaction web response system
† Based on stratified log-rank test.
# ORR result was not statistically significant.
19
Reference ID: 5501873
100
90
80
'0'
~
70
-~
:0
60
"'
.0
50
0
a:
ro
40
·;;;
·;;;
30
:5
U)
20
"'
co
10
>
0
0
+=censored
0
2
4
No. at Risk:
NALIRIFOX 383
337
308
Gem+NabP387
345
298
6
8
274
241
261
218
10
209
179
12
14
16
18
162
140
Time (Months)
98
80
59
50
32
28
20
13
15
22
7
10
24
2
3
Arm
---+-- NALIRIFOX
---+-- Gem+NabP
26
28
0
0
30
0
0
Figure 1 Kaplan-Meier Curve for Overall Survival in all randomized Patients in
NAPOLI 3
Previously treated metastatic pancreatic adenocarcinoma in combination with fluorouracil and
leucovorin
The efficacy of ONIVYDE was evaluated in NAPOLI-1 (NCT01494506), a three-arm,
randomized, open-label trial in patients with metastatic pancreatic adenocarcinoma with
documented disease progression, after gemcitabine or gemcitabine-based therapy. Key eligibility
criteria included Karnofsky Performance Status (KPS) ≥70, serum bilirubin within institution
limits of normal, and albumin ≥3.0 g/dL. Patients were randomized to receive ONIVYDE plus
fluorouracil/leucovorin (ONIVYDE/FU/LV), ONIVYDE, or fluorouracil/leucovorin (FU/LV).
Randomization was stratified by ethnicity (White vs. East Asian vs. other), KPS (70-80 vs. 90
100), and baseline albumin level (≥ 4 g/dL vs. 3.0-3.9 g/dL). Patients randomized to
ONIVYDE/FU/LV received ONIVYDE 70 mg/m2 as an intravenous infusion over 90 minutes,
followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400
mg/m2 intravenously over 46 hours, every 2 weeks. The ONIVYDE dose of 70 mg/m2 is based
on irinotecan free base (equivalent to 80 mg/m2 of irinotecan as the hydrochloride trihydrate).
Patients randomized to ONIVYDE as a single agent received ONIVYDE 100 mg/m2 as an
intravenous infusion over 90 minutes every 3 weeks. Patients randomized to FU/LV received
leucovorin 200 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2000 mg/m2
intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of a 6-week cycle. Patients
homozygous for the UGT1A1*28 allele initiated ONIVYDE at a reduced dose (50 mg/m2
ONIVYDE, if given with FU/LV or 70 mg/m2 ONIVYDE as a single agent). When ONIVYDE
was withheld or discontinued for adverse reactions, FU was also withheld or discontinued. When
the dose of ONIVYDE was reduced for adverse reactions, the dose of FU was reduced by 25%.
Treatment continued until disease progression or unacceptable toxicity.
The major efficacy outcome measure was overall survival (OS) with two pair-wise comparisons:
ONIVYDE versus FU/LV and ONIVYDE/FU/LV versus FU/LV. Additional efficacy outcome
20
Reference ID: 5501873
measures were progression-free survival (PFS) and objective response rate (ORR). Tumor status
assessments were conducted at baseline and every 6 weeks thereafter. The trial was initiated as a
two-arm study and amended after initiation to include a third arm (ONIVYDE/FU/LV). The
comparisons between the ONIVYDE/FU/LV and the FU/LV arms are limited to patients
enrolled in the FU/LV arm after this protocol amendment.
Four hundred seventeen patients were randomized to: ONIVYDE/FU/LV (N=117), ONIVYDE
(N=151), or FU/LV (N=149). Baseline demographics and tumor characteristics for the 236
patients randomized to ONIVYDE/FU/LV or FU/LV (N=119) after the addition of the third arm
to the study were a median age of 63 years (range 34-81 years) and with 41% ≥ 65 years of age;
58% were men; 63% were White, 30% were Asian, 3% were Black or African American, and
5% were other. Mean baseline albumin level was 3.97 g/dL, and baseline KPS was 90-100 in
53% of patients. Disease characteristics included liver metastasis (67%) and lung metastasis
(31%). A total of 13% of patients received gemcitabine in the neoadjuvant/adjuvant setting only,
55% of patients had 1 prior line of therapy for metastatic disease, and 33% of patients had 2 or
more prior lines of therapy for metastatic disease. All patients received prior gemcitabine (alone
or in combination with another agent), 54% received prior gemcitabine in combination with
another agent, and 13% received prior gemcitabine in combination with nab-paclitaxel.
NAPOLI-1 demonstrated a statistically significant improvement in overall survival for the
ONIVYDE/FU/LV arm over the FU/LV arm as summarized in Table 9 and Figure 2.
There was no improvement in overall survival for the ONIVYDE arm over the FU/LV arm
(hazard ratio=1.00, p-value=0.97 (two-sided log-rank test)).
Table 9
Efficacy Results from NAPOLI-1†
ONIVYDE/FU/LV
(N=117)
FU/LV
(N=119)
Overall Survival
Number of Deaths, n (%)
77 (66)
86 (72)
Median Overall Survival (months)
6.1
4.2
(95% CI)
(4.8, 8.5)
(3.3, 5.3)
Hazard Ratio (95% CI)
0.68 (0.50, 0.93)
p-value (log-rank test)
0.014
Progression-Free Survival
Death or Progression, n (%)
83 (71)
94 (79)
Median Progression-Free Survival
(months)
3.1
1.5
(95% CI)
(2.7, 4.2)
(1.4, 1.8)
Hazard Ratio (95% CI)
0.55 (0.41, 0.75)
Objective Response Rate
Confirmed Complete or Partial Response
n (%)
9 (7.7%)
1 (0.8%)
†
FU/LV=5-fluorouracil/leucovorin; CI=confidence interval
21
Reference ID: 5501873
1.0
0.9
0.8
~ 0,7
-~
~ 0.6
0
-~ 0.5
:0
"> 0.4
,g e
CL. 0.3
02
0.1
-
._
I
~ •,
I -, ·-
' ., ,_
'• I -,, ~.
•-.,
..... __
I ·-,
I
._ __ ,_ __ I
---•----,
ONIVYDEJS-FU/LV
S-~FU/LV
0-1-----..... ---------------,.-----------
0
3
ff .rtrl~ .
ONL\l'r DEiS-FUILV:
1V
S,F'Ufl"':
119
6
9
12
Time ftorn r,mdom,z.itlon (rnor,ttisl
SJ.
37
20
12
e
7
15
D
i
18
Figure 2 Kaplan-Meier Curve for Overall Survival in all randomized Patients in
NAPOLI-1
22
Reference ID: 5501873
15
REFERENCES
1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
ONIVYDE is available in a single-dose vial containing 43 mg irinotecan free base at a
concentration of 4.3 mg/mL.
NDC: 15054-0043-1
Storage and Handling
Store ONIVYDE at 2ºC to 8ºC (36°F to 46°F). Do NOT freeze. Protect from light.
ONIVYDE is a hazardous drug. Follow applicable special handling and disposal procedures.1
17
PATIENT COUNSELING INFORMATION
Advise patients of the following:
Severe Neutropenia
Advise patients of the risk of neutropenia leading to severe and life-threatening infections and
the need for monitoring of blood counts. Instruct patients to contact their healthcare provider
immediately if experiencing signs of infection, such as fever, chills, dizziness, or shortness of
breath [see Warnings and Precautions (5.1)].
Severe Diarrhea
Inform patients of the risk of severe and life-threatening diarrhea. Advise patients to stop lactose-
containing products, maintain hydration, and eat frequent small meals with a low-fat diet. Advise
patients to contact their healthcare provider if they experience persistent vomiting or diarrhea;
black or bloody stools; or symptoms of dehydration such as lightheadedness, dizziness, or
faintness [see Warnings and Precautions (5.2)].
Interstitial Lung Disease
Inform patients of the potential risk of ILD. Advise patients to contact their healthcare provider
as soon as possible for new onset cough or dyspnea [see Interstitial Lung Disease (5.3)].
Hypersensitivity to irinotecan HCl or ONIVYDE
Advise patients of the potential risk of severe hypersensitivity and that ONIVYDE is
contraindicated in patients with a history of severe allergic reactions with irinotecan HCl or
ONIVYDE. Instruct patients to seek immediate medical attention for signs of severe
hypersensitivity reaction such as chest tightness; shortness of breath; wheezing; dizziness or
faintness; or swelling of the face, eyelids, or lips [see Contraindications (4) and Warnings and
Precautions (5.4)].
23
Reference ID: 5501873
Females and males of reproductive potential
Embryo-fetal toxicity: Inform females of reproductive potential of the potential risk to a fetus, to
use effective contraception during treatment and for seven months after the last dose, and to
inform their healthcare provider of a known or suspected pregnancy [see Warnings and
Precautions (5.5), Use in Specific Populations (8.1, 8.3)].
Contraception: Advise male patients with female partners of reproductive potential to use
condoms during treatment with ONIVYDE and for four months after the last dose [see Females
and Males of Reproductive Potential (8.3)].
Lactation
Advise women not to breastfeed during treatment with ONIVYDE and for one month after the
last dose [see Use in Special Populations (8.2)].
Manufactured for:
Ipsen Biopharmaceuticals, Inc. Cambridge, MA 02142
ONIVYDE is a registered trademark of Ipsen Biopharm Ltd.
24
Reference ID: 5501873
| custom-source | 2025-02-12T15:48:13.691753 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/207793s018lbl.pdf', 'application_number': 207793, 'submission_type': 'SUPPL ', 'submission_number': 18} |
80,752 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
CARDIOGEN-82 safely and effectively. See full prescribing
information for CARDIOGEN-82.
CARDIOGEN-82® (rubidium Rb 82 generator) to produce rubidium
chloride Rb 82 injection, for intravenous use
Initial U.S. Approval: 1989
WARNING: HIGH LEVEL RADIATION EXPOSURE WITH
USE OF INCORRECT ELUENT and FAILURE TO FOLLOW
THE ELUATE TESTING PROTOCOL
See full prescribing information for complete boxed warning.
High Level Radiation Exposure with Use of Incorrect Eluent
Using the incorrect eluent can cause high Strontium (Sr) 82
and Sr 85 breakthrough levels.
• Use only additive-free 0.9% Sodium Chloride Injection to
elute CardioGen-82.
• If an incorrect solution is used to elute CardioGen-82:
o Immediately stop the patient infusion;
o Evaluate the patient’s radiation absorbed dose and
monitor for the effects of radiation to critical organs such
as bone marrow;
o Permanently discontinue use of the affected generator.
(2.5, 2.10, 5.1)
Excess Radiation Exposure with Failure to Follow the Eluate
Testing Protocol
Excess radiation exposure occurs when the levels of Sr 82 or Sr
85 in the Rubidium Chloride Rb 82 Injection exceed limits.
• Record eluate volume, including waste and test volumes.
• Strictly adhere to the generator eluate testing protocol.
• Stop using the generator if it reaches any of its Expiration
Limits. (2.5, 2.6, 2.7, 2.8, 5.2)
----------------------------RECENT MAJOR CHANGES----------------------
Dosage and Administration,
12/2024
Dosing and Administration of Rubidium Chloride Rb 82 Injection (2.2)
Infusion System (2.4)
-----------------------------INDICATIONS AND USAGE----------------------
CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, is a
radioactive diagnostic agent indicated for positron emission tomography
(PET) of the myocardium under rest or pharmacologic stress conditions to
evaluate regional myocardial perfusion in adult patients with suspected or
existing coronary artery disease. (1)
-----------------------DOSAGE AND ADMINISTRATION-------------------
• Dosing when using the Model 510 Infusion System: 1,480 MBq (40
mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi) per
rest or stress component of a procedure via intravenous infusion at 50
mL/min. (2.2)
• Dosing when using the Model 1700 Infusion System: 10 MBq/kg to 30
MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) per rest or
stress component of a procedure via intravenous infusion at 50
mL/minute or 20 mL/minute. (2.2)
• Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum
volume of 100 mL per rest or stress component of a procedure. (2.2)
• The minimum interval between the rest and stress doses is 10 minutes to
allow sufficient Rb 82 decay. (2.2)
• Start image acquisition 60 seconds to 90 seconds after completion of the
infusion; if a longer circulation time is anticipated, wait for 120 seconds.
Image acquisition is 5 minutes long. (2.3)
• For radiation safety, infusion systems, elution instruction, eluate testing,
dose delivery, and expiration limits of CardioGen-82, and radiation
dosimetry see full prescribing information. (2.1, 2.5, 2.6,2.7, 2.8, 2.9,
2.10)
---------------------DOSAGE FORMS AND STRENGTHS------------------
Rubidium Rb 82 generator used to produce Rubidium Chloride Rb 82
Injection: 3,330 MBq to 5,550 MBq (90 mCi to 150 mCi) of strontium-82
(Sr 82) at calibration time, adsorbed on a hydrous stannic oxide column. (3)
------------------------------CONTRAINDICATIONS---------------------------
None. (4)
------------------------WARNINGS AND PRECAUTIONS-------------------
Risk Associated with Pharmacological Stress: Pharmacologic induction of
cardiovascular stress may cause serious adverse reactions such as
myocardial infarction, arrhythmia, hypotension, broncho-constriction, and
cerebrovascular events. Perform testing only in setting where cardiac
resuscitation equipment and trained staff are readily available. (5.3)
-------------------------------ADVERSE REACTIONS--------------------------
To report SUSPECTED ADVERSE REACTIONS, contact Bracco
Diagnostics Inc. at 1-800-257-8151 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
--------------------------USE IN SPECIFIC POPULATIONS-----------------
Lactation: Do not resume breastfeeding until at least one hour after
administration of Rubidium Chloride Rb 82 Injection. (8.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE
OF INCORRECT ELUENT and FAILURE TO FOLLOW THE
ELUATE TESTING PROTOCOL
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Radiation Safety – Drug Handling
2.2 Dosing and Administration of Rubidium Chloride Rb 82 Injection
2.3 Image Acquisition Instructions
2.4 Infusion System
2.5 Directions for Eluting Rubidium Chloride Rb 82 Injection
2.6 Eluate Testing Protocol for Infusion System Model 510
2.7 Eluate Testing Protocol for Infusion System Model 1700
2.8 Expiration Limits of CardioGen-82
2.9 Dose Delivery Limit of CardioGen-82
2.10 Radiation Dosimetry
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 High Level Radiation Exposure with Use of Incorrect Eluent
5.2 Excess Radiation Exposure with Failure to Follow the Eluate
Testing Protocol
5.3 Risks Associated with Pharmacologic Stress
5.4 Cumulative Radiation Exposure: Long-Term Risk of Cancer
6 ADVERSE REACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
11.1 Generator Characteristics
11.2 Nuclear Physical Characteristics
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5497536
1
FULL PRESCRIBING INFORMATION
WARNING: HIGH LEVEL RADIATION EXPOSURE WITH USE OF INCORRECT ELUENT and
FAILURE TO FOLLOW THE ELUATE TESTING PROTOCOL
High Level Radiation Exposure with Use of Incorrect Eluent
Patients are exposed to high radiation levels when the CardioGen-82 generator is eluted with the incorrect
eluent due to high strontium (Sr) 82 and Sr 85 breakthrough levels.
• Use only additive-free 0.9% Sodium Chloride Injection to elute the generator.
• If an incorrect solution is used to elute the CardioGen-82 generator:
o Immediately stop the patient infusion;
o Evaluate the patient’s radiation absorbed dose, and monitor for the effects of radiation
to critical organs such as bone marrow;
o Permanently discontinue the use of the affected generator [see Dosage and Administration (2.5)
and Warnings and Precautions (5.1)].
Excess Radiation Exposure with Failure to Follow the Eluate Testing Protocol
Excess radiation exposure occurs when the levels of Sr 82 or Sr 85 in the Rubidium Chloride Rb 82
Injection exceed specified limits.
• Record each generator eluate volume, including waste and test volumes, and keep a record of the
cumulative eluate volume.
• Strictly adhere to the generator eluate testing protocol, to minimize the risk of excess radiation
exposure, including daily testing and additional testing at Alert Limits.
• Stop using the generator if it reaches any of its Expiration Limits:
o 17 L for the generator’s cumulative eluate volume
o 42 days post generator calibration date
o An eluate Sr 82 level of 0.01 microCi /mCi Rb 82
o An eluate Sr 85 level of 0.1 microCi /mCi Rb 82 [see Dosage and Administration
(2.5, 2.6, 2.7, 2.8) and Warnings and Precautions (5.2)]
1
INDICATIONS AND USAGE
CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, is indicated for positron emission tomography (PET)
of the myocardium under rest or pharmacologic stress conditions to evaluate regional myocardial perfusion in adult
patients with suspected or existing coronary artery disease.
2
DOSAGE AND ADMINISTRATION
2.1
Radiation Safety - Drug Handling
CardioGen-82, when eluted with additive-free 0.9% Sodium Chloride Injection, produces Rubidium Chloride Rb 82
Injection. Handle CardioGen-82, Rubidium Chloride Rb 82 Injection, and Infusion Systems with appropriate safety
measures to minimize radiation exposure. Wear waterproof gloves and effective shielding throughout the entire
preparation and handling [See Warnings and Precautions (5.4)].
Limit the use of radiopharmaceuticals to healthcare providers who are qualified by specific training and experience in the
safe use and handling of radionuclides and whose experience and training have been approved by the appropriate
government agency authorized to license the use of radionuclides.
2.2
Dosing and Administration of Rubidium Chloride Rb 82 Injection
Important Dosing and Administration Instructions
• Observe aseptic techniques in all drug handling and administration.
• Use CardioGen-82 with the CardioGen-82 Infusion System to elute and administer Rubidium Chloride Rb 82 Injection.
• There are two infusion systems that are different in dosing, elution, and eluate testing. Ensure use of the correct
infusion system when following the instructions for dosing, elution, and eluate testing.
• Use the lowest dose necessary, consistent with the goal of as low as reasonably achievable (ALARA), to obtain
adequate cardiac visualization based on patient body weight and the imaging equipment and acquisition methodology
used to perform the procedure. For example, 3D image acquisition may require doses at the lower end of the
recommended range, compared to 2D imaging.
• Administer two single doses to complete rest and stress myocardial perfusion imaging (MPI) [see Dosage and
Administration (2.3)].
• The minimum interval between the rest and stress doses is 10 minutes to allow sufficient Rb 82 decay.
• Instruct patients to void as soon as a study is completed and as often as possible thereafter for at least one hour [see
Warnings and Precautions (5.4)].
Dosing When Using the CardioGen-82 Model 510 Infusion System
Reference ID: 5497536
2
The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in
adults is 1,480 MBq (40 mCi), with a range of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), administered by
intravenous infusion at 50 mL/minute through a catheter inserted into a large peripheral vein.
Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component
of a procedure.
Dosing When Using the CardioGen-82 Model 1700 Infusion System
The recommended dose of Rubidium Chloride Rb 82 Injection per rest or stress component of a PET MPI procedure in
adults is 10 MBq/kg to 30 MBq/kg actual body weight (0.27 mCi/kg to 0.81 mCi/kg) administered by intravenous
infusion at 50 mL/minute or 20 mL/minute through a catheter inserted into a large peripheral vein.
Do not exceed a maximum dose of 2,220 MBq (60 mCi) or a maximum volume of 100 mL per rest or stress component
of a procedure.
2.3
Image Acquisition Instructions
Rest Imaging
• Administer a single dose of Rubidium Chloride Rb 82 Injection.
• Start imaging 60 seconds to 90 seconds after completion of the first dose infusion and acquire images for 5 minutes.
Stress Imaging
• Begin the study at least 10 minutes after completion of the resting dose infusion, to allow for sufficient Rb 82 decay.
• Administer a pharmacologic stress agent in accordance with its prescribing information.
• After the administration of the pharmacologic stress agent, administer the second dose of Rubidium Chloride Rb 82
Injection at the time interval according to the prescribing information of the pharmacologic stress agent.
• Start imaging 60 seconds to 90 seconds after completion of the second dose infusion and acquire images for 5 minutes.
Rest and Stress Imaging
• If a longer circulation time is anticipated (e.g., in a patient with severe left ventricular dysfunction), start imaging 120
seconds after the dose.
• Acquisition may be started immediately post-injection if dynamic imaging is needed.
2.4
Infusion System
• Use CardioGen-82 only with the CardioGen-82 Infusion System Model 510 or the CardioGen-82 Infusion System
Model 1700, which are specifically designed for use with the generator and capable of accurate measurement and
delivery of doses of Rubidium Chloride Rb 82 Injection.
• Follow instructions in the CardioGen-82 Infusion System Model 510 or Model 1700 Operator’s Manual for the set up
and administration of Rubidium Chloride Rb 82 Injection.
• The CardioGen-82 Infusion System Model 510 provides ± 10% accuracy for measuring Rubidium Chloride Rb 82
Injection doses of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi).
• The CardioGen-82 Infusion System Model 1700 provides ± 10% accuracy for measuring Rubidium Rb 82 Chloride
Injection doses of 1,110 MBq to 2,220 MBq (30 mCi to 60 mCi), and ± 15% accuracy for doses of 370 MBq to 1,110
MBq (10 mCi to 30 mCi).
2.5
Directions for Eluting Rubidium Chloride Rb 82 Injection
• Use only additive-free 0.9 % Sodium Chloride Injection to elute the generator [see Warnings and Precautions
(5.1)].
• Prepare the 0.9 % Sodium Chloride Injection for use with the Saline Tag
o Prepare the intravenous port in accordance with the approved prescribing information of the 0.9 % Sodium
Chloride Injection.
o The intravenous administration port of the 0.9% Sodium Chloride Injection container must be penetrated only
one time.
o Strap the saline tag provided with the CardioGen-82 Infusion System on the additive-free 0.9% Sodium
Chloride Injection container and install on the CardioGen-82 Infusion System.
o Once the container port closure is penetrated, it should remain installed on the CardioGen-82 Infusion System for
its entire period of use. A maximum of 12 hours from the initial port closure penetration is permitted, after which
the bag must be replaced for the next patient.
• Allow at least 10 minutes between elutions for regeneration of Rb 82.
• If the CardioGen-82 Infusion System Model 510 is used:
o Discard the first 50 mL eluate each day the generator is eluted and employ proper safety precautions since the
eluate contains radioactivity.
o Maintain an on-going record of all eluate volumes (washing, testing, dosing volumes), including a summary of the
cumulative volume of eluate from the generator.
Reference ID: 5497536
3
o Perform eluate testing according to the Eluate Testing Protocol for Infusion System Model 510 [see Dosage and
Administration (2.6)].
• If the CardioGen-82 Infusion System Model 1700 is used:
o The system software automatically discards the first 50 mL of eluate each day the generator is eluted and records
and saves all eluate volumes (all flushing, quality control (QC) testing, and patient infusions), representing the
cumulative volume of eluate each day the generator is eluted.
o Perform eluate testing according to the Eluate Testing Protocol for Infusions System Model 1700 [see Dosage and
Administration (2.7)].
• Stop using the generator when the expiration limits are reached [see Dosage and Administration (2.8)].
• The maximum available activity of Rb 82 (dose delivery limit) will decrease as the generator ages. See Table 3 for the
estimated maximum available Rb 82 activity as a function of generator age [see Dosage and Administration (2.9)].
2.6
Eluate Testing Protocol for Infusion System Model 510
Use only additive-free 0.9% Sodium Chloride Injection for all elutions [see Warnings and Precautions (5.1)].
Observe aseptic technique throughout.
Follow all instructions in the CardioGen-82 Infusion System Model 510 Operator’s Manual for performing all eluate
testing as described.
Before administering Rubidium Chloride Rb 82 Injection to the first patient each day, perform the following testing:
Strontium Alert Limits and Mandatory Eluate Testing:
• Use an ionization chamber-type dose calibrator for eluate testing.
• Daily, before administering Rubidium Chloride Rb 82 Injection to any patient, perform an eluate testing to determine
Rb 82, Sr 82, and Sr 85 levels
• Perform additional daily eluate tests after detecting any of the following Alert Limits:
o 14 L total elution volume has passed through the generator column, or
o Sr 82 level reaches 0.002 microCi per mCi Rb 82, or
o Sr 85 level reaches 0.02 microCi per mCi Rb 82.
• Perform the additional daily eluate tests at time points determined by the day’s elution volume; tests are performed
every 750 mL.
o For example, if an Alert Limit were reached and the clinical site eluted less than 750 mL from the generator
during the day, then no additional eluate tests would have been performed that day.
o If the same clinical site the next day eluted 1,500 mL from the generator, then the site would have performed
three tests that day: 1) the required daily test that precedes any patient dosing, 2) a test at the 750 mL elution
point, and 3) a test at the 1,500 mL elution points.
o If a generator’s Alert Limit is reached, the clinical site performs the additional daily tests (at intervals of 750
mL) each subsequent day the generator is used. The additional tests are necessary to promptly detect excessive
Sr 82 and/or Sr 85 in eluates.
Rubidium Eluate Level Testing:
1.
Set a dose calibrator for Rb 82 as recommended by the manufacturer or use the Co-60 setting and divide the reading
obtained by 0.548. Obtain the reading from the instrument in millicuries.
2.
Elute the generator with 50 mL of 0.9% Sodium Chloride Injection and discard the eluate (first elution).
3.
Allow at least 10 minutes for the regeneration of Rb 82, then elute the generator with 50 mL of 0.9% Sodium
Chloride Injection at a rate of 50 mL/min and collect the eluate in a stoppered glass vial (plastic containers are not
suitable). Note the exact time of end of elution (E.O.E.).
4.
Using the dose calibrator, determine the activity of Rb 82 and note the time of the reading. Correct the reading for
decay to the E.O.E. using the appropriate decay factor for Rb 82 (see Table 1). Note: If the reading is taken 2 ½
minutes after end of elution, multiply the dose calibrator reading by 4 to correct for decay.
Strontium Eluate Level Testing:
5.
Using the sample obtained for the Rb 82 activity determination, allow the sample to stand for at least one hour to
allow for the complete decay of Rb 82.
6.
Measure the activity of the sample in a dose calibrator at the setting recommended by the manufacturer for Rb 82
and/or Sr 82. As an alternative, use the Co-60 setting and the reading obtained divided by 0.548. Set the instrument
to read in microcuries and record in the display.
7.
Calculate the ratio (R) of Sr 85/Sr 82 on the day (post-calibration) of the measurement using the ratio of Sr 85/Sr 82
on the day of calibration provided on the generator label and the Sr 85/Sr 82 Ratio Factor from Table 2. Determine R
using the following equation:
[Sr 85]
R= ———— on calibration date X Ratio Factor on the day (post-calibration) of measurement
[Sr 82]
8.
Use a correction factor (F) of 0.478 to compensate for the contribution of Sr 85 to the reading.
9.
Calculate the amount of Sr 82 in the sample using the following equation:
dose calibration reading (microCi)
Sr 82 (microCi) = —————————————
Reference ID: 5497536
4
[1 + (R) (F)]
Example: dose calibrator reading (microCi) = 0.8; Sr85/Sr82 ratio (R) = 1.48; correction factor (F) = 0.478.
0.8
Sr 82 (microCi) = ———————— = 0.47
[1 + (1.48) (0.478)]
10. Determine if Sr 82 in the eluate exceeds an Alert or Expiration Limit by dividing the microCi of Sr 82 by the mCi of
Rb 82 at End of Elution (see below for further instructions based on the Sr 82 level)
Example: 0.47 microCi or Sr 82; 50 mCi of Rb 82 E.O.E.
0.47 microCi Sr 82
———————— = 0.0094 microCi/mCi Rb 82 (is above Alert Limit of 0.002; additional daily eluate
50 mCi Rb 82
testing must be performed)
11. Determine if Sr 85 in the eluate exceeds an Alert or Expiration Limit by multiplying the result obtained in step 10 by
(R) as calculated in step 7 (above).
Example: 0.0094 x 1.48 = 0.014 microCi Sr 85/mCi Rb 82 (test result is below Alert and Expiration Limits)
Use Table 1 to calculate the decay factor for Rb 82; step 4 (above).
Table 1. Physical Decay Chart: Rb 82 half-life 75 seconds
Seconds
Fraction
Seconds
Fraction
Remaining
Remaining
0*
1
165
0.218
15
0.871
180
0.19
30
0.758
195
0.165
45
0.66
210
0.144
60
0.574
225
0.125
75
0.5
240
0.109
90
0.435
255
0.095
105
0.379
270
0.083
120
0.33
285
0.072
135
0.287
300
0.063
150
0.25
*Elution time
Use Table 2 to calculate the ratio (R) of Sr 85/Sr 82; step 7 (above).
Table 2. Sr 85/Sr 82 Ratio Chart (Sr 85 T½ = 65 days, Sr 82 T½ = 25 days)
Days
Ratio
Days
Ratio
Days
Ratio
Factor
Factor
Factor
0*
1
15
1.29
30
1.67
1
1.02
16
1.31
31
1.7
2
1.03
17
1.34
32
1.73
3
1.05
18
1.36
33
1.76
4
1.07
19
1.38
34
1.79
5
1.09
20
1.41
35
1.82
6
1.11
21
1.43
36
1.85
7
1.13
22
1.46
37
1.88
8
1.15
23
1.48
38
1.91
9
1.17
24
1.51
39
1.95
10
11
1.19
1.21
25
26
1.53
1.56
40
41
1.98
2.01
12
1.23
27
1.58
42
2.05
13
1.25
28
1.61
14
1.27
29
1.64
*Day of calibration
2.7
Eluate Testing Protocol for Infusion System Model 1700
Use only additive-free 0.9% Sodium Chloride Injection for all elutions [see Warnings and Precautions
(5.1)].
Observe aseptic technique throughout.
Reference ID: 5497536
5
Follow all instructions in the CardioGen-82 Infusion System Model 1700 Operator’s Manual for performing all eluate
testing as described.
Perform Mandatory Eluate Testing to determine Rb 82, Sr 82, and Sr 85 levels:
1. Daily – Before administering Rubidium Chloride Rb 82 Injection to the first patient each day.
2. Repeat as indicated after an Alert Limit has been detected.
Alert Limits:
•
14 L total elution volume has passed through the generator column, or
•
Sr 82 level reaches 0.002 microCi per mCi Rb 82, or
•
Sr 85 level reaches 0.02 microCi per mCi Rb 82.
3. The CardioGen-82 Infusion System Model 1700 will automatically indicate when alert limits have been reached, and
will require that additional tests be performed, to facilitate the prompt detection of excessive levels of Sr 82 and/or Sr
85 should they occur.
4. These additional daily eluate tests will be performed at intervals determined by the day’s elution volume and will be
enforced by the System software. Specifically, the infusion system will require the user to perform additional eluate
testing after each 750 mL of elution volume when any Alert Limit parameter has been reached.
Infusion System Calibration: Before administering Rubidium Chloride Rb 82 Injection to the first patient:
After installation of a new generator and / or installation of a new CardioGen-82 Accessory Package, Item # 001710,
perform the Rubidium Chloride Rb 82 Injection Dose Calibration (performed using an external dose calibrator).
1. Set a dose calibrator for Rb 82 as recommended by the manufacturer. Obtain the reading from the instrument in
millicuries.
2. Following the prompts in the Graphical User Interface (GUI) for the CardioGen-82 Infusion System Model 1700,
elute the generator with additive-free 0.9% Sodium Chloride Injection at a rate of 50 mL/min and collect the eluate in
the stoppered vial specifically provided for use with the CardioGen-82 Infusion System Model 1700 (alternative vials,
glass or plastic are not suitable). Note the exact time of end of elution (EOE).
3. Using the external dose calibrator, assay the eluate at exactly 2:30, 3:45, or 5:00 minutes after EOE.
4. Following the prompts in the GUI for the CardioGen-82 Infusion System Model 1700, enter the Rb 82 reading from
the dose calibrator and the time since EOE.
5. The infusion system software will automatically calculate the Calibration Ratio.
•
If the ratio is within +/- 2% (0.98 to 1.02), the infusion system will allow acceptance of the calibration factor that
was used for the elution.
•
If the ratio is not within +/- 2% (0.98 to 1.02), the system requires another calibration elution (steps 1 through 4).
6.
Repeat steps 1 through 4 for a flow rate of 20 mL/min.
Perform additional system calibration every 14 days.
Daily Quality Control: Eluate (Strontium Level) Testing and Dose Constancy
Each day, before administering Rubidium Chloride Rb 82 Injection, perform the following test, including Mandatory
Eluate Testing:
Daily Quality Control (performed on-board the CardioGen-82 Infusion System Model 1700, using the gamma (Sr)
detector):
1. Place the stoppered vial, which is specifically provided for use with the CardioGen-82 Infusion System, Model 1700
(alternative vials, glass or plastic are not suitable) in the Sr detector well on the CardioGen-82 Infusion System Model
1700 and, following the prompts in the GUI for the infusion system, initiate the Daily Quality Control workflow.
2. The infusion system will automatically perform the Sr Detector Background Reading.
3. The infusion system will automatically perform the Generator Column Wash.
4. Strontium Level Test and Dose Constancy:
a.
The infusion system will elute the generator with 50 mL of additive-free 0.9% Sodium Chloride Injection at a
rate of 50 mL/min into the stoppered vial (which is specifically provided for use with the CardioGen-82 Infusion
System Model 1700).
b.
The Sr detector measures the Rb 82 and strontium in the 50 mL elution.
c.
The infusion system software will automatically calculate the Sr 82 and Sr 85 levels on the day (post calibration)
of the measurement using the ratio of Sr 85/Sr 82 on the day of calibration provided on the generator label, and
using the full exponential decay calculation for each, accounting for the generator’s age.
d.
Using the Rb 82 and strontium measurements, the infusion system software will automatically calculate microCi
Sr 82/mCi Rb 82 and microCi Sr 85/mCi Rb 82. The GUI will automatically indicate if the results exceed Alert
or Expiration Limits.
e.
The infusion system software will automatically calculate Dose Constancy.
5. Constancy Check of the Sr detector: The infusion system GUI will prompt the user to perform the constancy check of
the Sr detector.
a.
Place the external constancy source in the detector well of the infusion system.
b.
The infusion system software will automatically calculate the constancy of the Sr detector versus the external
constancy source when instructed.
Reference ID: 5497536
6
2.8
Expiration Limits of CardioGen-82
If using the Infusion System Model 510, stop use of CardioGen-82 once any one of the following Expiration Limits is
reached:
•
A total elution volume of 17 L has passed through the generator column
•
42 days post calibration date
•
An eluate Sr 82 level of 0.01 microCi/mCi Rb 82
•
An eluate Sr 85 level of 0.1 microCi/mCi Rb 82
If using the Infusion System Model 1700, the software will automatically indicate, and will stop use of CardioGen-82,
once any one of the above Expiration Limits is reached.
2.9
Dose Delivery Limit of CardioGen-82
The maximum available Rb 82 activity per elution (dose delivery limit) will decrease as the generator ages. Table 3
provides an estimate of the maximum available activity of Rb 82 as a function of generator age.
Table 3. Maximum Available Rb 82 Activity Based on Generator Age1
Generator Age (days)2
Maximum Rb 82 Activity per Elution
0-17
60 mCi (2,220 MBq)
24
50 mCi (1,850 MBq)
32
40 mCi (1,480 MBq)
42
30 mCi (1,110 MBq)
1Estimate is based on a 100 mCi (3,700 MBq) Sr 82 generator at calibration.
2Generator age at which delivery limit is reached varies with generator activity at release. For example, a 90 mCi
(3,330 MBq) generator and a 150 mCi (5,550 MBq) generator will reach a delivery limit <60 mCi at ≥ 14 days and
≥ 33 days, respectively.
2.10 Radiation Dosimetry
The estimated absorbed radiation doses for Rb 82, Sr 82, and Sr 85 from an intravenous injection of Rubidium Chloride
Rb 82 Injection are shown in Table 4.
Table 4. Estimated Absorbed Radiation Dose Coefficient in Adults
Organa,b
Rb 82
Sr 82
Sr 85
(Average for Rest and Stress)
mrem/microCi
mrem/microCi
mrem/mCi (microSv/3.7MBq)c
(microSv/3.7kBq)c
(microSv/3.7kBq)c
Adrenals
7.56
10.6
5.03
Bone – Osteogenic cells Bone
1.86
---
--
Surface
----
107
9.81
Brain
0.6
8.29
2.96
Breast
0.82
7.03
1.72
Gall Bladder Wall
3.17
8.47
2.82
Heart Wall
16.5
8.18
2.67
Kidneys
20.04
9.18
2.5
Liver
4.2
8.10
2.5
Lower Large Intestine Wall
2.84
51.8
5.14
Lungsd
10.7
8.25
2.84
Muscles
1.29
8.14
2.66
Ovaries
1.41
10.2
4.29
Pancreas
8.85
9.1
3.46
Red Marrow
1.19
91
9.84
Skin
1.14
7.03
1.75
Small Intestine
4.76
9.62
4.03
Spleen
6.61
8.1
2.54
Stomach
8.14
7.84
2.26
Testes
0.82
7.25
1.7
Thymus
1.49
7.84
2.33
Thyroid
6.11
8.07
2.57
Upper Large Intestine
5.94
23.7
3.62
Urinary Bladder Wall
1.61
21.9
2.9
Uterus
3.72
9.14
3.32
Total Body
1.77
Not calculated
Not calculated
Effective Dosee
4.74f
23.4
4.03
a Rb 82 doses are averages of rest and stress dosimetry data. To calculate organ doses (mrem) from Rb 82, multiply the dose coefficient for each
Reference ID: 5497536
7
organ by the administered activity in mCi.
b Sr 82 and Sr 85 doses are calculated using software package DCAL and ICRP dose coefficients. To calculate organ doses (mrem) attributable to
Sr 82, and Sr 85, multiply the dose coefficients by the calculated amounts of strontium in microCi.
c To convert to SI units, insert the dose coefficient into the formula in parentheses, e.g. for adrenals 7.56 mrem/mCi = 7.56 microSv/37 MBq =
2.04 x 10-13 Sv/Bq.
d Calculated from ICRP 66
e Calculated from ICRP 60
f Stress phase only
3
DOSAGE FORMS AND STRENGTHS
Rubidium Rb 82 generator used to produce Rubidium Chloride Rb 82 Injection: strontium-82 (Sr 82), with an activity of
3,330 MBq to 5,550 MBq (90 mCi to 150 mCi) at calibration time, adsorbed on a hydrous stannic oxide column.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
High Level Radiation Exposure with Use of Incorrect Eluent
Additives present in solutions (particularly calcium ions) used by mistake to elute CardioGen-82 expose patients to high
levels of radiation by causing the release of large amounts of Sr 82 and Sr 85 into the eluate regardless of the
generator’s age or prior use. When solutions containing calcium ions are used, high levels of radioactivity are present in
any subsequent eluate even with the use of additive-free 0.9% Sodium Chloride Injection.
Use only additive-free 0.9% Sodium Chloride Injection to elute CardioGen-82. If an incorrect eluent is used, immediately
stop the patient infusion, evaluate the patient’s radiation absorbed dose, and monitor for the effects of radiation to critical
organs such as bone marrow. Permanently discontinue use of the affected CardioGen-82 generator [see Dosage and
Administration (2.5)].
5.2
Excess Radiation Exposure with Failure to Follow Eluate Testing Protocol
Excess radiation exposure occurs when the Sr 82 and Sr 85 levels in the Rubidium Chloride Rb 82 Injection exceed the
specified generator eluate limits.
Strictly adhere to the eluate testing protocol to minimize radiation exposure to the patient. Stop using the CardioGen-82
generator when the expiration limits are reached [see Dosage and Administration (2.6, 2.7, 2.8)].
5.3
Risk Associated with Pharmacologic Stress
Pharmacologic induction of cardiovascular stress may be associated with serious adverse reactions such as myocardial
infarction, arrhythmia, hypotension, bronchoconstriction, and cerebrovascular events. Perform pharmacologic stress
testing in accordance with the pharmacologic stress agent’s prescribing information and only in the setting where cardiac
resuscitation equipment and trained staff are readily available.
5.4
Cumulative Radiation Exposure: Long-Term Risk of Cancer
Rubidium chloride Rb 82 contributes to a patient’s overall long-term cumulative radiation exposure. Long-term
cumulative radiation exposure is associated with an increased risk of cancer. Use the lowest dose of Rubidium Chloride
Rb 82 Injection necessary for imaging and ensure safe handling to protect the patient and health care providers.
Encourage patients to void as soon as a study is completed and as often as possible thereafter for a least one hour [see
Dosage and Administration (2.1, 2.2)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
•
High Level Radiation Exposure with Use of Incorrect Eluent [see Warnings and Precautions (5.1)]
•
Excess Radiation Exposure with Failure to Follow Eluate Testing Protocol [see Warnings and Precautions (5.2)]
The following serious adverse reactions have been identified during post-approval use of CardioGen-82. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Radiation Exposure
High level radiation exposure to the bone marrow from using an incorrect eluent.
Excess radiation exposure due to insufficient eluate testing.
Reference ID: 5497536
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8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no data available on the use of rubidium chloride Rb 82 in pregnant women. Animal reproductive studies have
not been conducted with rubidium chloride Rb 82. However, all radiopharmaceuticals, including Rubidium Chloride Rb
82 Injection generated by CardioGen-82, have the potential to cause fetal harm depending on the fetal stage of
development and the magnitude of the radiation dose. If considering Rubidium Chloride Rb 82 Injection administration to
a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose
from rubidium-82 (Rb 82) and the gestational timing of exposure.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to20%, respectively.
8.2
Lactation
Risk Summary
There is no information regarding the presence of rubidium chloride Rb 82 in human milk, the effects on the breastfed
infant or the effects on milk production. Due to the short half-life of Rb 82 (75 seconds), exposure of a breastfed infant
through breast milk can be minimized by temporary discontinuation of breastfeeding (see Clinical Considerations). The
developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for
Rubidium Chloride Rb 82 Injection, any potential adverse effects on the breastfed child from Rb 82 or from the
underlying maternal condition.
Clinical Considerations
Exposure to Rb 82 through breast milk can be minimized if breastfeeding is discontinued when Rubidium Chloride Rb
82 Injection is administered. Do not resume breastfeeding until at least one hour after administration of Rubidium
Chloride Rb 82 Injection.
8.4
Pediatric Use
The safety and effectiveness of CardioGen-82, used to produce Rubidium Chloride Rb 82 Injection, in pediatric patients
have not been established.
8.5
Geriatric Use
In elderly patients with a clinically important decrease in cardiac function, lengthen the delay between infusion and image
acquisition [see Dosage and Administration (2.3)]. Observe for the possibility of fluid overload.
11
DESCRIPTION
11.1 Generator Characteristics
CardioGen-82 (rubidium Rb 82 generator) contains accelerator-produced Sr 82 adsorbed on stannic oxide in a lead-
shielded column and provides a means to produce sterile nonpyrogenic Rubidium Chloride Rb 82 Injection, a radioactive
diagnostic agent, for intravenous use. The chemical form of Rb 82 is 82RbCl.
The amount (mCi) of Rb 82 obtained in each elution will depend on the potency of the generator. When eluted at a rate of
50 mL/minute, each generator eluate at the end of elution should not contain more than 0.02 microCi of Sr 82 and not
more than 0.2 microCi of Sr 85 per mCi of Rubidium Chloride Rb 82 Injection, and not more than 1 mcg of tin per mL of
eluate.
11.2 Nuclear Physical Characteristics
Rb 82 decays by positron emission and associated gamma emission with a physical half-life of 75 seconds. Table 5
shows the annihilation photons released following positron emission which are useful for detection and imaging studies.
The decay modes of Rb 82 are: 95.5% by positron emission, resulting in the production of annihilation radiation, i.e., two
511 keV gamma rays; and 4.5% by electron capture, resulting in the emission of “prompt” gamma rays of predominantly
776.5 keV. Both decay modes lead directly to the formation of stable krypton 82 (Kr 82).
Table 5. Principal Radiation Emission Data for Rb 82
Mean Percent
Mean Energy
Radiation
Per Disintegration
(keV)
Annihilation photons (2)
191.01
511 (each)
Gamma rays
13-15
776.5
Reference ID: 5497536
9
The specific gamma ray constant for Rb 82 is 6.1 R/hour-mCi at 1 cm. The first half-value layer is 0.7 cm of lead (Pb).
Table 6 shows a range of values for the relative attenuation of the radiation emitted by this radionuclide that results from
interposition of various thicknesses of lead. For example, the use of a 7.0 cm thickness of Pb will attenuate the radiation
emitted by a factor of about 1,000.
Table 6. Radiation Attenuation by Lead Shielding
Shield Thickness (Pb) cm
Attenuation Factor
0.7
0.5
2.3
10-1
4.7
10-2
7.0
10-3
9.3
10-4
Sr 82 (half-life of 25 days (600 hrs.) decays to Rb 82. To correct for physical decay of Sr 82, Table 7 shows the fractions
that remain at selected intervals after the time of calibration.
Table 7. Physical Decay Chart: Sr 82 half-life 25 days
Days
Fraction
Days
Fraction
Days
Fraction
Remaining
Remaining
Remaining
0*
1
15
0.660
30
0.435
1
0.973
16
0.642
31
0.423
2
0.946
17
0.624
32
0.412
3
0.920
18
0.607
33
0.401
4
0.895
19
0.591
34
0.390
5
0.871
20
0.574
35
0.379
6
0.847
21
0.559
36
0.369
7
0.824
22
0.543
37
0.359
8
0.801
23
0.529
38
0.349
9
0.779
24
0.514
39
0.339
10
11
0.758
0.737
25
26
0.500
0.486
40
41
0.330
0.321
12
0.717
27
0.473
42
0.312
13
0.697
28
0.460
14
0.678
29
0.448
*Calibration time
To correct for physical decay of Rb 82, Table 1 shows the fraction of Rb 82 remaining in all 15 second intervals up to 300
seconds after time of calibration [see Dosage and Administration (2.6, 2.7)].
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Rb 82 is analogous to potassium ion (K+) in its biochemical behavior and is extracted by the myocardium in proportion to
the blood flow. Rb+ participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell
membranes. The intracellular uptake of Rb 82 requires maintenance of ionic gradient across cell membranes. Rb 82
radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared from necrotic
or infarcted tissue.
12.2 Pharmacodynamics
In human studies, myocardial activity was noted within the first minute after peripheral intravenous injection of rubidium
chloride Rb 82. When areas of infarction or ischemia are present in the myocardium, they are visualized within 2 minutes
to7 minutes after injection as photon-deficient, or “cold”, areas on the myocardial scan. In patients with reduced cardiac
function, transit of the injected dose from the peripheral infusion site to the myocardium may be delayed [see Dosage and
Administration (2.3)].
Blood flow brings Rb 82 to all areas of the body during the first pass of circulation. Accordingly, visible uptake is also
observed in other highly vascularized organs, such as the kidneys, liver, spleen, and lungs.
Reference ID: 5497536
10
12.3 Pharmacokinetics
With a physical half-life of 75 seconds, Rb 82 is converted by radioactive decay into stable Kr 82 gas, which is passively
expired by the lungs.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies have been performed to evaluate carcinogenic potential, mutagenicity potential, or to determine
whether rubidium chloride Rb 82 may affect fertility in males or females.
14
CLINICAL STUDIES
In a descriptive, prospective, blinded image interpretation study of adult patients with known or suspected coronary artery
disease, myocardial perfusion deficits in stress and rest PET images obtained with ammonia N 13 (n = 111) or rubidium
chloride Rb 82 (n = 82) were compared to changes in stenosis flow reserve (SFR) as determined by coronary
angiography. PET perfusion defects at rest and stress for seven cardiac regions (anterior, apical, anteroseptal,
posterolateral, anterolateral, posterolateral, and inferior walls) were graded on a scale of 0 (normal) to 5 (severe). Values
for stenosis flow reserve, defined as flow at maximum coronary vasodilatation relative to rest flow, ranged from 0 (total
occlusion) to 5 (normal). With increasing impairment of flow reserve, the subjective PET defect severity increased. A
PET defect score of 2 or higher was positively correlated with flow reserve impairment (SFR<3).
A systematic review of published literature was conducted using pre-defined inclusion/exclusion criteria which resulted in
identification of 10 studies evaluating the use of Rb 82 PET myocardial perfusion imaging (MPI) for the identification of
coronary artery disease as defined by catheter-based angiography. In these studies, the patient was the unit of analysis and
50% stenosis was the threshold for clinically significant coronary artery disease (CAD). Of these 10 studies, 9 studies
were included in a meta-analysis for sensitivity (excluding one study with 100% sensitivity) and 7 studies were included
in a meta-analysis of specificity (excluding 3 studies with 100% specificity). A random effects model yielded overall
estimates of sensitivity and specificity of 92% (95% CI: 89% to 95%) and 81% (95% CI: 76% to 86%), respectively. The
use of meta-analysis in establishing performance characteristics is limited, particularly by the possibility of publication
bias (positive results being more likely to be published than negative results) which is difficult to detect especially when
based on a limited number of small studies.
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
CardioGen-82 (rubidium Rb 82 generator), used to produce Rubidium Chloride Rb 82 Injection, is supplied in a lead
shield surrounded by a labeled plastic container with an activity at calibration time of 3,330 MBq to 5,550 MBq (90 mCi
to 150 mCi) of Sr 82 adsorbed on a hydrous stannic oxide column (NDC 0270-0091-01).
The container label provides complete assay data for each generator.
Storage and Handling
Store the generator at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].
Receipt, transfer, possession, storage, disposal or use of this product is subject to the radioactive material regulations and
licensing requirements of the U.S. Nuclear Regulatory Commission (NRC), Agreement States or Licensing States as
appropriate. Do not dispose of the generator in regular refuse systems.
For questions about the disposal of the CardioGen-82 generator, contact Bracco Diagnostics Inc. at 1-800-447-6883,
option 3.
17
PATIENT COUNSELING INFORMATION
Post-Study Voiding
Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after
completion of the PET scan [see Warnings and Precautions (5.4)].
Pregnancy
Advise a pregnant woman of the potential risk to a fetus [see Use in Specific Populations (8.1)].
Lactation
Advise lactating women that exposure to Rb 82 through breast milk can be minimized if breastfeeding is discontinued
when Rubidium Chloride Rb 82 Injection is administered. Advise lactating women not to resume breastfeeding for at
least one hour after administration of Rubidium Chloride Rb 82 Injection [see Use in Specific Populations (8.2)].
Manufactured for
Bracco Diagnostics Inc.
Reference ID: 5497536
11
Princeton, NJ 08540
Manufactured By
GE Healthcare, Medi-Physics, Inc.
Arlington Heights, IL 60004
CardioGen-82® Rubidium 82 Generators, Infusion Systems, and Accessories contain proprietary technology covered by
one or more patents listed at www.braccoimaging.com/us-en/patents.
Reference ID: 5497536
12
| custom-source | 2025-02-12T15:48:14.010808 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/019414s034lbl.pdf', 'application_number': 19414, 'submission_type': 'SUPPL ', 'submission_number': 34} |
80,750 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SOVALDI safely and effectively. See full prescribing information
for SOVALDI.
SOVALDI® (sofosbuvir) tablets, for oral use
SOVALDI® (sofosbuvir) oral pellets
Initial U.S. Approval: 2013
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
See full prescribing information for complete boxed warning.
Hepatitis B virus (HBV) reactivation has been reported, in some
cases resulting in fulminant hepatitis, hepatic failure, and death.
(5.1)
------------------------------INDICATIONS AND USAGE-------------------------
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B
polymerase inhibitor indicated for the treatment of:
• Adult patients with genotype 1, 2, 3 or 4 chronic HCV infection
without cirrhosis or with compensated cirrhosis as a component of a
combination antiviral treatment regimen. (1)
• Pediatric patients 3 years of age and older with genotype 2 or 3
chronic HCV infection without cirrhosis or with compensated
cirrhosis in combination with ribavirin. (1)
------------------------DOSAGE AND ADMINISTRATION---------------------
• Testing Prior to the Initiation of Therapy: Test all patients for HBV
infection by measuring HBsAg and anti-HBc. (2.1)
• Recommended dosage in adults: One 400 mg tablet taken once
daily with or without food. (2.2)
• Recommended dosage in pediatric patients 3 years of age and
older: Recommended dosage of SOVALDI in pediatric patients 3
years of age and older with genotype 2 or 3 HCV using SOVALDI
tablets or oral pellets is based on weight. Refer to Table 3 of the full
prescribing information for specific dosing guidelines based on body
weight. (2.3)
• HCV/HIV-1 coinfection: For adult and pediatric patients with
HCV/HIV-1 coinfection, follow the dosage recommendations in the
tables below, respectively. (2.2, 2.3)
• Recommended adult treatment regimen and duration: (2.2)
Adult Patient Population
Regimen
and
Duration
Genotype
1 or 4
Treatment-naïve without cirrhosis
or with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
peginterferon
alfa + ribavirin
12 weeks
Genotype
2
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
12 weeks
Genotype
3
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
24 weeks
• SOVALDI in combination with ribavirin for 24 weeks can be
considered for adult patients with genotype 1 infection who are
interferon ineligible. (2.2)
• Should be used in combination with ribavirin for treatment of HCV in
adult patients with hepatocellular carcinoma awaiting liver
transplantation for up to 48 weeks or until liver transplantation,
whichever occurs first. (2.2)
• Recommended treatment regimen and duration for pediatric patients
3 years of age and older: (2.3, 2.4)
Pediatric Patient Population
3 Years of Age and Older
Regimen
and
Duration
Genotype
2
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
12 weeks
Genotype
3
Treatment-naïve and treatment-
experienced without cirrhosis or
with compensated cirrhosis
(Child-Pugh A)
SOVALDI +
ribavirin
24 weeks
• A dosage recommendation cannot be made for patients with severe
renal impairment or end stage renal disease. (2.7, 8.6)
• Instructions for Use should be followed for preparation and
administration of SOVALDI oral pellets. (2.4)
-----------------------DOSAGE FORMS AND STRENGTHS-------------------
• Tablets: 400 mg and 200 mg of sofosbuvir. (3)
• Oral Pellets: 200 mg and 150 mg of sofosbuvir. (3)
--------------------------------CONTRAINDICATIONS-----------------------------
• When used in combination with peginterferon alfa/ribavirin or ribavirin
alone, all contraindications to peginterferon alfa and/or ribavirin also
apply to SOVALDI combination therapy. (4)
-------------------------WARNINGS AND PRECAUTIONS---------------------
• Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of
current or prior HBV infection before initiation of HCV treatment.
Monitor HCV/HBV coinfected patients for HBV reactivation and
hepatitis flare during HCV treatment and post-treatment follow-up.
Initiate appropriate patient management for HBV infection as clinically
indicated. (5.1)
• Bradycardia with amiodarone coadministration: Serious symptomatic
bradycardia may occur in patients taking amiodarone with a
sofosbuvir-containing regimen, particularly in patients also receiving
beta blockers, or those with underlying cardiac comorbidities and/or
advanced liver disease. Coadministration of amiodarone with
SOVALDI is not recommended. In patients without alternative, viable
treatment options, cardiac monitoring is recommended. (5.2, 6.2, 7.1)
--------------------------------ADVERSE REACTIONS----------------------------
• The most common adverse events (incidence greater than or equal to
20%, all grades) observed with SOVALDI in combination with ribavirin
were fatigue and headache. The most common adverse events
observed with SOVALDI in combination with peginterferon alfa and
ribavirin were fatigue, headache, nausea, insomnia and anemia.
(6.1). The most common adverse events observed with SOVALDI in
combination with ribavirin oral solution in pediatric patients was
decreased appetite. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
---------------------------------DRUG INTERACTIONS----------------------------
• Coadministration of amiodarone with a sofosbuvir-containing regimen
may result in serious symptomatic bradycardia. (5.2, 6.2, 7.1)
• Drugs that are intestinal P-gp inducers (e.g., rifampin, St. John’s wort)
may alter the concentrations of sofosbuvir. (5.3, 7, 12.3)
• Consult the full prescribing information prior to use for potential drug-
drug interactions. (5.2, 5.3, 7, 12.3)
• Clearance of HCV infection with direct acting antivirals may lead to
changes in hepatic function, which may impact safe and effective use
of concomitant medications. Frequent monitoring of relevant
laboratory parameters (INR or blood glucose) and dose adjustments
of certain concomitant medications may be necessary. (7.1)
---------------------------USE IN SPECIFIC POPULATIONS-------------------
• Patients with HCV/HIV-1 coinfection: Safety and efficacy have been
studied. (14.4)
• Patients with hepatocellular carcinoma awaiting liver transplantation:
Safety and efficacy have been studied. (8.8)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 12/2024
Reference ID: 5501595
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FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
PATIENTS COINFECTED WITH HCV AND HBV
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
2.2 Recommended Dosage in Adults
2.3 Recommended Dosage in Pediatric Patients 3 Years of
Age and Older with Genotype 2 or 3 HCV
2.4 Preparation and Administration of Oral Pellets
2.5 Dosage Modification
2.6 Discontinuation of Dosing
2.7 Severe Renal Impairment and End Stage Renal Disease
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Hepatitis B Virus Reactivation in Patients
Coinfected with HCV and HBV
5.2 Serious Symptomatic Bradycardia When Coadministered
with Amiodarone
5.3 Risk of Reduced Therapeutic Effect Due to Use with P-gp
Inducers
5.4 Risks Associated with Combination Treatment
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Potentially Significant Drug Interactions
7.2 Drugs without Clinically Significant Interactions with
SOVALDI
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
8.8 Patients with Hepatocellular Carcinoma Awaiting Liver
Transplantation
8.9 Post-Liver Transplant Patients
8.10 Patients with Genotype 5 or 6 HCV Infection
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV
14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV
14.4 Clinical Trials in Adult Subjects Coinfected with HCV and
HIV-1 – Photon-1 (Study 0123)
14.5 Clinical Trial in Pediatrics (Study 1112)
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5501595
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FULL PRESCRIBING INFORMATION
WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
COINFECTED WITH HCV AND HBV
Test all patients for evidence of current or prior hepatitis B virus (HBV) infection
before initiating treatment with SOVALDI. HBV reactivation has been reported in
HCV/HBV coinfected patients who were undergoing or had completed treatment
with HCV direct acting antivirals and were not receiving HBV antiviral therapy.
Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation
during HCV treatment and post-treatment follow-up. Initiate appropriate patient
management for HBV infection as clinically indicated [see Warnings and
Precautions (5.1)].
1
INDICATIONS AND USAGE
Adult Patients:
SOVALDI is indicated for the treatment of adult patients with chronic hepatitis C virus
(HCV) infection as a component of a combination antiviral treatment regimen [see
Dosage and Administration (2.2), and Clinical Studies (14)]:
• genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis for use
in combination with pegylated interferon and ribavirin
• genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use
in combination with ribavirin.
Pediatric Patients:
SOVALDI is indicated for the treatment of chronic HCV genotype 2 or 3 infection in
pediatric patients 3 years of age and older without cirrhosis or with compensated
cirrhosis for use in combination with ribavirin [see Dosage and Administration (2.3) and
Clinical Studies (14.5)].
2
DOSAGE AND ADMINISTRATION
2.1
Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV
treatment with SOVALDI [see Warnings and Precautions (5.1)].
2.2
Recommended Dosage in Adults
The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily
with or without food [see Clinical Pharmacology (12.3)].
Reference ID: 5501595
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Administer SOVALDI in combination with ribavirin or in combination with pegylated
interferon and ribavirin for the treatment of HCV. The recommended treatment regimen
and duration for SOVALDI combination therapy is provided in Table 1.
For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table
1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1
antiviral drugs.
Table 1
Recommended Treatment Regimen and Duration in Adult Patients
with Genotype 1, 2, 3, or 4 HCV
Patient Population
Treatment Regimen and
Duration
Genotype 1 or 4
Treatment-naïve without cirrhosis or with
compensated cirrhosis (Child-Pugh A)
SOVALDI + peginterferon alfaa
+ ribavirinb 12 weeks
Genotype 2
Treatment-naïve and treatment-experiencedc
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 12 weeks
Genotype 3
Treatment-naïve and treatment-experiencedc
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 24 weeks
a. See peginterferon alfa prescribing information for dosage recommendation for patients with genotype 1 or 4 HCV.
b. Dosage of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dosage of ribavirin is
administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require
ribavirin dosage reduction; refer to ribavirin tablet prescribing information.
c. Treatment-experienced patients have failed an interferon-based regimen with or without ribavirin.
Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based
Regimen
SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic
option for patients with genotype 1 infection who are ineligible to receive an interferon-
based regimen [see Clinical Studies (14.4)]. Treatment decision should be guided by an
assessment of the potential benefits and risks for the individual patient.
Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
Administer SOVALDI in combination with ribavirin for up to 48 weeks or until the time of
liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection
[see Use in Specific Populations (8.8)].
2.3
Recommended Dosage in Pediatric Patients 3 Years of Age and Older with
Genotype 2 or 3 HCV
The recommended treatment regimen, duration, and recommended dosage for
SOVALDI combination therapy is provided in Table 2 and Table 3. Table 4 provides the
weight-based dosage of ribavirin when used in combination with SOVALDI for pediatric
patients. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations
in Table 3 and Table 4. Refer to Drug Interactions (7) for dosage recommendations for
concomitant HIV-1 antiviral drugs. In pediatric patients with hepatocellular carcinoma
Reference ID: 5501595
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awaiting liver transplantation, administer SOVALDI in combination with ribavirin for up to
48 weeks or until the time of liver transplantation, whichever occurs first, to prevent
post-transplant HCV reinfection [see Use in Specific Populations (8.8)].
Table 2
Recommended Treatment Regimen and Duration in Pediatric
Patients 3 Years and Older with Genotype 2 or 3 HCV
Patient Population
Treatment Regimen and
Duration
Genotype 2
Treatment-naïve and treatment-experienceda
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 12 weeks
Genotype 3
Treatment-naïve and treatment-experienceda
without cirrhosis or with compensated cirrhosis
(Child-Pugh A)
SOVALDI + ribavirinb 24 weeks
a. Treatment-experienced patients have failed an interferon based regimen with or without ribavirin.
b. See Table 4 for weight-based ribavirin dosing recommendations.
The recommended dosage of SOVALDI in pediatric patients 3 years and older with
genotype 2 or 3 HCV using SOVALDI tablets or oral pellets (with or without food) is
based on weight (Table 3), and is to be taken orally once daily in combination with
ribavirin [see Dosage and Administration (2.4), Use in Specific Populations (8.4),
Clinical Pharmacology (12.3), and Clinical Studies (14.5)]. SOVALDI pellets can be
taken by pediatric patients who cannot swallow the tablet formulation [see Dosage and
Administration (2.4)].
Table 3
Dosing for Pediatric Patients 3 Years and Older Using SOVALDI
Tablets or Oral Pellets
Body Weight (kg)
Dosing of SOVALDI Tablets or Oral Pellets
SOVALDI Daily Dose
at least 35
one 400 mg tablet once daily
or
two 200 mg tablets once daily
or
two 200 mg packets of pellets once daily
400 mg per day
17 to less than 35
one 200 mg tablet once daily
or
one 200 mg packet of pellets once daily
200 mg per day
less than 17
one 150 mg packet of pellets once daily
150 mg per day
Reference ID: 5501595
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Table 4
Recommended Dosing for Ribavirin in Combination Therapy with
SOVALDI for Pediatric Patients 3 Years and Older
Body Weight (kg)
Oral Ribavirin Daily Dosagea
less than 47
15 mg per kg per day
(divided dose AM and PM)
47–49
600 mg per day
(1 x 200 mg AM, 2 x 200 mg PM)
50–65
800 mg per day
(2 x 200 mg AM, 2 x 200 mg PM)
66–80
1000 mg per day
(2 x 200 mg AM, 3 x 200 mg PM)
greater than 80
1200 mg per day
(3 x 200 mg AM, 3 x 200 mg PM)
a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
2.4
Preparation and Administration of Oral Pellets
See the SOVALDI oral pellets full Instructions for Use for details on the preparation and
administration of SOVALDI pellets.
Do not chew SOVALDI pellets. If SOVALDI pellets are administered with food, sprinkle
the pellets on one or more spoonfuls of non-acidic soft food at or below room
temperature. Examples of non-acidic foods include pudding, chocolate syrup, mashed
potato, and ice cream. Take SOVALDI pellets within 30 minutes of gently mixing with
food and swallow the entire contents without chewing to avoid a bitter aftertaste.
2.5
Dosage Modification
Dosage reduction of SOVALDI is not recommended.
If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or
ribavirin, the peginterferon alfa and/or ribavirin dosage should be reduced or
discontinued, if appropriate, until the adverse reaction abates or decreases in severity.
Refer to the peginterferon alfa and ribavirin prescribing information for additional
information about how to reduce and/or discontinue the peginterferon alfa and/or
ribavirin dosage.
2.6
Discontinuation of Dosing
If the other agents used in combination with SOVALDI are permanently discontinued,
SOVALDI should also be discontinued.
2.7
Severe Renal Impairment and End Stage Renal Disease
No dosage recommendation can be given for patients with severe renal impairment
(estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m2) or with end
stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant
sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology
(12.3)].
Reference ID: 5501595
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3
DOSAGE FORMS AND STRENGTHS
SOVALDI is available as tablets or pellets for oral use. Each dosage form is available in
two dose strengths.
• 400 mg Tablets: 400 mg sofosbuvir: yellow, capsule-shaped, film-coated tablet
debossed with “GSI” on one side and “7977” on the other side.
• 200 mg Tablets: 200 mg sofosbuvir: yellow, oval-shaped, film-coated tablet
debossed with “GSI” on one side and “200” on the other side.
• 200 mg Pellets: 200 mg sofosbuvir: white to off-white pellets in unit-dose
packets.
• 150 mg Pellets: 150 mg sofosbuvir: white to off-white pellets in unit-dose
packets.
4
CONTRAINDICATIONS
When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, the
contraindications applicable to those agents are applicable to combination therapies.
Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their
contraindications.
5
WARNINGS AND PRECAUTIONS
5.1
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and
HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients
who were undergoing or had completed treatment with HCV direct acting antivirals, and
who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
hepatitis, hepatic failure, and death. Cases have been reported in patients who are
HBsAg positive and also in patients with serologic evidence of resolved HBV infection
(i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported
in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of
HBV reactivation associated with treatment with HCV direct-acting antivirals may be
increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting
as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection,
reappearance of HBsAg can occur. Reactivation of HBV replication may be
accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe
cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and
anti-HBc before initiating HCV treatment with SOVALDI. In patients with serologic
evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or
HBV reactivation during HCV treatment with SOVALDI and during post-treatment follow
up. Initiate appropriate patient management for HBV infection as clinically indicated.
Reference ID: 5501595
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5.2
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker
intervention have been reported when amiodarone is coadministered with a sofosbuvir
containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone
who was coadministered a sofosbuvir-containing regimen (HARVONI
[ledipasvir/sofosbuvir]). Bradycardia has generally occurred within hours to days, but
cases have been observed up to 2 weeks after initiating HCV treatment. Patients also
taking beta blockers, or those with underlying cardiac comorbidities and/or advanced
liver disease may be at increased risk for symptomatic bradycardia with
coadministration of amiodarone. Bradycardia generally resolved after discontinuation of
HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with SOVALDI is not recommended. For patients taking
amiodarone who have no other alternative, viable treatment options and who will be
coadministered SOVALDI:
• Counsel patients about the risk of serious symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of
coadministration is recommended, after which outpatient or self-monitoring of the
heart rate should occur on a daily basis through at least the first 2 weeks of
treatment.
Patients who are taking SOVALDI who need to start amiodarone therapy due to no
other alternative, viable treatment options should undergo similar cardiac monitoring as
outlined above.
Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to
starting SOVALDI should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation
immediately. Symptoms may include near-fainting or fainting, dizziness or
lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest
pains, confusion or memory problems [see Adverse Reactions (6.2), Drug Interactions
(7.1)].
5.3
Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
Drugs that are P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may
significantly decrease sofosbuvir plasma concentrations and may lead to a reduced
therapeutic effect of SOVALDI. The use of rifampin and St. John’s wort with SOVALDI is
not recommended [see Drug Interactions (7.1)].
5.4
Risks Associated with Combination Treatment
Because SOVALDI is used in combination with other antiviral drugs for treatment of
HCV infection, consult the prescribing information for these drugs used in combination
with SOVALDI. Warnings and Precautions related to these drugs also apply to their use
in SOVALDI combination treatment.
Reference ID: 5501595
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6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the
labeling:
• Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see
Warnings and Precautions (5.2)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the
respective prescribing information for a description of adverse reactions associated with
their use.
Adverse Reactions in Adult Subjects
The safety assessment of SOVALDI was based on pooled Phase 3 clinical trial data
(both controlled and uncontrolled) including:
• 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for
12 weeks,
• 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks,
• 250 subjects who received SOVALDI + ribavirin combination therapy for
24 weeks,
• 327 subjects who received SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin
combination therapy for 12 weeks,
• 243 subjects who received peginterferon alfa + ribavirin for 24 weeks, and
• 71 subjects who received placebo (PBO) for 12 weeks [see Clinical Studies (14)].
The proportion of subjects who permanently discontinued treatment due to adverse
events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI +
ribavirin for 12 weeks, less than 1% for subjects receiving SOVALDI + ribavirin for 24
weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for
subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks.
Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials
outlined above are provided in Table 5. A side-by-side tabulation is displayed to simplify
presentation; direct comparison across trials should not be made due to differing trial
designs.
The most common adverse events (at least 20%) for SOVALDI + ribavirin combination
therapy were fatigue and headache. The most common adverse events (at least 20%)
for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue,
headache, nausea, insomnia and anemia.
Reference ID: 5501595
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Table 5
Adverse Events (All Grades and without Regard to Causality)
Reported in ≥15% of Subjects with HCV in Any Treatment Arm
Interferon-free Regimens
Interferon-containing Regimens
PBO
12 weeks
SOVALDI
+ RBVa
12 weeks
SOVALDI
+ RBVa
24 weeks
Peg-IFN alfa +
RBVb
24 weeks
SOVALDI
+ Peg-IFN alfa
+ RBVa
12 weeks
N=71
N=650
N=250
N=243
N=327
Fatigue
24%
38%
30%
55%
59%
Headache
20%
24%
30%
44%
36%
Nausea
18%
22%
13%
29%
34%
Insomnia
4%
15%
16%
29%
25%
Pruritus
8%
11%
27%
17%
17%
Anemia
0%
10%
6%
12%
21%
Asthenia
3%
6%
21%
3%
5%
Rash
8%
8%
9%
18%
18%
Decreased
Appetite
10%
6%
6%
18%
18%
Chills
1%
2%
2%
18%
17%
Influenza
Like Illness
3%
3%
6%
18%
16%
Pyrexia
0%
4%
4%
14%
18%
Diarrhea
6%
9%
12%
17%
12%
Neutropenia
0%
<1%
<1%
12%
17%
Myalgia
0%
6%
9%
16%
14%
Irritability
1%
10%
10%
16%
13%
a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
≥75 kg).
b. Subjects received 800 mg ribavirin per day regardless of weight.
With the exception of anemia and neutropenia, the majority of events presented in
Table 5 occurred at severity of grade 1 in SOVALDI-containing regimens.
Less Common Adverse Reactions Reported in Clinical Trials (less than 1%): The
following adverse reactions occurred in less than 1% of subjects receiving SOVALDI in
a combination regimen in any one trial. These events have been included because of
their seriousness or assessment of potential causal relationship.
Hematologic Effects: pancytopenia (particularly in subjects receiving concomitant
pegylated interferon).
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Psychiatric Disorders: severe depression (particularly in subjects with pre-existing
history of psychiatric illness), including suicidal ideation and suicide.
Laboratory Abnormalities:
Changes in selected hematological parameters are described in Table 6. A side-by-side
tabulation is displayed to simplify presentation; direct comparison across trials should
not be made due to differing trial designs.
Table 6
Percentage of Subjects Reporting Selected Hematological
Parameters
Hematological
Parameters
Interferon-free Regimens
Interferon-containing Regimens
PBO
12 weeks
SOVALDI +
RBVa
12 weeks
SOVALDI +
RBVa
24 weeks
Peg-IFN
+ RBVb
24 weeks
SOVALDI
+ Peg-IFN + RBVa
12 weeks
N=71
N=647
N=250
N=242
N=327
Hemoglobin (g/dL)
<10
0
8%
6%
14%
23%
<8.5
0
1%
<1%
2%
2%
Neutrophils (x109/L)
≥0.5 – <0.75
1%
<1%
0
12%
15%
<0.5
0
<1%
0
2%
5%
Platelets (x109/L)
≥25 – <50
3%
<1%
1%
7%
<1%
<25
0
0
0
0
0
a. Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing
≥75 kg).
b. Subjects received 800 mg ribavirin per day regardless of weight.
Bilirubin Elevations
Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in
the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of
subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks
and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during
the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline
levels by post-treatment Week 4. These bilirubin elevations were not associated with
transaminase elevations.
Creatine Kinase Elevations
Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated,
asymptomatic creatine kinase elevation of greater than or equal to 10xULN was
observed in less than 1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin
24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin
12 weeks groups, respectively.
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Lipase Elevations
Isolated, asymptomatic lipase elevation of greater than 3xULN was observed in less
than 1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12
weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and
peginterferon alfa + ribavirin 24 weeks groups, respectively.
Patients with HCV/HIV-1 Coinfection
SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 coinfected
subjects [see Clinical Studies (14.4)]. The safety profile in HCV/HIV-1 coinfected
subjects was similar to that observed in HCV mono-infected subjects. Elevated total
bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as
part of the antiretroviral regimen. None of the subjects had concomitant transaminase
increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin
was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected
subjects receiving SOVALDI + ribavirin in Phase 3 trials.
Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
The safety assessment of SOVALDI in pediatric subjects 3 years of age and older is
based on data from 106 subjects who were treated with SOVALDI plus ribavirin for
12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open-
label clinical trial. The adverse reactions observed were consistent with those observed
in clinical studies of SOVALDI plus ribavirin in adults. Among pediatric subjects 3 years
to < 12 years of age taking SOVALDI in combination with ribavirin oral solution,
decreased appetite was observed in 13% (7/54) of subjects [see Clinical Studies 14.5)].
In a 5-year follow-up study, 88 of the 106 subjects from the Phase 2 open-label clinical
trial (Study 1112) were followed for a median (Q1, Q3) duration of 239 (179, 244)
weeks. No notable effects on growth as assessed by changes from baseline through
end of study were observed for height, weight, BMI percentiles, and Z-scores for any
age group. No notable effects were observed on the development of secondary sexual
characteristics of subjects as assessed by changes from baseline through end of study
in Tanner pubertal stages [see Use in Specific Populations (8.4)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of
SOVALDI. Because postmarketing reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Cardiac Disorders
Serious symptomatic bradycardia has been reported in patients taking amiodarone who
initiate treatment with a sofosbuvir-containing regimen [see Warnings and Precautions
(5.2), Drug Interactions (7.1)].
Reference ID: 5501595
12
Skin and Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling
Angioedema
7
DRUG INTERACTIONS
7.1
Potentially Significant Drug Interactions
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein
(BCRP) while the predominant circulating metabolite GS-331007 is not. Drugs that are
P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease
sofosbuvir plasma concentration, leading to reduced therapeutic effect of SOVALDI,
and thus concomitant use with SOVALDI is not recommended [see Warnings and
Precautions (5.3)].
Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic
function, which may impact the safe and effective use of concomitant medications. For
example, altered blood glucose control resulting in serious symptomatic hypoglycemia
has been reported in diabetic patients in postmarketing case reports and published
epidemiological studies. Management of hypoglycemia in these cases required either
discontinuation or dose modification of concomitant medications used for diabetes
treatment.
Frequent monitoring of relevant laboratory parameters (e.g. International Normalized
Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug
concentrations of concomitant medications such as cytochrome P450 substrates with a
narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure
safe and effective use. Dose adjustments of concomitant medications may be
necessary.
Information on potential drug interactions with SOVALDI is summarized in Table 7. The
table is not all-inclusive [see Warnings and Precautions (5.2, 5.3) and Clinical
Pharmacology (12.3)].
Table 7
Potentially Significant Drug Interactions: Alteration in Dosage or
Regimen May Be Recommended Based on Drug Interaction Studies
or Predicted Interactiona
Concomitant Drug
Class: Drug Name
Effect on
Concentrationb
Clinical Comment
Antiarrhythmics:
amiodarone
Effect on
amiodarone and
sofosbuvir
concentrations
unknown
Coadministration of amiodarone with a sofosbuvir
containing regimen may result in serious symptomatic
bradycardia. The mechanism of this effect is unknown.
Coadministration of amiodarone with SOVALDI is not
recommended; if coadministration is required, cardiac
monitoring is recommended [see Warnings and
Precautions (5.2), Adverse Reactions (6.2)].
Reference ID: 5501595
13
Anticonvulsants:
↓ sofosbuvir
Coadministration of SOVALDI with carbamazepine,
Carbamazepine
phenytoin
↓ GS-331007
phenytoin, phenobarbital or oxcarbazepine is expected
to decrease the concentration of sofosbuvir, leading to
phenobarbital
reduced therapeutic effect of SOVALDI.
oxcarbazepine
Coadministration is not recommended.
Antimycobacterials:
↓ sofosbuvir
Coadministration of SOVALDI with rifabutin or
Rifabutin
↓ GS-331007
rifapentine is expected to decrease the concentration of
sofosbuvir, leading to reduced therapeutic effect of
rifampin
SOVALDI. Coadministration is not recommended.
rifapentine
Coadministration of SOVALDI with rifampin, an
intestinal P-gp inducer, is not recommended [see
Warnings and Precautions (5.3)].
Herbal Supplements:
St. John’s wort
(Hypericum
perforatum)
↓ sofosbuvir
↓ GS-331007
Coadministration of SOVALDI with St. John’s wort, an
intestinal P-gp inducer, is not recommended [see
Warnings and Precautions (5.3)].
HIV Protease
Inhibitors:
tipranavir/ritonavir
↓ sofosbuvir
↓ GS-331007
Coadministration of SOVALDI with tipranavir/ritonavir is
expected to decrease the concentration of sofosbuvir,
leading to reduced therapeutic effect of SOVALDI.
Coadministration is not recommended.
a. This table is not all-inclusive.
b. ↓ = decrease.
7.2
Drugs without Clinically Significant Interactions with SOVALDI
Based on drug interaction studies conducted with SOVALDI, no clinically significant
drug interactions have been either observed or are expected when SOVALDI is
combined with the following drugs [see Clinical Pharmacology (12.3)]: cyclosporine,
darunavir/ritonavir, efavirenz, emtricitabine, methadone, oral contraceptives, raltegravir,
rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
If SOVALDI is administered with ribavirin or peginterferon alfa and ribavirin, the
combination regimen is contraindicated in pregnant women and in men whose female
partners are pregnant. Refer to the ribavirin and/or peginterferon alfa prescribing
information for more information on ribavirin- and peginterferon alfa-associated risks of
use during pregnancy.
No adequate human data are available to establish whether or not SOVALDI poses a
risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse
developmental outcomes was observed with sofosbuvir at exposures greater than those
in humans at the recommended human dose (RHD) [see Data]. During organogenesis
in the rat and rabbit, systemic exposures (AUC) to the predominant circulating
metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and 12 (rabbits) times the
exposure in humans at the RHD. In the rat pre/postnatal development study, maternal
Reference ID: 5501595
14
systemic exposure (AUC) to GS-331007 was ≥6 times the exposure in humans at the
RHD.
The background risk of major birth defects and miscarriage for the indicated population
is unknown. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
respectively.
Data
Animal Data
Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits
(up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to
rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-partum
day 20. No significant effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats)
development were observed at the highest doses tested. Systemic exposures (AUC) to
the predominant circulating metabolite of sofosbuvir (GS-331007) were ≥5 (rats) and
12 (rabbits) times the exposure in humans at the RHD, with exposures increasing
during gestation from approximately 5 to 10 (rats) and 12 to 28 (rabbits) times the
exposure in humans at the RHD.
8.2
Lactation
Risk Summary
It is not known whether sofosbuvir or its metabolites are present in human breast milk,
affect human milk production or have effects on the breastfed infant. The predominant
circulating metabolite of sofosbuvir (GS-331007) was the primary component observed
in the milk of lactating rats, without effect on nursing pups [see Data].
The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for SOVALDI and any potential adverse effects on the
breastfed child from SOVALDI or from the underlying maternal condition.
If SOVALDI is administered with ribavirin, the nursing mother’s information for ribavirin
also applies to this combination regimen. Refer to the ribavirin prescribing information
for more information on use during lactation.
Data
Animal Data
No effects of sofosbuvir on growth and postnatal development were observed in nursing
pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the
predominant circulating metabolite of sofosbuvir (GS-331007) was approximately
12 times the exposure in humans at the RHD, with exposure of approximately 2% that
of maternal exposure observed in nursing pups on lactation day 10. In a lactation study,
sofosbuvir metabolites (primarily GS-331007) were excreted into the milk of lactating
rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation
day 2, with milk concentrations of approximately 10% that of maternal plasma
concentrations observed 1 hour post-dose.
Reference ID: 5501595
15
8.3
Females and Males of Reproductive Potential
If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the information
for ribavirin and peginterferon with regard to pregnancy testing, contraception, and
infertility also applies to these combination regimens. Refer to ribavirin and/or
peginterferon prescribing information for additional information.
8.4
Pediatric Use
The safety, pharmacokinetics, and efficacy of SOVALDI in pediatric patients 3 years of
age and older with genotype 2 and 3 infection have been established. SOVALDI was
evaluated in an open-label clinical trial (Study 1112), which included 106 subjects (31
genotype 2; 75 genotype 3) 3 years of age and older. The safety, pharmacokinetics,
and efficacy were comparable to that observed in adults [see Dosage and
Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and
Clinical Studies (14.5)].
The safety and efficacy of SOVALDI in pediatric patients 3 years of age and older with
compensated cirrhosis is supported by comparable sofosbuvir and GS-331007
exposures between: 1) adults and pediatric patients without cirrhosis and 2) adults
without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be
expected for pediatric patients with compensated cirrhosis as adults with compensated
cirrhosis.
The safety and efficacy of SOVALDI have not been established in pediatric patients less
than 3 years of age with HCV genotype 2 or 3. The safety and efficacy of SOVALDI
have not been established in pediatric patients with HCV genotype 1 or 4.
In a 5-year follow-up study, the long-term effects of SOVALDI on pediatric growth were
assessed in 88 pediatric subjects 3 years of age and older treated with SOVALDI in
Study 1112. No notable effects on growth from baseline through end of study were
observed [see Adverse Reactions (6.1)]. All subjects who had achieved SVR12
maintained SVR through end of study.
8.5
Geriatric Use
SOVALDI was administered to 90 subjects aged 65 and over. The response rates
observed for subjects over 65 years of age were similar to that of younger subjects
across treatment groups. No dosage adjustment of SOVALDI is warranted in geriatric
patients [see Clinical Pharmacology (12.3)].
8.6
Renal Impairment
No dosage adjustment of SOVALDI is required for patients with mild or moderate renal
impairment. The safety and efficacy of SOVALDI have not been established in patients
with severe renal impairment (eGFR less than 30 mL/min/1.73m2) or ESRD requiring
hemodialysis. No dosage recommendation can be given for patients with severe renal
impairment or ESRD [see Dosage and Administration (2.7) and Clinical Pharmacology
(12.3)]. Refer also to ribavirin and peginterferon alfa prescribing information for patients
with CrCl less than 50 mL/min.
Reference ID: 5501595
16
8.7
Hepatic Impairment
No dosage adjustment of SOVALDI is required for patients with mild, moderate or
severe hepatic impairment (Child-Pugh Class A, B or C) [see Clinical Pharmacology
(12.3)]. Safety and efficacy of SOVALDI have not been established in patients with
decompensated cirrhosis. See peginterferon alfa prescribing information for
contraindication in hepatic decompensation.
8.8
Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
SOVALDI was studied in HCV-infected adult subjects with hepatocellular carcinoma
prior to undergoing liver transplantation in an open-label clinical trial evaluating the
safety and efficacy of SOVALDI and ribavirin administered pre-transplant to prevent
post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant
virologic response (pTVR) defined as HCV RNA less than lower limit of quantification
(LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype,
with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the
presence of a tumor 5 cm or less in diameter in patients with single hepatocellular
carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in
patients with multiple tumors and no extrahepatic manifestations of the cancer or
evidence of vascular invasion of tumor) received 400 mg SOVALDI and weight-based
1000-1200 mg ribavirin daily for 24-48 weeks or until the time of liver transplantation,
whichever occurred first. An interim analysis was conducted on 61 subjects who
received SOVALDI and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a
baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score
up to 14. Of these 61 subjects, 41 subjects underwent liver transplantation following up
to 48 weeks of treatment with SOVALDI and ribavirin; 37 had HCV RNA less than LLOQ
at the time of transplantation. Of the 37 subjects, the post-transplant virologic response
(pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week
post-transplant time point. The safety profile of SOVALDI and ribavirin in HCV-infected
subjects prior to liver transplantation was comparable to that observed in subjects
treated with SOVALDI and ribavirin in Phase 3 clinical trials.
8.9
Post-Liver Transplant Patients
The safety and efficacy of SOVALDI have not been established in post-liver transplant
patients.
8.10 Patients with Genotype 5 or 6 HCV Infection
Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing
recommendations.
10
OVERDOSAGE
The highest documented dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg
(three times the recommended dosage) administered to 59 healthy subjects. In that trial,
there were no untoward effects observed at this dosage level, and adverse events were
Reference ID: 5501595
17
y
Q )' .. ,,
... =
I
,,.)
"t--< -f
½
similar in frequency and severity to those reported in the placebo and sofosbuvir
400 mg treatment groups. The effects of higher dosages are not known.
No specific antidote is available for overdose with SOVALDI. If overdose occurs, the
patient must be monitored for evidence of toxicity. Treatment of overdose with
SOVALDI consists of general supportive measures including monitoring of vital signs as
well as observation of the clinical status of the patient. A 4-hour hemodialysis session
removed 18% of the administered dose.
11
DESCRIPTION
SOVALDI (sofosbuvir) is a nucleotide analog inhibitor of HCV NS5B polymerase.
The IUPAC name for sofosbuvir is (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo
3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2
yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of
C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:
O
N
F
HO
O
H
N
O
O
P
O
HN
O
O
O
Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across
the pH range of 2-7.7 at 37 oC and is slightly soluble in water.
SOVALDI tablets, 200 mg or 400 mg, are for oral administration. Each tablet contains
200 mg or 400 mg of sofosbuvir. The tablets include the following inactive ingredients:
colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and
microcrystalline cellulose. The tablets are film-coated with a coating material containing
the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium
dioxide, and yellow iron oxide.
SOVALDI pellets, 150 mg or 200 mg, are for oral administration, supplied as white to
off-white pellets in unit-dose packets. Each unit-dose packet contains 150 mg or 200 mg
of sofosbuvir. The pellets include the following inactive ingredients: amino methacrylate
copolymer, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose,
hypromellose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol,
silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, and talc.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sofosbuvir is a direct-acting antiviral agent against the hepatitis C virus [see
Microbiology (12.4)].
Reference ID: 5501595
18
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of sofosbuvir 400 and 1200 mg (three times the recommended dosage) on
QTc interval was evaluated in a randomized, single-dose, placebo- and active-
controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy
subjects. At a dosage three times the maximum recommended dosage, SOVALDI does
not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
Absorption
The pharmacokinetic properties of sofosbuvir and the predominant circulating
metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects
with chronic hepatitis C. Following oral administration of SOVALDI, sofosbuvir was
absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose,
regardless of dose level. Peak plasma concentration of GS-331007 was observed
between 2 to 4 hours post-dose. Based on population pharmacokinetic analysis in
subjects with genotype 1 to 6 HCV infection who were coadministered ribavirin (with or
without pegylated interferon), geometric mean steady state AUC0-24 was 969 ng•hr/mL
for sofosbuvir (N=838), and 6790 ng•hr/mL for GS-331007 (N=1695). Relative to
healthy subjects administered sofosbuvir alone (N=272), the sofosbuvir AUC0-24 was
60% higher; and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected
subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose
range of 200 mg to 1200 mg.
Effect of Food
Relative to fasting conditions, the administration of a single dose of SOVALDI with a
standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf.
The exposure of GS-331007 was not altered in the presence of a high-fat meal.
Therefore, SOVALDI can be administered without regard to food.
Distribution
Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding
is independent of drug concentration over the range of 1 microgram/mL to
20 microgram/mL. Protein binding of GS-331007 was minimal in human plasma. After a
single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of
14C-radioactivity was approximately 0.7.
Metabolism
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves
sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A
(CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad
nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine
Reference ID: 5501595
19
nucleotide biosynthesis pathway. Dephosphorylation results in the formation of
nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks
anti-HCV activity in vitro.
After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007
accounted for approximately 4% and greater than 90% of drug related material (sum of
molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure,
respectively.
Elimination
Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose
was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in
urine, feces, and expired air, respectively. The majority of the sofosbuvir dose
recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir.
These data indicate that renal clearance is the major elimination pathway for
GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and
27 hours, respectively.
Specific Populations
Race
Population pharmacokinetics analysis in HCV-infected subjects indicated that race had
no clinically relevant effect on the exposure of sofosbuvir and GS-331007.
Gender
No clinically relevant pharmacokinetic differences have been observed between men
and women for sofosbuvir and GS-331007.
Pediatric Patients
The pharmacokinetics of sofosbuvir and GS-331007 were determined in HCV genotype
2 or 3 infected pediatric subjects 3 years of age and older receiving a daily dose of
SOVALDI as described in Table 8. Exposures in pediatric subjects were similar to those
observed in adults.
Table 8
Pharmacokinetic Properties of SOVALDI in HCV-infected Pediatric
Subjects 3 Years of Age and Oldera
Geometric Mean (%CV)
Weight Group
Dose
PK Parameter
Sofosbuvir
GS-331007
≥35 kgb
400 mg
AUCtau (ng•hr/mL)
1060 (50.6)
7570 (32.8)
Cmax (ng/mL)
472 (53.0)
572 (40.7)
17 to <35 kgc
200 mg
AUCtau (ng•hr/mL)
891 (36.1)
10400 (31.6)
Cmax (ng/mL)
438 (26.4)
866 (27.1)
<17 kgd
150 mg
AUCtau (ng•hr/mL)
851 (41.7)
9060 (37.6)
Cmax (ng/mL)
418 (26.8)
767 (28.3)
a.
Population PK derived parameters
b.
Sofosbuvir N=28; GS-331007 N=50
c.
Sofosbuvir N=29; GS-331007 N=30
d.
Sofosbuvir N=7; GS-331007 N=7
Reference ID: 5501595
20
The pharmacokinetics of sofosbuvir and GS-331007 have not been established in
pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and
Clinical Studies (14.5)].
Geriatric Patients
Population pharmacokinetic analysis in HCV-infected subjects showed that within the
age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the
exposure to sofosbuvir and GS-331007 [see Use in Specific Populations (8.5)].
Patients with Renal Impairment
The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild
(eGFR between 50 to less than 80 mL/min/1.73m2), moderate (eGFR between 30 to
less than 50 mL/min/1.73m2), severe renal impairment (eGFR less than
30 mL/min/1.73m2) and subjects with end stage renal disease (ESRD) requiring
hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with
normal renal function (eGFR greater than 80 mL/min/1.73m2), the sofosbuvir AUC0-inf
was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while
the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with
ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC0
inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis
compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after
hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18%
of administered dose. No dosage adjustment is required for patients with mild or
moderate renal impairment. The safety and efficacy of SOVALDI have not been
established in patients with severe renal impairment or ESRD. No dosage
recommendation can be given for patients with severe renal impairment or ESRD [see
Dosage and Administration (2.6) and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg
sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment
(Child-Pugh Class B and C). Relative to subjects with normal hepatic function, the
sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic
impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively.
Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis
had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No
dosage adjustment of SOVALDI is recommended for patients with mild, moderate or
severe hepatic impairment [see Use in Specific Populations (8.7)].
Assessment of Drug Interactions
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein
(BCRP) while GS-331007 is not. Drugs that are P-gp inducers in the intestine (e.g.,
rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to
reduced therapeutic effect of SOVALDI, and thus concomitant use with SOVALDI is not
recommended [see Warnings and Precautions (5.3) and Drug Interactions (7.1)].
Reference ID: 5501595
21
Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase
sofosbuvir plasma concentration without increasing GS-331007 plasma concentration;
accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors.
Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not
expected to increase exposures of drugs that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low
affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are
unlikely to be affected by concomitant drugs.
The effects of coadministered drugs on the exposure of sofosbuvir and GS-331007 are
shown in Table 9. The effects of sofosbuvir on the exposure of coadministered drugs
are shown in Table 10 [see Drug Interactions (7.1, 7.2)].
Table 9
Drug Interactions: Changes in Pharmacokinetic Parameters for
Sofosbuvir and the Predominant Circulating Metabolite GS-331007
in the Presence of the Coadministered Druga
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Sofosbuvir
Dose (mg)
N
Mean Ratio (90% CI) of Sofosbuvir and GS
331007 PK With/Without Coadministered Drug
No Effect=1.00
Cmax
AUC
Cmin
Cyclosporine
600 single dose
400 single
dose
19
sofosbuvir
2.54
(1.87, 3.45)
4.53
(3.26, 6.30)
NA
GS-331007
0.60
(0.53, 0.69)
1.04
(0.90, 1.20)
NA
Darunavir
(boosted with
ritonavir)
800/100 once
daily
400 single
dose
18
sofosbuvir
1.45
(1.10, 1.92)
1.34
(1.12, 1.59)
NA
GS-331007
0.97
(0.90, 1.05)
1.24
(1.18, 1.30)
NA
Efavirenzb
600 once daily
400 single
dose
16
sofosbuvir
0.81
(0.60, 1.10)
0.94
(0.76, 1.16)
NA
Emtricitabineb
200 once daily
Tenofovir
disoproxil
fumarateb
300 once daily
GS-331007
0.77
(0.70, 0.84)
0.84
(0.76, 0.92)
NA
Methadone
30 to 130 once
daily
400 once
daily
14
sofosbuvir
0.95c
(0.68, 1.33)
1.30c
(1.00, 1.69)
NA
GS-331007
0.73c
(0.65, 0.83)
1.04c
(0.89, 1.22)
NA
Rilpivirine
25 once daily
400 single
dose
17
sofosbuvir
1.21
(0.90, 1.62)
1.09
(0.94, 1.27)
NA
GS-331007
1.06
(0.99, 1.14)
1.01
(0.97, 1.04)
NA
Tacrolimus
5 single dose
400 single
dose
16
sofosbuvir
0.97
(0.65, 1.43)
1.13
(0.81, 1.57)
NA
GS-331007
0.97
(0.83, 1.14)
1.00
(0.87, 1.13)
NA
NA = not available/not applicable
Reference ID: 5501595
22
a. All interaction studies conducted in healthy volunteers
b. Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet
c. Comparison based on historic control
No effect on the pharmacokinetic parameters of sofosbuvir and GS-331007 was
observed with raltegravir.
Table 10
Drug Interactions: Changes in Pharmacokinetic Parameters for
Coadministered Drug in the Presence of Sofosbuvira
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Sofosbuvir
Dose (mg)
N
Mean Ratio (90% CI) of Coadministered Drug
PK With/Without Sofosbuvir
No Effect=1.00
Cmax
AUC
Cmin
Norelgestromin
norgestimate
0.18/0.215/0.25/
ethinyl estradiol
0.025 once daily
400 once
daily
15
1.07
(0.94, 1.22)
1.06
(0.92, 1.21)
1.07
(0.89, 1.28)
Norgestrel
1.18
(0.99, 1.41)
1.19
(0.98, 1.45)
1.23
(1.00, 1.51)
Ethinyl estradiol
1.15
(0.97, 1.36)
1.09
(0.94, 1.26)
0.99
(0.80, 1.23)
Raltegravir
400 twice daily
400 single
dose
19
0.57
(0.44, 0.75)
0.73
(0.59, 0.91)
0.95
(0.81, 1.12)
Tacrolimus
5 single dose
400 single
dose
16
0.73
(0.59, 0.90)
1.09
(0.84, 1.40)
NA
Tenofovir
disoproxil
fumarateb
300 once daily
400 single
dose
16
1.25
(1.08, 1.45)
0.98
(0.91, 1.05)
0.99
(0.91, 1.07)
NA = not available/not applicable
a. All interaction studies conducted in healthy volunteers
b. Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet
No effect on the pharmacokinetic parameters of the following coadministered drugs was
observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine,
methadone, or rilpivirine.
12.4 Microbiology
Mechanism of Action
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is
essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes
intracellular metabolism to form the pharmacologically active uridine analog
triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B
polymerase and acts as a chain terminator. In a biochemical assay, GS-461203
inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a,
3a and 4a with IC50 values ranging from 0.7 to 2.6 micromolar. GS-461203 is neither an
inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA
polymerase.
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Antiviral Activity
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from
genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from
genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median EC50 value of
sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates
was 0.062 micromolar for genotype 1a (range 0.029–0.128 micromolar; N=67),
0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29),
0.029 micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and
0.081 micromolar for genotype 3a (range 0.024–0.181 micromolar; N=106). In infectious
virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and
0.02 micromolar, respectively. The presence of 40% human serum had no effect on the
anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon
alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon
cells.
Resistance
In Cell Culture
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell
culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced
susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in
all replicon genotypes examined. An M289L substitution developed along with the
S282T substitution in genotype 2a, 5 and 6 replicons. Site-directed mutagenesis of the
S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced
susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99%
compared to the corresponding wild-type. In biochemical assays, recombinant NS5B
polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution
showed reduced susceptibility to GS-461203 compared to respective wild-types.
In Clinical Trials
In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials,
224 subjects had post-baseline NS5B genotypic data from next generation nucleotide
sequencing (assay cutoff of 1%).
Treatment-emergent substitutions L159F (n=6) and V321A (n=5) were detected in post-
baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable
shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or
V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T
was not detected at baseline or in the failure isolates from Phase 3 trials. However, an
S282T substitution was detected in one genotype 2b subject who relapsed at Week 4
post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977
0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced
susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer
detectable at Week 12 post-treatment by next generation sequencing with an assay
cutoff of 1%.
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In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation
where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F
substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced
virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions
L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and
relapse post-transplant in multiple subjects infected with GT1b HCV. In addition, S282R
and L320F substitutions were detected on-treatment by next generation sequencing in a
subject infected with GT1a HCV with a partial treatment response.
The clinical significance of these substitutions is not known.
Cross Resistance
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were
susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin
associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir
was active against HCV replicons with NS3/4A protease inhibitor, NS5B non-nucleoside
inhibitor and NS5A inhibitor resistant variants.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for
ribavirin and/or peginterferon alfa for information on carcinogenesis and mutagenesis.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial
mutagenicity, chromosome aberration using human peripheral blood lymphocytes and
in vivo mouse micronucleus assays.
Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice
were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in
females, while rats were administered doses of up to 750 mg/kg/day in males and
females. No increase in the incidence of drug-related neoplasms were observed at the
highest doses tested in mice and rats, resulting in AUC exposure to the predominant
circulating metabolite GS-331007 of approximately 7 and 30 times (in mice) and 13 and
17 times (in rats), in males and females respectively, the exposure in humans at the
recommended clinical dose.
Impairment of Fertility
Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for
ribavirin and/or peginterferon alfa for information on impairment of fertility.
Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats.
At the highest dose tested, AUC exposure to the predominant circulating metabolite
GS-331007 was approximately 8 times the exposure in humans at the recommended
clinical dose.
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14
CLINICAL STUDIES
14.1 Description of Clinical Trials
The safety and efficacy of SOVALDI was evaluated in five Phase 3 trials in a total of
1724 HCV mono-infected subjects with genotypes 1 to 6 chronic hepatitis C virus, one
Phase 3 trial in 223 HCV/HIV-1 coinfected subjects with genotype 1, 2 or 3 HCV, and
one trial in 106 pediatric subjects 3 years of age and older with genotype 2 or 3 HCV, as
summarized in Table 11 [see Clinical Studies (14.2, 14.3, 14.4, and 14.5)].
Table 11
Trials Conducted with SOVALDI with Peginterferon Alfa and/or
Ribavirin in Subjects with Chronic HCV Genotype 1, 2, 3, or 4
Infection
Trial
Population
Study Arms (Number of Subjects Treated)
NEUTRINO a
(NCT01641640)
Treatment naïve (TN) (GT1, 4, 5
or 6)
SOVALDI+Peg-IFN alfa+RBV 12 weeks (327)
FISSION a
(NCT01497366)
TN (GT2 or 3)
SOVALDI+RBV 12 Weeks (256)
Peg-IFN alfa+RBV 24 weeks (243)
POSITRON b
(NCT01542788)
Interferon intolerant, ineligible or
unwilling subjects (GT2 or 3)
SOVALDI+RBV 12 Weeks (207)
Placebo 12 weeks (71)
FUSION b
(NCT01604850)
Previous interferon relapsers or
nonresponders (GT2 or 3)
SOVALDI+RBV 12 Weeks (103)
SOVALDI+RBV 16 Weeks (98)
VALENCE b
(NCT01682720)
TN or previous interferon
relapsers or nonresponders
(GT2 or 3)
SOVALDI+RBV 12 Weeks for GT2 (73)
SOVALDI+RBV 12 Weeks for GT3 (11)
SOVALDI+RBV 24 Weeks for GT3 (250)
Placebo for 12 weeks (85)
PHOTON-1 a
(NCT01667731)
•
HCV/HIV-1 coinfected TN
(GT1)
•
HCV/HIV-1 coinfected TN or
previous interferon relapsers
or nonresponders (GT2 or
3)
SOVALDI+RBV 24 Weeks for GT1 (114)
SOVALDI+RBV 12 Weeks for GT2 or 3 TN (68)
SOVALDI+RBV 24 Weeks for GT2 or 3 previous
interferon relapsers or nonresponders (41)
1112
(NCT02175758)a
GT2 or GT3 pediatric subjects 3
years of age and older
SOVALDI+RBV 12 Weeks for GT2 (31)
SOVALDI+RBV 24 Weeks for GT3 (75)
a. Open label.
b. Double-blind, placebo-controlled.
Subjects in the adult trials did not have cirrhosis or had compensated cirrhosis.
SOVALDI was administered at a dose of 400 mg once daily. The ribavirin (RBV) dosage
for adult subjects was weight-based at 1000-1200 mg daily administered in two divided
doses when used in combination with SOVALDI, and the peginterferon alfa 2a dosage,
where applicable, was 180 micrograms per week. Treatment duration was fixed in each
trial and was not guided by subjects’ HCV RNA levels (no response guided algorithm).
Plasma HCV RNA values were measured during the clinical trials using the COBAS
TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a
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lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response
(SVR12) was the primary endpoint which was defined as HCV RNA less than LLOQ at
12 weeks after the end of treatment.
14.2 Clinical Trials in Subjects with Genotype 1 or 4 HCV
Treatment-Naïve Adults ─ NEUTRINO (Study 110)
NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment
with SOVALDI in combination with peginterferon alfa 2a and ribavirin in treatment-naïve
subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical
control.
Treated subjects (N=327) had a median age of 54 years (range: 19 to 70); 64% of the
subjects were male; 79% were White, 17% were Black; 14% were Hispanic or Latino;
mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV
RNA greater than 6 log10 IU per mL; 17% had cirrhosis; 89% had HCV genotype 1; 9%
had HCV genotype 4 and 2% had HCV genotype 5 or 6. Table 12 presents the SVR12
for the treatment group of SOVALDI + peginterferon alfa + ribavirin in subjects with
genotype 1 or 4 HCV. Available data on subjects with genotype 5 or 6 HCV treated with
SOVALDI + peginterferon alfa + ribavirin for 12 weeks were insufficient for dosing
recommendations; therefore these results are not presented in Table 12 [see Use in
Specific Populations (8.10)].
Table 12
Study NEUTRINO: SVR12 for Treatment-Naïve Subjects with
Genotype 1 or 4 HCV
SOVALDI + Peg-IFN alfa + RBV 12 weeks
N=320
Overall SVR
90% (289/320)
Genotype 1a
90% (262/292)
Genotype 1a
92% (206/225)
Genotype 1b
83% (55/66)
Genotype 4
96% (27/28)
Outcome for subjects without SVR
On-treatment virologic failure
0/320
Relapseb
9% (28/319)
Otherc
1% (3/320)
a. One subject had genotype 1a/1b mixed infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
SVR12 for selected subgroups are presented in Table 13.
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Table 13
SVR12 Rates for Selected Subgroups in NEUTRINO in Subjects with
Genotype 1 or 4 HCV
SOVALDI + Peg-IFN alfa + RBV 12 weeks
Cirrhosis
No
93% (247/267)
Yes
79% (42/53)
Race
Black
87% (47/54)
Non-black
91% (242/266)
Multiple Baseline Factors
Genotype 1, Metavir F3/F4
fibrosis, IL28B non-C/C, HCV
RNA >800,000 IU/mL
71% (37/52)
SVR12 rates were 99% (89/90) in subjects with genotype 1 or 4 HCV and baseline
IL28B C/C allele and 87% (200/230) in subjects with genotype 1 or 4 HCV and baseline
IL28B non-C/C alleles.
It is estimated that the SVR12 in patients who previously failed pegylated interferon and
ribavirin therapy will approximate the observed SVR12 in NEUTRINO subjects with
multiple baseline factors traditionally associated with a lower response to interferon-
based treatment (Table 13).
The SVR12 rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C
alleles, HCV RNA greater than 800,000 IU/mL and Metavir F3/F4 fibrosis was 71%
(37/52).
14.3 Clinical Trials in Subjects with Genotype 2 or 3 HCV
Treatment-Naïve Adults ─ FISSION (Study 1231)
FISSION was a randomized, open-label, active-controlled trial that evaluated 12 weeks
of treatment with SOVALDI and ribavirin compared to 24 weeks of treatment with
peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 2 and 3
HCV. The ribavirin dosage used in the SOVALDI + ribavirin and peginterferon alfa 2a +
ribavirin arms were weight-based 1000-1200 mg per day and 800 mg per day
regardless of weight, respectively. Subjects were randomized in a 1:1 ratio and stratified
by cirrhosis (presence vs. absence), HCV genotype (2 vs. 3) and baseline HCV RNA
level (less than 6 log10 IU/mL vs. at least 6 log10 IU/mL). Subjects with genotype 2 or 3
HCV were enrolled in an approximately 1:3 ratio.
Treated subjects (N=499) had a median age of 50 years (range: 19 to 77); 66% of the
subjects were male; 87% were White, 3% were Black; 14% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 17 to 52 kg/m2); 57% had baseline HCV
RNA levels greater than 6 log10 IU per mL; 20% had cirrhosis; 72% had HCV genotype
3. Table 14 presents the SVR12 for the treatment groups of SOVALDI + ribavirin and
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peginterferon alfa + ribavirin in subjects with genotype 2 HCV. SVR12 for genotype 3
subjects treated with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these
results are not presented in Table 14.
Table 14
Study FISSION: SVR12 in Treatment-Naïve Subjects with Genotype 2
HCV
SOVALDI + RBV 12 weeks
Peg-IFN alfa + RBV 24 weeks
N=73a
N=67a
SVR12
95% (69/73)
78% (52/67)
Outcome for subjects without SVR12
On-treatment virologic failure
0/73
4% (3/67)
Relapseb
5% (4/73)
15% (9/62)
Otherc
0/73
4% (3/67)
a. Including three subjects with recombinant genotype 2/1 HCV infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
SVR12 for genotype 2 HCV-infected subjects with cirrhosis at baseline are presented in
Table 15.
Table 15
SVR12 Rates by Cirrhosis in Study FISSION in Subjects with
Genotype 2 HCV
SOVALDI + RBV
12 weeks
Peg-IFN alfa + RBV
24 weeks
N=73
N=67
Cirrhosis
No
97% (59/61)
81% (44/54)
Yes
83% (10/12)
62% (8/13)
Interferon Intolerant, Ineligible or Unwilling Adults ─ POSITRON (Study 0107)
POSITRON was a randomized, double-blinded, placebo-controlled trial that evaluated
12 weeks of treatment with SOVALDI and ribavirin (N=207) compared to placebo
(N=71) in subjects who are interferon intolerant, ineligible or unwilling. Subjects were
randomized in 3:1 ratio and stratified by cirrhosis (presence vs. absence).
Treated subjects (N=278) had a median age of 54 years (range: 21 to 75); 54% of the
subjects were male; 91% were White, 5% were Black; 11% were Hispanic or Latino;
mean body mass index was 28 kg/m2 (range: 18 to 53 kg/m2); 70% had baseline HCV
RNA levels greater than 6 log10 IU per mL; 16% had cirrhosis; 49% had HCV genotype
3. The proportions of subjects who were interferon intolerant, ineligible, or unwilling
were 9%, 44%, and 47%, respectively. Most subjects had no prior HCV treatment
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(81%). Table 16 presents the SVR12 for the treatment groups of SOVALDI + ribavirin
and placebo in subjects with genotype 2 HCV. SVR12 for genotype 3 subjects treated
with SOVALDI + ribavirin for 12 weeks was suboptimal; therefore these results are not
presented in Table 16.
Table 16
Study POSITRON: SVR12 in Interferon Intolerant, Ineligible or
Unwilling Subjects with Genotype 2 HCV
SOVALDI + RBV 12 weeks
Placebo 12 weeks
N=109
N= 34
SVR12
93% (101/109)
0/34
Outcome for subjects without SVR12
On-treatment virologic failure
0/109
97% (33/34)
Relapsea
5% (5/107)
0/0
Otherb
3% (3/109)
3% (1/34)
a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
Table 17 presents the subgroup analysis for cirrhosis and interferon classification in
subjects with genotype 2 HCV.
Table 17
SVR12 Rates for Selected Subgroups in POSITRON in Subjects with
Genotype 2 HCV
SOVALDI + RBV 12 weeks
N=109
Cirrhosis
No
92% (85/92)
Yes
94% (16/17)
Interferon Classification
Ineligible
88% (36/41)
Intolerant
100% (9/9)
Unwilling
95% (56/59)
Previously Treated Adults ─ FUSION (Study 0108)
FUSION was a randomized, double-blinded trial that evaluated 12 or 16 weeks of
treatment with SOVALDI and ribavirin in subjects who did not achieve SVR with prior
interferon-based treatment (relapsers and nonresponders). Subjects were randomized
in a 1:1 ratio and stratified by cirrhosis (presence vs. absence) and HCV genotype (2 vs.
3).
Treated subjects (N=201) had a median age of 56 years (range: 24 to 70); 70% of the
subjects were male; 87% were White; 3% were Black; 9% were Hispanic or Latino;
mean body mass index was 29 kg/m2 (range: 19 to 44 kg/m2); 73% had baseline HCV
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RNA levels greater than 6 log10 IU per mL; 34% had cirrhosis; 63% had HCV genotype
3; 75% were prior relapsers. Table 18 presents the SVR12 for the treatment groups of
SOVALDI + ribavirin for 12 weeks in subjects with genotype 2 HCV. Treatment of
16 weeks in subjects with genotype 2 HCV was not shown to increase the SVR12
observed with 12 weeks of treatment. SVR12 for genotype 3 subjects treated with
SOVALDI + ribavirin for 12 or 16 weeks was suboptimal; therefore these results are not
presented in Table 18.
Table 18
Study FUSION: SVR12 in Previous Interferon Relapsers and
Nonresponders with Genotype 2 HCV
SOVALDI + RBV
12 weeks
N=39a
SVR12
82% (32/39)
Outcome for subjects without SVR12
On-treatment virologic failure
0/39
Relapseb
18% (7/39)
Otherc
0/39
a. Including three subjects with recombinant genotype 2/1 HCV infection.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).
Table 19 presents the subgroup analysis for cirrhosis and response to prior HCV
treatment in subjects with genotype 2 HCV.
Table 19
SVR12 Rates for Selected Subgroups in Study FUSION in Subjects
with Genotype 2 HCV
SOVALDI + RBV 12 weeks
N=39
Cirrhosis
No
90% (26/29)
Yes
60% (6/10)
Response to prior HCV treatment
Relapser/ breakthrough
86% (25/29)
Nonresponder
70% (7/10)
Treatment-Naïve and Previously Treated Adults ─ VALENCE (Study 0133)
The VALENCE trial evaluated SOVALDI in combination with weight-based ribavirin for
the treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or subjects
who did not achieve SVR with prior interferon-based treatment, including subjects with
compensated cirrhosis. The original trial design was a 4 to 1 randomization to SOVALDI
+ ribavirin for 12 weeks or placebo. Based on emerging data, this trial was unblinded
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and all genotype 2 HCV-infected subjects continued the original planned treatment and
received SOVALDI + ribavirin for 12 weeks, and duration of treatment with SOVALDI +
ribavirin in genotype 3 HCV-infected subjects was extended to 24 weeks. Eleven
genotype 3 subjects had already completed SOVALDI + ribavirin for 12 weeks at the
time of the amendment.
Treated subjects (N=419) had a median age of 51 years (range: 19 to 74); 60% of the
subjects were male; mean body mass index was 26 kg/m2 (range: 17 to 44 kg/m2); the
mean baseline HCV RNA level was 6.4 log10 IU per mL; 78% had HCV genotype 3; 58%
of the subjects were treatment-experienced and 65% of those subjects experienced
relapse/breakthrough to prior HCV treatment.
Table 20 presents the SVR12 for the treatment groups of SOVALDI + ribavirin for
12 weeks and 24 weeks.
Table 20
Study VALENCEa: SVR12 in Subjects with Genotype 2 or 3 HCV Who
were Treatment-Naïve or Who Did Not Achieve SVR12 with Prior
Interferon-Based Treatment
Genotype 2 SOVALDI
+ RBV 12 weeks
Genotype 3 SOVALDI
+ RBV 24 weeks
N=73
N=250
Overall SVR
93% (68/73)
84% (210/250)
Outcome for subjects without SVR
On-treatment virologic failure
0% (0/73)
<1% (1/250)
Relapseb
7% (5/73)
14% (34/249)
Treatment-naïve
3% (1/32)
5% (5/105)
Treatment-experienced
10% (4/41)
20% (29/144)
Otherc
0% (0/73)
2% (5/250)
a. Placebo subjects (N=85) were not included as none achieved SVR12.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to
follow-up).
Table 21 presents the subgroup analysis by genotype for cirrhosis and prior HCV
treatment experience.
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Table 21
SVR12 Rates for Selected Subgroups by Genotype in Study
VALENCE in Subjects with Genotype 2 or 3 HCV
Genotype 2 SOVALDI +
RBV 12 weeks
Genotype 3 SOVALDI
+ RBV 24 weeks
N=73
N=250
Treatment-naïve
97% (31/32)
93% (98/105)
Non-cirrhotic
97% (29/30)
93% (86/92)
Cirrhotic
100% (2/2)
92% (12/13)
Treatment-experienced
90% (37/41)
77% (112/145)
Non-cirrhotic
91% (30/33)
85% (85/100)
Cirrhotic
88% (7/8)
60% (27/45)
14.4 Clinical Trials in Adult Subjects Coinfected with HCV and HIV-1 ─ Photon-1
(Study 0123)
SOVALDI was studied in an open-label clinical trial (Study PHOTON-1) evaluating the
safety and efficacy of 12 or 24 weeks of treatment with SOVALDI and ribavirin in adult
subjects with genotype 1, 2 or 3 chronic hepatitis C coinfected with HIV-1. Genotype 2
and 3 subjects were either HCV treatment-naïve or experienced, whereas genotype 1
subjects were all treatment-naïve. Subjects received 400 mg SOVALDI and weight-
based ribavirin (1000 mg for subjects weighing less than 75 kg or 1200 mg for subjects
weighing at least 75 kg) daily for 12 or 24 weeks based on genotype and prior treatment
history. Subjects were either not on antiretroviral therapy with a CD4+ cell count greater
than 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count
greater than 200 cells/mm3. Efficacy data 12 weeks post treatment are available for
210 subjects (see Table 22).
Table 22
Study PHOTON-1a: SVR12 in Treatment-Naïve or Treatment-
Experienced Subjects with Genotype 1, 2, or 3 HCV
HCV genotype 1
HCV genotype 2
HCV genotype 3
SOVALDI + RBV
24 weeks
TN (N=114)
SOVALDI + RBV
12 weeks
TN (N=26)
SOVALDI + RBV
24 weeks
TE (N=13)
Overall
76% (87/114)
88% (23/26)
92% (12/13)
Outcome for subjects without SVR12
On-treatment virologic
failure
1% (1/114)
4% (1/26)
0/13
Relapseb
22% (25/113)
0/25
8% (1/13)
Otherc
1% (1/114)
8% (2/26)
0/13
TN = Treatment-naïve; TE = Treatment-experienced
a. Subjects with genotype 2 HCV treated with SOVALDI + RBV for 24 weeks (N=15) and subjects with genotype 3
HCV treated with SOVALDI + RBV for 12 weeks (N=42) are not included in the table.
b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment
assessment.
c. Other includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (e.g., lost to
follow-up).
Reference ID: 5501595
33
In subjects with HCV genotype 1 infection, the SVR12 rate was 82% (74/90) in subjects
with genotype 1a infection and 54% (13/24) in subjects with genotype 1b infection, with
relapse accounting for the majority of treatment failures. SVR12 rates in subjects with
HCV genotype 1 infection were 80% (24/30) in subjects with baseline IL28B C/C allele
and 75% (62/83) in subjects with baseline IL28B non-C/C alleles.
In the 223 HCV subjects with HIV-1 coinfection, the percentage of CD4+ cells did not
change during treatment. Median CD4+ cell count decreases of 85 cells/mm3 and
84 cells/mm3 were observed at the end of treatment with SOVALDI + ribavirin for 12 or
24 weeks, respectively. HIV-1 rebound during SOVALDI + ribavirin treatment occurred
in 2 subjects (0.9%) on antiretroviral therapy.
14.5 Clinical Trial in Pediatrics (Study 1112)
The efficacy of SOVALDI in HCV-infected pediatric subjects 3 years of age and older
was evaluated in 106 subjects with HCV genotype 2 (N = 31) or genotype 3 (N = 75) in
a Phase 2, open label clinical trial. Subjects with HCV genotype 2 or 3 infection in the
trial were treated with SOVALDI and weight-based ribavirin for 12 or 24 weeks,
respectively [see Dosage and Administration (2.3)].
Subjects 12 Years to <18 Years of Age: SOVALDI was evaluated in 52 subjects12
years to <18 years of age with HCV genotype 2 (N = 13) or genotype 3 (N = 39)
infection. The median age was 15 years (range: 12 to 17); 40% of the subjects were
female; 90% were White, 4% were Black, and 2% were Asian; 4% were
Hispanic/Latino; mean body mass index was 22 kg/m2 (range: 16 to 32 kg/m2);mean
weight was 60 kg (range: 30 to 101 kg); 17% were treatment experienced; 65% had
baseline HCV RNA levels greater than or equal to 800,000 IU/mL; and no subjects had
known cirrhosis. The majority of subjects (71%) had been infected through vertical
transmission.
The SVR12 rate was 100% [13/13] in genotype 2 subjects and 97% [38/39] in genotype
3 subjects. No subject experienced on-treatment virologic failure or relapse.
Subjects 6 Years to <12 Years of Age: SOVALDI was evaluated in 41 subjects 6 years
to <12 years of age with HCV genotype 2 (N = 13) or genotype 3 (N = 28) infection. The
median age was 9 years (range: 6 to 11); 73% of the subjects were female; 71% were
White and 20% were Asian; 15% were Hispanic/Latino; mean body mass index was 19
kg/m2 (range: 13 to 32 kg/m2); mean weight was 34 kg (range 15 to 80 kg); 98% were
treatment naive; 46% had baseline HCV RNA levels greater than or equal to 800,000
IU/mL; and no subjects had known cirrhosis. The majority of subjects (98%) had been
infected through vertical transmission.
The SVR12 rate was 100% (13/13) in genotype 2 and 100% (28/28) in genotype 3
subjects.). No subjects experienced on-treatment virologic failure or relapse.
Subjects 3 Years to <6 Years of Age: SOVALDI was evaluated in 13 subjects 3 years to
<6 years of age with HCV genotype 2 (N = 5) or genotype 3 (N = 8) infection. The
median age was 4 years (range: 3 to 5); 77% of the subjects were female; 69% were
Reference ID: 5501595
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White, 8% were Black, and 8% were Asian; 8% were Hispanic/Latino; mean body mass
index was 15 kg/m2 (range: 13 to 17 kg/m2); mean weight was 17 kg (range 13 to 19
kg); 100% were treatment naive; 23% had baseline HCV RNA levels greater than or
equal to 800,000 IU/mL; and no subjects had known cirrhosis. The majority of subjects
(85%) had been infected through vertical transmission.
The SVR12 rate was 80% (4/5) in genotype 2 subjects and 100% (8/8) in genotype 3
subjects. No subjects experienced on-treatment virologic failure or relapse. One subject
prematurely discontinued study treatment due to an adverse event.
16
HOW SUPPLIED/STORAGE AND HANDLING
Tablets
SOVALDI tablets, 400 mg, are yellow, capsule-shaped, film-coated tablets containing
400 mg sofosbuvir debossed with “GSI” on one side and “7977” on the other side. Each
bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant and polyester coil
with a child-resistant closure.
SOVALDI tablets, 200 mg, are yellow, oval-shaped, film-coated tablets containing 200
mg sofosbuvir debossed with “GSI” on one side and “200” on the other side. Each bottle
contains 28 tablets (NDC 61958-1503-1) and a polyester coil with a child-resistant
closure.
Store below 30 °C (86 °F).
•
Dispense only in original container
•
Do not use if seal over bottle opening is broken or missing
Oral Pellets
SOVALDI pellets, 150 mg, are white to off-white pellets supplied as unit-dose packets in
cartons. Each carton contains 28 packets (NDC 61958-1504-1)
SOVALDI pellets, 200 mg, are white to off-white pellets supplied as unit-dose packets in
cartons. Each carton contains 28 packets (NDC 61958-1505-1)
• Store below 30 °C (86 °F).
• Do not use if carton tamper-evident or packet seal is broken or damaged.
Reference ID: 5501595
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17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Inform patients that HBV reactivation can occur in patients coinfected with HBV during
or after treatment of HCV infection. Advise patients to tell their healthcare provider if
they have a history of HBV infection [see Warnings and Precautions (5.1)].
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Advise patients to seek medical evaluation immediately for symptoms of bradycardia
such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness,
excessive tiredness, shortness of breath, chest pain, confusion or memory problems
[see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Drug Interactions
(7.1)].
Pregnancy
Advise patients to avoid pregnancy during combination treatment with SOVALDI and
ribavirin or SOVALDI and peginterferon and ribavirin. Inform patients to notify their
health care provider immediately in the event of a pregnancy [see Use in Specific
Populations (8.1)].
Drug Interactions
Advise patients that SOVALDI may interact with some drugs; therefore, patients should
be advised to report the use of any prescription, non-prescription medication or herbal
products to their healthcare provider [see Warnings and Precautions (5.3) and Drug
Interactions (7.1)].
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C infection on transmission is not
known, and that appropriate precautions to prevent transmission of the hepatitis C virus
during treatment or in the event of treatment failure should be taken.
Administration
Advise patients to take SOVALDI every day at the regularly scheduled time with or
without food. Inform patients that it is important not to miss or skip doses and to take
SOVALDI for the duration that is recommended by the physician.
For SOVALDI oral pellets, advise patients or caregivers to read and follow the
Instructions for Use for preparing the correct dose.
Important Information on Coadministration with Ribavirin or Peginterferon and Ribavirin
Advise patients that the recommended regimen for patients with genotype 1 or 4 HCV
infection is SOVALDI administered in combination with peginterferon alfa and ribavirin
Reference ID: 5501595
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and the recommended regimen for patients with genotype 2 or 3 HCV infection is
SOVALDI administered in combination with ribavirin. If peginterferon and/or ribavirin are
permanently discontinued, SOVALDI should also be discontinued.
Manufactured and distributed by:
Gilead Sciences, Inc.
Foster City, CA 94404
SOVALDI and HARVONI are trademarks of Gilead Sciences, Inc., or its related
companies. All other trademarks referenced herein are the property of their respective
owners.
©2024 Gilead Sciences, Inc. All rights reserved.
204671-GS-0011
Reference ID: 5501595
37
Patient Information
SOVALDI® (soh-VAHL-dee)
SOVALDI® (soh-VAHL-dee)
(sofosbuvir)
(sofosbuvir)
tablets
oral pellets
Important: SOVALDI is used in combination with other antiviral medicines. When taking
SOVALDI with ribavirin or in combination with peginterferon alfa and ribavirin you should also
read those Medication Guides. The information in this Patient Information Leaflet talks about
SOVALDI when it is used with ribavirin and in combination with peginterferon alfa and ribavirin.
What is the most important information I should know about SOVALDI?
SOVALDI can cause serious side effects, including:
•
Hepatitis B virus reactivation: Before starting treatment with SOVALDI, your healthcare provider
will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus
infection, the hepatitis B virus could become active again during or after treatment of hepatitis C
virus with SOVALDI. Hepatitis B virus becoming active again (called reactivation) may cause
serious liver problems including liver failure and death. Your healthcare provider will monitor you if
you are at risk for hepatitis B virus reactivation during treatment and after you stop taking
SOVALDI.
For more information about side effects, see the section “What are the possible side effects of
SOVALDI?”
What is SOVALDI?
SOVALDI is a prescription medicine used with other antiviral medicines to treat adults with chronic
(lasting a long time) hepatitis C virus (HCV):
•
genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with
peginterferon alfa and ribavirin
•
genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis in combination with
ribavirin
SOVALDI is used to treat children 3 years of age and older with chronic HCV genotype 2 or 3 infection
without cirrhosis or with compensated cirrhosis in combination with ribavirin.
It is not known if SOVALDI is safe and effective in children under 3 years of age with HCV genotype 2
or 3 infection, or with HCV genotype 1 or 4 infection.
It is not known if SOVALDI is safe and effective in people who have had a liver transplant.
Before taking SOVALDI, tell your healthcare provider about all of your medical conditions,
including if you:
•
have ever had hepatitis B virus infection
•
have liver problems other than hepatitis C infection
•
have had a liver transplant
•
have severe kidney problems or you are on dialysis
•
have HIV infection
•
are pregnant or plan to become pregnant. It is not known if SOVALDI will harm your unborn
baby.
•
Males and females who take SOVALDI in combination with ribavirin should also
read the ribavirin Medication Guide for important pregnancy, contraception, and
infertility information.
•
are breastfeeding or plan to breastfeed. It is not known if SOVALDI passes into your breast
milk. Talk to your healthcare provider about the best way to feed your baby during treatment
with SOVALDI.
Tell your healthcare provider about all the medicines you take, including prescription and over-the
counter medicines, vitamins, and herbal supplements. SOVALDI and other medicines may affect each
Reference ID: 5501595
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other. This can cause you to have too much or not enough SOVALDI or other medicines in your body.
This may affect the way SOVALDI or your other medicines work, or may cause side effects.
Keep a list of your medicines to show your healthcare provider and pharmacist.
•
You can ask your healthcare provider or pharmacist for a list of medicines that interact with
SOVALDI.
•
Do not start taking a new medicine without telling your healthcare provider. Your
healthcare provider can tell you if it is safe to take SOVALDI with other medicines.
How should I take SOVALDI?
•
Take SOVALDI exactly as your healthcare provider tells you to take it. Do not change your
dose unless your healthcare provider tells you to.
•
Do not stop taking SOVALDI without first talking with your healthcare provider.
•
Take SOVALDI tablets or oral pellets by mouth, with or without food.
•
For adults the usual dose of SOVALDI is one 400 mg tablet each day.
•
For children 3 years of age and older, your healthcare provider will prescribe the right dose of
SOVALDI tablets or oral pellets based on your child’s body weight.
o
Tell your healthcare provider if your child has problems with swallowing tablets.
o
If your healthcare provider prescribes SOVALDI pellets for your child, see “How
should I give SOVALDI oral pellets to my child.”
•
Do not miss a dose of SOVALDI. Missing a dose lowers the amount of medicine in your blood.
Refill your SOVALDI prescription before you run out of medicine.
•
If you take too much SOVALDI, call your healthcare provider or go to the nearest hospital
emergency room right away.
How should I give SOVALDI oral pellets to my child?
See the detailed Instructions for Use for information about how to give or take a dose of
SOVALDI oral pellets.
•
Administer SOVALDI oral pellets exactly as instructed by your healthcare provider.
•
Do not open the packet until ready to use.
•
Hold the SOVALDI pellets packet with the cut line on top.
•
Shake the SOVALDI pellets packet gently to settle the pellets.
•
Tear or cut the SOVALDI packet along the cut line.
•
SOVALDI pellets can be taken right in the mouth without chewing, or with food.
•
If SOVALDI pellets are taken with food, sprinkle the pellets on one or more spoonfuls of non-
acidic soft food at or below room temperature. Examples of non-acidic foods include pudding,
chocolate syrup, mashed potato, and ice cream. Take SOVALDI pellets within 30 minutes of
gently mixing with food and swallow the entire contents without chewing to avoid a bitter taste.
•
Do not store any leftover SOVALDI mixture (oral pellets mixed with food) for use at a later time.
Throw away any unused portion.
What are the possible side effects of SOVALDI?
SOVALDI can cause serious side effects, including:
•
Hepatitis B virus reactivation. See “What is the most important information I should know
about SOVALDI?”
•
Slow heart rate (bradycardia). SOVALDI treatment may result in slowing of the heart rate
along with other symptoms when taken with amiodarone (Cordarone®, Nexterone®,
Pacerone®), a medicine used to treat certain heart problems. In some cases bradycardia has
led to death or the need for a heart pacemaker when amiodarone is taken with SOVALDI. Get
medical help right away if you take amiodarone with SOVALDI and get any of the following
symptoms:
•
fainting or near-fainting
•
weakness
•
chest pain
•
dizziness or
•
extreme tiredness
•
confusion
lightheadedness
•
shortness of breath
•
memory problems
•
not feeling well
The most common side effects of SOVALDI when used in combination with ribavirin include:
•
tiredness
• headache
Reference ID: 5501595
2
The most common side effects of SOVALDI when used in combination with peginterferon alfa and
ribavirin include:
•
tiredness
•
nausea
• low red blood cell count
•
headache
•
difficulty sleeping
These are not all the possible side effects of SOVALDI. For more information, ask your healthcare
provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store SOVALDI?
•
Store SOVALDI tablets or pellets below 86°F (30°C).
•
Keep SOVALDI tablets in the original container.
•
Do not use SOVALDI tablets if the seal over the bottle opening is broken or missing.
•
Do not use SOVALDI pellets if the carton tamper-evident seal, or the pellets packet seal, is
broken or damaged.
Keep SOVALDI and all medicines out of the reach of children.
General information about the safe and effective use of SOVALDI.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
leaflet. Do not use SOVALDI for a condition for which it was not prescribed. Do not give SOVALDI to
other people, even if they have the same symptoms you have. It may harm them. You can ask your
healthcare provider or pharmacist for information about SOVALDI that is written for health
professionals. For more information, call 1-800-445-3235 or go to www.SOVALDI.com.
What are the ingredients in SOVALDI?
Active ingredient: sofosbuvir
Inactive ingredients, Tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate,
mannitol, and microcrystalline cellulose. The tablet film-coat contains polyethylene glycol, polyvinyl
alcohol, talc, titanium dioxide, and yellow iron oxide.
Inactive ingredients, Oral Pellets: amino methacrylate copolymer, colloidal silicon dioxide,
croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, microcrystalline
cellulose, polyethylene glycol, silicon dioxide, sodium lauryl sulfate, sodium stearyl fumarate, stearic
acid, and talc.
Gilead Sciences, Inc., Foster City, CA 94404
For more information, call 1-800-445-3235 or go to www.SOVALDI.com.
SOVALDI is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks
referenced herein are the property of their respective owners.
©2024 Gilead Sciences, Inc. All rights reserved.
204671-GS-011
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 03/2020
Reference ID: 5501595
3
I
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~
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,.d
j
INSTRUCTIONS FOR USE
SOVALDI® (soh-VAHL-dee)
(sofosbuvir)
pellets, for oral use
Read the Patient Information that comes with SOVALDI oral pellets for important information about SOVALDI.
This Instructions for Use contains information on how to take SOVALDI oral pellets. Be sure you understand and follow
the instructions. If you have any questions, ask your healthcare provider or pharmacist.
Important Information You Need to Know Before Taking SOVALDI oral pellets
•
For oral use only (take by mouth with or without food).
•
Do not open the SOVALDI oral pellet packet(s) until ready to use.
•
SOVALDI oral pellets are white to off-white pellets supplied as single-use packets in cartons. Each carton
contains 28 packets.
•
Do not use SOVALDI oral pellets if the carton tamper-evident seal, or the pellets packet seal, is broken or
damaged.
Preparing a dose of SOVALDI oral pellets to be taken with food:
Before you prepare a dose of SOVALDI oral pellets to be taken with food, gather the following supplies:
•
Daily SOVALDI oral pellet packet(s), as prescribed by your healthcare provider
•
One or more spoonfuls of non-acidic soft food such as pudding, chocolate syrup, mashed potato, or ice cream
•
Bowl
•
Spoon
•
Scissors (optional)
Step 1: Add one or more spoonfuls of non-acidic soft food to the bowl first.
Step 2: Hold the SOVALDI oral pellets packet
Step 3: Shake the packet gently to settle the
with the cut line on top (see Figure A).
pellets to the bottom of the packet (see Figure B).
Figure A
Figure B
Reference ID: 5501595
Step 4: Cut the packet along the cut line with scissors (see Figure C), or fold the packet back at the tear line (see
Figure D) and tear open (see Figure E).
OR
Figure C
Figure D
Figure E
Step 5: Carefully pour the entire contents of the prescribed number of SOVALDI oral pellet packet(s) onto the food in the
bowl and gently mix with a spoon (see Figure F). Make sure that no SOVALDI oral pellets remain in the packet(s).
Figure F
Step 6: Take the SOVALDI oral pellets and food mixture within 30 minutes without chewing to avoid a bitter taste. Ensure
all of the SOVALDI oral pellets are taken.
Preparing a dose of SOVALDI oral pellets to be taken without food:
Before you prepare a dose of SOVALDI oral pellets to be taken without food, gather the following supplies:
•
Daily SOVALDI oral pellet packet(s), as prescribed by your healthcare provider
•
Scissors (optional)
•
Water (optional)
Reference ID: 5501595
i
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~
I
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Step 1: Hold the SOVALDI oral pellets packet
Step 2: Shake the packet gently to settle the
with the cut line on top (see Figure G).
pellets to the bottom of the packet (see Figure H).
Figure G
Figure H
Step 3: Cut the packet along the cut line with scissors (see Figure I), or fold the packet back at the tear line (see
Figure J) and tear open (see Figure K).
OR
Figure I
Figure J
Figure K
Reference ID: 5501595
Step 4: Pour the entire contents of the SOVALDI oral pellets packet directly in the mouth and swallow without chewing to
avoid a bitter taste (see Figure L). Water may be taken after swallowing the pellets, if needed. Make sure that no SOVALDI
oral pellets remain in the packet. If your healthcare provider prescribed more than one SOVALDI oral pellets packet, repeat
Steps 1 through 4.
Figure L
Storing SOVALDI oral pellets
•
Store SOVALDI pellets below 86°F (30°C).
•
Keep SOVALDI oral pellets and all medicines out of the reach of children.
Disposing of SOVALDI oral pellets
•
Throw away any unused portion. Do not store and reuse any leftover SOVALDI mixture (pellets mixed with food).
For more information, call 1-800-445-3235 or go to www.SOVALDI.com.
Manufactured for and distributed by: Gilead Sciences, Inc., Foster City, CA 94404
SOVALDI is a trademark of Gilead Sciences, Inc., or its related companies.
© 2024 Gilead Sciences, Inc. All rights reserved.
204671-GS-011
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: March 2020
Reference ID: 5501595
| custom-source | 2025-02-12T15:48:14.108206 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212480s004,204671s019lbl.pdf', 'application_number': 204671, 'submission_type': 'SUPPL ', 'submission_number': 19} |
80,754 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XROMI
safely and effectively. See full prescribing information for XROMI.
XROMI (hydroxyurea) oral solution
Initial U.S. Approval: 1967
WARNING: MYELOSUPPRESSION and MALIGNANCIES
See full prescribing information for complete boxed warning.
• Myelosuppression: XROMI may cause severe myelosuppression. Do
not give if bone marrow function is markedly depressed. Monitor
blood counts at baseline and throughout treatment. Interrupt
treatment and reduce dose as necessary (5.1).
• Malignancies: Hydroxyurea is carcinogenic. Advise sun protection
and monitor patients for malignancies (5.3).
----------------------------INDICATIONSANDUSAGE--------------------------
• XROMI is an antimetabolite indicated to reduce the frequency of painful
crises and reduce the need for blood transfusions in pediatric patients 6
months of age and older with sickle cell anemia with recurrent moderate
to severe painful crises. (1)
----------------------DOSAGEANDADMINISTRATION----------------------
• Initial dose: 15 mg/kg orally once daily. Monitor the patient’s blood count
every two weeks. (2.1)
• The dose may be increased by 5 mg/kg/day every 8 to12 weeks until a
maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in
an acceptable range. (2.1)
• The dose is not increased if blood counts are below the acceptable range
and toxic. Discontinue XROMI until hematologic recovery if blood counts
are considered toxic. Treatment may be resumed after reducing the dose
by 2.5 mg/kg/day to 5 mg/kg/day from the dose associated with
hematological toxicity. (2.1)
• Renal impairment: Reduce the dose of XROMI by 50% in patients
with creatinine clearance less than 60 mL/min. (2.2, 8.6, 12.3)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
• Oral Solution: 100 mg/mL in a 148 mL multiple-dose bottle. (3)
-------------------------------CONTRAINDICATIONS----------------------------
• In patients who have demonstrated a previous hypersensitivity to
hydroxyurea or any other component of its formulation. (4)
-----------------------WARNINGSANDPRECAUTIONS-----------------------
• Hemolytic anemia: Monitor blood counts throughout treatment. If
hemolysis persists, discontinue XROMI. (5.2)
• Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk
to a fetus and use of effective contraception. (5.4, 8.1, 8.3)
• Vasculitic toxicities: Institute treatment and discontinue XROMI if this
occurs. (5.5)
• Live Vaccinations: Avoid live vaccine use in a patient taking
XROMI. (5.6)
• Risks with concomitant use of antiretroviral drugs: Pancreatitis,
hepatotoxicity, and neuropathy have occurred. Monitor for signs and
symptoms in patients with HIV infection using antiretroviral drugs;
discontinue XROMI and implement treatment. (5.7)
------------------------------ADVERSE REACTIONS----------------------------------
Most common adverse reactions (incidence > 5%) are neutropenia,
thrombocytopenia, and papular rash. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Rare Disease
Therapeutics, Inc. at 844-472-7389 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
----------------------------------DRUG INTERACTIONS------------------------------
• Antiretroviral drug. (7.1)
• Laboratory Test Interference. (7.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: MYLEOSUPPRESSION AND MALIGNACIES
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Administration Instructions
2.3 Dosage Modifications in Renal Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Myelosuppression
5.2 Hemolytic Anemia
5.3 Malignancies
5.4 Embryo-Fetal Toxicity with Unapproved Use
in Adolescents and Adults
5.5 Vasculitic Toxicities
5.6 Live Vaccinations
5.7 Risks with Concomitant Use of Antiretroviral
Drugs
5.8 Macrocytosis
5.9 Pulmonary Toxicity
5.10Laboratory Test Interference
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post marketing Experience
7 DRUGINTERACTIONS
7.1 Increased Toxicity with Concomitant Use of
Antiretroviral Drugs
7.2 Laboratory Test Interference
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICALPHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICALTOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Handling and Disposal
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 5502171
FULL PRESCRIBING INFORMATION
WARNING: MYELOSUPPRESSION and MALIGNANCIES
•
•
Myelosuppression: XROMI may cause severe myelosuppression. Do not give if bone
marrow function is markedly depressed. Monitor blood counts at baseline and
throughout treatment. Interrupt treatment and reduce dose as necessary [see Warnings
and Precautions (5.1)].
Malignancies: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients
for malignancies [see Warnings and Precautions (5.3)].
1
INDICATIONS AND USAGE
XROMI is indicated to reduce the frequency of painful crises and reduce the need for blood transfusions in pediatric patients 6
months of age and older with sickle cell anemia with recurrent moderate to severe painful crises.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
The recommended XROMI dosage in pediatric patients aged 6 months and older is described in Table 1.
Table 1. Dosing Recommendation Based on Blood Count
Dosing Regimen
Dose
Dose modification
criteria
Monitoring parameters
Initial Recommended
dosing
15 mg/kg/day (rounded to nearest
10 mg) orally as a single dose
once daily based on the patient’s
actual body weight.
Monitor the patient’s complete blood
count (CBC) with differential and
reticulocyte count every 2 weeks while
adjusting dosage [see Warnings and
Precautions (5.1)].
Dosing Adjustment
Increase dose 5 mg/kg/day every
Increase dose only if
Target Blood Counts
Based on Blood Counts
8 to12 weeks.
blood counts are in
Absolute neutrophil count (ANC) 1 to 3
in the acceptable range
Maximal dose: 35 mg/kg/day.*
*Maximal dose is the highest
dose that does not produce toxic
blood counts over 24 consecutive
weeks.
an acceptable range.
Do not increase if
myelosuppression
occurs.
x 109/L and platelets at least 80 x 109/L
Dosing Adjustment
Based on Blood Counts
below acceptable range
Do not increase dose.
If blood counts are
considered toxic,
discontinue XROMI
until hematologic
recovery.
Blood Counts Toxic Range
•
ANC less than 1 x 109/L
•
Platelets less than 80 x109/L
•
Hemoglobin 20% decrease from
baseline or hemoglobin less than
4.5 g/dL
•
Reticulocytes less than 80, x109/L
if the hemoglobin concentration is
less than 9 g/dL.
Dosing after
If hematologic toxicity resolved
Once a stable dose is established,
Hematologic Recovery
within 1 week, restart at the same
XROMI dose.
If hematologic toxicity persisted
for more than 1 week or occurred
twice in a 3 month period, reduce
dose by 5 mg/kg/day.
monitor CBC with differential and
reticulocyte count every 4 weeks for 2
months and then as clinically indicated.
Reference ID: 5502171
Caregivers must be able to follow directions regarding drug administration and their monitoring and care.
If a dose of XROMI is missed at the scheduled time, the patient should take the missed dose as soon as possible once it is
noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as
prescribed.
The patient should not take two doses to make up for a missed dose.
Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of XROMI in clinical use. Obtain HbF levels every three
to four months. Monitor for an increase in HbF of at least two-fold over the baseline value.
XROMI causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic
administration of folic acid is recommended.
2.2
Administration Instructions
XROMI is for oral use. See Instructions for Use for details on preparation and administration of XROMI for oral solution.
Do not shake.
Two oral dosing syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 mL) are
provided for accurate measurement of the prescribed dose of the oral solution. It is recommended that the healthcare
professional advises the caregiver which oral dosing syringe to use to ensure that the correct volume is administered.
The smaller 3 mL oral dosing syringe, marked from 0.5 mL to 3 mL, is for measuring doses of less than or equal to 3 mL.
This oral dosing syringe should be recommended for doses less than or equal to 3 mL (each graduation of 0.1 mL contains 10
mg of hydroxyurea).
The larger 10 mL oral dosing syringe, marked 1 mL to 10 mL, is for measuring doses of more than 3 mL. This oral dosing
syringe should be recommended for doses greater than 3 mL (each graduation of 0.25 mL contains 25 mg of hydroxyurea).
XROMI may be taken with or after meals at any time of the day but caregivers should standardize the method of
administration and time of day.
XROMI is a hazardous drug. Follow applicable special handling and disposal procedures [see References (15)].
2.3
Dosage Modifications in Renal Impairment
Reduce the dose of XROMI by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal
disease (ESRD) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Creatinine clearance were
obtained using 24-hour urine collection.
Table 2. Creatinine Clearance
Creatinine Clearance (mL/ min)
Recommended XROMI Initial Dose
Greater than or equal to 60
15 mg/kg once daily
Less than 60 or ESRD*
7.5 mg/kg once daily
* On dialysis days, administer XROMI to patients with ESRD following hemodialysis
Monitor the hematologic parameters closely in these patients.
3
DOSAGE FORMS AND STRENGTHS
Oral solution: 100 mg/mL clear colorless to pale yellow liquid in a multiple-dose amber bottle.
4
CONTRAINDICATIONS
XROMI is contraindicated in patients:
•
who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its
formulation [see Adverse Reactions (6)].
5
WARNINGS AND PRECAUTIONS
5.1
Myelosuppression
Reference ID: 5502171
Hydroxyurea causes severe myelosuppression. Do not initiate treatment with XROMI in patients if bone marrow function is
markedly depressed. Bone marrow suppression may occur, and leukopenia is generally its first and most common
manifestation. Thrombocytopenia and anemia occur less often and are seldom seen without a preceding leukopenia.
Some patients, treated at the recommended initial dose of 15 mg/kg/day, have experienced severe or life-threatening
myelosuppression.
Evaluate hematologic status (CBC, reticulocyte count) prior to and every 2 weeks during dose-escalation period of XROMI
treatment. Once a stable dose of XROMI is achieved, monitor every 4 weeks. Provide supportive care and modify dose or
discontinue XROMI as needed. Recovery from myelosuppression is usually rapid when therapy is interrupted [see Dosage
and Administration (2.1)].
5.2
Hemolytic Anemia
Cases of hemolytic anemia in patients treated with hydroxyurea for myeloproliferative diseases have been reported [see Adverse
Reactions (6.1)]. Patients who develop acute jaundice or hematuria in the presence of persistent or worsening of anemia should
have laboratory tests evaluated for hemolysis (e.g., measurement of serum lactate dehydrogenase, haptoglobin, reticulocyte,
unconjugated bilirubin levels, urinalysis, and direct and indirect antiglobulin [Coombs] tests). In the setting of confirmed
diagnosis of hemolytic anemia and in the absence of other causes, discontinue XROMI.
5.3
Malignancies
Hydroxyurea is a human carcinogen. In patients receiving long-term hydroxyurea for myeloproliferative disorders (a
condition for which XROMI is not approved), secondary leukemia has been reported.
Secondary leukemia has also been reported in patients treated with long-term hydroxyurea for sickle cell anemia. Leukemia
has also been reported in patients with sickle cell anemia and no prior history of treatment with hydroxyurea.
All patients using XROMI should be followed up on a long-term basis with regular blood counts to detect development of
leukemia.
Skin cancer has also been reported in patients receiving long-term hydroxyurea. Advise protection from sun exposure and
monitor for the development of secondary malignancies.
5.4
Embryo-Fetal Toxicity with Unapproved Use in Adolescents and Adults
Based on the mechanism of action and findings in animals, XROMI can cause fetal harm when administered to a pregnant
woman. Hydroxyurea was embryotoxic and teratogenic in rats and rabbits at doses 0.8 times and 0.3 times, respectively, the
maximum recommended human daily dose on a mg/m2 basis.
5.5
Vasculitic Toxicities
Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with
myeloproliferative disorders during therapy with hydroxyurea. These vasculitic toxicities were reported most often in patients
with a history of, or currently receiving, interferon therapy. If cutaneous vasculitic ulcers occur, institute treatment and
discontinue XROMI.
5.6
Live Vaccinations
Avoid use of live vaccines in patients taking XROMI. Concomitant use of XROMI with a live virus vaccine may potentiate the
replication of the virus and/or may increase the adverse reaction of the vaccine because normal defense mechanisms may be
suppressed by XROMI. Vaccination with live vaccines in a patient receiving XROMI may result in severe infection [see Drug
Interactions (7.2)]. Patient’s antibody response to vaccines may be decreased. Consider consultation with a specialist.
5.7
Risks with Concomitant Use of Antiretroviral Drugs
Pancreatitis, hepatotoxicity, and peripheral neuropathy have occurred when hydroxyurea was administered concomitantly with
antiretroviral drugs, including didanosine and stavudine [see Drug Interactions (7.1)].
5.8
Macrocytosis
XROMI may cause macrocytosis, which is self-limiting, and is often seen early in the course of treatment. The morphologic
change resembles pernicious anemia, but is not related to vitamin B12 or folic acid deficiency. This may mask the diagnosis of
pernicious anemia. Prophylactic administration of folic acid is recommended.
Reference ID: 5502171
5.9
Pulmonary Toxicity
Interstitial lung disease including pulmonary fibrosis, lung infiltration, pneumonitis, and alveolitis/allergic alveolitis (including
fatal cases) have been reported in patients treated for myeloproliferative neoplasm. Safety and effectiveness have not been
established for the use of XROMI in the treatment of myeloproliferative neoplasms and the use is not approved by the FDA.
Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate and treat promptly.
Discontinue XROMI and manage with corticosteroids [see Adverse Reactions (6.1)].
5.10
Laboratory Test Interference
Interference with uric acid, urea, or lactic acid assays is possible, rendering falsely elevated results of these in patients treated
with hydroxyurea [see Drug Interactions (7.2)].
Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may
lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.
If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose
monitoring methods [see Drug Interactions (7.2)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described in detail in other labeling sections:
•
Myelosuppression [see Warnings and Precautions (5.1)]
•
Hemolytic anemia [see Warnings and Precautions (5.2)]
•
Malignancies [see Warnings and Precautions (5.3)]
•
Vasculitic toxicities [see Warnings and Precautions (5.5)]
•
Live vaccinations [see Warnings and Precautions (5.6)]
•
Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.7)]
•
Macrocytosis [see Warnings and Precautions (5.8)]
•
Pulmonary toxicity [see Warnings and Precautions (5.9)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of
a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in
practice.
The safety of XROMI was evaluated in 32 pediatric patients aged 10months -16 years with sickle cell anemia in a single-arm,
open-label, prospective, multi-center, pharmacokinetic, safety and efficacy study (HUPK study). Only adverse reactions
associated with the use of XROMI in pediatric patients aged 10 months to less than 2 years are presented.
The most frequently reported adverse reactions in HUPK study (>33%) were neutropenia and thrombocytopenia [see Table
3].
Table 3. Adverse Reactions Reported in Pediatric Patients Aged 10 Months and Older Enrolled in HUPK
10 Months–
<2 Years
2 – <6 Years
6 –<18 Years
Overall
Adverse Reactions
(n=6)
%
(n=16)
%
(n=10)
%
(n=32)
%
Neutropenia
3 (50)
1 (6)
0
4 (13)
Thrombocytopenia
2 (33)
1 (6)
0
3 (9)
Diarrhea
1 (17)
0
0
1 (3)
GGT Increased
0
0
1 (10)
1 (3)
Absolute Reticulocyte
Count Decreased
1 (17)
0
0
1 (3)
Alopecia
0
1 (6)
0
1 (3)
Nail Discolouration
0
0
1 (10)
1 (3)
Reference ID: 5502171
Rash
0
0
1 (10)
1 (3)
Rash Papular
0
1 (6)
1 (10)
2 (6)
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of hydroxyurea. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
•
Reproductive System and Breast disorders: azoospermia, and oligospermia
•
Gastrointestinal disorders: stomatitis, nausea, vomiting, diarrhea, and constipation
•
Metabolism and Nutrition disorders: anorexia
•
Skin and subcutaneous tissue disorders: maculopapular rash, skin ulceration, cutaneous lupus erythematosus,
dermatomyositis-like skin changes, peripheral and facial erythema, hyperpigmentation, nail hyperpigmentation,
atrophy of skin and nails, scaling, violet papules, and alopecia
•
Renal and urinary disorders: dysuria, elevations in serum uric acid, blood urea nitrogen (BUN), and creatinine levels
•
Nervous system disorders: headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions
•
General disorders: fever, chills, malaise, edema, and asthenia
•
Hepatobiliary disorders: elevation of hepatic enzymes, cholestasis, and hepatitis
•
Respiratory disorders: diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis, interstitial lung disease,
pneumonitis, alveolitis, allergic alveolitis and cough
•
Immune disorders: systemic lupus erythematosus
•
Hypersensitivity: Drug-induced fever (pyrexia) (>39°C, >102°F) requiring hospitalization has been reported
concurrently with gastrointestinal, pulmonary, musculoskeletal, hepatobiliary, dermatological or cardiovascular
manifestations. Onset typically occurred within 6 weeks of initiation and resolved upon discontinuation of
hydroxyurea. Upon re-administration fever reoccurred typically within 24 hours.
•
Blood and lymphatic system disorders: hemolytic anemia
7
DRUG INTERACTIONS
7.1
Increased Toxicity with Concomitant Use of Antiretroviral Drugs
Pancreatitis
In patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine, fatal and nonfatal
cases of pancreatitis have occurred. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with
HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, close
monitoring for signs and symptoms of pancreatitis is recommended. Permanently discontinue therapy with hydroxyurea in
patients who develop signs and symptoms of pancreatitis.
Hepatotoxicity
Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with
HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in
patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination.
Peripheral Neuropathy
Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea
in combination with antiretroviral drugs, including didanosine, with or without stavudine.
7.2
Laboratory Test Interference
Interference with Uric Acid, Urea, or Lactic Acid Assays
Studies have shown that there is an analytical interference of hydroxyurea with the enzymes (urease, uricase, and lactate
dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients
treated with hydroxyurea.
Interference with Continuous Glucose Monitoring Systems
Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may
lead to hypoglycemia if sensor glucose results are relied upon to dose insulin.
Reference ID: 5502171
If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose
monitoring methods.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
XROMI can cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical
Pharmacology (12.1)]. There are no data with XROMI use in pregnant women to inform a drug-associated risk. In animal
reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic
and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a
mg/m2 basis (see Data). Advise women of the potential risk to a fetus and to avoid becoming pregnant while being treated
with XROMI.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2%–4% and 15%–20%, respectively.
Data
Animal Data
Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters,
cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Hydroxyurea is
embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite
sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a
mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis)
in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays.
Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily
dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability.
8.2
Lactation
Risk Summary
It is not known whether XROMI is excreted in human milk, the effects of XROMI on the breastfed child, or the effects of
XROMI on milk production. Because of the potential for serious adverse reactions in a breastfed child from XROMI,
including carcinogenicity, advise patients not to breastfeed during treatment with XROMI.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating XROMI therapy.
Contraception
Females
XROMI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise
females of reproductive potential to use effective contraception during and after treatment with XROMI for at least 6 months
after therapy. Advise females to immediately report pregnancy.
Males
XROMI may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual
partners of reproductive potential should use effective contraception during and after treatment with XROMI for at least 1
year after therapy [see Nonclinical Toxicology (13.1)].
Infertility
Males
Based on findings in animals and humans, male fertility may be compromised by treatment with XROMI. Azoospermia or
oligospermia, sometimes reversible, has been observed in men. Inform male patients about the possibility of sperm
conservation before the start of therapy [see Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
Reference ID: 5502171
The safety and effectiveness of XROMI have been established in pediatric patients aged 6 months and older with sickle cell
anemia with recurrent moderate to severe painful crises. Use of XROMI in these age groups is supported by evidence from a
pharmacokinetic, efficacy and safety study, in which 32 pediatric patients ages 6 months to <18 years were enrolled. Among
the 32 pediatric patients treated with XROMI, 6 were infants (6 months – 2 years), 16 children (2-6 years) and 10 were
adolescents (6-18 years) [see Clinical Studies (14)].
Continuous follow-up of the growth of treated children is recommended.
8.6
Renal Impairment
The exposure to XROMI is higher in patients with creatinine clearance of less than 60 mL/min. Reduce dosage and closely
monitor the hematologic parameters when XROMI is to be administered to these patients [see Dosage and Administration
(2.2) and Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring
of hematologic parameters is advised in these patients.
10
OVERDOSAGE
Acute mucocutaneous toxicity and neutropenia has been reported in patients receiving hydroxyurea at doses several times
above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet,
severe generalized hyperpigmentation of the skin and stomatitis have been observed.
11
DESCRIPTION
XROMI (hydroxyurea) is available for oral use as oral solution containing 100 mg/mL hydroxyurea. Inactive ingredients
include methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose, and xanthan gum.
Hydroxyurea is a white to off-white crystalline powder. It is hygroscopic and freely soluble in water, but practically insoluble
in alcohol. The empirical formula is CH4N2O2 and it has a molecular weight of 76.05. Its structural formula is:
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However,
various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a
ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.
The mechanisms by which XROMI produces its beneficial effects in patients with sickle cell anemia are uncertain. Known
pharmacologic effects of XROMI that may contribute to its beneficial effects include increasing HbF levels in red blood cells
(RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering
the adhesion of RBCs to endothelium.
12.2
Pharmacodynamics
In pediatric patients treated with hydroxyurea for up to 15 months, the ratio of fetal hemoglobin to total hemoglobin was 25%,
23.6% and 11.2% at the end of the study, representing a change from baseline increase of 9%, 148% and 167% in patients aged
6 months to <2 years, 2 to <6 years and 6 to <18 years, respectively.
12.3
Pharmacokinetics
Absorption
Reference ID: 5502171
Following oral administration of XROMI, hydroxyurea reaches peak plasma concentrations in 0 to 2 hours. Mean peak
plasma concentrations and AUCs increase more than proportionally with increase of dose.
Effect of Food
There are no data on the effect of food on the absorption of hydroxyurea.
Distribution
Hydroxyurea distributes throughout the body with a volume of distribution approximating total body water. Hydroxyurea
concentrates in leukocytes and erythrocytes.
Elimination
Metabolism
Up to 60% of an oral dose undergoes conversion through saturable hepatic metabolism and a minor pathway of degradation
by urease found in intestinal bacteria.
Excretion
In patients with sickle cell anemia, the mean cumulative urinary recovery of hydroxyurea was about 40% of the administered
dose.
Specific Populations
Renal Impairment
The effect of renal impairment on the pharmacokinetics of hydroxyurea was assessed in adult patients with sickle cell anemia
and renal impairment. Patients with normal renal function (creatinine clearance [CrCl] >80 mL/min), mild (CrCl 50-80
mL/min), moderate (CrCl =30-<50 mL/min), or severe (<30 mL/min) renal impairment received a single oral dose of 15
mg/kg hydroxyurea. Creatinine clearance values were obtained using 24-hour urine collections. Patients with ESRD received
two doses of 15 mg/kg separated by 7 days; the first was given following a 4-hour hemodialysis session, the second prior to
hemodialysis. The exposure to hydroxyurea (mean AUC) in patients with CrCl <60 mL/min and those with ESRD was 64%
higher than in patients with normal renal function (CrCl >60 mL/min) [see Dosage and Administration (2.2) and Use in
Specific Populations (8.6)].
Pediatric Patients
The model estimated steady state exposures (AUC) in pediatric patients receiving a daily dose of 15 mg/kg is lower in
patients aged 6 months to <2 years and 2 to <6 years by 40% and 28 % compared to adults receiving the same dose while the
exposures in 6 to < 18 year old patients are similar to adult exposures. (XROMI is not approved for use in adults).
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Conventional long-term studies to evaluate the carcinogenic potential of hydroxyurea have not been performed. However,
intraperitoneal administration of 125 to 250 mg/kg hydroxyurea (about 0.6-1.2 times the maximum recommended human oral
daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats
surviving to 18 months compared to control. Hydroxyurea is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian
cells. Hydroxyurea is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse
micronucleus assay). Hydroxyurea causes the transformation of rodent embryo cells to a tumorigenic
phenotype [see Warnings and Precautions (5.3 , 5.4)].
Hydroxyurea administered to male rats at 60 mg/kg /day (about 0.3 times the maximum recommended human daily dose on a
mg/m2 basis) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate
females [see Use in Specific Populations (8.3)].
14
CLINICAL STUDIES
The effectiveness of XROMI has been established for the indication, “to reduce the frequency of painful crises and to reduce
the need for blood transfusions in pediatric patients aged 6 months and older with sickle cell anemia with recurrent moderate
to severe painful crises” based on an adequate and well-controlled study of hydroxyurea capsules in adult patients with sickle
cell anemia with recurrent moderate to severe pain crises and additional pharmacokinetic data from a single-arm, open-label
study of XROMI in pediatric patients aged 10 months to less than 18 years with sickle cell anemia, who were treatment naïve
or had not received hydroxyurea in the 6 months prior to enrollment: HUPK study [see Adverse Reactions (6.1)].
15
REFERENCES
OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
Reference ID: 5502171
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
XROMI (hydroxyurea) 100 mg/mL is a colorless to pale yellow liquid supplied in an Amber type III glass bottle with tamper
evident child-resistant closure (HDPE with expanded polyethylene liner) containing 148 mL of oral solution.
Each carton NDC 62484-0015-5 contains 1 bottle XROMI NDC 62484-0015-4, an LDPE bottle adaptor and 2 oral dosing
syringes (one oral dosing syringe graduated to 3 mL and one oral dosing syringe graduated to 10 mL).
16.2
Storage
Store XROMI between 2°C to 8°C (35°F to 46°F) excursions permitted to 25°C (77°F) for up to 72 hours. Keep the bottle
tightly closed to protect the integrity of the product and minimize the risk of accidental spillage. Do not freeze.
Use within 12 weeks after initially opening the bottle. Discard unused XROMI remaining after 12 weeks of first opening the
bottle.
16.3
Handling and Disposal
XROMI is a hazardous drug. Follow applicable special handling and disposal procedures [see References (15)].
Anyone handling XROMI should wash their hands before and after administering a dose. To decrease the risk of exposure,
parents and caregivers should wear disposable gloves when handling XROMI. To minimize air bubbles, the bottle should not
be shaken prior to dosing. XROMI contact with skin or mucous membrane must be avoided. If XROMI comes into contact
with skin or mucosa, it should be washed immediately and thoroughly with soap and water. Spillages must be wiped
immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The spill areas should
be cleaned three times using a detergent solution followed by clean water. If contact with XROMI occurs in the eye(s), flush
the eye(s) thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. Parents / caregivers
should be advised to keep hydroxyurea out of the sight and reach of children. Accidental ingestion can be lethal for children.
Oral dosing syringes should be rinsed and washed with cold or warm water and dried completely before the next use. Store
oral dosing syringes in a hygienic place with the medicine.
17
PATIENT COUNSELING INFORMATION
Advise the caregiver to read the FDA-approved patient labeling (Instructions for Use and Medication Guide).
•
There is a risk of myelosuppression. Emphasize the importance of monitoring blood counts every two weeks throughout
the duration of therapy to caregivers of patients taking XROMI [see Warnings and Precautions (5.1)]. Advise caregivers
to report signs and symptoms of infection or bleeding in patients immediately.
•
Advise caregivers of the risk of hemolytic anemia. Advise caregivers that the patient will have blood tests to evaluate for
this if they develop persistent anemia. [see Warnings and Precautions (5.2)].
•
Advise caregivers that there is a risk of cutaneous vasculitic toxicities and secondary malignancies including leukemia.
Advise use of sun protection [see Warnings and Precautions (5.3, 5.5)].
•
Advise caregivers to inform the patient’s healthcare provider if they have received or are planning to receive
vaccinations while taking XROMI as this may result in a severe infection [see Warnings and Precautions (5.6)].
•
Advise females of reproductive potential of the potential risk to a fetus should they become pregnant while taking
XROMI. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise females and
males of reproductive potential to use contraception during and after treatment with XROMI [see Warnings and
Precautions (5.4) and Use in Specific Populations (8.1,8.3)].
•
Advise females to discontinue breastfeeding during treatment with XROMI [see Use in Specific Populations (8.2)].
•
Advise male patients of potential risk to fertility.
•
Advise patients with HIV infection to contact their physician for signs and symptoms of pancreatitis, hepatic events, and
peripheral neuropathy [see Warnings and Precautions (5.7)].
•
Advise caregivers of patients to notify their healthcare provider if they are using a continuous glucose monitoring system
while taking XROMI [see Warnings and Precautions (5.9)].Advise caregivers of the symptoms of potential pulmonary
toxicity and instruct them to seek prompt medical attention for the patient in the event of pyrexia, cough, dyspnea, or
other respiratory symptoms [see Warnings and Precautions (5.9)].
Because XROMI package includes two oral dosing syringes, advise patients on which oral dosing syringe they should use.
Reference ID: 5502171
Manufactured by:
Nova Laboratories Ltd
Leicester
LE18 4YL
United Kingdom
Manufactured for:
Rare Disease Therapeutics, Inc.
2550 Meridian Blvd., Suite 150
Franklin, Tennessee 37067
www.raretx.com
Part Number: D001427/1
Reference ID: 5502171
MEDICATION GUIDE
XROMI® (ex-ro-mee)
(hydroxyurea)
oral solution
What is the most important information I should know about XROMI?
XROMI can cause serious side effects including:
• Low blood cell counts are common with XROMI, including low red blood cells, white blood cells, and platelets, and can
be severe and life-threatening. If your child’s white blood cell count becomes very low, your child is at increased risk for
infection. Your child’s healthcare provider will check your child’s blood cell counts before and during treatment with XROMI.
Your child’s healthcare provider may change your child’s dose or tell your child to stop taking XROMI if your child has low
blood cell counts. Tell your child’s healthcare provider right away if your child gets any of the following symptoms:
• fever or chills
● shortness of breath
• body aches
● bleeding or unexplained bruising
• feeling very tired
• Hemolytic Anemia, the fast breakdown of red blood cells, has happened in people who take XROMI. Tell your child’s
healthcare provider if your child develops yellowing of their skin (jaundice) or blood in their urine. Your child’s healthcare
provider may do blood tests if your child has persistent or worsening anemia not related to sickle cell anemia.
• Cancer. Some people have developed cancer, such as leukemia and skin cancer, after taking XROMI for a long time. Your
child’s healthcare provider will check your child for cancer. You should protect your child’s skin from the sun using sunblock,
hats, and sun-protective clothing.
• XROMI can harm an unborn baby.
Females taking XROMI who can become pregnant should:
• avoid becoming pregnant during treatment with XROMI.
• talk with your healthcare provider about the risks of XROMI to your unborn baby.
• use effective birth control during treatment with XROMI and for at least 6 months after treatment.
• expect that their healthcare provider will perform a pregnancy test before they start treatment with XROMI.
• tell their healthcare provider right away if you become pregnant or think you may be pregnant.
For males taking XROMI:
If your child has a female sexual partner who can become pregnant, your child should use effective birth control during
treatment with XROMI and for at least 6 months after treatment.
XROMI may cause fertility problems in males. Talk to your child’s healthcare provider if this is a concern for you.
What is XROMI?
XROMI is a prescription medicine that is used to reduce the frequency of painful crises and reduce the need for blood transfusions in
pediatric patients 6 months of age and older with sickle cell anemia with recurrent moderate to severe painful crises.
XROMI is not for use in adults.
It is not known if XROMI is safe and effective in children less than 6 months old.
Your child should not take XROMI if your child is allergic to hydroxyurea or any of the ingredients in XROMI. See the
end of this Medication Guide for a list of the ingredients in XROMI.
Before taking XROMI, tell your healthcare provider about all of your medical conditions, including if you:
• have kidney problems or are receiving hemodialysis.
• have liver problems.
• have human immunodeficiency virus (HIV) or take HIV medicines. Taking XROMI with certain HIV medicines can
cause serious reactions and may lead to death. Tell your healthcare provider if you take an HIV medicine.
• have increased levels of uric acid in your blood (hyperuricemia).
• have a history of receiving interferon therapy or are currently receiving interferon therapy.
• have leg wounds or ulcers.
• plan to receive any vaccinations. You should not receive “live vaccines” during treatment with XROMI.
• are pregnant or plan to become pregnant. See “What is the most important information I should know about XROMI?”
• are breastfeeding or plan to breastfeed. It is not known if XROMI can pass into your breast milk. Do not breastfeed during
treatment with XROMI.
• are using a continuous glucose monitor (CGM) to test your blood glucose. Hydroxyurea may affect your sensor glucose results
and may lead to low blood sugar (hypoglycemia). Talk to the healthcare provider that prescribed your CGM about whether it
is safe to use while you are taking XROMI.
Tell your child’s healthcare provider about all the medicines your child takes, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Reference ID: 5502171
How should your child take XROMI?
Read the Instructions for Use that comes with XROMI for information about the right way to measure and give a
dose of XROMI. If you have any questions, talk to your child’s healthcare provider or pharmacist.
• Administer XROMI exactly as your child’s healthcare provider tells you to administer it. XROMI is taken 1 time a day at the same
time each day.
• Administer XROMI with or after meals. Administer XROMI the same way each day.
• Drink some water after each dose of XROMI.
• If your child takes too much XROMI, call your child’s healthcare provider or go to the nearest hospital emergency room.
• If you miss a dose of XROMI, call your healthcare provider for advice.
• XROMI oral solution should be handled with care. To decrease the risk of exposure, caregivers should do the following
when handling XROMI:
• Wear disposable gloves when handling oral dosing syringes or bottles containing XROMI.
• Wash your hands with soap and water before and after handling oral dosing syringes or bottles containing XROMI.
• Avoid contact with the oral solution. If contact with the oral solution happens on the skin, wash the skin area right away and
thoroughly with soap and water. If contact with the oral solution happens in the eyes, flush the eyes thoroughly with water and
isotonic eyewash used for that purpose for at least 15 minutes.
• If the oral solution is spilled, wipe it up right away with a damp disposable towel. Throw the damp disposable towel away in a
closed container such as a plastic bag. The spill area should then be cleaned up using a detergent solution followed by clean
water.
• During treatment with XROMI, your child’s healthcare provider will do blood tests regularly to check your child’s blood cell
counts and liver function. Your healthcare provider may change your child’s dose if you have side effects.
What are the possible side effects of XROMI?
XROMI may cause serious side effects, including:
See “What is the most important information I should know about XROMI?”
• Skin ulcers and death of tissue (gangrene) have happened in people who take XROMI. This has happened most often in people
who receive interferon therapy or have a history of interferon therapy. Your child’s healthcare provider will decrease your dose
or stop treatment with XROMI if your child develops any skin ulcers.
• Enlarged red blood cells (macrocytosis). Macrocytosis is common in people who take XROMI and can make it difficult to
detect a decrease of folic acid. Your child’s healthcare provider may prescribe a folic acid supplement for your child.
• Respiratory (breathing) problems. Some people have developed life-threatening respiratory conditions called interstitial lung
disease. Your child’s healthcare provider may tell your child to stop taking XROMI if your child develops respiratory
problems. Tell your child’s healthcare provider right away if your child gets any of the following symptoms:
•
fever
•
cough
•
shortness of breath
The most common side effects of XROMI include:
•
low blood levels of a type of white blood cell (neutropenia)
•
low blood levels of platelets (thrombocytopenia)
•
raised bumps on the skin (papular rash)
These are not all the possible side effects of XROMI.
Call your child’s doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store XROMI?
• XROMI comes in a bottle with a child-resistant cap.
• Refrigerate XROMI between 35°F to 46°F (2°C to 8°C). Do not freeze.
• XROMI comes in a bottle with a child-resistant cap. Keep bottle tightly closed.
• Store the XROMI bottle and oral dosing syringe in a clean place.
• XROMI oral solution should be used within 12 weeks after opening the bottle. Dispose of (throw away) any unused medicine
and the dosing syringes after 12 weeks.
• Do not use after the expiration date on the carton and bottle.
Keep XROMI and all medicines out of the reach of children.
General information about the safe and effective use of XROMI
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use XROMI for a condition
for which it was not prescribed. Do not give XROMI to other people, even if they have the same symptoms your child has. It may
harm them. You can ask your child’s healthcare provider or pharmacist for information about XROMI that is written for health
professionals.
Reference ID: 5502171
What are the ingredients of XROMI?
Active ingredient: hydroxyurea
Inactive ingredients: methyl parahydroxybenzoate, purified water, sodium hydroxide, strawberry flavor, sucralose and xanthan
gum.
Manufactured by: Nova Laboratories Ltd., Leicester LE18 4YL, United Kingdom
Manufactured for: Rare Disease Therapeutics, Inc., 2550 Meridian Blvd., Suite 150, Franklin, TN 37067
For more information, go to www.xromi-us.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: DEC 2024
Reference ID: 5502171
Packaging Contents
10 ml oral dosing syringe
(for doses more than 3 ml)
3 ml oral dosing syringe
(for doses of 3 ml or less)
e
Bottle adapter
Bottle
INSTRUCTIONS FOR USE
XROMI® (ex-ro-mee)
(hydroxyurea)
oral solution
Read these Instructions for Use before your child starts taking XROMI, and each time you get a refill.
There may be new information. This Instructions for Use does not take the place of talking to your child’s
healthcare provider about your child’s medical condition or treatment.
Important information:
•
Always use the oral dosing syringe provided with your child’s XROMI oral solution to measure
your child’s prescribed dose. Ask your child’s healthcare provider or pharmacist to show you which
oral dosing syringe to use and how to measure your child’s prescribed dose if you are not sure.
•
Wash your hands with soap and water before and after handling XROMI oral solution and oral dosing
syringes.
•
Wear disposable gloves when handling XROMI oral solution and oral dosing syringes.
•
Avoid contact with the oral solution. If contact with the oral solution happens on the skin, nose, or
mouth, wash the area right away and thoroughly with soap and water. If contact with the oral solution
happens in the eyes, flush the eyes thoroughly with water and isotonic eyewash used for that purpose
for at least 15 minutes.
•
If the oral solution is spilled, wipe it up right away with a damp disposable towel. Throw the damp
disposable towel away in a closed container such as a plastic bag. The spill area should then be
cleaned up using a detergent solution followed by clean water.
•
Do not shake the bottle.
Each carton of XROMI oral solution contains:
•
1 bottle of XROMI oral solution
•
1 bottle adapter
•
One 3 mL oral dosing syringe (for doses of 3 mL or less)
•
One 10 mL oral dosing syringe (for doses more than 3 mL)
If your carton does not contain two oral dosing syringes, contact your pharmacist.
Reference ID: 5502171
10 ml oral dosing syringe
(for doses more than 3 ml )
•
3 ml oral dosing syringe
(for doses o f 3 ml or less)
You will also need disposable gloves.
Before giving XROMI:
Step 1. Wash your hands well with soap and water.
Step 2. Put on disposable gloves.
Step 3. Place the items from the carton on a clean flat surface.
Step 4. Open the bottle by pushing down firmly on the child-
resistant cap and turning it counter-clockwise (See Figure A).
Do not throw away the child-resistant cap.
Figure A
Step 5. First time use only; Insert the bottle adapter.
Push the ribbed end of the bottle adapter into the neck of the
bottle until it is firmly in place. The bottom edge of the adapter
should fully contact the top rim of the bottle (See Figure B).
Do not remove the adapter from the bottle after it is
inserted.
Figure B
Measuring your child’s prescribed dose of XROMI:
Step 6. Choose the oral dosing syringe you need to measure
your child’s prescribed dose (See Figure C).
Check the dose in mL as prescribed by your child’s
healthcare provider. Choose the right oral dosing syringe for
your child’s dose.
• Use the 3 mL oral dosing syringe for doses of 3 mL or
less.
• Use the 10 mL oral dosing syringe for doses more
than 3 mL.
Find the marking for your child’s prescribed dose on the right
oral dosing syringe.
Figure C
Step 7. Push the plunger of the oral dosing syringe all the way
down to remove any air in the oral dosing syringe (see Figure
D).
Reference ID: 5502171
8
9
Figure D
Step 8. Hold the bottle upright. Insert the tip of the oral dosing
syringe into the opening of the bottle adapter until it is firmly in
place (See Figure E).
Figure E
Step 9. Turn the bottle upside down with the oral dosing
syringe in place. Pull back slowly on the plunger of the oral
dosing syringe until the top of the plunger is even with the mL
mark on the oral dosing syringe that corresponds to your
child’s prescribed dose.
See Figure F for an example of a dose of 6 mL. Your dose
may be different than the example shown.
Reference ID: 5502171
Figure F
Step 10. Leave the oral dosing syringe in the bottle adapter
and turn the bottle upright. Place the bottle onto a flat surface.
Hold the oral dosing syringe by the barrel and carefully
remove it from the adapter. Do not hold the oral dosing
syringe by the plunger (See Figure G).
Figure G
Step 11. Hold the oral dosing syringe with the oral dosing
syringe tip pointing up. Check that the correct dose was
drawn up into the oral syringe (See Figure H).
If there are large air bubbles in the oral dosing syringe (See
Figure I) or if you have drawn up the wrong dose, re-insert the
oral dosing syringe tip firmly into the bottle adapter while the
bottle is in an upright position. Fully push in the plunger so the
oral solution flows back into the bottle. Repeat Steps 8 and 9.
Figure H
Reference ID: 5502171
Figure I
Giving the prescribed dose of XROMI:
Step 12. Place the tip of the oral dosing syringe in your child’s
mouth and place the tip against the inside of your child’s
cheek.
Gently push the plunger all the way down to give all the
medicine in the oral dosing syringe and then remove the oral
dosing syringe from your child’s mouth (See Figure J).
Make sure the child has time to swallow the medicine.
If your child’s prescribed dose is more than 10 mL, you will
need to divide the dose. Follow the instructions given to you
by your healthcare provider or pharmacist about how to divide
the dose and repeat Steps 6 through 12.
Figure J
Step 13. Have your child drink some water to make sure no
medicine is left in your child’s mouth.
Step 14. Close the bottle tightly by turning the child-resistant
cap clockwise, leaving the bottle adapter in place.
Step 15. Wash your hands well with soap and water. Rinse
and wash the oral dosing syringes with cold or warm water
and dry completely before next use. Hold the oral dosing
syringe under water and move the plunger up and down
several times to make sure the inside of the oral dosing
syringe is clean. Let the oral dosing syringe dry completely
before you use it again. Do not throw away the oral dosing
syringe after use.
Storing XROMI
•
Store XROMI in a refrigerator between 35°F to 46°F (2°C to 8°C). Do not freeze.
•
Store the XROMI bottle and oral dosing syringe in a clean place.
•
XROMI oral solution should be used within 12 weeks after opening the bottle. Dispose of (throw
away) any unused medicine and the dosing syringes after 12 weeks.
•
Do not use after the expiration date on the carton and the bottle.
•
Keep XROMI and all medicines out of the reach of children.
Disposing of XROMI
•
Ask your pharmacist for instructions on how to throw away (dispose of) XROMI that is expired or no
longer needed.
Reference ID: 5502171
Manufactured by: Nova Laboratories, Ltd., Leicester LE18 4YL, United Kingdom
Manufactured for: Rare Disease Therapeutics, Inc. 2550 Meridian Blvd., Suite 150
Franklin, TN 37067
Part Number: D001426/1
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised:
12/2024
Reference ID: 5502171
| custom-source | 2025-02-12T15:48:14.771366 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216593Orig2s000lbl.pdf', 'application_number': 216593, 'submission_type': 'ORIG ', 'submission_number': 2} |
80,753 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ARIXTRA safely and effectively. See full prescribing information for
ARIXTRA.
ARIXTRA (fondaparinux sodium injection), for subcutaneous use
Initial U.S. Approval: 2001
WARNING: SPINAL/EPIDURAL HEMATOMAS
See full prescribing information for complete boxed warning.
Epidural or spinal hematomas may occur in patients who are
anticoagulated with low molecular weight heparins (LMWH),
heparinoids, or fondaparinux sodium and are receiving neuraxial
anesthesia or undergoing spinal puncture. These hematomas may result
in long-term or permanent paralysis. Consider these risks when
scheduling patients for spinal procedures. Factors that can increase the
risk of developing epidural or spinal hematomas in these patients include:
•
use of indwelling epidural catheters
•
concomitant use of other drugs that affect hemostasis, such as non-
steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or
other anticoagulants
•
a history of traumatic or repeated epidural or spinal puncture
•
a history of spinal deformity or spinal surgery
Monitor patients frequently for signs and symptoms of neurologic
impairment. If neurologic compromise is noted, urgent treatment is
necessary.
Consider the benefit and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated for thromboprophylaxis [see
Warnings and Precautions (5.1) and Drug Interactions (7)].
--------------------------- RECENT MAJOR CHANGES -------------------------
Indications and Usage (1.4)
12/2024
Dosage and Administration (2.1, 2.5, 2.7, 2.8)
12/2024
Warnings and Precautions (5.2)
12/2024
--------------------------- INDICATIONS AND USAGE --------------------------
ARIXTRA is a Factor Xa inhibitor (anticoagulant) indicated for:
•
Prophylaxis of deep vein thrombosis (DVT) in adult patients undergoing
hip fracture surgery (including extended prophylaxis), hip replacement
surgery, knee replacement surgery, or abdominal surgery. (1.1)
•
Treatment of DVT or acute pulmonary embolism (PE) in adult patients
when administered in conjunction with warfarin sodium. (1.2, 1.3)
•
Treatment of venous thromboembolism (VTE) in pediatric patients aged 1
year or older weighing at least 10 kg. (1.4)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
•
For subcutaneous use, do not mix with other injections or infusions. (2.1)
•
Prophylaxis of deep vein thrombosis in adults: ARIXTRA 2.5 mg
subcutaneously once daily after hemostasis has been established. The
initial dose should be given no earlier than 6 hours to 8 hours after surgery
and continued for 5 days to 9 days. For patients undergoing hip fracture
surgery, extended prophylaxis up to 24 additional days is recommended.
(2.2, 2.3)
•
Treatment of deep vein thrombosis and pulmonary embolism in adults:
ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (50 kg to 100 kg),
or 10 mg (greater than 100 kg) subcutaneously once daily. Treatment
should continue for at least 5 days until INR 2 to 3 is achieved with
warfarin sodium. (2.4)
•
Treatment of venous thromboembolism in pediatric patients weighing at
least 10 kg: ARIXTRA 0.1 mg/kg subcutaneously once daily. (2.5)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Single-dose, prefilled syringes containing 2.5 mg/0.5 mL, 5 mg/0.4 mL, 7.5
mg/0.6 mL, or 10 mg/0.8 mL of fondaparinux sodium. (3)
------------------------------ CONTRAINDICATIONS ----------------------------
ARIXTRA is contraindicated in the following conditions: (4)
•
Severe renal impairment (creatinine clearance less than 30 mL/min) in
prophylaxis or treatment of venous thromboembolism.
•
Active major bleeding.
•
Bacterial endocarditis.
•
Thrombocytopenia associated with a positive in vitro test for anti-platelet
antibody in the presence of fondaparinux sodium.
•
Body weight less than 50 kg (venous thromboembolism prophylaxis in
adults only).
•
History of serious hypersensitivity reaction (e.g., angioedema,
anaphylactoid/anaphylactic reactions) to ARIXTRA.
----------------------- WARNINGS AND PRECAUTIONS ----------------------
•
Spinal or epidural hematomas, which may result in long-term or
permanent paralysis, can occur. (5.1)
•
Patients taking ARIXTRA with risk factors for bleeding are at increased
risk of hemorrhage. (5.2)
•
Bleeding risk is increased in renal impairment and in adult patients with
low body weight less than 50 kg. (5.3, 5.4)
•
Thrombocytopenia can occur with administration of ARIXTRA. (5.5)
•
Periodic routine complete blood counts (including platelet counts), serum
creatinine level, and stool occult blood tests are recommended. (5.6)
•
The packaging (needle guard) contains dry natural rubber and may cause
allergic reactions in latex sensitive individuals. (5.7)
------------------------------ ADVERSE REACTIONS ----------------------------
The most serious adverse reactions associated with the use of ARIXTRA are
bleeding complications. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1
877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS -----------------------------
Discontinue agents that may enhance the risk of hemorrhage prior to initiation
of therapy with ARIXTRA unless essential. If co-administration is necessary,
monitor patients closely for hemorrhage. (7)
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
•
Because elderly patients are more likely to have reduced renal function,
ARIXTRA should be used with caution in these patients. (8.5)
•
The risk of bleeding is increased with reduced renal or hepatic function.
(8.6, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 12/2024
Reference ID: 5502191
1
FULL PRESCRIBING INFORMATION: CONTENTS*
7
DRUG INTERACTIONS
WARNING: SPINAL/EPIDURAL HEMATOMAS
8
USE IN SPECIFIC POPULATIONS
1
INDICATIONS AND USAGE
8.1
Pregnancy
1.1
Prophylaxis of Deep Vein Thrombosis in Adult Patients
8.2
Lactation
1.2
Treatment of Acute Deep Vein Thrombosis in Adult
8.4
Pediatric Use
Patients
8.5
Geriatric Use
1.3
Treatment of Acute Pulmonary Embolism in Adult
8.6
Renal Impairment
Patients
8.7
Hepatic Impairment
1.4
Treatment of Venous Thromboembolism in Pediatric
10
OVERDOSAGE
Patients
11
DESCRIPTION
2
DOSAGE AND ADMINISTRATION
12
CLINICAL PHARMACOLOGY
2.1
Important Dosing Information
12.1
Mechanism of Action
2.2
Deep Vein Thrombosis Prophylaxis Following Hip
12.2
Pharmacodynamics
Fracture, Hip Replacement, and Knee Replacement
12.3
Pharmacokinetics
Surgery in Adults
12.4
Special Populations
2.3
Deep Vein Thrombosis Prophylaxis Following
13
NONCLINICAL TOXICOLOGY
Abdominal Surgery in Adults
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
2.4
Deep Vein Thrombosis and Pulmonary Embolism
14
CLINICAL STUDIES
Treatment in Adults
14.1
Prophylaxis of Thromboembolic Events Following Hip
2.5
Venous Thromboembolism Treatment in Pediatric
Fracture Surgery in Adult Patients
Patients Aged 1 Year or Older Weighing at Least 10 kg
14.2
Extended Prophylaxis of Thromboembolic Events
2.6
Hepatic Impairment
Following Hip Fracture Surgery in Adult Patients
2.7
Instructions for Use for Prefilled Syringe
14.3
Prophylaxis of Thromboembolic Events Following Hip
2.8
Instructions for Preparation of Individual Pediatric
Replacement Surgery in Adult Patients
Doses in Pharmacies
14.4
Prophylaxis of Thromboembolic Events Following
3
DOSAGE FORMS AND STRENGTHS
Knee Replacement Surgery in Adult Patients
4
CONTRAINDICATIONS
14.5
Prophylaxis of Thromboembolic Events Following
5
WARNINGS AND PRECAUTIONS
Abdominal Surgery in Patients at Risk for
5.1
Neuraxial Anesthesia and Post-operative Indwelling
Thromboembolic Complications in Adult Patients
Epidural Catheter Use
14.6
Treatment of Deep Vein Thrombosis in Adult Patients
5.2
Hemorrhage
14.7
Treatment of Pulmonary Embolism in Adult Patients
5.3
Renal Impairment and Bleeding Risk in Adult Patients
14.8
Treatment of Venous Thromboembolism in Pediatric
5.4
Body Weight Less than 50 kg and Bleeding Risk in
Patients
Adults
16
HOW SUPPLIED/STORAGE AND HANDLING
5.5
Thrombocytopenia
17
PATIENT COUNSELING INFORMATION
5.6
Monitoring: Laboratory Tests
17.1
Patient Advice
5.7
Latex
6
ADVERSE REACTIONS
*Sections or subsections omitted from the full prescribing information are not
6.1
Clinical Trials Experience
listed.
6.2
Postmarketing Experience
Reference ID: 5502191
2
FULL PRESCRIBING INFORMATION
WARNING: SPINAL/EPIDURAL HEMATOMAS
Epidural or spinal hematomas may occur in patients who are anticoagulated with low
molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are
receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may
result in long-term or permanent paralysis. Consider these risks when scheduling patients
for spinal procedures. Factors that can increase the risk of developing epidural or spinal
hematomas in these patients include:
• use of indwelling epidural catheters
• concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-
inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants
• a history of traumatic or repeated epidural or spinal puncture
• a history of spinal deformity or spinal surgery
• Optimal timing between the administration of ARIXTRA and neuraxial procedures is
not known.
Monitor patients frequently for signs and symptoms of neurologic impairment. If
neurologic compromise is noted, urgent treatment is necessary.
Consider the benefit and risks before neuraxial intervention in patients anticoagulated or
to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug
Interactions (7)].
1
INDICATIONS AND USAGE
1.1
Prophylaxis of Deep Vein Thrombosis in Adult Patients
ARIXTRA® is indicated for the prophylaxis of deep vein thrombosis (DVT) in adults, which
may lead to pulmonary embolism (PE):
• in patients undergoing hip fracture surgery, including extended prophylaxis;
• in patients undergoing hip replacement surgery;
• in patients undergoing knee replacement surgery;
• in patients undergoing abdominal surgery who are at risk for thromboembolic complications.
1.2
Treatment of Acute Deep Vein Thrombosis in Adult Patients
ARIXTRA is indicated for the treatment of acute deep vein thrombosis in adults when
administered in conjunction with warfarin sodium.
1.3
Treatment of Acute Pulmonary Embolism in Adult Patients
ARIXTRA is indicated for the treatment of acute pulmonary embolism in adults when
administered in conjunction with warfarin sodium when initial therapy is administered in the
hospital.
Reference ID: 5502191
3
1.4
Treatment of Venous Thromboembolism in Pediatric Patients
ARIXTRA is indicated for the treatment of venous thromboembolism (VTE) in pediatric patients
aged 1 year or older weighing at least 10 kg.
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosing Information
Do not mix other medications or solutions with ARIXTRA. Administer ARIXTRA only
subcutaneously. Discard unused portion.
Monitor routine complete blood counts (including platelet count), serum creatinine level, and
stool occult blood periodically [see Warnings and Precautions (5.6)].
2.2
Deep Vein Thrombosis Prophylaxis Following Hip Fracture, Hip Replacement, and
Knee Replacement Surgery in Adults
In adult patients undergoing hip fracture, hip replacement, or knee replacement surgery, the
recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily
after hemostasis has been established. Administer the initial dose no earlier than 6 hours to 8
hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the
risk of major bleeding. The usual duration of therapy is 5 days to 9 days; up to 11 days of
therapy was administered in clinical trials.
In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24
additional days is recommended. In patients undergoing hip fracture surgery, a total of 32 days
(peri-operative and extended prophylaxis) was administered in clinical trials [see Warnings and
Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14)].
2.3
Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery in Adults
In adult patients undergoing abdominal surgery, the recommended dose of ARIXTRA is 2.5 mg
administered by subcutaneous injection once daily after hemostasis has been established.
Administer the initial dose no earlier than 6 hours to 8 hours after surgery. Administration of
ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual
duration of administration is 5 days to 9 days, and up to 10 days of ARIXTRA was administered
in clinical trials.
2.4
Deep Vein Thrombosis and Pulmonary Embolism Treatment in Adults
In adult patients with acute symptomatic DVT and in patients with acute symptomatic PE, the
recommended dose of ARIXTRA is 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50
kg to 100 kg), or 10 mg (body weight greater than 100 kg) by subcutaneous injection once daily
Reference ID: 5502191
4
(ARIXTRA treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as
possible, usually within 72 hours. Continue treatment with ARIXTRA for at least 5 days and
until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of
administration of ARIXTRA is 5 days to 9 days; up to 26 days of ARIXTRA injection was
administered in clinical trials [see Warnings and Precautions (5.6), Adverse Reactions (6), and
Clinical Studies (14)].
2.5
Venous Thromboembolism Treatment in Pediatric Patients Aged 1 Year or Older
Weighing at Least 10 kg
For patients weighing 10 kg to 20 kg, the recommended initial dose is 0.1 mg/kg subcutaneously
once daily. There is no available prefilled syringe for patients in this weight range, and a patient
specific dose should be prepared (see section 2.8 Instructions for Preparation of Individual
Pediatric Doses in Pharmacies). The dose should be exact and rounded to the nearest 0.1 mg
(see Table 1).
Table 1. Recommended Initial Dose of ARIXTRA for Treatment of VTE in Pediatric
Patients Weighing 10 kg to 20 kg
Body Weight (kg)
Initial Dose
10 kg to 20 kg
Dosing should be exact and rounded to the nearest
0.1 mg
For patients weighing over 20 kg, the recommended initial dose is 0.1 mg/kg subcutaneously
once daily with doses rounded to the nearest prefilled syringe according to Table 2.
There is no available information for dosing pediatric patients who weigh less than 10 kg.
Table 2. Recommended Prefilled Syringe Selection for Initial Dose of ARIXTRA for
Treatment of VTE in Pediatric Patients Weighing More Than 20 kg
Body Weight (kg)
Prefilled Syringe Selection
Greater than 20 kg to 40 kg*
2.5 mg/0.5 mL
Greater than 40 kg to 60 kg*
5 mg/0.4 mL
Greater than 60 kg*
7.5 mg/0.6 mL
*Whenever possible, patients weighing more than 20 kg should receive a full prefilled syringe
for dosing. If therapeutic levels are not achievable using the prefilled syringe available strengths
and dose adjustments are needed, a patient specific dose may be prepared (see section 2.8
Instructions for Preparation of Individual Pediatric Doses in Pharmacies).
Monitor fondaparinux levels 2 hours to 4 hours after the second or third dose and then weekly
for a month followed by every 1 month to 3 months for the duration of treatment using a
fondaparinux-based anti-Xa assay with a therapeutic goal range of 0.5 mg/L to 1 mg/L.
Dosing adjustments may be necessary to achieve peak blood concentration within the therapeutic
target of 0.5 mg/L to 1 mg/L (see Table 3). Do not exceed the maximum dose of 7.5 mg/day.
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Table 3. Recommended Dose Adjustments
Fondaparinux-Based Anti-Xa Level (mg/L) Dose Adjustment
Less than 0.3 mg/L
Increase dose by 0.03 mg/kg*
0.3 mg/L to 0.49 mg/L
Increase dose by 0.01 mg/kg*
0.5 mg/L to 1 mg/L
No change
1.01 mg/L to 1.2 mg/L
Decrease dose by 0.01 mg/kg*
Greater than 1.2 mg/L
Decrease dose by 0.03 mg/kg*
*Adjust the dose to the nearest 0.1 mg.
There is no adequate data to support the use of ARIXTRA in pediatric patients below 1 year of
age.
2.6
Hepatic Impairment
No dose adjustment is recommended in patients with mild to moderate hepatic impairment,
based upon single-dose pharmacokinetic data. Pharmacokinetic data are not available for patients
with severe hepatic impairment. Patients with hepatic impairment may be particularly vulnerable
to bleeding during ARIXTRA therapy. Observe these patients closely for signs and symptoms of
bleeding [see Clinical Pharmacology (12.4)].
2.7
Instructions for Use for Prefilled Syringe
ARIXTRA Injection is provided in a single-dose, prefilled syringe affixed with an automatic
needle protection system. ARIXTRA is administered by subcutaneous injection. It must not be
administered by intramuscular injection. ARIXTRA is intended for use under a physician’s
guidance. Patients may self-inject only if their physician determines that it is appropriate, and the
patients are trained in subcutaneous injection techniques.
Prior to administration, visually inspect ARIXTRA to ensure the solution is clear and free of
particulate matter.
To avoid the loss of drug when using the prefilled syringe, do not expel the air bubble from
the syringe before the injection. Administration should be made in the fatty tissue, alternating
injection sites (e.g., between the left and right anterolateral or the left and right posterolateral
abdominal wall).
To administer ARIXTRA:
1. Wipe the surface of the injection site with an alcohol swab.
2. Hold the syringe with either hand and use your other hand to twist the rigid needle guard
(covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle
(Figure A). Discard the needle guard.
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Figure A
3. Do not try to remove the air bubbles from the syringe before giving the injection.
4. Pinch a fold of skin at the injection site between your thumb and forefinger and hold it
throughout the injection.
5. Hold the syringe with your thumb on the top pad of the plunger rod and your next 2 fingers
on the finger grips on the syringe barrel. Pay attention to avoid sticking yourself with the
exposed needle.
6. Insert the full length of the syringe needle perpendicularly into the skin fold held between the
thumb and forefinger (Figure B).
Figure B
7. Push the plunger rod firmly with your thumb as far as it will go. This will ensure you have
injected all the contents of the syringe (Figure C).
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Figure C
8. When you have injected all the contents of the syringe, the plunger should be released. The
plunger will then rise automatically while the needle withdraws from the skin and retracts
into the security sleeve. Discard the syringe into the sharps container.
9. You will know that the syringe has worked when:
• The needle is pulled back into the security sleeve and the white safety indicator appears
above the upper body.
• You may also hear or feel a soft click when the plunger rod is released fully.
2.8
Instructions for Preparation of Individual Pediatric Doses in Pharmacies
For pediatric patients weighing 10 kg to 20 kg, a patient-specific dose may be prepared by a
pharmacist under aseptic conditions per the instructions below.
These instructions may also be used to prepare pediatric patient-specific doses for patients
weighing over 20 kg when dose adjustments are needed and therapeutic levels are not achievable
using the prefilled syringe available strengths.
Prior to preparing ARIXTRA, visually inspect ARIXTRA prefilled syringe to ensure the solution
is clear and free of particulate matter.
General Aseptic Preparation Practices
Strictly observe aseptic technique when preparing patient specific pediatric doses of ARIXTRA.
To prevent accidental contamination, prepare ARIXTRA according to aseptic standards,
including but not limited to:
• Prepare ARIXTRA in an ISO Class 5 laminar airflow (LAF) hood
• Ensure that the dose preparation area, including the LAF hood, has appropriate
environmental specifications, confirmed by periodic monitoring.
• Ensure that personnel are appropriately trained in aseptic manipulations of sterile products.
• Ensure that personnel wear appropriate clothing and gloves.
• Ensure that gloves and surfaces are disinfected.
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All steps should be completed in accordance with aseptic techniques:
1. Determine the total dose and volume per the duration, and the appropriate number of
ARIXTRA prefilled syringes. One ARIXTRA prefilled syringe is used in cases where the
total required dose is less than 0.5 mL. Where the total dose required is greater than or equal
to 0.5 mL, only two ARIXTRA prefilled syringes may be pooled together. The maximum
number of ARIXTRA prefilled syringes that may be pooled together is two.
Do not combine ARIXTRA prefilled syringes of different concentrations in one injection to
give the prescribed dose.
2. Gather the required supplies including the appropriate ARIXTRA prefilled syringe(s), a
sterile, closed/sealed, empty glass vial (recommended 5 mL), and required number of
suitable sized graduated tuberculin sterile syringes with 27 gauge x ½” staked needles or
sterile needles (if not pre-attached to syringe).
3. Verify the required supplies are correct and within expiry date. Ensure only the materials
required for the preparation are present in the work area.
4. While wearing sterile gloves, clean the LAF hood and wipe it down with sterile 70% alcohol.
Ensure the LAF hood is within specification and continually monitored.
5. Ensure equipment and consumables are cleaned with isopropyl alcohol (IPA).
6. Before transferring into the LAF hood, clean all supplies including ancillary items (such as
vial holder jigs, syringe cap holder jigs, sharps containers) with IPA.
7. Perform all the dose preparation steps within the LAF hood.
8. Pre-sterilize gloves with IPA. While wearing sterile gloves, hold the ARIXTRA prefilled
syringe with either gloved hand and use your other gloved hand to twist the rigid needle
guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the
needle. Discard the needle guard.
9. Dispense the full contents of the ARIXTRA prefilled syringe into the vial by fully depressing
the plunger.
10. When you have injected all the contents of the ARIXTRA prefilled syringe, the plunger
should be released. The plunger will then rise automatically while the needle retracts into the
security sleeve. Discard the ARIXTRA prefilled syringe into a sharps container.
11. Take an empty graduated tuberculin sterile syringe and attach a suitable sterile needle if not
already supplied pre-attached.
12. Remove needle cap.
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13. Withdraw required dose from vial into the tuberculin syringe.
14. Replace needle cap over the needle. Clean the external surfaces of the filled tuberculin
syringe with IPA.
15. Repeat steps 11 to 14 as required for the appropriate number of tuberculin syringes necessary
for the patient.
16. Label each ARIXTRA tuberculin syringe with patient specific information (e.g., dosing
instructions, patient information), storage information (e.g., store refrigerated between 36°F
to 46°F (2°C to 8°C), do not freeze, and the beyond use date). The beyond use date should be
the earlier of the product expiration date of the ARIXTRA prefilled syringe or 30 days after
preparation of the tuberculin syringe.
17. Prepared tuberculin syringes may be dispensed in an empty plastic bag. Include Patient
Information and Instructions for Use for the tuberculin syringe within the plastic bag to be
dispensed to patients. They may be stored at refrigerated temperatures between 36°F to 46°F
(2°C to 8°C) for up to the beyond use date. Do not freeze.
Do not store the pediatric preparations at room temperature as they are growth promoting at
room temperature.
Discard unused portion.
3
DOSAGE FORMS AND STRENGTHS
Injection: Single-dose, prefilled syringes containing clear to practically clear and colorless liquid
containing either 2.5 mg/0.5 mL, 5 mg/0.4 mL, 7.5 mg/0.6 mL, or 10 mg/0.8 mL of
fondaparinux sodium.
4
CONTRAINDICATIONS
ARIXTRA is contraindicated in the following conditions:
• Severe renal impairment (creatinine clearance [CrCl] less than 30 mL/min) [see Warnings
and Precautions (5.3) and Use in Specific Populations (8.6)].
• Active major bleeding.
• Bacterial endocarditis.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the
presence of fondaparinux sodium.
• Body weight less than 50 kg (venous thromboembolism [VTE] prophylaxis in adults only)
[see Warnings and Precautions (5.4)].
• History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic
reactions) to ARIXTRA.
5
WARNINGS AND PRECAUTIONS
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5.1
Neuraxial Anesthesia and Post-operative Indwelling Epidural Catheter Use
Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur
with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture. The
risk of these events may be higher with post-operative use of indwelling epidural catheters or
concomitant use of other drugs affecting hemostasis such as NSAIDs [see Boxed Warning]. In
the postmarketing experience, epidural or spinal hematoma has been reported in association with
the use of ARIXTRA by subcutaneous (SC) injection. Optimal timing between the
administration of ARIXTRA and neuraxial procedures is not known. Monitor patients
undergoing these procedures for signs and symptoms of neurologic impairment such as midline
back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and
bowel or bladder dysfunction. Consider the potential risks and benefits before neuraxial
intervention in patients anticoagulated or who may be anticoagulated for thromboprophylaxis.
5.2
Hemorrhage
ARIXTRA increases the risk of hemorrhage in patients at risk for bleeding, including conditions
such as congenital or acquired bleeding disorders, active ulcerative and angiodysplastic
gastrointestinal disease, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic
retinopathy, or shortly after brain, spinal, or ophthalmological surgery. Cases of elevated aPTT
temporally associated with bleeding events have been reported following administration of
ARIXTRA (with or without concomitant administration of other anticoagulants) [see Adverse
Reactions (6.2)].
Conditions associated with increased bleeding in pediatric patients include systemic lupus
erythematosus, Wilms tumor, antiphospholipid syndrome, antithrombin III deficiency, Factor V
Leiden, malignancy, pancytopenia, indwelling chest tubes, thoracotomy, invasive infections,
hypertensive encephalopathy, intestinal lymphangiectasia and von Willebrand disease.
Do not administer agents that enhance the risk of hemorrhage with ARIXTRA unless essential
for the management of the underlying condition, such as vitamin K antagonists for the treatment
of VTE. If co-administration is essential, closely monitor patients for signs and symptoms of
bleeding.
Do not administer the initial dose of ARIXTRA earlier than 6 to 8 hours after surgery.
Administration earlier than 6 hours after surgery increases risk of major bleeding [see Dosage
and Administration (2) and Adverse Reactions (6.1)].
5.3
Renal Impairment and Bleeding Risk in Adult Patients
ARIXTRA increases the risk of bleeding in adult patients with impaired renal function due to
reduced clearance [see Clinical Pharmacology (12.4)].
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The incidence of major bleeding by renal function status reported in clinical trials of adult
patients receiving ARIXTRA for VTE surgical prophylaxis is provided in Table 4. In these
patient populations, the following is recommended:
• Do not use ARIXTRA for VTE prophylaxis and treatment in patients with CrCl less than 30
mL/min [see Contraindications (4)].
• ARIXTRA may cause prolonged anticoagulation in patients with CrCl 30 mL/min to 50
mL/min.
Table 4. Incidence of Major Bleeding in Adult Patients Treated with ARIXTRA by Renal
Function Status for Surgical Prophylaxis and Treatment of Deep Vein Thrombosis (DVT)
and Pulmonary Embolism (PE)
Population
Timing of
Dose
Degree of Renal Impairment
Normal
%
(n/N)
Mild
%
(n/N)
Moderate
%
(n/N)
Severe
%
(n/N)
CrCl (mL/min)
Greater
than or
equal to
80
Greater
than or
equal to 50
to less than
80
Greater
than or
equal to 30
to less than
50
Less than
30
Orthopedic
surgerya
Overall
1.6%
(25/1,565)
2.4%
(31/1,288)
3.8%
(19/504)
4.8%
(4/83)
6 hours to 8
hours after
surgery
1.8%
(16/905)
2.2%
(15/675)
2.3%
(6/265)
0%
(0/40)
Abdominal
surgery
Overall
2.1%
(13/606)
3.6%
(22/613)
6.7%
(12/179)
7.1%
(1/14)
6 hours to 8
hours after
surgery
2.1%
(10/467)
3.3%
(16/481)
5.8%
(8/137)
7.7%
(1/13)
DVT and PE
Treatment
0.4%
(4/1,132)
1.6%
(12/733)
2.2%
(7/318)
7.3%
(4/55)
CrCl = creatinine clearance.
a
Hip fracture, hip replacement, and knee replacement surgery prophylaxis.
Assess renal function periodically in patients receiving ARIXTRA. Discontinue the drug
immediately in patients who develop severe renal impairment while on therapy. After
discontinuation of ARIXTRA, its anticoagulant effects may persist for 2 days to 4 days in
patients with normal renal function (i.e., at least 3 to 5 half-lives). The anticoagulant effects of
ARIXTRA may persist even longer in patients with renal impairment [see Clinical
Pharmacology (12.4)].
5.4
Body Weight Less than 50 kg and Bleeding Risk in Adults
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ARIXTRA increases the risk for bleeding in adults who weigh less than 50 kg, compared to
adults with higher weights.
In adults who weigh less than 50 kg:
• Do not administer ARIXTRA as prophylactic therapy for adults undergoing hip fracture, hip
replacement, or knee replacement surgery and abdominal surgery [see Contraindications
(4)].
In randomized clinical trials of VTE prophylaxis in adults during the peri-operative period
following hip fracture, hip or knee replacement surgery, and abdominal surgery, major bleeding
occurred at a higher rate among adults with a body weight less than 50 kg compared to those
with a body weight greater than 50 kg (5.4% versus 2.1% in adults undergoing hip fracture, hip
replacement, or knee replacement surgery; 5.3% versus 3.3% in adults undergoing abdominal
surgery).
5.5
Thrombocytopenia
Thrombocytopenia can occur with the administration of ARIXTRA. Thrombocytopenia of any
degree should be monitored closely. Discontinue ARIXTRA if the platelet count falls below
100,000/mm3. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and
50,000/mm3) occurred at a rate of 3% in patients given ARIXTRA 2.5 mg in the peri-operative
hip fracture, hip replacement, or knee replacement surgery and abdominal surgery clinical trials.
Severe thrombocytopenia (platelet counts less than 50,000/mm3) occurred at a rate of 0.2% in
patients given ARIXTRA 2.5 mg in these clinical trials. During extended prophylaxis, no cases
of moderate or severe thrombocytopenia were reported.
Moderate thrombocytopenia occurred at a rate of 0.5% in patients given the ARIXTRA treatment
regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate
of 0.04% in patients given the ARIXTRA treatment regimen in the DVT and PE treatment
clinical trials.
Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced
thrombocytopenia have been reported with the use of ARIXTRA in postmarketing experience
[see Adverse Reactions (6.2)].
5.6
Monitoring: Laboratory Tests
Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin
Time (aPTT) are relatively insensitive measures of the activity of ARIXTRA and international
standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of
ARIXTRA. If unexpected changes in coagulation parameters or major bleeding occur during
therapy with ARIXTRA, discontinue ARIXTRA. In postmarketing experience, occurrences of
aPTT elevations have been reported following administration of ARIXTRA [see Adverse
Reactions (6.2)].
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Periodic routine complete blood counts (including platelet count), serum creatinine level, and
stool occult blood tests are recommended during the course of treatment with ARIXTRA.
The anti-Factor Xa activity of fondaparinux sodium can be measured by anti-Xa assay using the
appropriate calibrator (fondaparinux). The activity of fondaparinux sodium is expressed in
milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or low
molecular weight heparins [see Clinical Pharmacology (12.2, 12.3)].
5.7
Latex
The packaging (needle guard) of the prefilled syringe of ARIXTRA contains dry natural latex
rubber that may cause allergic reactions in latex sensitive individuals.
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Spinal or epidural hematomas [see Warnings and Precautions (5.1)]
• Hemorrhage [see Warnings and Precautions (5.2)]
• Renal impairment and bleeding risk [see Warnings and Precautions (5.3)]
• Body weight less than 50 kg and bleeding risk [see Warnings and Precautions (5.4)]
• Thrombocytopenia [see Warnings and Precautions (5.5)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience in Adults
The adverse reaction information below is based on data from 8,877 patients exposed to
ARIXTRA in controlled trials of hip fracture, hip replacement, major knee, or abdominal
surgeries, and DVT and PE treatment.
Hemorrhage
During administration of ARIXTRA, the most common adverse reactions were bleeding
complications [see Warnings and Precautions (5.2)].
Hip Fracture, Hip Replacement, and Knee Replacement Surgery
The rates of major bleeding events reported during 3 active-controlled peri-operative VTE
prophylaxis trials with enoxaparin sodium in hip fracture, hip replacement, or knee replacement
surgery (N = 3,616) and in an extended VTE prophylaxis trial (n = 327) with ARIXTRA 2.5 mg
are provided in Table 5.
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Table 5. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and
Knee Replacement Surgery Studies
Peri-Operative Prophylaxis
(Day 1 to Day 7 ± 1 post-
surgery)
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-
surgery)
ARIXTRA
2.5 mg
subcutaneously
once daily
N = 3,616
Enoxaparin
Sodiuma, b
N = 3,956
ARIXTRA
2.5 mg
subcutaneously
once daily
N = 327
Placebo
subcutaneously
once daily
N = 329
Major bleedingc
96 (2.7%)
75 (1.9%)
8 (2.4%)
2 (0.6%)
Hip fracture
18/831 (2.2%)
19/842 (2.3%)
8/327 (2.4%)
2/329 (0.6%)
Hip replacement
67/2,268 (3.0%) 55/2,597 (2.1%)
—
—
Knee replacement
11/517 (2.1%)
1/517 (0.2%)
—
—
Fatal bleeding
0 (0%)
1 (less than
0.1%)
0 (0%)
0 (0%)
Non-fatal bleeding at
critical site
0 (0%)
1 (less than
0.1%)
0 (0%)
0 (0%)
Re-operation due to
bleeding
12 (0.3%)
10 (0.3%)
2 (0.6%)
2 (0.6%)
BI greater than or
equal to 2d
84 (2.3%)
63 (1.6%)
6 (1.8%)
0 (0%)
Minor bleedinge
109 (3%)
116 (2.9%)
5 (1.5%)
2 (0.6%)
a
Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
b
Not approved for use in patients undergoing hip fracture surgery.
c
Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at
critical site (e.g., intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal
gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI)
greater than or equal to 2.
d
BI greater than or equal to 2: Overt bleeding associated only with a bleeding index (BI)
greater than or equal to 2 calculated as [number of whole blood or packed red blood cell units
transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values].
e
Minor bleeding was defined as clinically overt bleeding that was not major.
A separate analysis of major bleeding across all randomized, controlled, peri-operative,
prophylaxis clinical studies of hip fracture, hip replacement, or knee replacement surgery
according to the time of the first injection of ARIXTRA after surgical closure was performed in
patients who received ARIXTRA only post-operatively. In this analysis, the incidences of major
bleeding were as follows: less than 4 hours was 4.8% (5/104), 4 to 6 hours was 2.3% (28/1,196),
6 to 8 hours was 1.9% (38/1,965). In all studies, the majority (greater than or equal to 75%) of
the major bleeding events occurred during the first 4 days after surgery.
Abdominal Surgery
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In a randomized study of patients undergoing abdominal surgery, ARIXTRA 2.5 mg once daily
(n = 1,433) was compared with dalteparin 5,000 IU once daily (n = 1,425). Bleeding rates are
shown in Table 6.
Table 6. Bleeding in the Abdominal Surgery Study
ARIXTRA
2.5 mg subcutaneously
once daily
Dalteparin Sodium
5,000 IU subcutaneously
once daily
N = 1,433
N = 1,425
Major bleedinga
49 (3.4%)
34 (2.4%)
Fatal bleeding
2 (0.1%)
2 (0.1%)
Non-fatal bleeding at critical site
0 (0%)
0 (0%)
Other non-fatal major bleeding
Surgical site
Non-surgical site
38 (2.7%)
9 (0.6%)
26 (1.8%)
6 (0.4%)
Minor bleedingb
31 (2.2%)
23 (1.6%)
a
Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site
leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial,
retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an
intervention, and/or with a bleeding index (BI) greater than or equal to 2.
b
Minor bleeding was defined as clinically overt bleeding that was not major.
The rates of major bleeding according to the time interval following the first ARIXTRA injection
were as follows: less than 6 hours was 3.4% (9/263) and 6 hours to 8 hours was 2.9% (32/1,112).
Treatment of Deep Vein Thrombosis and Pulmonary Embolism
The rates of bleeding events reported during a dose-response trial (n = 111) and an active-
controlled trial with enoxaparin sodium in DVT treatment (n = 1,091) and an active-controlled
trial with heparin in PE treatment (n = 1,092) with ARIXTRA are provided in Table 7.
Table 7. Bleedinga in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies
ARIXTRA
N = 2,294
Enoxaparin
Sodium
N = 1,101
Heparin
aPTT adjusted IV
N = 1,092
Major bleedingb
28 (1.2%)
13 (1.2%)
12 (1.1%)
Fatal bleeding
3 (0.1%)
0 (0%)
1 (0.1%)
Non-fatal bleeding
at a critical site
3 (0.1%)
0 (0%)
2 (0.2%)
Intracranial bleeding
3 (0.1%)
0 (0%)
1 (0.1%)
Retro-peritoneal
bleeding
0 (0%)
0 (0%)
1 (0.1%)
Other clinically
overt bleedingc
22 (1%)
13 (1.2%)
10 (0.9%)
Minor bleedingd
70 (3.1%)
33 (3%)
57 (5.2%)
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a
Bleeding rates are during the study drug treatment period (approximately 7 days). Patients
were also treated with vitamin K antagonists initiated within 72 hours after the first study
b
drug administration.
Major bleeding was defined as clinically overt: – and/or contributing to death – and/or in a
critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or
adrenal gland – and/or associated with a fall in hemoglobin level greater than or equal to 2
g/dL – and/or leading to a transfusion greater than or equal to 2 units of packed red blood
cells or whole blood.
c
Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of
d
PRBC or whole blood greater than or equal to 2 units.
Minor bleeding was defined as clinically overt bleeding that was not major.
Local Reactions
Local irritation (injection site bleeding, rash, and pruritus) has occurred following subcutaneous
injection of ARIXTRA.
Elevations of Serum Aminotransferases
In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days, asymptomatic
increases in aspartate (AST) and alanine (ALT) aminotransferase levels greater than 3 times the
upper limit of normal were reported in 1.7% and 2.6% of patients, respectively, during treatment
with ARIXTRA 2.5 mg once daily versus 3.2% and 3.9% of patients, respectively, during
treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg once daily enoxaparin
sodium. These elevations are reversible and may be associated with increases in bilirubin. In the
extended prophylaxis clinical trial, no significant differences in AST and ALT levels between
ARIXTRA 2.5 mg and placebo-treated patients were observed.
In the DVT and PE treatment clinical trials, asymptomatic increases in AST and ALT levels
greater than 3 times the upper limit of normal of the laboratory reference range were reported in
0.7% and 1.3% of patients, respectively, during treatment with ARIXTRA. In comparison, these
increases were reported in 4.8% and 12.3% of patients, respectively, in the DVT treatment trial
during treatment with enoxaparin sodium 1 mg/kg every 12 hours and in 2.9% and 8.7% of
patients, respectively, in the PE treatment trial during treatment with aPTT adjusted heparin.
Since aminotransferase determinations are important in the differential diagnosis of myocardial
infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like
ARIXTRA should be interpreted with caution.
Other Adverse Reactions
Other adverse reactions that occurred during treatment with ARIXTRA in clinical trials with
patients undergoing hip fracture, hip replacement, or knee replacement surgery are provided in
Table 8.
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Table 8. Adverse Reactions Across Randomized, Controlled, Hip Fracture Surgery, Hip
Replacement Surgery, and Knee Replacement Surgery Studies
Adverse
Reactions
Peri-Operative Prophylaxis
(Day 1 to Day 7 ± 1 post-surgery)
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-surgery)
ARIXTRA
2.5 mg
subcutaneously
once daily
Enoxaparin
Sodiuma, b
ARIXTRA
2.5 mg
subcutaneously
once daily
Placebo
subcutaneously
once daily
N = 3,616
N = 3,956
N = 327
N = 329
Anemia
707 (19.6%)
670 (16.9%)
5 (1.5%)
4 (1.2%)
Insomnia
179 (5%)
214 (5.4%)
3 (0.9%)
1 (0.3%)
Wound drainage
increased
161 (4.5%)
184 (4.7%)
2 (0.6%)
0 (0%)
Hypokalemia
152 (4.2%)
164 (4.1%)
0 (0%)
0 (0%)
Dizziness
131 (3.6%)
165 (4.2%)
2 (0.6%)
0 (0%)
Purpura
128 (3.5%)
137 (3.5%)
0 (0%)
0 (0%)
Hypotension
126 (3.5%)
125 (3.2%)
1 (0.3%)
0 (0%)
Confusion
113 (3.1%)
132 (3.3%)
4 (1.2%)
1 (0.3%)
Bullous eruptionc
112 (3.1%)
102 (2.6%)
0 (0%)
1 (0.3%)
Hematoma
103 (2.8%)
109 (2.8%)
7 (2.1%)
1 (0.3%)
Post-operative
hemorrhage
85 (2.4%)
69 (1.7%)
2 (0.6%)
2 (0.6%)
a
Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
b
Not approved for use in patients undergoing hip fracture surgery.
c
Localized blister coded as bullous eruption.
The most common adverse reaction in the abdominal surgery trial was post-operative wound
infection (4.9%), and the most common adverse reaction in the VTE treatment trials was
epistaxis (1.3%).
Clinical Trials Experience in Pediatric Patients
Safety data for use of ARIXTRA in the treatment of VTE in pediatric patients aged 1 year or
older is available from Study FDPX-IJS-7001. In Study FDPX-IJS-7001 (n = 366), the median
duration of treatment with fondaparinux sodium injection, including ARIXTRA, was 85 days
(range 1 day to 3,768 days).
The incidence of major bleeding events, defined as per the ISTH criteria, was the primary safety
outcome of interest in Study FDPX-IJS-7001. Seven patients (1.9%) had composite major
bleeding events: 1 patient (0.3%) had clinically overt bleeding (associated with a decrease in
hemoglobin of at least 20 g/L (2 g/dL) in a 24-hour period), 3 patients (0.8%) had bleeding that
was retroperitoneal, pulmonary, intracranial, or otherwise involved the central nervous system,
and 3 patients (0.8%) had major bleeding that required surgical intervention in an operating suite.
Major bleeding events resulted in the interruption of fondaparinux sodium injection treatment for
4 patients and the discontinuation of fondaparinux sodium injection for 3 patients. All major
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bleeding events were reported in patients between the ages of greater than or equal to 2 years to
less than 18 years.
Eleven patients (3%) had non-major bleeding events: 8 patients (2.2%) had overt bleeding for
which a blood product was administered, and which was not directly attributable to the patient’s
underlying medical condition and 4 patients (1.1%) had bleeding that required medical or
surgical intervention to restore hemostasis other than in an operating room. All non-major
bleeding events warranted either interruption or withdrawal of fondaparinux sodium injection
treatment except for 1 patient for whom the action taken with fondaparinux was not reported. All
non-major bleeding events were reported in patients between the ages of greater than or equal to
2 years to less than 18 years.
Overall, 65 patients (18%) had composite minor bleeding events: 64 patients (18%) had overt or
macroscopic evidence of bleeding that did not fulfill the criteria for either major bleeding or
clinically relevant, non-major bleeding and two patients (0.5%) had non-major menstrual
bleeding which resulted in a medical consultation and/or intervention.
Other Adverse Reactions
Other adverse reactions that occurred during treatment with fondaparinux sodium injection in
pediatric studies included: anemia, thrombocytopenia, allergic reactions, generalized skin
associated events, abnormal liver function, hypokalemia, and hypotension.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ARIXTRA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
In the postmarketing experience, epidural or spinal hematoma has been reported in association
with the use of ARIXTRA by subcutaneous (SC) injection [see Warnings and Precautions
(5.1)]. Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-
induced thrombocytopenia have been reported in the postmarketing experience and cases of
elevated aPTT temporally associated with bleeding events have been reported following
administration of ARIXTRA (with or without concomitant administration of other
anticoagulants) [see Warnings and Precautions (5.5)].
Serious allergic reactions, including angioedema, anaphylactoid/anaphylactic reactions have
been reported with the use of ARIXTRA [see Contraindications (4)].
Elevations of hepatic transaminases have been reported in pediatric patients with elevations
greater than 10x ULN.
7
DRUG INTERACTIONS
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In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants
(warfarin sodium), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin
did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium. In
addition, ARIXTRA neither influenced the pharmacodynamics of warfarin sodium,
acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state.
Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of
therapy with ARIXTRA unless these agents are essential. If co-administration is necessary,
monitor patients closely for hemorrhage [see Warnings and Precautions (5.2)].
In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of
coumarin by fondaparinux (200 micromolar i.e., 350 mg/L) was 17% to 28%. Inhibition of the
other isozymes evaluated (CYPs 1A2, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0% to 16%. Since
fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, or CYP3A4) in vitro, fondaparinux sodium is not expected to significantly
interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes.
Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII, no
drug interactions by protein-binding displacement are expected.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Available data from published literature and postmarketing reports have not reported a clear
association with fondaparinux sodium and adverse developmental outcomes. Fondaparinux
sodium plasma concentrations obtained from four women treated with ARIXTRA during
pregnancy and their newborn infants demonstrated low placental transfer of fondaparinux
sodium (see Data). There are risks to the mother associated with untreated venous
thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with
use of anticoagulants (see Clinical Considerations). In animal reproduction studies, there was no
evidence of adverse developmental outcomes when fondaparinux sodium was administered to
pregnant rats and rabbits during organogenesis at doses 32 times and 65 times, respectively, the
recommended human dose based on body surface area.
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
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---
Pregnancy confers an increased risk for thromboembolism that is higher for women with
underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data
describe that women with a previous history of venous thrombosis are at high risk for recurrence
during pregnancy.
Fetal/Neonatal Adverse Reactions
Fondaparinux sodium has been demonstrated to cross the placenta in humans (see Data). Use of
anticoagulants, including fondaparinux sodium, may increase the risk of bleeding in the fetus and
neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.2, 5.4, 5.6)].
Labor or Delivery
All patients receiving anticoagulants, including pregnant women, are at risk for bleeding.
Fondaparinux sodium use during labor or delivery in women who are receiving neuraxial
anesthesia may result in epidural or spinal hematomas. Pregnant women receiving fondaparinux
sodium should be carefully monitored for evidence of bleeding or unexpected changes in
coagulation parameters. Consideration for use of a shorter acting anticoagulant should be
specifically addressed as delivery approaches [see Warnings and Precautions (5.1, 5.6)].
Data
Human Data
In a study of five pregnant women treated with fondaparinux sodium during the third trimester of
pregnancy at a dose of 2.5 mg/day, four of the women had elevated anti-factor Xa activity noted
in the cord blood. Anti-factor Xa clotting times in these four cases were between 37.5 seconds
and 50.9 seconds. The patient who did not have elevated anti-factor Xa activity had received
only one dose of fondaparinux sodium 22 hours prior to delivery. The concentration of
fondaparinux sodium in umbilical cord plasma was approximately 1/10th the level of
fondaparinux sodium in maternal plasma. None of the infants experienced adverse effects.
Animal Data
Embryo-fetal development studies have been conducted with fondaparinux sodium in pregnant
rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose
based on body surface area) administered from days 6 to 17 of gestation and pregnant rabbits at
subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on
body surface area) administered from days 6 to 18 of gestation. These studies have revealed no
evidence of adverse developmental outcomes when fondaparinux sodium was administered to
pregnant rats and rabbits during organogenesis. Additionally, there were no effects on pre- and
postnatal development in a study conducted in rats at subcutaneous doses up to 10 mg/kg/day
(about 32 times the recommended human dose based on body surface area).
8.2
Lactation
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Risk Summary
There are no data on the presence of fondaparinux sodium in human milk, or the effects on milk
production. Limited clinical data during lactation preclude a clear determination of the risk of
ARIXTRA to an infant during lactation; therefore, the developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for ARIXTRA and any
potential adverse effects on the breastfed infant from ARIXTRA or from the underlying maternal
condition.
8.4
Pediatric Use
The safety and effectiveness of ARIXTRA for the treatment of venous thromboembolism have
been established in pediatric patients aged 1 year and older weighing at least 10 kg. Use of
ARIXTRA for this indication is supported by evidence from adequate and well-controlled
studies in adults with additional pharmacokinetic, pharmacodynamic, safety, and efficacy data in
pediatric patients aged 0.3 years and older [see Adverse Reactions (6.1), Clinical Pharmacology
(12.4), and Clinical Studies (14.8)]. The frequency, type, and severity of adverse reactions
observed were generally consistent with those observed in adults.
The safety and effectiveness of ARIXTRA have not been established in pediatric patients for the
treatment of venous thromboembolism who are younger than 1 year old, weigh less than 10 kg,
or with any category of renal or hepatic impairment.
The safety and effectiveness of ARIXTRA have not been established in pediatric patients for the
prophylaxis of DVT and treatment of DVT or PE in conjunction with warfarin sodium.
8.5
Geriatric Use
Over 3,000 patients 65 years and older have received ARIXTRA in randomized clinical trials for
the treatment or prophylaxis of DVT and PE. There were over 2,000 patients 65 years of age and
older in the orthopedic surgery clinical studies for prophylaxis of DVT and PE [see Clinical
Studies (14)]. Of the total number of ARIXTRA-treated patients in these orthopedic surgery
studies, 1,111 (30.9%) were 65 years of age to 74 years of age, while 1,227 (34.2%) were 75
years of age and older. No overall differences in effectiveness of ARIXTRA have been observed
between patients 65 years of age and older and younger adult patients. Serious adverse events
were more frequent in patients 65 years of age and older. When using ARIXTRA in elderly
patients, pay particular attention to dosing directions and concomitant medications (especially
anti-platelet medication) [see Warnings and Precautions (5.2)].
Fondaparinux sodium is substantially excreted by the kidney, and the risk of adverse reactions to
ARIXTRA may be greater in patients with impaired renal function. Because geriatric patients are
more likely to have decreased renal function, assess renal function prior to ARIXTRA
administration [see Contraindications (4), Warnings and Precautions (5.3), and Clinical
Pharmacology (12.4)].
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22
In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials
with patients receiving ARIXTRA 2.5 mg, serious adverse events increased with age for patients
receiving ARIXTRA. The incidence of major bleeding in clinical trials of ARIXTRA by age is
provided in Table 9.
Table 9. Incidence of Major Bleeding in Patients Treated with ARIXTRA by Age
Age
Less than 65 years
% (n/N)
65 years to 74
years
% (n/N)
Greater than or
equal to 75 years
% (n/N)
Orthopedic surgerya
Extended prophylaxis
1.8% (23/1,253)
1.9% (1/52)
2.2% (24/1,111)
1.4% (1/71)
2.7% (33/1,277)
2.9% (6/204)
Abdominal surgery
3% (19/644)
3.2% (16/507)
5% (14/282)
DVT and PE treatment
0.6% (7/1,151)
1.6% (9/560)
2.1% (12/583)
a
Includes hip fracture, hip replacement, and knee replacement surgery prophylaxis.
8.6
Renal Impairment
Patients with impaired renal function are at increased risk of bleeding due to reduced clearance
of ARIXTRA [see Contraindications (4) and Warnings and Precautions (5.3)]. Assess renal
function periodically in patients receiving ARIXTRA. Discontinue ARIXTRA immediately in
patients who develop severe renal impairment while on therapy. After discontinuation of
ARIXTRA, its anticoagulant effects may persist for 2 days to 4 days in patients with normal
renal function (i.e., at least 3 to 5 half-lives). The anticoagulant effects of ARIXTRA may persist
even longer in patients with renal impairment [see Clinical Pharmacology (12.4)].
There is no adequate data to support safe and effective use of ARIXTRA in pediatric patients
with renal impairment.
8.7
Hepatic Impairment
Following a single, subcutaneous dose of 7.5 mg of ARIXTRA in patients with moderate hepatic
impairment (Child-Pugh Category B) compared to subjects with normal liver function, changes
from baseline in aPTT, PT/INR, and antithrombin III were similar in the two groups. However, a
higher incidence of hemorrhage was observed in subjects with moderate hepatic impairment than
in normal subjects, especially mild hematomas at the blood sampling or injection site. The
pharmacokinetics of fondaparinux have not been studied in patients with severe hepatic
impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.4)]. There is
no adequate data to support safe and effective use of ARIXTRA in pediatric patients with hepatic
impairment.
10
OVERDOSAGE
Overdose of ARIXTRA may lead to hemorrhagic complications. Discontinue treatment and
initiate appropriate therapy if bleeding complications associated with overdosage occur. There is
no known antidote for ARIXTRA.
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Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of
ARIXTRA can increase by 20% during hemodialysis.
11
DESCRIPTION
ARIXTRA (fondaparinux sodium injection, USP) is a sterile solution containing fondaparinux
sodium. It is a synthetic and specific inhibitor of activated Factor X (Xa). Fondaparinux sodium
is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-β-D-glucopyra
nuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-O
sulfo-α-L-idopyranuronosyl-(1→4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside,
decasodium salt.
The molecular formula of fondaparinux sodium is C31H43N3Na10O49S8 and its molecular weight
is 1728. The structural formula is provided below:
ARIXTRA is supplied as a sterile, preservative-free injectable solution for subcutaneous use.
Each single-dose, prefilled syringe of ARIXTRA, affixed with an automatic needle protection
system, contains 2.5 mg of fondaparinux sodium in 0.5 mL, 5 mg of fondaparinux sodium in 0.4
mL, 7.5 mg of fondaparinux sodium in 0.6 mL, or 10 mg of fondaparinux sodium in 0.8 mL of
an isotonic solution of sodium chloride and water for injection. May also contain sodium
hydroxide and/or hydrochloric acid as pH adjusters. The final drug product is a clear and
colorless to slightly yellow liquid with a pH between 5 and 8.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)
mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium
potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of
Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and
thrombus development.
Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect
on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic
activity or bleeding time.
12.2
Pharmacodynamics
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Anti-Xa Activity: The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived
from fondaparinux plasma concentrations quantified via anti-Factor Xa activity. Only
fondaparinux can be used to calibrate the anti-Xa assay. (The international standards of heparin
or LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is
expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug
increases with increasing drug concentration, reaching maximum values in approximately three
hours.
12.3
Pharmacokinetics
Absorption: Fondaparinux sodium administered by subcutaneous injection is rapidly and
completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of
fondaparinux sodium 2.5 mg in young male subjects, Cmax of 0.34 mg/L is reached in
approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5
mg, once daily, the peak steady-state plasma concentration is, on average, 0.39 mg/L to 0.5 mg/L
and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state
plasma concentration is 0.14 mg/L to 0.19 mg/L. In patients with symptomatic deep vein
thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection
5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 kg to 100 kg), and 10 mg (body
weight greater than 100 kg) once daily, the body-weight-adjusted doses provide similar mean
steady-state peaks and minimum plasma concentrations across all body weight categories. The
mean peak steady-state plasma concentration is in the range of 1.20 mg/L to 1.26 mg/L. In these
patients, the mean minimum steady-state plasma concentration is in the range of 0.46 mg/L to
0.62 mg/L.
Distribution: In healthy adults, intravenously or subcutaneously administered fondaparinux
sodium distributes mainly in blood and only to a minor extent in extravascular fluid as evidenced
by steady state and non-steady state apparent volume of distribution of 7 L to 11 L. Similar
fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture
surgery. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to
antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including
platelet Factor 4 [PF4]) or red blood cells.
Metabolism: In vivo metabolism of fondaparinux has not been investigated since the majority of
the administered dose is eliminated unchanged in urine in individuals with normal kidney
function.
Elimination: In individuals with normal kidney function, fondaparinux is eliminated in urine
mainly as unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single
subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72
hours. The elimination half-life is 17 hours to 21 hours.
12.4
Special Populations
Renal Impairment: Fondaparinux elimination is prolonged in patients with renal impairment
since the major route of elimination is urinary excretion of unchanged drug. In patients
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25
undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance
of fondaparinux is approximately 25% lower in patients with mild renal impairment (CrCl 50
mL/min to 80 mL/min), approximately 40% lower in patients with moderate renal impairment
(CrCl 30 mL/min to 50 mL/min), and approximately 55% lower in patients with severe renal
impairment (less than 30 mL/min) compared to patients with normal renal function. A similar
relationship between fondaparinux clearance and extent of renal impairment was observed in
DVT treatment patients [see Contraindications (4) and Warnings and Precautions (5.3)].
Hepatic Impairment: Following a single, subcutaneous dose of 7.5 mg of ARIXTRA in patients
with moderate hepatic impairment (Child-Pugh Category B), Cmax and AUC were decreased by
22% and 39%, respectively, compared to subjects with normal liver function. The changes from
baseline in pharmacodynamic parameters, such as aPTT, PT/INR, and antithrombin III, were
similar in normal subjects and in patients with moderate hepatic impairment. Based on these
data, no dosage adjustment is recommended in these patients. However, a higher incidence of
hemorrhage was observed in subjects with moderate hepatic impairment than in normal subjects
[see Use in Specific Populations (8.7)]. The pharmacokinetics of fondaparinux have not been
studied in patients with severe hepatic impairment [see Dosage and Administration (2.6)].
Pediatric: Study FDPX-IJS-7001 characterized the fondaparinux peak level of once-daily
subcutaneous fondaparinux sodium injection in 336 pediatric patients by measuring anti-Factor
Xa activity. Of these patients, 93% achieved a therapeutic blood concentration of fondaparinux
(0.5 mg/L to 1 mg/L) during the course of their treatment following the recommended dose
adjustments, as necessary. The median time to reach therapeutic levels across all age groups was
approximately 3 days, with an interquartile range of 2 days to 6 days. Less than 3% of patients
remained in subtherapeutic levels and 5% of patients remained in supratherapeutic levels during
the course of their treatment. Approximately 55% of patients did not require any dose adjustment
to reach a therapeutic blood concentration of fondaparinux during the course of their treatment;
nearly 20% required one dose adjustment, 11% required 2 dose adjustments, and approximately
10% required more than two dose adjustments during the course of treatment to reach therapeutic
concentrations of fondaparinux [see Contraindications (4), Warnings and Precautions (5.4), and
Use in Specific Populations (8.4)].
Geriatric: Fondaparinux elimination is prolonged in patients older than 75 years. In studies
evaluating fondaparinux sodium 2.5 mg prophylaxis in hip fracture surgery or elective hip
surgery, the total clearance of fondaparinux was approximately 25% lower in patients older than
75 years as compared to patients younger than 65 years. A similar relationship between
fondaparinux clearance and age was observed in DVT treatment patients [see Use in Specific
Populations (8.5)].
Patients Weighing Less than 50 kg: Total clearance of fondaparinux sodium is decreased by
approximately 30% in patients weighing less than 50 kg [see Dosage and Administration (2.4)
and Contraindications (4)].
Gender: The pharmacokinetic properties of fondaparinux sodium are not significantly affected
by gender.
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26
Race: Pharmacokinetic differences due to race have not been studied prospectively. However,
studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic
profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were
observed between black and Caucasian patients undergoing orthopedic surgery.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of
fondaparinux sodium.
Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell
(L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, the
rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test.
At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based
on body surface area), fondaparinux sodium was found to have no effect on fertility and
reproductive performance of male and female rats.
14
CLINICAL STUDIES
14.1
Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery in Adult
Patients
In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery,
ARIXTRA 2.5 mg subcutaneously once daily was compared to enoxaparin sodium 40 mg
subcutaneously once daily, which is not approved for use in patients undergoing hip fracture
surgery. A total of 1,711 patients were randomized and 1,673 were treated. Patients ranged in
age from 17 years to 101 years (mean age 77 years) with 25% men and 75% women. Patients
were 99% Caucasian, 1% other races. Patients with multiple traumas affecting more than one
organ system, serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less
than 100,000/mm3 were excluded from the trial. ARIXTRA was initiated after surgery in 88% of
patients (mean 6 hours) and enoxaparin sodium was initiated after surgery in 74% of patients
(mean 18 hours). For both drugs, treatment was continued for 7 ± 2 days. The primary efficacy
endpoint, venous thromboembolism (VTE), was a composite of documented deep vein
thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported up to
Day 11. The efficacy data are provided in Table 10 and demonstrate that under the conditions of
the trial ARIXTRA was associated with a VTE rate of 8.3% compared with a VTE rate of 19.1%
for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 39%, 70%; P <0.001).
Major bleeding episodes occurred in 2.2% of patients receiving ARIXTRA and 2.3% of
enoxaparin sodium patients [see Adverse Reactions (6.1)].
Table 10. Efficacy of ARIXTRA in the Peri-operative Prophylaxis of Thromboembolic
Events Following Hip Fracture Surgery
Endpoint
Peri-operative Prophylaxis
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(Day 1 to Day 7 ± 2 post-surgery)
ARIXTRA
2.5 mg subcutaneously once
daily
Enoxaparin Sodium
40 mg subcutaneously once
daily
n/Na
% (95% CI)
n/Na
% (95% CI)
VTE
52/626
8.3%b (6.3, 10.8)
119/624
19.1% (16.1, 22.4)
All DVT
49/624
7.9%b (5.9, 10.2)
117/623
18.8% (15.8, 22.1)
Proximal DVT
6/650
0.9%b (0.3, 2)
28/646
4.3% (2.9, 6.2)
Symptomatic PE
3/831
0.4%c (0.1, 1.1)
3/840
0.4% (0.1, 1)
a
N = all evaluable hip fracture surgery patients. Evaluable patients were those who were
treated and underwent the appropriate surgery (i.e., hip fracture surgery of the upper third of
the femur), with an adequate efficacy assessment up to Day 11.
b
P value versus enoxaparin sodium <0.001.
c
P value versus enoxaparin sodium: NS.
14.2
Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery
in Adult Patients
In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were
initially treated during the peri-operative period with ARIXTRA 2.5 mg once daily for 7 ± 1
days. Eighty-one (81) of the 737 patients were not eligible for randomization into the 3-week
double-blind period. Three hundred twenty-six (326) patients and 330 patients were randomized
to receive ARIXTRA 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21
± 2 days. Patients ranged in age from 23 years to 96 years (mean age 75 years) and were 29%
men and 71% women. Patients were 99% Caucasian and 1% other races. Patients with multiple
traumas affecting more than one organ system or serum creatinine level more than 2 mg/dL (180
micromol/L) were excluded from the trial. The primary efficacy endpoint, venous
thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or
documented symptomatic pulmonary embolism (PE) reported for up to 24 days following
randomization. The efficacy data are provided in Table 11 and demonstrate that extended
prophylaxis with ARIXTRA was associated with a VTE rate of 1.4% compared with a VTE rate
of 35% for placebo for a relative risk reduction of 95.9% (95% CI = [98.7; 87.1], P <0.0001).
Major bleeding rates during the 3-week extended prophylaxis period for ARIXTRA occurred in
2.4% of patients receiving ARIXTRA and 0.6% of placebo-treated patients [see Adverse
Reactions (6.1)].
Table 11. Efficacy of ARIXTRA Injection in the Extended Prophylaxis of Thromboembolic
Events Following Hip Fracture Surgery
Endpoint
Extended Prophylaxis
(Day 8 to Day 28 ± 2 post-surgery)
ARIXTRA
2.5 mg subcutaneously
once daily
Placebo
subcutaneously
once daily
n/Na
% (95% CI)
n/Na
% (95% CI)
VTE
3/208
1.4%b (0.3, 4.2)
77/220
35% (28.7, 41.7)
All DVT
3/208
1.4%b (0.3, 4.2)
74/218
33.9% (27.7, 40.6)
Reference ID: 5502191
28
Proximal DVT
2/221
0.9%b (0.1, 3.2)
35/222
15.8% (11.2, 21.2)
Symptomatic VTE (all)
1/326
0.3%c (0, 1.7)
9/330
2.7% (1.3, 5.1)
Symptomatic PE
0/326
0%d (0, 1.1)
3/330
0.9% (0.2, 2.6)
a
N = all randomized evaluable hip fracture surgery patients. Evaluable patients were those
who were treated in the post-randomization period, with an adequate efficacy assessment for
up to 24 days following randomization.
b
P value versus placebo <0.001
c
P value versus placebo = 0.021.
d
P value versus placebo = NS.
14.3
Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery in
Adult Patients
In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery,
ARIXTRA 2.5 mg subcutaneously once daily was compared to either enoxaparin sodium 30 mg
subcutaneously every 12 hours (Study 1) or to enoxaparin sodium 40 mg subcutaneously once a
day (Study 2). In Study 1, a total of 2,275 patients were randomized and 2,257 were treated.
Patients ranged in age from 18 years to 92 years (mean age 65 years) with 48% men and 52%
women. Patients were 94% Caucasian, 4% black, less than 1% Asian, and 2% others. In Study 2,
a total of 2,309 patients were randomized and 2,273 were treated. Patients ranged in age from 24
years to 97 years (mean age 65 years) with 42% men and 58% women. Patients were 99%
Caucasian, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180
micromol/L), or platelet count less than 100,000/mm3 were excluded from both trials. In Study 1,
ARIXTRA was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and
enoxaparin sodium was initiated 12 hours to 24 hours (mean 20.25 hours) after surgery in 97%
of patients. In Study 2, ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in
86% of patients and enoxaparin sodium was initiated 12 hours before surgery in 78% of patients.
The first post-operative enoxaparin sodium dose was given within 12 hours after surgery in 60%
of patients and 12 hours to 24 hours after surgery in 35% of patients with a mean of 13 hours.
For both studies, both study treatments were continued for 7 ± 2 days. The efficacy data are
provided in Table 12. Under the conditions of Study 1, ARIXTRA was associated with a VTE
rate of 6.1% compared with a VTE rate of 8.3% for enoxaparin sodium for a relative risk
reduction of 26% (95% CI: -11%, 53%; P = NS). Under the conditions of Study 2, fondaparinux
sodium was associated with a VTE rate of 4.1% compared with a VTE rate of 9.2% for
enoxaparin sodium for a relative risk reduction of 56% (95% CI: 33%, 73%; P <0.001). For the 2
studies combined, the major bleeding episodes occurred in 3% of patients receiving ARIXTRA
and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1)].
Table 12. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following
Hip Replacement Surgery
Study 1
n/Na
% (95% CI)
Study 2
n/Na
% (95% CI)
Endpoint
ARIXTRA
2.5 mg
subcutaneously
Enoxaparin
Sodium
ARIXTRA
2.5 mg
subcutaneously
Enoxaparin
Sodium
Reference ID: 5502191
29
once daily
30 mg
subcutaneously
every 12 hr
once daily
40 mg
subcutaneously
once daily
VTEb
48/787
6.1%c (4.5, 8)
66/797
8.3% (6.5, 10.4)
37/908
4.1%e (2.9, 5.6)
85/919
9.2% (7.5, 11.3)
All DVT
44/784
5.6%d (4.1, 7.5)
65/796
8.2% (6.4, 10.3)
36/908
4.0%e (2.8, 5.4)
83/918
9.0% (7.3, 11.1)
Proximal DVT
14/816
1.7%c (0.9, 2.9)
10/830
1.2% (0.6, 2.2)
6/922
0.7%f (0.2, 1.4)
23/927
2.5% (1.6, 3.7)
Symptomatic PE
5/1,126
0.4%c (0.1, 1)
1/1,128
0.1% (0, 0.5)
2/1,129
0.2%c (0, 0.6)
2/1,123
0.2% (0, 0.6)
a
N = all evaluable hip replacement surgery patients. Evaluable patients were those who were
treated and underwent the appropriate surgery (i.e., hip replacement surgery), with an
adequate efficacy assessment up to Day 11.
b
VTE was a composite of documented DVT and/or documented symptomatic PE reported up
to Day 11.
c
P value versus enoxaparin sodium: NS.
d
P value versus enoxaparin sodium in study 1: <0.05.
e
P value versus enoxaparin sodium in study 2: <0.001.
f
P value versus enoxaparin sodium in study 2: <0.01.
14.4
Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery in
Adult Patients
In a randomized, double-blind, clinical trial in patients undergoing knee replacement surgery
(i.e., surgery requiring resection of the distal end of the femur or proximal end of the tibia),
ARIXTRA 2.5 mg subcutaneously once daily was compared to enoxaparin sodium 30 mg
subcutaneously every 12 hours. A total of 1,049 patients were randomized and 1,034 were
treated. Patients ranged in age from 19 years to 94 years (mean age 68 years) with 41% men and
59% women. Patients were 88% Caucasian, 8% black, less 1% Asian, and 3% others. Patients
with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than
100,000/mm3 were excluded from the trial. ARIXTRA was initiated 6 ± 2 hours (mean 6.25
hours) after surgery in 94% of patients, and enoxaparin sodium was initiated 12 hours to 24
hours (mean 21 hours) after surgery in 96% of patients. For both drugs, treatment was continued
for 7 ± 2 days. The efficacy data are provided in Table 13 and demonstrate that under the
conditions of the trial, ARIXTRA was associated with a VTE rate of 12.5% compared with a
VTE rate of 27.8% for enoxaparin sodium for a relative risk reduction of 55% (95% CI: 36%,
70%; P <0.001). Major bleeding episodes occurred in 2.1% of patients receiving ARIXTRA and
0.2% of enoxaparin sodium patients [see Adverse Reactions (6.1)].
Table 13. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following
Knee Replacement Surgery
Endpoint
ARIXTRA
2.5 mg subcutaneously
once daily
Enoxaparin Sodium
30 mg subcutaneously
every 12 hours
n/Na
% (95% CI)
n/Na
% (95% CI)
Reference ID: 5502191
30
VTEb
45/361
12.5%c (9.2, 16.3)
101/363
27.8% (23.3, 32.7)
All DVT
45/361
12.5%c (9.2, 16.3)
98/361
27.1% (22.6, 32)
Proximal DVT
9/368
2.4%d (1.1, 4.6)
20/372
5.4% (3.3, 8.2)
Symptomatic PE
1/517
0.2%d (0, 1.1)
4/517
0.8% (0.2, 2)
a
N = all evaluable knee replacement surgery patients. Evaluable patients were those who were
treated and underwent the appropriate surgery (i.e., knee replacement surgery), with an
adequate efficacy assessment up to Day 11.
b
VTE was a composite of documented DVT and/or documented symptomatic PE reported up
to Day 11.
c
P value versus enoxaparin sodium <0.001.
d
P value versus enoxaparin sodium: NS.
14.5
Prophylaxis of Thromboembolic Events Following Abdominal Surgery in Patients
at Risk for Thromboembolic Complications in Adult Patients
Abdominal surgery patients at risk included the following: Those undergoing surgery under
general anesthesia lasting longer than 45 minutes who are older than 60 years with or without
additional risk factors; and those undergoing surgery under general anesthesia lasting longer than
45 minutes who are older than 40 years with additional risk factors. Risk factors included
neoplastic disease, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease,
history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or congestive heart failure.
In a randomized, double-blind, clinical trial in patients undergoing abdominal surgery,
ARIXTRA 2.5 mg subcutaneously once daily started postoperatively was compared to dalteparin
sodium 5,000 IU subcutaneously once daily, with one 2,500 IU subcutaneously preoperative
injection and a 2,500 IU subcutaneously first postoperative injection. A total of 2,927 patients
were randomized and 2,858 were treated. Patients ranged in age from 17 years to 93 years (mean
age 65 years) with 55% men and 45% women. Patients were 97% Caucasian, 1% black, 1%
Asian, and 1% others. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L),
or platelet count less than 100,000/mm3 were excluded from the trial. Sixty-nine percent (69%)
of study patients underwent cancer-related abdominal surgery. Study treatment was continued for
7 ± 2 days. The efficacy data are provided in Table 14 and demonstrate that prophylaxis with
ARIXTRA was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for
dalteparin sodium (P = NS).
Table 14. Efficacy of ARIXTRA in the Prophylaxis of Thromboembolic Events Following
Abdominal Surgery
Endpoint
ARIXTRA
2.5 mg subcutaneously
once daily
Dalteparin Sodium
5,000 IU subcutaneously
once daily
n/Na
% (95% CI)
n/Na
% (95% CI)
VTEb
47/1,027
4.6%c (3.4, 6)
62/1,021
6.1% (4.7, 7.7)
All DVT
43/1,024
4.2% (3.1, 5.6)
59/1,018
5.8% (4.4, 7.4)
Proximal DVT
5/1,076
0.5% (0.2, 1.1)
5/1,077
0.5% (0.2, 1.1)
Symptomatic VTE
6/1,465
0.4% (0.2, 0.9)
5/1,462
0.3% (0.1, 0.8)
Reference ID: 5502191
31
a
N = all evaluable abdominal surgery patients. Evaluable patients were those who were
randomized and had an adequate efficacy assessment up to Day 10; non-treated patients and
patients who did not undergo surgery did not get a VTE assessment.
b
VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or
fatal PE reported up to Day 10.
c
P value versus dalteparin sodium: NS.
14.6
Treatment of Deep Vein Thrombosis in Adult Patients
In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute
symptomatic DVT without PE, ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (body
weight 50 kg to 100 kg), or 10 mg (body weight greater than 100 kg) subcutaneously once daily
(ARIXTRA treatment regimen) was compared to enoxaparin sodium 1 mg/kg subcutaneously
every 12 hours. Almost all patients started study treatment in hospital. Approximately 30% of
patients in both groups were discharged home from the hospital while receiving study treatment.
A total of 2,205 patients were randomized and 2,192 were treated. Patients ranged in age from 18
years to 95 years (mean age 61 years) with 53% men and 47% women. Patients were 97%
Caucasian, 2% black, and 1% other races. Patients with serum creatinine level more than 2
mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from the trial.
For both groups, treatment continued for at least 5 days with a treatment duration range of 7 ± 2
days, and both treatment groups received vitamin K antagonist therapy initiated within 72 hours
after the first study drug administration and continued for 90 ± 7 days, with regular dose
adjustments to achieve an INR of 2 to 3. The primary efficacy endpoint was confirmed,
symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 15.
Table 15. Efficacy of ARIXTRA in the Treatment of Deep Vein Thrombosis (All
Randomized)
Endpoint
ARIXTRA
5 mg, 7.5 mg, or 10 mg
subcutaneously
once daily
N = 1,098
Enoxaparin Sodium
1 mg/kg
subcutaneously
every 12 hours
N = 1,107
n
% (95% CI)
n
% (95% CI)
Total VTEa
43
3.9% (2.8, 5.2)
45
4.1% (3, 5.4)
DVT only
18
1.6% (1, 2.6)
28
2.5% (1.7, 3.6)
Non-fatal PE
20
1.8% (1.1, 2.8)
12
1.1% (0.6, 1.9)
Fatal PE
5
0.5% (0.1, 1.1)
5
0.5% (0.1, 1.1)
a
VTE was a composite of symptomatic recurrent non-fatal VTE or fatal PE reported up to
Day 97. The 95% confidence interval for the treatment difference for total VTE was: (-1.8%
to 1.5%).
During the initial treatment period, 18 (1.6%) of patients treated with fondaparinux sodium and
10 (0.9%) of patients treated with enoxaparin sodium had a VTE endpoint (95% CI for the
treatment difference [fondaparinux sodium-enoxaparin sodium] for VTE rates: -0.2%; 1.7%).
14.7
Treatment of Pulmonary Embolism in Adult Patients
Reference ID: 5502191
32
In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute
symptomatic PE, with or without DVT, ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg
(body weight 50 kg to 100 kg), or 10 mg (body weight greater than 100 kg) subcutaneously once
daily (ARIXTRA treatment regimen) was compared to heparin IV bolus (5,000 USP units)
followed by a continuous IV infusion adjusted to maintain 1.5 to 2.5 times aPTT control value.
Patients with a PE requiring thrombolysis or surgical thrombectomy were excluded from the
trial. All patients started study treatment in hospital. Approximately 15% of patients were
discharged home from the hospital while receiving ARIXTRA therapy. A total of 2,213 patients
were randomized and 2,184 were treated. Patients ranged in age from 18 years to 97 years (mean
age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% black, and 1%
other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or
platelet count less than 100,000/mm3 were excluded from the trial. For both groups, treatment
continued for at least 5 days with a treatment duration range 7 ± 2 days, and both treatment
groups received vitamin K antagonist therapy initiated within 72 hours after the first study drug
administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR
of 2 to 3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported
up to Day 97. The efficacy data are provided in Table 16.
Table 16. Efficacy of ARIXTRA in the Treatment of Pulmonary Embolism (All
Randomized)
Endpoint
ARIXTRA
5 mg, 7.5 mg, or 10 mg
subcutaneously
once daily
N = 1,103
Heparin
aPTT adjusted IV
N = 1,110
n
% (95% CI)
n
% (95% CI)
Total VTEa
42
3.8% (2.8, 5.1)
56
5% (3.8, 6.5)
DVT only
12
1.1% (0.6, 1.9)
17
1.5% (0.9, 2.4)
Non-fatal PE
14
1.3% (0.7, 2.1)
24
2.2% (1.4, 3.2)
Fatal PE
16
1.5% (0.8, 2.3)
15
1.4% (0.8, 2.2)
a
VTE was a composite of symptomatic recurrent non-fatal VTE or fatal PE reported up to
Day 97. The 95% confidence interval for the treatment difference for total VTE was: (-3% to
0.5%).
During the initial treatment period, 12 (1.1%) of patients treated with fondaparinux sodium and
19 (1.7%) of patients treated with heparin had a VTE endpoint (95% CI for the treatment
difference [fondaparinux sodium-heparin] for VTE rates: -1.6%; 0.4%).
14.8
Treatment of Venous Thromboembolism in Pediatric Patients
The efficacy of ARIXTRA for the treatment of VTE in pediatric patients aged 1 year and older is
based on an open-label, single-arm retrospective clinical study (FDPX-IJS-7001) in 366 pediatric
patients aged 0.3 years to 17 years with VTE who were treated with fondaparinux sodium
injection, including ARIXTRA, at a single center in a tertiary care pediatric hospital. Out of
these 366 patients, 325 patients with diagnosis of VTE were included in the efficacy analysis set.
Reference ID: 5502191
33
Of the 325 total patients, 30 patients were less than 2 years, 65 patients were 2 years to less than
6 years, 78 patients were 6 years to less than 12 years, and 152 patients were 12 years to less
than18 years. Patients were started on fondaparinux sodium injection 0.1 mg/kg once daily with
doses rounded to the nearest prefilled syringe (2.5 mg, 5 mg, or 7.5 mg) for patients weighing
over 20 kg. For patients weighing 10 kg to 20 kg, dosing was based on body weight without
rounding to the nearest prefilled syringe. Fondaparinux levels were monitored after the second or
third dose until therapeutic levels were achieved. Fondaparinux levels were then monitored
weekly while patients were admitted within the hospital and, after approximately every 1 month
to 3 months while outpatient for the duration of treatment. Dosing adjustments were made to
achieve peak fondaparinux blood concentration within the therapeutic target of 0.5 mg/L to 1
mg/L.
Patients received an initial median dose of approximately 0.1 mg/kg body weight of
fondaparinux sodium injection, which translates into a median dose of 1.37 mg in the less than
20 kg weight group, 2.5 mg in the 20 kg to less than 40 kg weight group, 5 mg in the 40 kg to
less than 60 kg, and 7.5 mg in the greater than or equal to 60 kg weight group. Based on median
values, it took approximately 3 days (range 1 day to 929 days) to achieve therapeutic levels
across all age groups.
The efficacy of ARIXTRA was based on measuring the proportion of pediatric patients with
complete clot resolution up to 3 months (±15 days). Among the 325 pediatric patients in the
efficacy analysis set, 146 (44.9%; 95% CI: 39.6, 50.4) experienced complete resolution of at
least one clot, while 143 (44%; 95% CI: 38.7, 49.4) had complete resolution of all clots.
Summaries of complete clot resolution of patients’ main VTEs at month 3 are provided by age
group (see Table 17) and weight group (see Table 18).
Table 17. Summary of Complete Clot Resolution of Main VTEs Up to Month 3 by Age
Group
Parameter
Less than 2 years
(N=30)
n (%)
Greater than or
equal to 2 years
to less than 6
years
(N=65)
n (%)
Greater than or
equal to 6 years
to less than 12
years
(N=78)
n (%)
Greater than or
equal to 12 years
to less than 18
years
(N=152)
n (%)
Complete Resolution of At
Least One Clot, n (%)
95% Confidence Interval
14 (46.7)
(30.2, 63.9)
26 (40)
(29, 52.1)
40 (51.3)
(40.4, 62.1)
66 (43.4)
(35.8, 51.4)
Complete Resolution of All
Clots, n (%)
95% Confidence Interval
14 (46.7)
(30.2, 63.9)
25 (38.5)
(27.6, 50.6)
39 (50)
(39.2, 60.8)
65 (42.8)
(35.2, 50.7)
Table 18. Summary of Complete Clot Resolution of Main VTEs Up to Month 3 by Weight
Group
Parameter
Less than 20 kg
(N=95)
n (%)
20 kg to less than
40 kg
(N=84)
n (%)
40 kg to less than
60 kg
(N=72)
n (%)
Greater than or
equal to 60 kg
(N=73)
n (%)
Reference ID: 5502191
34
Complete Resolution of At
Least One Clot, n (%)
95% Confidence Interval
42 (44.2)
(34.6, 54.2)
45 (53.6)
(43, 63.8)
30 (41.7)
(31, 53.2)
28 (38.4)
(28.1, 49.8)
Complete Resolution of All
Clots, n (%)
95% Confidence Interval
41 (43.2)
(33.7, 53.2)
45 (53.6)
(43, 63.8)
29 (40.3)
(29.7, 51.8)
27 (37)
(26.8, 48.5)
16
HOW SUPPLIED/STORAGE AND HANDLING
ARIXTRA (fondaparinux sodium injection, USP) is available in single-dose, prefilled syringes
containing clear to practically clear and colorless liquid in the following strengths:
2.5 mg/0.5 mL ARIXTRA in single-dose prefilled syringe, affixed with a 27-gauge x ½-inch
needle and an automatic needle protection system with white plunger rod.
NDC 67457-592-10
10 Single Unit Syringes
5 mg/0.4 mL ARIXTRA in single-dose prefilled syringe, affixed with a 27-gauge x ½-inch
needle and an automatic needle protection system with white plunger rod.
NDC 67457-593-04
10 Single Unit Syringes
7.5 mg/0.6 mL ARIXTRA in single-dose prefilled syringe, affixed with a 27-gauge x ½-inch
needle and an automatic needle protection system with white plunger rod.
NDC 67457-594-06
10 Single Unit Syringes
10 mg/0.8 mL ARIXTRA in single-dose prefilled syringe, affixed with a 27-gauge x ½-inch
needle and an automatic needle protection system with white plunger rod.
NDC 67457-595-08
10 Single Unit Syringes
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to
86°F) [See USP Controlled Room Temperature].
Discard unused portion.
PHARMACIST: Dispense a Patient Information Leaflet with each prescription.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and
Instructions for Use).
17.1
Patient Advice
Reference ID: 5502191
35
[iii] Mylan®
If the patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are
taking concomitant NSAIDS, platelet inhibitors, or other anticoagulants, inform patients to watch
for signs and symptoms of spinal or epidural hematomas, such as back pain, tingling, numbness
(especially in the lower limbs), muscular weakness, and stool or urine incontinence. If any of
these symptoms occur, advise patients to contact his or her physician immediately.
The use of aspirin and other NSAIDS may enhance the risk of hemorrhage. Advise patients to
discontinue use prior to ARIXTRA therapy whenever possible; if co-administration is essential,
the patient’s clinical and laboratory status should be closely monitored [see Drug Interactions
(7)].
If patients must self-administer ARIXTRA or if administered by a caregiver, (e.g., if ARIXTRA
is used at home), advise patients of the following:
• Advise patients that ARIXTRA should be given by subcutaneous injection. Instruct patients
in the proper technique for administration.
• Instruct patients that if they miss a dose of ARIXTRA, to inject the dose as soon as they
remember. Advise patients not to inject two doses at the same time.
• The most important risk with ARIXTRA administration is bleeding. Counsel patients on
signs and symptoms of possible bleeding.
• Advise patients that it may take them longer than usual to stop bleeding.
• Advise patients that they may bruise and/or bleed more easily when they are treated with
ARIXTRA.
• Advise patients to report any unusual bleeding, bruising, or signs of thrombocytopenia (such
as a rash of dark red spots under the skin) to their physician [see Warnings and Precautions
(5.2, 5.5)].
• Advise patients to tell their physicians and dentists they are taking ARIXTRA and/or any
other product known to affect bleeding before any surgery is scheduled and before any new
drug is taken [see Warnings and Precautions (5.2)].
• Advise patients to tell their physicians and dentists of all medications they are taking,
including those obtained without a prescription, such as aspirin or other NSAIDs [see Drug
Interactions (7)].
Manufactured for:
Mylan Institutional LLC
Morgantown, WV 26505 U.S.A.
Manufactured by:
Aspen Notre Dame de Bondeville
Notre Dame de Bondeville, France
MI:ARXTIJ:R7p
36
Reference ID: 5502191
PATIENT INFORMATION
ARIXTRA® (Ah-RIX-trah)
(fondaparinux sodium injection)
for subcutaneous use
What is the most important information I should know about ARIXTRA?
ARIXTRA may cause serious side effects, including:
•
Spinal or epidural blood clots (hematoma). People who take a blood thinner medicine (anticoagulant) like
ARIXTRA, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of
forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of
developing a spinal or epidural blood clot is higher if:
o
a thin tube called an epidural catheter is placed in your back to give you certain medicine
o
you take non-steroidal anti-inflammatory drugs (NSAIDs) or a medicine to help prevent blood from clotting
o
you have a history of difficult or repeated epidural or spinal punctures
o
you have a history of problems with your spine or have had surgery on your spine
If you use ARIXTRA and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely
for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have back pain, tingling,
numbness, muscle weakness (especially in your legs and feet), and loss of control of your bowels or bladder
(incontinence).
Because the risk of bleeding may be higher, tell your doctor before using ARIXTRA if you:
o
are also taking certain other medicines that affect blood clotting such as aspirin, an NSAID (for example,
ibuprofen or naproxen), clopidogrel, or warfarin sodium
o
have bleeding problems
o
had problems in the past with pain medication given through the spine
o
have had surgery to your spine
o
have a spinal deformity
See “What are the possible side effects of ARIXTRA?” for more information about side effects.
What is ARIXTRA?
ARIXTRA is a prescription medicine that is used to:
•
help prevent blood clots from forming in adults who have had certain surgeries of the hip, knee, or the stomach-
area (abdominal surgery).
•
treat adults who have blood clots in their legs or blood clots that travel to their lungs, along with the blood thinner
medicine called warfarin sodium.
•
treat children 1 year of age or older weighing at least 22 pounds (10 kg) who have blood clots.
It is not known if ARIXTRA is safe and effective for use in children:
•
younger than 1 year of age and weighing less than 22 pounds (10 kg) who have blood clots.
•
younger than 1 year of age with kidney problems.
•
for the prevention of blood clots in the legs and to treat blood clots in the legs or lungs when given with warfarin
sodium.
•
with liver problems.
Who should not use ARIXTRA?
Do not use ARIXTRA if you:
•
have certain kidney problems
•
have active bleeding problems
•
have an infection in your heart
•
have low platelet counts and if you test positive for a certain antibody during treatment with ARIXTRA
•
weigh less than 110 pounds (50 kg) and ARIXTRA will be used to help prevent blood clots in adults undergoing
certain surgery. See “What are the possible side effects of ARIXTRA?”
•
had a serious allergic reaction to ARIXTRA
Before using ARIXTRA, tell your doctor about all of your medical conditions, including if you:
•
have had any bleeding problems (such as stomach ulcers)
•
have had a stroke
•
have had recent surgeries, including eye surgery
•
have diabetic eye disease
•
have kidney or liver problems
•
have uncontrolled high blood pressure
•
have a latex allergy. The packaging (needle guard) for ARIXTRA contains dry natural latex rubber.
Reference ID: 5502191
•
are pregnant or plan to become pregnant. ARIXTRA may harm your unborn baby. If you are pregnant, talk to your
doctor about the best way for you to prevent or treat blood clots.
•
are breastfeeding or plan to breastfeed. It is not known if ARIXTRA passes into breast milk. You and your doctor
should decide if you will breastfeed during treatment with ARIXTRA.
Tell your doctor about all the medicines you take including prescriptions and over-the-counter medicines, vitamins,
and herbal supplements. Some medicines can increase your risk of bleeding.
See “What is the most important information I should know about ARIXTRA?” Do not start taking any new
medicines without first talking to your doctor.
Tell all your doctors and dentist that you use ARIXTRA, especially if you need to have any kind of surgery or a dental
procedure. Keep a list of your medicines and show it to all your doctors and pharmacist before you start a new
medicine.
How should I use ARIXTRA?
•
ARIXTRA is available in different types of syringes. Your doctor will decide which type of syringe is best for you or
your child. See the Instructions for Use to confirm the prescribed syringe and how to give an ARIXTRA injection.
•
If your doctor tells you that you may give yourself or your child injections of ARIXTRA at home, you will be shown
how to give the injections first before you do them on your own.
•
Use ARIXTRA exactly as your doctor tells you to.
•
ARIXTRA is given as an injection under your skin (subcutaneous injection).
•
If you miss a dose of ARIXTRA, inject your dose as soon as you remember. Do not inject 2 doses at the same time.
•
Your doctor may perform blood tests and test for blood in your stool as needed during treatment with ARIXTRA to
check for side effects.
•
If you inject too much ARIXTRA, call your doctor right away.
What are possible side effects of ARIXTRA?
ARIXTRA can cause serious side effects. See “What is the most important information I should know about
ARIXTRA?”
•
Severe bleeding. Certain conditions can increase your risk for severe bleeding, including:
o
some bleeding problems
o
some gastrointestinal problems including ulcers
o
some types of strokes
o
uncontrolled high blood pressure
o
diabetic eye disease
o
soon after brain, spine, or eye surgery
In children, certain conditions that can increase risk of bleeding, include:
o
systemic lupus erythematous (also known as Lupus)
o
Wilms tumor
o
antiphospholipid syndrome
o
genetic conditions that affect blood clotting
o
cancer
o
decreased red blood cells, white blood cells and platelets (pancytopenia)
o
indwelling chest tubes
o
chest surgery
o
infection
o
severe high blood pressure that affects the brain
o
enlarged or blocked lymph vessels in the small intestine (intestinal lymphangiectasia)
•
Certain kidney problems can also increase your risk of bleeding with ARIXTRA. Your doctor may check your
kidney function during your treatment with ARIXTRA.
•
Increased bleeding risk in adults who weigh less than 110 pounds (50 kg) undergoing certain surgeries.
•
Low blood platelets (thrombocytopenia). Platelets are blood cells that help your blood to clot normally. Your
doctor may check your platelet counts during your treatment with ARIXTRA.
You may bruise or bleed more easily during your treatment with ARIXTRA, and it may take longer than usual for
bleeding to stop. Tell your doctor if you have any signs or symptoms of bleeding, bruising or rash of dark red spots
under the skin during your treatment with ARIXTRA.
The most common side effects of ARIXTRA in adults include:
•
bleeding problems
•
purplish spots on skin (purpura)
•
bleeding, rash, and itching at the injection site
•
low blood pressure (hypotension)
(injection site reactions)
•
confusion
•
increased blood levels of certain liver tests
•
fluid-filled blisters (bullous eruption)
•
low red blood cell counts (anemia)
•
blood clots (hematoma)
Reference ID: 5502191
[fil)Mylan®
•
sleep problems (insomnia)
•
severe bleeding after surgery (post-operative
•
increased wound drainage
hemorrhage)
•
low potassium in your blood (hypokalemia)
•
infection
•
dizziness
The most common side effects of ARIXTRA in children include:
•
bleeding problems
•
skin problems
•
low red blood cell counts (anemia)
•
abnormal blood levels of certain liver tests
•
low blood platelet counts
•
low potassium in your blood (hypokalemia)
•
allergic reaction, such as sudden swelling of your
•
low blood pressure (hypotension)
face, tongue, throat, or troubled swallowing
These are not all the possible side effects of ARIXTRA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ARIXTRA?
•
See the product label for complete instructions on how to store ARIXTRA.
•
Throw away (discard) ARIXTRA that is out of date (expired) or unused.
Keep ARIXTRA and all medicines out of the reach of children.
General information about the safe and effective use of ARIXTRA
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use
ARIXTRA for a condition for which it was not prescribed. Do not give ARIXTRA to other people, even if they have the
same symptoms that you have. It may harm them.
You can ask your pharmacist or doctor for information about ARIXTRA that is written for healthcare professionals.
What are the ingredients in ARIXTRA?
Active ingredient: fondaparinux sodium
Inactive ingredients: sodium chloride and water for injection. May also contain sodium hydroxide and/or hydrochloric
acid as pH adjusters.
Manufactured for:
Mylan Institutional LLC
Morgantown, WV 26505 U.S.A.
Manufactured by:
Aspen Notre Dame de Bondeville
Notre Dame de Bondeville, France
For more information about ARIXTRA, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX).
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
MI:PL:ARXTIJ:R7p
Reference ID: 5502191
c
INSTRUCTIONS FOR USE
ARIXTRA® (Ah-RIX-trah)
(fondaparinux sodium injection)
for subcutaneous use
This Instructions for Use contains information on how to inject ARIXTRA. Before you use ARIXTRA, read
and follow the step-by-step instructions. Talk to your child’s doctor or pharmacist if you have any
questions.
Important Information You Need to Know Before Injecting ARIXTRA
•
ARIXTRA is available in different types of syringes. Confirm the syringe looks like the figure
below before you continue:
•
Your healthcare provider should show you how to prepare and inject ARIXTRA. Do not inject your
child until you have been shown how to inject ARIXTRA.
•
Each ARIXTRA syringe is 1 dose of ARIXTRA. The syringe is for a one-time use only.
•
Use ARIXTRA exactly as prescribed by your doctor.
How should I store ARIXTRA syringes?
•
Store ARIXTRA syringes in a refrigerator between 36°F to 46°F (2°C to 8°C) for up to the beyond use
date on the syringe.
•
Do not freeze.
•
Store syringes in a clean container in the refrigerator.
•
Do not store ARIXTRA syringes at room temperature between 68°F to 77°F (20°C to 25°C).
•
Take ARIXTRA syringe out of the refrigerator and allow it to reach room temperature. Inject right
away after the syringe reaches room temperature.
•
Throw away (dispose of) ARIXTRA syringes that has been left at room temperature for longer than 4
hours.
•
Keep ARIXTRA syringes and all medicines out of the reach of children.
Do not use ARIXTRA if:
•
the solution appears discolored (the solution should normally appear clear)
•
you see any particles in the solution
•
the syringe is damaged, including:
o
cracks, breaks, or bends in the syringe or the plunger
o
broken, bent, or detached needle
o
medicine leaking from the plunger or needle
•
past the beyond use date on the syringe labeled by the pharmacy
How should I give an injection of ARIXTRA?
ARIXTRA is injected into a skin fold of the lower stomach-area (abdomen) as directed by your child’s
doctor. Do not inject ARIXTRA into muscle.
Instructions for injecting ARIXTRA
Parts of the ARIXTRA syringe:
Reference ID: 5502191
(
A
Lower Stomach
Area (Abdomen)
1. Rigid needle guard
2. Finger-grip
3. Plunger
1. Wash your hands well with soap and water, rinse, and towel dry.
2. Instruct your child to sit or lie
down in a comfortable position.
Choose a spot on the lower
stomach-area (abdomen), at
least 2 inches below the belly
button (Figure A). Change
(alternate) between using the
left and right side of the lower
abdomen for each injection
Figure A.
3. Clean the injection area with an alcohol swab.
4. Remove the needle guard, by
pulling it in a straight line away
from the body of the syringe
(Figure B). Throw away
(discard) the needle guard.
•
Do not touch the needle
or let it come in contact
with any surface before
the injection. A small air
bubble in the syringe is
normal.
•
To be sure that you do not
lose any medicine from the
syringe, do not try to
remove air bubbles from
the syringe before giving
the injection.
Figure B.
Reference ID: 5502191
5. Gently pinch the skin that has
been cleaned to make a fold.
Hold the fold between the
thumb and the forefinger of one
hand during the entire injection
(Figure C).
Figure C.
6. Hold the syringe firmly in your
other hand using the finger grip.
Insert the full length of the
needle straight down into your
skinfold (at an angle of 90°)
(Figure D).
Figure D.
7. Inject all of the medicine in the
syringe by using your thumb to
firmly press down on the
plunger as far as it goes (Figure
E).
Reference ID: 5502191
[iii] Mylan®
Figure E.
8. Pull out the needle at the same
angle you inserted in (Figure F).
Figure F.
9. Throw away (dispose of) used and unused ARIXTRA needles and syringes:
•
Put your used ARIXTRA needles and syringes in an FDA-cleared sharps disposal container right
away after use. Do not throw away (dispose of) loose needles and syringes in your household
trash.
•
If you do not have an FDA-cleared sharps disposal container, you may use a household container
that is:
o
made of a heavy-duty plastic,
o
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
o
upright and stable during use,
o
leak-resistant, and
o
properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be state or
local laws about how you should throw away used needles and syringes. For more information
about safe sharps disposal, and for specific information about sharps disposal in the state that you
live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
This Instructions for Use has been approved by the U.S. Food and Drug Administration
Revised: 12/2024
Manufactured for:
Mylan Institutional LLC
Morgantown, WV 26505 U.S.A.
Manufactured by:
Aspen Notre Dame de Bondeville
Notre Dame de Bondeville, France
MI:IFU2:ARXTIJ:R1p
Reference ID: 5502191
G) Cl© tl
0
INSTRUCTIONS FOR USE
ARIXTRA® (Ah-RIX-trah)
(fondaparinux sodium injection)
for subcutaneous use
This Instructions for Use contains information on how to inject ARIXTRA. Before you use ARIXTRA, read
and follow the step-by-step instructions. Talk to your or your child’s doctor or pharmacist if you have any
questions.
Important Information You Need to Know Before Injecting ARIXTRA
•
ARIXTRA is available in different types of syringes. Confirm the syringe looks like the figure
below before you continue:
•
Your healthcare provider should show you how to prepare and inject ARIXTRA. Do not inject yourself
or someone else until you have been shown how to inject ARIXTRA.
•
Each ARIXTRA syringe is 1 dose of ARIXTRA. The syringe is for a one-time use only.
•
Use ARIXTRA exactly as prescribed by your doctor.
•
The packaging (needle guard) for ARIXTRA contains dry natural latex rubber.
How should I store ARIXTRA syringes?
•
Store ARIXTRA at room temperature between 68°F to 77°F (20°C to 25°C).
•
Keep ARIXTRA syringes and all medicines out of the reach of children.
Do not use ARIXTRA if:
•
the solution appears discolored (the solution should normally appear clear)
•
you see any particles in the solution
•
the syringe is damaged
•
it is out of date (expired)
How should I give an injection of ARIXTRA?
ARIXTRA is injected into a skinfold of the lower stomach-area (abdomen) as directed by your or your
child’s doctor. Do not inject ARIXTRA into muscle.
Instructions for injecting ARIXTRA
Parts of the ARIXTRA syringe:
1. Rigid needle guard
2. Plunger
3. Finger-grip
4. Security sleeve
Syringe Before Use
Syringe After Use
Reference ID: 5502191
0
A
Lower Stomach
Area (Abdomen)
1. Wash your hands well with soap and water, rinse, and towel dry.
2. Sit or lie down in a comfortable position. If
giving the injection to a child, instruct child to
sit or lie down in a comfortable position.
Choose a spot on the lower stomach-area
(abdomen), at least 2 inches below the belly
button (Figure A). Change (alternate) between
using the left and right side of the lower
abdomen for each injection.
Figure A.
3. Clean the injection area with an alcohol swab.
4. Remove the needle guard, by first twisting it
counter-clockwise and then pulling it in a
straight line away from the body of the syringe
(Figure B). Throw away (discard) the needle
guard.
•
Do not touch the needle or let it come
in contact with any surface before the
injection. A small air bubble in the
syringe is normal.
•
To be sure that you do not lose any
medicine from the syringe, do not try to
remove air bubbles from the syringe
before giving the injection.
Figure B.
Reference ID: 5502191
5. Gently pinch the skin that has been cleaned
to make a fold. Hold the fold between the
thumb and the forefinger of one hand during
the entire injection (Figure C).
Figure C.
6. Hold the syringe firmly in your other hand
using the finger grip. Insert the full length of
the needle straight into your skinfold at an
angle of 90° (Figure D).
Figure D.
7. Inject all of the medicine in the syringe by
using your thumb to firmly press down on the
plunger as far as it goes. This will activate the
automatic needle protection system (Figure
E).
Figure E.
Reference ID: 5502191
[ig]Mylan®
8. Release the plunger.
•
The needle will withdraw automatically
from the skin and pull back (retract) into
the security sleeve where it will be locked
(Figure F).
•
A white safety indicator will appear above
the upper body of the syringe.
•
You may hear or feel a soft click after the
plunger rod is released.
Figure F.
9. Throw away (dispose of) used and unused ARIXTRA syringes:
•
Put your used ARIXTRA needles and syringes in an FDA-cleared sharps disposal container right
away after use. Do not throw away (dispose of) loose needles and syringes in your household
trash.
•
If you do not have an FDA-cleared sharps disposal container, you may use a household container
that is:
o
made of a heavy-duty plastic,
o
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
o
upright and stable during use,
o
leak-resistant, and
o
properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow your community
guidelines for the right way to dispose of your sharps disposal container. There may be state or
local laws about how you should throw away used needles and syringes. For more information
about safe sharps disposal, and for specific information about sharps disposal in the state that you
live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal container.
This Instructions for Use has been approved by the U.S. Food and Drug Administration
Revised: 12/2024
Manufactured for:
Mylan Institutional LLC
Morgantown, WV 26505 U.S.A.
Manufactured by:
Aspen Notre Dame de Bondeville
Notre Dame de Bondeville, France
MI:IFU1:ARXTIJ:R7p
Reference ID: 5502191
| custom-source | 2025-02-12T15:48:14.832462 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021345s052lbl.pdf', 'application_number': 21345, 'submission_type': 'SUPPL ', 'submission_number': 52} |
80,758 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
TEVIMBRA safely and effectively. See full prescribing information for
TEVIMBRA.
TEVIMBRA® (tislelizumab-jsgr) injection, for intravenous use
Initial U.S. Approval: 2024
----------------------------RECENT MAJOR CHANGES-------------------------
Indications and Usage (1.2)
12/2024
Dosage and Administration (2.1, 2.2)
12/2024
----------------------------INDICATIONS AND USAGE--------------------------
TEVIMBRA is a programmed death receptor-1 (PD-1)-blocking antibody
indicated for:
Esophageal Cancer
x as a single agent in adults with unresectable or metastatic esophageal
squamous cell carcinoma (ESCC) after prior systemic chemotherapy that
did not include a PD-(L)1 inhibitor. (1.1)
Gastric Cancer
x in combination with platinum and fluoropyrimidine-based chemotherapy in
adults for the first line treatment of unresectable or metastatic HER2
negative gastric or gastroesophageal junction adenocarcinoma whose
tumors express PD-L1 (1). (1.2)
----------------------DOSAGE AND ADMINISTRATION----------------------
Recommended Dosage:
200 mg as an intravenous infusion once every 3 weeks. Administer the first
infusion over 60 minutes. If tolerated, subsequent infusions may be
administered over 30 minutes. (2.1)
-----------------------DOSAGE FORMS AND STRENGTHS -------------------
Injection: 100 mg/10 mL (10 mg/mL) solution in a single-dose vial. (3)
------------------------------CONTRAINDICATIONS ----------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS ----------------------
x Immune-Mediated Adverse Reactions: (5.1)
o Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue, including the following: immune-
mediated pneumonitis, immune-mediated colitis, immune-mediated
hepatitis, immune-mediated endocrinopathies, immune-mediated
nephritis with renal dysfunction, immune-mediated dermatologic adverse
reactions, and solid organ transplant rejection.
o Monitor for early identification and management. Evaluate liver enzymes,
creatinine, and thyroid function at baseline and periodically during
treatment.
o Withhold or permanently discontinue TEVIMBRA based on the severity
of reaction.
x Infusion-Related Reactions: Slow the rate of infusion, interrupt, or
permanently discontinue based on severity of infusion reaction. (5.2)
x Complications of Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT): Fatal and other serious complications can occur in patients who
receive allogeneic HSCT before or after being treated with a PD-1/PD-L1
blocking antibody. (5.3)
x Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use of effective
contraception. (5.4, 8.1, 8.3)
------------------------------ADVERSE REACTIONS ----------------------------
The most common adverse reactions (20%) of TEVIMBRA as a single
agent, including laboratory abnormalities with TEVIMBRA were: increased
glucose, decreased hemoglobin, decreased lymphocytes, decreased sodium,
decreased albumin, increased alkaline phosphatase, anemia, fatigue, increased
AST, musculoskeletal pain, decreased weight, increased ALT, and cough.
The most common adverse reactions (20%), including laboratory
abnormalities of TEVIMBRA in combination with platinum and
fluoropyrimidine-based chemotherapy: nausea, fatigue, decreased appetite,
anemia, peripheral sensory neuropathy, vomiting, decreased platelet count ,
decreased neutrophil count, increased aspartate aminotransferase, diarrhea,
abdominal pain, increased alanine aminotransferase, decreased white blood
cell count, decreased weight, and pyrexia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact BeiGene at 1
877-828-5596 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Esophageal Cancer
1.2 Gastric Cancer
2
DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Dosage
2.2 Dosage Modifications for Adverse Reactions
2.3 Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Severe and Fatal Immune-Mediated Adverse Reactions
5.2 Infusion-Related Reactions
5.3 Complications of Allogeneic HSCT
5.4 Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 Immunogenicity
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Esophageal Squamous Cell Carcinoma
14.2 Gastric Cancer
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5502689
1
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Esophageal Cancer
TEVIMBRA, as a single agent, is indicated for the treatment of adults with unresectable or metastatic esophageal
squamous cell carcinoma after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor.
1.2
Gastric Cancer
TEVIMBRA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line
treatment of adults with unresectable or metastatic HER2-negative gastric or gastroesophageal junction
adenocarcinoma (G/GEJ) whose tumors express PD-L1 (1).
2
DOSAGE AND ADMINISTRATION
2.1
Patient Selection
Select patients for the first-line treatment of unresectable or metastatic HER2-negative gastric or gastroesophageal
junction adenocarcinoma (G/GEJ) based on the presence of PD-L1 in tumor specimens [see Clinical Studies (14.2)].
An FDA-approved companion diagnostic for the detection of PD-L1 in patients with unresectable or metastatic
HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ) is not available.
2.2
Recommended Dosage
The recommended dosage of TEVIMBRA as a single agent or in combination with platinum and fluoropyrimidine
containing chemotherapy is 200 mg administered as an intravenous (IV) infusion every 3 weeks until disease
progression or unacceptable toxicity [see Clinical Studies (14)].
Refer to the respective Prescribing Information for each therapeutic agent administered in combination with
TEVIMBRA for the recommended dosage information, as appropriate.
2.2
Dosage Modifications for Adverse Reactions
No dose reduction of TEVIMBRA is recommended. In general, withhold TEVIMBRA for severe (Grade 3)
immune-mediated adverse reactions. Permanently discontinue TEVIMBRA for life-threatening (Grade 4) immune-
mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic
immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent
per day within 12 weeks of initiating steroids [see Warnings and Precautions (5.1)].
Dosage modifications for TEVIMBRA for adverse reactions that require management different from these general
guidelines are summarized in Table 1.
Refer to the respective Prescribing Information for dosage modifications for the platinum and fluoropyrimidine
agent administered in combination with TEVIMBRA.
Table 1: Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction
Severity of Adverse Reactiona
Dosage Modifications
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Pneumonitis
Grade 2
Withholdb
Grade 3 or 4 or recurrent Grade 2
Permanently discontinue
Colitis
Grade 2 or 3
Withholdb
Grade 4
Permanently discontinue
Hepatitis with no tumor
involvement of the liver
AST or ALT increases to more
than 3 and up to 8 times ULN
or
Withholdb
Reference ID: 5502689
2
Adverse Reaction
Severity of Adverse Reactiona
Dosage Modifications
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Total bilirubin increases to more
than 1.5 and up to 3 times ULN
AST or ALT increases to more
than 8 times ULN
or
Total bilirubin increases to more
than 3 times ULN
Permanently discontinue
Hepatitis with tumor
involvement of the liverc
Baseline AST or ALT is more than
1 and up to 3 times ULN and
increases to more than 5 and up to
10 times ULN
or
Baseline AST or ALT is more than
3 and up to 5 times ULN and
increases to more than 8 and up to
10 times ULN
Withholdb
ALT or AST increases to more
than 10 times ULN
or
Total bilirubin increases to more
than 3 times ULN
Permanently discontinue
Endocrinopathies
Grade 3 or 4
Withhold until clinically stable or
permanently discontinue depending on
severity
Nephritis with renal
dysfunction
Grade 2 or 3 increased blood
creatinine
Withholdb
Grade 4 increased blood creatinine
Permanently discontinue
Exfoliative dermatologic
conditions
Grade 3, or suspected SJS, TEN,
or DRESS
Withholdb
Grade 4, or confirmed SJS, TEN,
or DRESS
Permanently discontinue
Myocarditis
Grade 2, 3, or 4
Permanently discontinue
Neurological toxicities
Grade 2
Withholdb
Grade 3 or 4
Permanently discontinue
Other Adverse Reactions
Infusion-related reactions [see
Warnings and Precautions
(5.2)]
Grade 1
Slow infusion rate by 50%
Grade 2
Interrupt infusiond
Grade 3 or 4
Permanently discontinue
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal, SJS = Stevens-Johnson syndrome, TEN =
toxic epidermal necrolysis, DRESS = drug rash with eosinophilia and systemic symptoms.
a Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.
Reference ID: 5502689
3
b Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or
partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks
of initiating steroids.
c If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TEVIMBRA based on recommendations for
hepatitis with no liver involvement.
d Resume infusion if resolved or decreased to Grade 1, and slow rate of infusion by 50% of the previous rate.
2.3
Preparation and Administration
Preparation
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. TEVIMBRA is a clear to slightly opalescent, colorless to slightly yellow
solution. Discard the vial if the solution is cloudy, discolored, or contains visible particles. Do not shake the vial.
Prepare the solution for infusion as follows:
x
Withdraw 20 mL of TEVIMBRA from two vials of TEVIMBRA (for a total of 200 mg in 20 mL).
x
Transfer solution into an intravenous infusion bag containing 0.9% Sodium Chloride Injection, USP to
prepare an infusion solution with a final concentration of 2 mg/mL to 5 mg/mL.
x
Mix diluted solution by gentle inversion to avoid foaming or excessive shearing of the solution. Do not
shake.
x
TEVIMBRA is for single use only. Discard any unused portion left in the vial.
Storage of Diluted Solution
This product does not contain any preservatives. If not used immediately, store the TEVIMBRA diluted solution
either:
x
At room temperature at 20°C to 25°C (68°F to 77°F) for no more than 4 hours, including preparation and
infusion duration. Discard after 4 hours.
x
Under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 20 hours, including preparation and infusion
duration. Allow the diluted solution to come to room temperature prior to administration. Discard after 20
hours.
Do not freeze the diluted solution.
Administration
x
Administer diluted solution by intravenous infusion through an intravenous line with a sterile,
nonpyrogenic, low protein–binding 0.2 micron or 0.22 micron in-line or add-on filter.
x
The initial infusion should be delivered over 60 minutes. If tolerated, all subsequent infusions may be
administered over 30 minutes.
x
Do NOT coadminister other drugs through the same infusion line.
x
Do NOT administer TEVIMBRA as an intravenous push or single bolus injection.
x
Flush the intravenous line at the end of infusion.
3
DOSAGE FORMS AND STRENGTHS
Injection: 100 mg/10 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-
dose vial.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Severe and Fatal Immune-Mediated Adverse Reactions
Reference ID: 5502689
4
TEVIMBRA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death
receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the
immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions.
Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all
possible severe and fatal immune-mediated reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue.
Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking
antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking
antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking
antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD
1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations
of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at
baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate
appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly,
including specialty consultation as appropriate.
Withhold or permanently discontinue TEVIMBRA depending on severity [see Dosage and Administration (2.2)]. In
general, if TEVIMBRA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2
mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less,
initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic
immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g.,
endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
TEVIMBRA can cause immune-mediated pneumonitis, which can be fatal. In patients treated with other PD-1/PD
L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic
radiation.
Immune-mediated pneumonitis occurred in 4.9% (96/1972) of patients receiving TEVIMBRA, including fatal
(0.1%), Grade 4 (0.3%), Grade 3 (1.6%), and Grade 2 (1.9%) adverse reactions. Pneumonitis led to permanent
discontinuation of TEVIMBRA in 38 (1.9%) patients and withholding of TEVIMBRA in 32 (1.6%) patients.
Seventy-four (77.1%) of the 96 patients received systemic corticosteroids. Sixty-five (67.7%) of the 96 patients
received high-dose systemic corticosteroids. Immune-mediated pneumonitis resolved in 50% of the 96 patients. Of
the 32 patients in whom TEVIMBRA was withheld for pneumonitis, 20 (62.5%) reinitiated TEVIMBRA after
symptom improvement; of these, 2 (10%) patients had recurrence of pneumonitis.
Immune-Mediated Colitis
TEVIMBRA can cause immune-mediated colitis, which can be fatal. Cytomegalovirus infection/reactivation has
been reported in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1 blocking
antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative
etiologies.
Immune-mediated colitis occurred in 0.8% (16/1972) of patients receiving TEVIMBRA, including Grade 3 (0.3%)
and Grade 2 (0.4%) adverse reactions. Colitis led to permanent discontinuation of TEVIMBRA in 4 (0.2%) patients
and withholding of TEVIMBRA in 5 (0.3%) patients. Twelve (75%) of the 16 patients received systemic
corticosteroids. Eight (50%) of the 16 patients received high-dose systemic corticosteroids. Two (12.5%) of the 16
patients received immunosuppressive treatment. Immune-mediated colitis resolved in 93.8% of the 16 patients. All 5
patients in whom TEVIMBRA was withheld for colitis reinitiated TEVIMBRA after symptom improvement; of
these, none of the patients had recurrence of colitis.
Immune-Mediated Hepatitis
TEVIMBRA can cause immune-mediated hepatitis, which can be fatal.
Immune-mediated hepatitis occurred in 1.2% (24/1972) of patients receiving TEVIMBRA, including fatal (0.1%),
Reference ID: 5502689
5
Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to
permanent discontinuation in 3 (0.2%) patients and withholding of TEVIMBRA in 13 (0.7%) patients. Eighteen
(75%) of the 24 patients received systemic corticosteroids. Thirteen (54.2%) of the 24 patients received high-dose
systemic corticosteroids. Two (8.3%) of the 24 patients received immunosuppressive treatment. Immune-mediated
hepatitis resolved in 70.8% of the 24 patients. Of the 13 patients in whom TEVIMBRA was withheld for hepatitis, 7
(53.8%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of
hepatitis.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
TEVIMBRA can cause immune-mediated adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate
symptomatic treatment, including hormone replacement as clinically indicated. Withhold TEVIMBRA depending on
severity [see Dosage and Administration (2.2)].
Immune-mediated adrenal insufficiency occurred in 0.4% (8/1972) of patients receiving TEVIMBRA, including
Grade 4 (0.1%), Grade 3 (0.1%), and Grade 2 (0.3%) adverse reactions. Adrenal insufficiency did not lead to
permanent discontinuation of TEVIMBRA. TEVIMBRA was withheld in 7 out of 8 patients. All 8 patients received
systemic corticosteroids. Three (37.5%) of the 8 patients received high-dose systemic corticosteroids. Adrenal
insufficiency resolved in 25% of the 8 patients. Of the 7 patients in whom TEVIMBRA was withheld for adrenal
insufficiency, 5 (71.4%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had
recurrence of adrenal insufficiency.
Hypophysitis
TEVIMBRA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated
with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism.
Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue TEVIMBRA depending
on severity [see Dosage and Administration (2.2)].
Hypophysitis/hypopituitarism occurred in 0.2% (4/1972) of patients receiving TEVIMBRA, including Grade 2
(0.2%) adverse reactions. Hypophysitis did not lead to permanent discontinuation in any patient, while treatment
was withheld in 1 (0.1%) patient. Three (75%) of the 4 patients received systemic corticosteroids. One (25%) of the
4 patients received high-dose systemic corticosteroids. Hypophysitis/hypopituitarism did not resolve in the 4
patients. For the 1 patient where TEVIMBRA was withheld for hypophysitis/hypopituitarism, there was no
recurrence of hypophysitis/hypopituitarism.
Thyroid Disorders
TEVIMBRA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy.
Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical
management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue TEVIMBRA
depending on severity [see Dosage and Administration (2.2)].
Thyroiditis: Immune-mediated thyroiditis occurred in 1.2% (24/1972) of patients receiving TEVIMBRA, including
Grade 2 (0.5%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TEVIMBRA.
TEVIMBRA was withheld in 3 (0.2%) patients. Two (8.3%) of the 24 patients received systemic corticosteroids.
Thyroiditis resolved in 41.7% of the 24 patients. All three patients in whom TEVIMBRA was withheld for
thyroiditis reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of
thyroiditis.
Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 4.8% (95/1972) of patients receiving
TEVIMBRA, including Grade 3 (0.1%) and Grade 2 (0.9%) adverse reactions. Hyperthyroidism led to the
permanent discontinuation of TEVIMBRA in 1 (0.1%) patient and withholding of TEVIMBRA in 4 (0.2%) patients.
One (1.1%) of the 95 patients received systemic corticosteroids. Hyperthyroidism resolved in 75.8% of the 95
patients. Of the 4 patients in whom TEVIMBRA was withheld for hyperthyroidism, 3 (75%) reinitiated
TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of hyperthyroidism.
Hypothyroidism: Immune-mediated hypothyroidism occurred in 12.7% (250/1972) of patients receiving
TEVIMBRA, including Grade 4 (0.1%) and Grade 2 (6.8%) adverse reactions. TEVIMBRA was not permanently
discontinued in any patient, while treatment was withheld in 7 (0.4%) patients. Two (0.8%) of the 250 patients
Reference ID: 5502689
6
received systemic corticosteroids. One hundred fifty-eight patients (63.2%) received hormone replacement therapy.
Hypothyroidism resolved in 31.6% of the 250 patients. The majority (54%) of patients with hypothyroidism required
long-term thyroid hormone replacement. Of the 7 patients in whom TEVIMBRA was withheld for hypothyroidism,
6 (85.7%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of
hypothyroidism.
Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis
Diabetes mellitus has been reported with PD-1/PD-L1 blocking antibodies. Monitor patients for hyperglycemia or
other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or
permanently discontinue TEVIMBRA depending on severity [see Dosage and Administration (2.2)].
Diabetes mellitus occurred in 0.9% (18/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3
(0.4%), and Grade 2 (0.4%) adverse reactions. TEVIMBRA was permanently discontinued in 3 (0.2%) patients and
TEVIMBRA treatment was withheld in 3 (0.2%) patients. Twelve (66.7%) patients received insulin therapy for
diabetes mellitus. Diabetes mellitus resolved in 27.8% of the 18 patients. Of the 3 patients in whom TEVIMBRA
was withheld for diabetes mellitus, none of the patients reinitiated TEVIMBRA after symptom improvement.
Immune-Mediated Nephritis with Renal Dysfunction
TEVIMBRA can cause immune-mediated nephritis, which can be fatal.
Immune-mediated nephritis with renal dysfunction occurred in 0.3% (6/1972) of patients receiving TEVIMBRA,
including Grade 3 (0.1%) and Grade 2 (0.2%) adverse reactions. TEVIMBRA was permanently discontinued in 1
(0.1%) patient and treatment was withheld in 3 (0.2%) patients. Three (50%) patients received systemic
corticosteroids. Three (50%) of the 6 patients received high-dose systemic corticosteroids. Nephritis with renal
dysfunction resolved in 33.3% of the 6 patients. Of the 3 patients in whom TEVIMBRA was withheld for nephritis,
2 (66.7%) reinitiated TEVIMBRA after symptom improvement; of these, one (50%) patient had recurrence of
nephritis.
Immune-Mediated Dermatologic Adverse Reactions
TEVIMBRA can cause immune-mediated rash or dermatitis. Cases of severe cutaneous adverse reactions (SCARs),
including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), have been
reported, some with fatal outcomes. Topical emollients and/or topical corticosteroids may be adequate to treat mild
to moderate non-exfoliative rashes. Withhold or permanently discontinue TEVIMBRA depending on severity [see
Dosage and Administration (2.2)].
Immune-mediated dermatologic adverse reactions occurred in 15.3% (301/1972) of patients receiving TEVIMBRA,
including Grade 4 (0.1%), Grade 3 (0.9%), and Grade 2 (3.5%) adverse reactions. Dermatologic adverse reactions
led to permanent discontinuation of TEVIMBRA in 2 (0.1%) patients and withholding of TEVIMBRA in 18 (0.9%)
patients, thirty (10%) of the 301 patients received systemic corticosteroids. Thirteen (4.3%) of the 301 patients
received high-dose systemic corticosteroids. Immune-mediated dermatologic adverse reactions resolved in 63.1% of
the 301 patients. Of the 18 patients in whom TEVIMBRA was withheld for dermatologic adverse reactions, 15
(83.3%) reinitiated TEVIMBRA after symptom improvement; of these, 1 (6.7%) patient had recurrence of immune-
mediated dermatologic adverse reaction.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than 1%
each in patients who received TEVIMBRA: myositis, myocarditis, arthritis, polymyalgia rheumatica, encephalitis,
myasthenia gravis, Sjogren’s syndrome, and pericarditis.
The following additional clinically significant immune-mediated adverse reactions have been reported with other
PD-1/PD-L1 blocking antibodies, including severe or fatal cases.
Cardiac/Vascular: Vasculitis.
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis
(including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy.
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal
detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination
Reference ID: 5502689
7
with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may
require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Polymyositis, rhabdomyolysis and associated sequelae including renal
failure.
Endocrine: Hypoparathyroidism
Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic
inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis,
immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft)
rejection.
5.2
Infusion-Related Reactions
TEVIMBRA can cause severe or life-threatening infusion-related reactions. Infusion-related reactions occurred in
5% (99/1972) patients receiving TEVIMBRA, including Grade 3 or higher (0.2%) reactions. Monitor patients for
signs and symptoms of infusion-related reactions.
Slow the rate of infusion for mild (Grade 1) and interrupt the infusion for moderate (Grade 2) infusion-related
reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and
permanently discontinue TEVIMBRA [see Dosage and Administration (2.2)].
5.3
Complications of Allogeneic HSCT
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell
transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related
complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno
occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and
allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the
benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
5.4
Embryo-Fetal Toxicity
Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman.
Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-
mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4
months after the last dose [see Use in Specific Populations (8.1, 8.3)].
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in more detail in other sections of the label:
x
Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)]
x
Infusion-related reactions [see Warnings and Precautions (5.2)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
The pooled safety population described in WARNINGS AND PRECAUTIONS reflect exposure to TEVIMBRA as
a single agent in 1972 patients enrolled in two randomized open-label, active-controlled studies (RATIONALE-302,
BGB-A317-303) and five open-label, single-arm studies (BGB-A317-208, BGB-A317-204, BGB-A317-203, BGB
A317-102, BGB-A317_Study_001), which enrolled 307 patients with esophageal squamous cell carcinoma and
1665 patients with advanced or recurrent tumors. TEVIMBRA was administered at a dose of 200 mg intravenously
Reference ID: 5502689
8
once every 3 weeks, except in study BGB-A317_Study_001 where patients also received other dosage regimens.
Among the 1972 patients, 37.8% were exposed for longer than 6 months, and 21.8% were exposed for longer than
12 months.
Previously Treated Unresectable Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
The safety of TEVIMBRA was evaluated in RATIONALE-302, a randomized, active-controlled, open-label,
multicenter study in 255 patients with unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies
(14.1)]. The trial excluded patients who had brain or leptomeningeal metastases that were symptomatic or required
treatment, active autoimmune disease, a medical condition requiring systemic corticosteroids or
immunosuppressants, or apparent tumor invasion of organs adjacent to the esophageal site.
Patients received TEVIMBRA 200 mg by intravenous infusion over 30-60 minutes every 3 weeks or investigator’s
choice: paclitaxel 135-175 mg/m2 every 3 weeks or 80-100 mg/m2 weekly, docetaxel 75 mg/m2 every 3 weeks, or
irinotecan 125 mg/m2 on Days 1 and 8 of every 3-week cycle. Patients were treated until disease progression or
unacceptable toxicity. The median duration of exposure was 2.8 months (range: 0.2 to 28.3 months) in TEVIMBRA-
treated patients and 1.5 months (range: 0.2 to 19.2 months) in paclitaxel, docetaxel, or irinotecan-treated patients.
Serious adverse reactions occurred in 41% of patients; the most frequent serious adverse reactions (2%) were
pneumonia, dysphagia, hemorrhage, pneumonitis (including pneumonitis and immune-mediated pneumonitis), and
esophageal obstruction. Fatal adverse reactions occurred in 7% of patients who received TEVIMBRA, including the
following which occurred in more than one patient: pneumonia/pneumonitis (5 patients), hemorrhage (3 patients),
and death due to an unknown cause (3 patients).
Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 19% of patients. Adverse
reactions which resulted in permanent discontinuation in 1% of patients were hemorrhage, pneumonitis (including
pneumonitis and immune-mediated pneumonitis), and pneumonia.
Dosage interruptions of TEVIMBRA due to an adverse reaction occurred in 23% of patients. Adverse reactions
which required dosage interruptions in 2% of patients were pneumonia, pneumonitis, and fatigue.
The most common (20%) adverse reactions were anemia, fatigue, musculoskeletal pain, decreased weight, and
cough.
Adverse reactions and laboratory abnormalities are listed in Table 2 and Table 3, respectively.
Table 2: Adverse Reactions (10%) in Patients With ESCC Receiving TEVIMBRA in RATIONALE-302
Adverse Reaction
TEVIMBRA
(N=255)
ICC
(N=240)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Blood Disorders
Anemia
31
6
45
11
General Disorders
Fatiguea
28
2
46
6
Pyrexia
16
0.4
14
0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painb
24
1
25
1
Investigations
Weight decreased
23
1
19
0
Respiratory, Thoracic and Mediastinal Disorders
Coughc
22
0.4
16
0.4
Metabolism and Nutrition Disorders
Decreased appetite
16
0.4
35
4
Reference ID: 5502689
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Adverse Reaction
TEVIMBRA
(N=255)
ICC
(N=240)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Infections and Infestations
Pneumoniad
16
6
12
7
Gastrointestinal Disorders
Constipation
15
0
19
0.4
Nausea
14
0.4
30
3
Diarrheae
13
1
32
7
Dysphagia
11
6
8
3
Abdominal painf
11
0.8
16
2
Vomiting
11
0.8
20
4
Endocrine Disorders
Hypothyroidismg
13
0.4
0.8
0
Skin and Subcutaneous Tissue Disorders
Rashh
13
0.4
6
0
Vascular Disorders
Hemorrhagei
12
2
10
3
ICC = investigator’s choice of chemotherapy
a Fatigue includes asthenia, fatigue, malaise.
b Musculoskeletal pain includes musculoskeletal pain, spinal pain, arthralgia, back pain, neck pain, musculoskeletal chest pain, myalgia, pain in
extremity, non-cardiac chest pain, bone pain, arthritis.
c Cough includes productive cough, cough.
d Pneumonia includes pneumonia aspiration, pneumonia, pneumonia bacterial, lower respiratory tract infection.
e Diarrhea includes diarrhea, colitis.
f Abdominal pain includes abdominal pain upper, abdominal pain, abdominal discomfort, abdominal pain lower, gastrointestinal pain.
g Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased.
h Rash includes dermatitis, dermatitis acneiform, dermatitis allergic, eczema, erythema, psoriasis, rash, rash follicular, rash maculo-papular, rash
pruritic.
i Hemorrhage includes tumor hemorrhage, upper gastrointestinal hemorrhage, gastrointestinal hemorrhage, hemoptysis, esophageal hemorrhage,
hematuria, gastric hemorrhage, epistaxis, tracheal hemorrhage, gingival bleeding, pulmonary hemorrhage, procedural hemorrhage, rectal
hemorrhage, stoma site hemorrhage.
Table 3: Laboratory Abnormalities Worsening From Baseline Occurring in 10% of Patients Receiving
TEVIMBRA in RATIONALE-302
Laboratory Abnormality
TEVIMBRAa
ICCa
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Chemistry
Glucose increased
46
4
40
2
Sodium decreased
34
9
36
8
Albumin decreased
33
0.8
37
1
Alkaline phosphatase increased
32
3
15
0.5
AST increased
27
0.8
12
0.5
ALT increased
23
0.8
15
1
Phosphate decreased
15
4
20
3
Creatine kinase increased
13
1
2
0
Potassium decreased
13
1
15
3
Reference ID: 5502689
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Laboratory Abnormality
TEVIMBRAa
ICCa
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Bilirubin increased
11
2
8
0.5
Glucose decreased
10
0.4
10
0.5
Hematology
Hemoglobin decreased
45
6
61
10
Lymphocytes decreased
43
11
60
28
Platelets decreased
11
1
11
0.9
Leukocytes decreased
10
0.8
66
31
a The denominator used to calculate the rate varied from 136 to 240 based on the number of patients with a baseline value and at least one post-
treatment value.
Treatment of Previously Untreated Unresectable or Metastatic Gastric or Gastroesophageal Junction
Adenocarcinoma (G/GEJ)
The safety of TEVIMBRA in combination with chemotherapy was evaluated in RATIONALE-305, a randomized,
multicenter, double-blind, placebo-controlled trial in patients with previously untreated unresectable or metastatic
G/GEJ adenocarcinoma [see Clinical Studies (14.2)].
Patients were randomized (1:1) to receive either TEVIMBRA 200 mg by intravenous infusion over 30-60 minutes
every 3 weeks or placebo plus a platinum and fluoropyrimidine-based chemotherapy. The chemotherapy regimens
consisted of:
x
Oxaliplatin 130 mg/m2 IV on Day 1 for up to 6 cycles and capecitabine 1000 mg/m2 orally twice daily for 14
consecutive days of every 3-week cycle.
or
x
Cisplatin 80 mg/m2 IV, Day 1, and 5-FU (5-fluorouracil) 800 mg/m2/day IV continuous infusion over 24 hours
daily Day 1-5, every 3 weeks for up to 6 cycles.
Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 5.91
months (range, 0.1 to 47 months) in TEVIMBRA-treated patients.
Serious adverse reactions occurred in 42% of patients receiving TEVIMBRA in combination with chemotherapy.
The most frequent serious adverse drug reactions (2%) were pneumonia (3.6%), decreased platelet count (3.2%),
gastrointestinal hemorrhage (3%), and colitis (2.2%). Fatal adverse reactions occurred in 4.2% of patients who
received TEVIMBRA in combination with chemotherapy; events occurring in 2 or more patients were death, sepsis,
pneumonia, pulmonary embolism, and respiratory failure.
Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 16% of patients. Adverse drug
reactions which resulted in permanent discontinuation in 1% of patients were death, fatigue, and pneumonitis.
Dosage interruption of TEVIMBRA due to an adverse drug reaction occurred in 49% of patients. Adverse drug
reactions which required dosage interruption in 2% of patients were decreased platelet count (12%), decreased
neutrophil count (10%), neutropenia (6%), decreased white blood cell count (6%), increased AST (4.8%), increased
ALT (3.8%), increased blood bilirubin (3%), COVID-19 (3%), thrombocytopenia (2.8%), leukopenia (2.6%),
pneumonitis (2.2%), and pneumonia (2%).
The most common (20%) adverse reactions, including laboratory abnormalities, for TEVIMBRA in combination
with chemotherapy were nausea, fatigue, decreased appetite, anemia, peripheral sensory neuropathy, vomiting,
decreased platelet count, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, abdominal pain,
increased alanine aminotransferase, white blood cell count decreased, decreased weight, and pyrexia.
Adverse reactions and laboratory abnormalities are listed in Table 4 and Table 5, respectively.
Reference ID: 5502689
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Table 4: Adverse Reactions (10%) in Patients with G/GEJ Receiving TEVIMBRA + Chemotherapy with a
Difference Between Arms of 5% for All Grades or 2% for Grades 3 and 4 vs Placebo +
Chemotherapy in RATIONALE-305
Adverse Drug Reaction
TEVIMBRA + Chemotherapy
(N=498)
Placebo + Chemotherapy
(N=494)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
General Disorders and Administration Site Conditions
Pyrexia
20
1.6
14
0.6
Skin and Subcutaneous Tissue Disorders
Rash
16
1.6
7
0
Pruritus
10
0.2
3.2
0
Endocrine Disorders
Hypothyroidism
13
0.2
2.8
0
a Represents a composite of multiple, related preferred terms.
Other Clinically Important Adverse Reactions Occurring in Less Than 10% include:
Stomatitis, infusion-related reaction, dyspnea, hepatitis, hyperthyroidism, pneumonitis, hyperglycemia, myalgia,
diabetes mellitus, pancreatitis, arthritis, Sjogren’s syndrome, thyroiditis, adrenal insufficiency, hypophysitis,
myasthenia gravis, uveitis, myocarditis, pericarditis, colitis, vitiligo, myositis, and nephritis.
Table 5: Select Laboratory Abnormalities Worsening from Baseline Occurring in 10% of Patients Receiving
TEVIMBRA+ Chemotherapy with a Difference Between Arms of 5% for All Grades or 2% for
Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE-305
Laboratory Abnormality
TEVIMBRA + Chemotherapya
(N=498)
Placebo + Chemotherapya
(N=494)
All Grades
(%)
Grade 3 or 4
(%)
All Grades
(%)
Grade 3 or 4
(%)
Chemistry
AST increased
58
6
56
3
Sodium decreased
42
7
36
5
ALT increased
41
4.8
36
2
Potassium decreased
33
9
28
6
Hematology
Lymphocytes decreased
53
12
46
9
Abbreviations: ALT, alanine aminotransferase; AST, aspartate amino transferase.
a The denominator used to calculate the rate varied from 480 to 494 based on the number of patients with a baseline value and at least one post-
treatment value.
Other Clinically Important Laboratory Abnormalities Occurring in <20% include:
Creatinine increased, potassium increased, glucose decreased, sodium increased, lymphocytes increased,
hemoglobin increased.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman [see
Clinical Pharmacology (12.1)]. There are no available data on the use of TEVIMBRA in pregnant women.
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Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-
mediated rejection of the developing fetus resulting in fetal death (see Data). Human IgG4 immunoglobulins (IgG4)
are known to cross the placental barrier; therefore, tislelizumab-jsgr has the potential to be transmitted from the
mother to the developing fetus. Advise women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Animal reproduction studies have not been conducted with TEVIMBRA to evaluate its effect on reproduction and
fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal
immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to
disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering
TEVIMBRA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there
were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however,
immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal
exposure to tislelizumab-jsgr may increase the risk of developing immune-mediated disorders or altering the normal
immune response.
8.2
Lactation
Risk Summary
There is no information regarding the presence of tislelizumab-jsgr in human milk, or its effects on the breastfed
child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise
women not to breastfeed during treatment and for 4 months after the last dose of TEVIMBRA.
8.3
Females and Males of Reproductive Potential
TEVIMBRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating TEVIMBRA [see Use in Specific
Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4
months after the last dose of TEVIMBRA.
8.4
Pediatric Use
The safety and effectiveness of TEVIMBRA have not been established in pediatric patients.
8.5
Geriatric Use
TEVIMBRA as a Single Agent
Of the 255 patients who were treated with TEVIMBRA for previously treated unresectable or metastatic ESCC in
the clinical study RATIONALE-302, 98 (38%) were 65 years and older, and 13 (5%) were 75 years and older. No
overall differences in safety or effectiveness were observed between elderly patients and younger patients.
TEVIMBRA in Combination with Chemotherapy
Of the 498 patients who were treated with TEVIMBRA in combination with platinum-containing chemotherapy for
G/GEJ adenocarcinoma in the clinical study RATIONALE-305, 161 (32%) were 65 years and older, and 28 (6%)
were 75 years and older. No overall differences in safety or effectiveness were observed between elderly patients
and younger patients.
11
DESCRIPTION
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Tislelizumab-jsgr is a programmed death receptor-1 (PD 1)-blocking antibody. Tislelizumab-jsgr is an Fc
engineered humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 147 kDa.
Tislelizumab-jsgr is produced in recombinant Chinese hamster ovary (CHO) cells.
TEVIMBRA (tislelizumab-jsgr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to
slightly yellow solution for intravenous use, supplied in single-dose vials. Each vial contains 100 mg of
tislelizumab-jsgr monoclonal antibody in 10 mL of solution, with a concentration of 10 mg/mL, and is formulated
in: citric acid monohydrate (4.2 mg), histidine (17.2 mg), L-histidine hydrochloride monohydrate (8.2 mg),
polysorbate 20 (2 mg), sodium citrate (59.3 mg), Sterile Water for Injection, USP, and trehalose (650.4 mg). The pH
is 6.5.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation
and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway
can contribute to inhibition of active T-cell immune surveillance of tumors.
Tislelizumab-jsgr binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-
mediated inhibition of the immune response, including the anti-tumor immune response. Tislelizumab-jsgr
decreased tumor growth in xenograft models and a human PD-1 transgenic mouse model.
12.2
Pharmacodynamics
The tislelizumab-jsgr exposure-response relationship for efficacy and safety and time course of pharmacodynamic
response has not been fully characterized.
12.3
Pharmacokinetics
Pharmacokinetic parameters are presented as geometric mean (% CV) unless otherwise specified.
The peak concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of tislelizumab
jsgr increased dose proportionally in the dose range of 0.5 (0.2 times the approved recommended dosage in a 70 kg
patient) to 10 mg/kg (3.5 times the approved recommended dosage in a 70 kg patient).
The steady-state AUCtau of tislelizumab-jsgr is 1,283 mcg/mL•day (28.7%) and the Cmax is 110 mcg/mL (22.2%)
following the approved recommended dosage. Steady-state concentration of tislelizumab-jsgr is reached after 12
weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.14-fold.
Distribution
The tislelizumab-jsgr steady-state total volume of distribution is 6.42 L (32.6%).
Elimination
The tislelizumab-jsgr total clearance is 0.153 L/day (29.5%) and the terminal half-life (t½) is 24 days (31%).
Specific Populations
No clinically significant differences in the pharmacokinetics of tislelizumab-jsgr were observed based on age (range,
18 to 90 years), weight (range, 32 to 130 kg), race (White, Asian, or Black), mild to moderate renal impairment
(CLcr 30 mL/min, estimated by Cockcroft-Gault), mild to moderate hepatic impairment (total bilirubin 3 times
ULN and any AST, estimated by NCI criteria). The effect of severe hepatic impairment (total bilirubin >3 times
ULN and any AST), severe renal impairment (CLcr 15-29 mL/min), or end stage renal disease (CLcr <15 mL/min)
on the pharmacokinetics of tislelizumab-jsgr is unknown.
12.6
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.
Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the
studies described below with the incidence of anti-drug antibodies in other studies, including those of tislelizumab
jsgr products.
In patients who received tislelizumab-jsgr in RATIONALE-302 for up to 22 months, the incidence of anti-
Reference ID: 5502689
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tislelizumab antibodies was 14.5% (32/221). Among the anti-tislelizumab antibody-positive patients, the incidence
of neutralizing antibodies was 3.1% (1/32).
In patients who received tislelizumab-jsgr in RATIONALE-305 throughout the treatment period and in the ADA
analysis set, the incidence of anti-tislelizumab antibodies was 22.7% (108/475). Among the anti-tislelizumab
antibody-positive patients, the incidence of neutralizing antibodies was 5.6% (6/108).
There was no significant effect of anti-drug antibodies on the pharmacokinetics of tislelizumab-jsgr. The effect of
anti-drug antibodies on pharmacodynamics, safety, or effectiveness of tislelizumab-jsgr has not been fully
characterized.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the potential of tislelizumab-jsgr for carcinogenicity or genotoxicity.
In a 3-month repeat-dose toxicology study in cynomolgus monkeys, there were no notable effects in the male and
female reproductive organs; however, most animals in the study were not sexually mature.
13.2
Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-L1/PD-1 signaling resulted in an increased severity of some infections and
enhanced inflammatory responses. Mycobacterium tuberculosis–infected PD-1 knockout mice exhibit markedly
decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and
inflammatory responses in these animals. PD-1 blockade using a primate anti-PD1 antibody was also shown to
exacerbate M. tuberculosis infection in rhesus macaques. PD-L1 and PD-1 knockout mice have also shown
decreased survival following infection with lymphocytic choriomeningitis virus.
14
CLINICAL STUDIES
14.1
Esophageal Squamous Cell Carcinoma
Previously Treated Unresectable or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
RATIONALE-302 (NCT03430843) was a multicenter, randomized (1:1), open-label trial in 512 adult patients with
unresectable advanced or metastatic ESCC who progressed on or after prior systemic chemotherapy.
Patients were enrolled regardless of their tumor PD-L1 expression level. PD-L1 expression was evaluated at a
central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1 staining on both tumor and tumor-
associated immune cells (Tumor Area Positivity or TAP). The trial excluded patients who received a prior immune
checkpoint inhibitor, had brain or leptomeningeal metastases that were symptomatic or required treatment, active
autoimmune disease, a medical condition requiring systemic corticosteroids or immunosuppressants, or apparent
tumor invasion of organs adjacent to the esophageal tumor.
Patients were randomized (1:1) to receive either TEVIMBRA 200 mg every 3 weeks or investigator’s choice of
chemotherapy (ICC), all given intravenously: paclitaxel 135-175 mg/m2 every 3 weeks or 80 to 100 mg/m2 weekly,
docetaxel 75 mg/m2 every 3 weeks, or irinotecan 125 mg/m2 on Days 1 and 8 of every 3-week cycle. Patients were
treated until disease progression assessed by the investigator or unacceptable toxicity.
Randomization was stratified by geographic region (Asia [excluding Japan] vs Japan vs US/EU), ECOG
performance status (0 vs 1), and ICC option. Tumor assessments were conducted every 6 weeks for the first 6
months, then every 9 weeks until disease progression.
The major efficacy outcome measure was overall survival (OS) in the Intent-to-Treat (ITT) population. Additional
efficacy outcome measures were investigator-assessed progression-free survival (PFS), overall response rate (ORR),
and duration of response (DOR) per RECIST v1.1.
A total of 512 patients were enrolled and randomized to TEVIMBRA (n=256) or ICC (n=256) (irinotecan [46%],
paclitaxel [33%], or docetaxel [21%]). Of the 512 patients, 142 (28%) had PD-L1 10%, 222 (43%) had PD-L1
<10%, and 148 (29%) had unknown baseline PD-L1 status.
The trial population characteristics were: median age of 62 years (range: 35 to 86), 38% age 65; 84% male; 19%
Reference ID: 5502689
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White and 80% Asian; 95% had metastatic disease. All patients had received at least one prior anti-cancer systemic
therapy. Baseline ECOG performance status was 0 (25%) or 1 (75%).
RATIONALE-302 demonstrated a statistically significant improvement in OS for patients randomized to
TEVIMBRA as compared with ICC. OS results by PD-L1 CPS level (<1 and 1) were not studied.
Efficacy results are shown in Table 6 and Figure 1.
Table 6: Efficacy Results in RATIONALE-302 in ITT Population
Endpoint
TEVIMBRA
(N=256)
ICC
(N=256)
Overall Survival
Deaths n (%)
197 (77)
213 (83.2)
Median (months)a (95% CI)
8.6 (7.5, 10.4)
6.3 (5.3, 7)
Hazard ratiob (95% CI)
0.7 (0.57, 0.85)
p-valuec
0.0001
Progression-Free Survival
Disease progression or death (%)
223 (87.1)
180 (70.3)
Median (months)a (95% CI)
1.6 (1.4, 2.7)
2.1 (1.5, 2.7)
Hazard ratiob (95% CI)
0.83 (0.67, 1.01)
Objective Response Rated
ORR (%) (95% CI)
15.2 (11.1, 20.2)
6.6 (3.9, 10.4)
Complete response n (%)
5 (2)
1 (0.4)
Partial response n (%)
34 (13.3)
16 (6.3)
Duration of Response
Median (months)a (95% CI)
10.3 (6.5, 13.2)
6.3 (2.8, 8.5)
CI = confidence interval, ORR = objective response rate
a Estimated using Kaplan-Meier method.
b Based on Cox regression model stratified by baseline ECOG status and ICC option.
c One-sided p-value based on log-rank test stratified by ECOG performance status and ICC option.
d Confirmed response.
Reference ID: 5502689
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1.0
0.9
Tevimbra
0.8
ICC
0.7
~
:.0
0.6
11
0
0:
0.5
,;
>
·;:
0.4
oil
0.3
0.2
0.1
0.0
0
2
4
6
8
IO
12
14
16
18
20
22
24
26
28
30
32
Time (Months)
Number of Patients at Risk:
Tevimbra
256
226
191
157
134
110
88
73
59
44
30
20
13
8
8
2
0
ICC
256
219
167
124
93
77
5 I
36
29
21
I 5
7
5
4
2
I
0
Figure 1: Kaplan-Meier Curve for Overall Survival in RATIONALE-302 (ITT)
14.2
Gastric Cancer
Previously Untreated, Unresectable, or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (G/GEJ)
Adenocarcinoma whose tumors express PD-L1 (1)
RATIONALE-305 (NCT03777657) was a randomized, multicenter, placebo-controlled, double-blind trial in
patients with HER2-negative previously untreated unresectable or metastatic G/GEJ adenocarcinoma.
Patients were enrolled regardless of their tumor PD-L1 expression level, which was evaluated prospectively at a
central laboratory using the VENTANA PD-L1(SP263) assay that identified PD-L1 staining on both tumor and
tumor-associated immune cells (TAP). A retrospective scoring of tumor PD-L1 status using Combined Positive
Score (CPS) was also conducted using the PD-L1-stained tumor specimens used for randomization.
The trial excluded patients who had active leptomeningeal disease or uncontrolled brain metastasis, and patients
with active autoimmune disease or history of autoimmune diseases, or a medical condition requiring systemic
corticosteroids or immunosuppressants.
Patients were randomized to receive either TEVIMBRA 200 mg every 3 weeks or placebo in combination with
investigator’s choice of chemotherapy on a 21-day cycle. TEVIMBRA (or placebo) was administered until disease
progression or unacceptable toxicity.
The chemotherapy doublets regimen consisted of:
x
CAPOX: Oxaliplatin 130 mg/m2 IV on Day 1 for up to 6 cycles and capecitabine 1000 mg/m2 orally twice daily
for 14 consecutive days. Capecitabine treatment could be continued beyond 6 cycles.
or
x
FP: Cisplatin 80 mg/m2 IV, Day 1, and 5-FU 800 mg/m2/day IV continuous infusion over 24 hours daily Day 1
5. Cisplatin and 5-FU were given for up to 6 cycles.
Cross-over between treatment arms was not allowed.
Patient randomization was stratified by geographic region (China [including Taiwan], vs Japan and South Korea vs
rest of the world, including US and Europe); PD-L1 expression (PD-L1 TAP score 5% vs PD-L1 TAP score <5%);
presence of peritoneal metastasis (yes vs no); and ICC option (oxaliplatin plus capecitabine vs cisplatin plus 5-FU).
Tumor assessments were performed every 6 weeks for the first 48 weeks and thereafter approximately every 9
Reference ID: 5502689
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weeks.
The primary efficacy outcome measures were OS in the PD-L1 TAP score 5% population and in the Intent-to-Treat
(ITT) population. Secondary outcome measures included progression-free survival (PFS), objective response rate
(ORR), and duration of response (DoR) as assessed by the investigator per RECIST v1.1. Additional analyses of
efficacy outcome measures were also conducted based on PD-L1 TAP 1% and CPS 1.
A total of 997 patients were randomized. The trial population characteristics were median age 61 years (range, 23 to
86 years), 35% 65 years of age, 69% male; 75% Asian, 22% White, and 0% Black or African American. Eighty
percent had primary stomach tumor; 89% had PD-L1 TAP 1% and 86% had PD-L1 CPS 1, and 99% of patients
had metastatic disease at baseline. Baseline ECOG performance status was 0 (32%) or 1 (68%). Ninety-three percent
of patients received CAPOX and 7% received FP.
RATIONALE-305 demonstrated a statistically significant improvement in OS for patients randomized to
TEVIMBRA in combination with chemotherapy compared with placebo plus chemotherapy in the PD-L1 TAP 5%
population and in the ITT population. Exploratory analyses of OS in the TAP <1% population and in the CPS <1
population showed hazard ratios of 0.98 (95% CI: 0.64, 1.50) and 1.01 (95% CI: 0.66, 1.52) respectively, indicating
that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of
patients with PD-L1 1.
Efficacy results are summarized in Table 7, Figure 2,Table Figure and Figure 3Figure 3:
Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 CPS 1)
.
Table 7: Efficacy results in RATIONALE-305
Endpoint
TEVIMBRA +
Chemotherapy
(N=432)
Placebo +
Chemotherapy
(N=453)
TEVIMBRA +
Chemotherapy
(N=420)
Placebo +
Chemotherapy
(N=434)
PD-L1 TAP 1%
PD-L1 CPS 1
Overall Survival
Deaths n (%)
318 (74)
370 (82)
308 (73)
356 (82)
Median (months)a (95% CI)
15.0 (13.3, 16.7)
12.8 (12.1, 14.1)
15.1 (13.6, 17.2)
12.9 (12.1, 14.1)
HRb (95% CI)
0.78 (0.67, 0.90)
0.78 (0.67, 0.91)
Progression-Free Survival
Events, n (%)
316 (73)
364 (80)
303 (72)
348 (80)
Medianc (months) (95% CI)
6.9 (5.7, 7.2)
5.9 (5.6, 6.9)
7.0 (5.7, 7.7)
6.4 (5.6, 6.9)
HRb (95% CI)
0.78 (0.67, 0.91)
0.77 (0.66, 0.90)
Objective Response Ratec
ORR, n
206
186
204
183
ORR, %
48
41
49
42
95% CI (%)d
(43, 53)
(37, 46)
(44, 53)
(37, 47)
Complete response, n (%)
15 (3.5)
15 (3.3)
16 (3.8)
16 (3.7)
Partial response, n (%)
191 (44)
171 (38)
188 (45)
167 (38)
Duration of Response
Median (months)a (95% CI)
8.6 (7.8, 10.4)
7.2 (5.8, 8.3)
8.6 (7.8, 10.4)
7.2 (5.8, 8.5)
Abbreviations: CI, confidence interval; HR, hazard ratio; ORR, objective response rate.
a Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
b Estimated by Cox proportional hazards model.
c Based on confirmed response.
d Exact Clopper-Pearson 2-sided confidence interval.
Reference ID: 5502689
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100
~ 90
e....
80
~ 70
:c
60
1G
.0
50
0 ...
D.
40
i;
30
>
'>
20
...
::I
10
"'
-e- TIS+C
0
-
PBO+C
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
Time (Months)
No. At Risk:
TIS+C
432 412 387 355 309 277 242 219 196 175 159 146 134 113 93
68
53
48
39
28
21
12
9
4
0
PBO+C
453 429 390 359 312 274 239 197 168 140 122 108 98
85
65
46
33
23
20
15
12
5
3
2
0
0
100 -
~ 90 -
~ 80 -
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ns
..c e 50 -
a.
40 -
iii
30 -
>
-~
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::s
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10 - ----e-- TIS+C
0- ------fr-- PBO+C
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
Time (Months)
No. At Risk:
TIS+C
420 400 376 345 301 270 235 215 193 173 156 144 132 111
89
64
51
46
37
26
19
10
7
3
0
PBO+C
434 417 379 351 307 270 233 192 162 134 116 104 94
83
63
44
32
22
20
15
12
5
3
2
0
0
Figure 2: Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 TAP 1%)
TIS+C, Tislelizumab + Chemotherapy; PBO+C, Placebo + Chemotherapy.
Figure 3: Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 CPS 1)
TIS+C, Tislelizumab + Chemotherapy; PBO+C, Placebo + Chemotherapy;
An exploratory subgroup analysis of OS in 40 patients with MSI-H tumors irrespective of PD-L1 status showed a HR
of 0.66 (0.3, 1.43).
16
How Supplied/Storage and Handling
How Supplied
TEVIMBRA injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied in a carton
containing one 100 mg/10 mL (10 mg/mL) single-dose vial (NDC 72579-121-01).
Storage
Reference ID: 5502689
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17
Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
Do not freeze. Do not shake.
PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after
discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of
TEVIMBRA. These reactions may include:
x
Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough,
chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
x
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, or severe abdominal pain
[see Warnings and Precautions (5.1)].
x
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or
vomiting, pain on the right side of the abdomen, or easy bruising or bleeding [see Warnings and Precautions
(5.1)].
x
Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of
hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, thyroiditis, or Type 1 diabetes mellitus
[see Warnings and Precautions (5.1)].
x
Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis
[see Warnings and Precautions (5.1)].
x
Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately for any signs
or symptoms of severe skin reactions, SJS, TEN, or DRESS [see Warnings and Precautions (5.1)].
x
Other Immune-Mediated Adverse Reactions:
o
Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and
to contact their healthcare provider immediately for any new or worsening signs or symptoms [see
Warnings and Precautions (5.1)].
o
Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft)
rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant
rejection [see Warnings and Precautions (5.1)].
Infusion-Related Reactions
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions
[see Warnings and Precautions (5.2)].
Complications of Allogeneic Hematopoietic Stem Cell Transplantation Complications
Advise patients of potential risk of post-allogeneic hematopoietic stem cell transplantation complications (HSCT)
[see Warnings and Precautions (5.3)].
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a
known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4
months after the last dose [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment with TEVIMBRA and for 4 months after the last dose [see Use in
Reference ID: 5502689
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Specific Populations (8.2)].
Manufactured by:
BeiGene USA, Inc.
San Mateo, CA 94404
U.S. License No. 2232
TEVIMBRA® is a registered trademark owned by BeiGene, Ltd.
© BeiGene, Ltd. 2024
Reference ID: 5502689
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Medication Guide
TEVIMBRA (teh-vim-brah)
(tislelizumab-jsgr)
injection
What is the most important information I should know about TEVIMBRA?
TEVIMBRA is a medicine that may treat certain cancers by working with your immune system. TEVIMBRA can cause
your immune system to attack normal organs and tissues in any area of your body and can affect the way they work.
These problems can sometimes become severe or life-threatening and can lead to death. You can have more than
one of these problems at the same time. These problems may happen anytime during treatment or even after your
treatment has ended.
Call or see your healthcare provider right away if you develop any new or worsening symptoms, including:
Lung problems
x
new or worsening cough
x
shortness of breath
x
chest pain
Intestinal problems
x
diarrhea (loose stools) or more bowel movements than usual
x
stools that are black, tarry, sticky, or have blood or mucus
x
severe stomach-area (abdomen) pain or tenderness
Liver problems
x
yellowing of your skin or the whites of your eyes
x
dark urine (tea colored)
x
severe nausea or vomiting
x
bleeding or bruising more easily than normal
x
pain on the right side of your stomach area (abdomen)
Hormone gland problems
x
headaches that will not go away or unusual
headaches
x
x
urinating more often than usual
hair loss
x
x
x
x
x
x
eye sensitivity to light
eye problems
rapid heartbeat
increased sweating
extreme tiredness
weight gain or weight loss
x
x
x
x
x
feeling cold
constipation
your voice gets deeper
dizziness or fainting
changes in mood or behavior, such as decreased
sex drive, irritability, or forgetfulness
x
feeling more hungry or thirsty than usual
Kidney problems
x
decrease in your amount of urine
x
swelling in your ankles
x
blood in your urine
x
loss of appetite
Skin problems
x
x
x
rash
itching
skin blistering or peeling
x
x
x
painful sores or ulcers in your mouth
or in your nose, throat, or genital area
fever or flu-like symptoms
swollen lymph nodes
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of
immune system problems that can happen with TEVIMBRA. Call or see your healthcare provider right away
for new or worsening symptoms, which may include:
x
chest pain, irregular heartbeat, shortness of breath, swelling of ankles
x
confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling
or numbness of the arms or legs
x
double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
x
persistent or severe muscle pain or weakness, muscle cramps
x
low red blood cells, bruising
Infusion reactions that can sometimes be severe or life-threatening. Signs or symptoms of infusion reactions
may include:
x
chills or shaking
x
dizziness
x
itching or rash
x
feeling like passing out
x
flushing
x
fever
x
shortness of breath or wheezing
x
back or neck pain
Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you
should report and monitor you, depending on the type of organ or tissue transplant that you have had.
Reference ID: 5502689
Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow
(stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to
death. These complications may happen if you underwent transplantation either before or after being treated with
TEVIMBRA. Your healthcare provider will monitor you for these complications.
Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during your treatment with TEVIMBRA. Your healthcare
provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also
need to delay or completely stop treatment with TEVIMBRA if you have severe side effects.
What is TEVIMBRA?
TEVIMBRA is a prescription medicine used to treat adults with:
x
cancer of the tube that connects your throat to your stomach (esophageal cancer). TEVIMBRA may be used
alone when your esophageal cancer:
o
is a type called squamous cell carcinoma, and
o
cannot be removed with surgery or has spread to other parts of the body (metastatic), and
o
you have had previous treatment that did not include a PD-(L)1 inhibitor medicine.
x
cancer of the stomach (gastric cancer) or cancer where the esophagus joins the stomach (gastroesophageal
junction cancer). TEVIMBRA may be used in combination with chemotherapy that contains platinum and
fluoropyrimidine as your first treatment when your gastric or gastroesophageal junction cancer:
o
cannot be removed with surgery or has spread to other parts of the body (metastatic), and
o
your tumor tests positive for “PD-L1”.
It is not known if TEVIMBRA is safe and effective in children.
Before receiving TEVIMBRA, tell your healthcare provider about all of your medical conditions, including if
you:
x
have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
x
have received an organ or tissue transplant, including corneal transplant
x
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
x
have received radiation treatment to your chest area
x
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
x
are pregnant or plan to become pregnant. TEVIMBRA can harm your unborn baby.
Females who are able to become pregnant:
o
Your healthcare provider will do a pregnancy test before you start treatment with TEVIMBRA.
o
You should use an effective method of birth control during your treatment and for 4 months after your last dose
of TEVIMBRA. Talk to your healthcare provider about birth control methods that you can use during this time.
o
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during
treatment with TEVIMBRA.
x
are breastfeeding or plan to breastfeed. It is not known if TEVIMBRA passes into your breast milk. Do not
breastfeed during treatment with TEVIMBRA and for 4 months after your last dose of TEVIMBRA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
How will I receive TEVIMBRA?
x
Your healthcare provider will give you TEVIMBRA into your vein through an intravenous (IV) line over 30 to 60
minutes.
x
TEVIMBRA is usually given every 3 weeks.
x
Your healthcare provider will decide how many treatments you need.
x
Your healthcare provider will do blood tests to check you for certain side effects.
x
If you miss any appointment, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of TEVIMBRA?
TEVIMBRA may cause serious side effects. See “What is the most important information I should know about
TEVIMBRA?”
The most common side effects of TEVIMBRA in combination with platinum and fluoropyrimidine-based
chemotherapy include:
x
nausea
x
vomiting
x
diarrhea
x
tiredness
x
decreased platelet count
x
stomach-area (abdominal) pain
x
decreased appetite
x
decreased white blood cell counts
x
decreased weight
Reference ID: 5502689
x
decreased red blood cell count
x
increase in certain liver blood
x
fever
(anemia)
tests
x
numbness, pain, tingling, or
burning in your hands or feet
The most common side effects of TEVIMBRA when used alone include:
x
increased blood sugar
x
decreased albumin in the blood
x
muscle and bone pain
x
decreased red blood cell and
x
increase in certain liver blood
x
decreased weight
white blood cell counts
tests
x
cough
x
decreased salt (sodium) in
x
tiredness
your blood
These are not all the possible side effects of TEVIMBRA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of TEVIMBRA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your
healthcare provider or pharmacist for more information about TEVIMBRA that is written for health professionals.
What are the ingredients in TEVIMBRA?
Active ingredient: tislelizumab-jsgr
Inactive ingredients: citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20,
sodium citrate, Sterile Water for Injection, and trehalose.
Manufactured by: BeiGene USA, Inc. San Mateo, CA 94404 U.S.
U.S. License No.2232
TEVIMBRATM is a registered trademark owned by BeiGene, Ltd.
© BeiGene, Ltd. 2024
For more information, call 1-833-969-2463 or go to www.TEVIMBRA.com
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
Reference ID: 5502689
| custom-source | 2025-02-12T15:48:15.098625 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761417s000lbl.pdf', 'application_number': 761417, 'submission_type': 'ORIG ', 'submission_number': 1} |
80,760 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
EBANGA™ safely and effectively. See full prescribing information
for EBANGA.
EBANGATM (ansuvimab-zykl) for injection, for intravenous
use Initial U.S. Approval: 2020
-----------------------------INDICATIONS AND USAGE--------------------------
EBANGA (ansuvimab-zykl) is an Orthoebolavirus zairense glycoprotein
(EBOV GP)-directed human monoclonal antibody indicated for the
treatment of infection caused by Orthoebolavirus zairense in adult and
pediatric patients, including neonates born to a mother who is RT-PCR
positive for Orthoebolavirus zairense infection. (1)
Limitation of Use
The efficacy of EBANGA has not been established for other
species of the Orthoebolavirus and Orthomarburgvirus genera.
Orthoebolavirus zairense can change over time, and factors
such as emergence of resistance or changes in viral virulence
could diminish the clinical benefit of antiviral drugs. Consider
available information on drug susceptibility patterns for
circulating Orthoebolavirus zairense strains when deciding
whether to use EBANGA.
------------------------DOSAGE AND ADMINISTRATION----------------------
The recommended dose of EBANGA for adult and pediatric patients is
50 mg/kg reconstituted, further diluted, and administered as a single
intravenous infusion over 60 minutes. (2.1, 2.2)
See Full Prescribing Information for instructions on preparation, dilution
and administration of EBANGA injection. (2.2)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
For injection: 400 mg lyophilized powder in a single-dose vial for
reconstitution and further dilution. (3)
-------------------------------CONTRAINDICATIONS------------------------------
None.
------------------------WARNINGS AND PRECAUTIONS----------------------
Hypersensitivity Reactions Including Infusion-Associated Events:
Hypersensitivity reactions including infusion-associated events have
been reported with EBANGA. These may include acute, life-
threatening reactions during and after the infusion. Monitor patients
and in the case of severe or life-threatening hypersensitivity reactions,
discontinue the administration of EBANGA immediately and administer
appropriate emergency care. (5.1)
-------------------------------ADVERSE REACTIONS-----------------------------
The most frequently reported adverse events (≥ 5%) after
administration of EBANGA were pyrexia, tachycardia, diarrhea,
vomiting, hypotension, tachypnea, and chills. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Emergent
BioSolutions at 1-800-768-2304 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Interaction with live vaccine indicated for prevention of Orthoebolavirus
zairense infection: No vaccine interaction studies have been performed.
EBANGA may reduce the efficacy of the live vaccine. The interval
between administration of EBANGA therapy and live vaccination
should be in accordance with current vaccination guidelines. (7.1)
--------------------------USE IN SPECIFIC POPULATIONS--------------------
Lactation: Patients infected with Orthoebolavirus zairense should be
instructed not to breastfeed due to the potential for Orthoebolavirus
zairense transmission. (8.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage for Adult and Pediatric Patients
2.2 Preparation, Administration, and Storage Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions Including Infusion-Associated
Events
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
7 DRUG INTERACTIONS
7.1 Vaccine Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment
of Fertility
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 5502671
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
EBANGA is indicated for the treatment of infection caused by Orthoebolavirus zairense (formerly
Zaire ebolavirus) in adult and pediatric patients, including neonates born to a mother who is RT-PCR
positive for Orthoebolavirus zairense infection [see Dosage and Administration (2.2) and Clinical
Studies (14)].
Limitations of Use:
The efficacy of EBANGA has not been established for other species of the Orthoebolavirus and
Orthomarburgvirus genera.
Orthoebolavirus zairense can change over time, and factors such as emergence of resistance, or
changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available
information on drug susceptibility patterns for circulating Orthoebolavirus zairense strains when
deciding whether to use EBANGA.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage for Adult and Pediatric Patients
The recommended dosage of EBANGA is 50 mg/kg administered as a single intravenous (IV)
infusion over 60 minutes. EBANGA must be reconstituted with Sterile Water for Injection, USP then
further diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to IV
infusion [see Dosage and Administration (2.2)].
2.2. Preparation, Administration, and Storage Instructions
EBANGA must be prepared and administered under the supervision of a health care professional.
Reconstitution Instructions
Aseptically reconstitute and further dilute EBANGA prior to IV infusion. Do not administer as an IV
push or bolus.
More than one vial may be needed for a full dose. Calculate the dose (mg) based on the patient’s
actual weight in kg and the number of EBANGA vials required [see Dosage and Administration
(2.1)].
Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to
81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately
upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at
ambient temperature, protected from light, for no more than 24 hours.
Immediately upon reaching ambient temperature, use a sterile 10 mL syringe and an 18-gauge
needle to withdraw 7.7 mL of Sterile Water for Injection, USP. Insert the needle tip into the
EBANGA vial. Holding horizontally, angle the needle down at an approximate 45° angle, above
the lyophilized powder, which has a cake-like appearance. Slowly inject the diluent along the wall
of the vial and without any air to avoid foaming and bubbles.
Gently swirl (do NOT shake) for approximately 10 seconds; then set the vial down to rest for at
least 10 seconds. Repeat until the cake is dissolved. This may take up to 20 minutes.
2
Reference ID: 5502671
Upon reconstitution, one vial delivers 8 mL of solution that is clear to slightly opalescent and
colorless to slightly yellow containing 50 mg/mL of ansuvimab-zykl. Do NOT administer and
discard the vial if the reconstituted solution is discolored or contains visible particles.
Dilute the EBANGA solution immediately upon reconstitution. If needed, the reconstituted
solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F), protected from light, for up
to 4 hours. This 4-hour window includes time required for further dilution and EBANGA
solution should be infused immediately upon further dilution.
Dilution Instructions
Following reconstitution, EBANGA must be further diluted prior to IV infusion.
o Use an 18-20 gauge, 1-1.5” needle with an appropriately sized syringe up to 60 mL to
perform the dilution steps.
o Prepare the EBANGA IV dosing solution using an appropriately sized syringe up to 60 mL.
For patients weighing ≥ 2 kg, prepare the diluent using either a latex-free, di
ethylhexylphthalate (DEHP)-free 0.9% Sodium Chloride Injection USP infusion bag, or latex-
free, DEHP-free 5% Dextrose Injection USP infusion bag. For patients weighing 0.5 to < 2 kg
use a pump-compatible syringe (Table 1).
o For adult and pediatric patients, either 0.9% Sodium Chloride Injection, USP or 5%
Dextrose Injection, USP can be used as the diluent.
o The total volume of the infusion solution to be administered is based on the patient’s body
weight and is specified in Table 1.
For patients weighing 0.5 to < 2 kg:
-
Use a 10 mL syringe compatible with the IV infusion pump.
-
Fill the 10 mL syringe with the appropriate amount of diluent (Table 1).
-
Add the calculated volume of EBANGA to the 10 mL syringe (Table 1).
-
Mix the diluted solution by gentle inversion (3 to 5 times) until admixed. Do not shake.
For patients weighing ≥ 2 kg:
-
Select a diluent solution infusion bag size of appropriate fill volume based on the patient’s
body weight (see Table 1).
-
Withdraw and discard from the bag a volume of diluent solution that will leave remaining in
the bag the appropriate volume based on the patient’s weight (see Table 1). Then add the
calculated volume of EBANGA to the bag based on the patient’s weight (see Table 1).
For example, for a 55 kg patient, withdraw and discard 150 mL of diluent from a 250 mL
infusion bag. Then add 55 mL of EBANGA to obtain a total infusion volume of 155 mL.
-
Gently invert the IV bag 5 to 10 times until the diluted solution is admixed. Do NOT shake.
Infuse the EBANGA solution immediately upon dilution. If needed, the diluted infusion solution
may be stored refrigerated at 2°C to 8°C (36°F to 46°F), for up to 4 hours. Do not freeze the
diluted solution. If refrigerated, allow approximately 20 minutes for the diluted solution to come to
ambient temperature prior to use. These time limits include reconstitution time.
Prepare a medical label including patient weight in kg, date, and time of reconstitution.
Discard vial(s) and all unused contents.
3
Reference ID: 5502671
Table 1: EBANGA Volume, Diluent Volume and Total Infusion Volume by Body Weight
Weight in kg
Volume of
EBANGA
Diluent Volume
(mL)a,b
Final Infusion
Volume (mL)
Syringe or Infusion
Bag Volume for IV
Administration
0.5 kg
1 mL/kg
2.5 mL
3 mL
10 mL syringe compatible
with IV infusion pump
1 kg
5 mL
6 mL
2 to 10 kg
10 mL
12 to 20 mL
25 mL IV bag
11 to 25 kg
25 mL
36 to 50 mL
50 mL IV bag
26 to 50 kg
50 mL
76 to 100 mL
100 mL IV bag
51 to 100 kg
100 mL
151 to 200 mL
250 mL IV bag
101 kg and above
150 mL
251 mL and above
500 mL IV bag
a The recommended diluent volume ensures the final concentration of the diluted solution is approximately 8-30 mg/mL.
b For IV bag administration, the diluent volume column includes the volume of diluent needed to remain in the infusion
bag.
Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior
to administration. Do not administer if discolored or if the vial contains visible particles.
Do not mix with or administer as an infusion with other medicinal products.
Prepare the IV infusion line with 1.2 micron in-line filter extension set.
Administer the IV infusion solution over 60 minutes.
o The diluted EBANGA IV solution can be infused via a central line or peripheral catheter.
Do not administer EBANGA as an IV push or bolus.
o Do not co-administer other drugs simultaneously through the same infusion line.
o Infusions may be slowed or stopped if necessary, to alleviate any side effects.
At the end of the infusion, if a syringe pump was used, then remove the syringe and flush the line
with 2 to 5 mL of diluent, but not to exceed the total infusion volume. If an infusion bag was used,
replace the empty bag and flush the line by infusing at least 25 mL of the diluent, to ensure
complete product administration.
3 DOSAGE FORMS AND STRENGTHS
For injection: 400 mg of ansuvimab-zykl, available as an off-white to white lyophilized powder in
single-dose vial for reconstitution and further dilution.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions Including Infusion-Associated Events
Hypersensitivity reactions including infusion-associated events have been reported with EBANGA.
These may include acute, life-threatening reactions during and after the infusion. Monitor all patients
4
Reference ID: 5502671
for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during
and following EBANGA infusion. In the case of severe or life-threatening hypersensitivity reactions,
discontinue the administration of EBANGA immediately and administer appropriate emergency care
[see Adverse Reactions (6.1)].
Infusion could not be completed in 1% of participants who received EBANGA due to infusion-
associated adverse events. The rate of infusion of EBANGA may be slowed or interrupted if the patient
develops any signs of infusion-associated events or other adverse events [see Adverse Reactions
(6.1)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
Hypersensitivity Reactions Including Infusion-Associated Events [see Warnings and
Precautions (5.1)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice.
Overall, 424 adult and pediatric participants with Orthoebolavirus zairense infection received
EBANGA in one clinical trial and as part of an expanded access program during the 2018
Orthoebolavirus zairense outbreak in the Democratic Republic of Congo (DRC).
In the PALM trial, the safety of EBANGA was evaluated in a multi-center, open-label, randomized
controlled trial, in which 173 participants (119 adults and 54 pediatric participants) with confirmed
Orthoebolavirus zairense infection received EBANGA as a single 50 mg/kg IV infusion and 168
participants received an investigational control [see Clinical Studies (14)]. All participants received
optimized standard of care treatment (oSOC). The median age of the study population that received
EBANGA was 26 years (range: 1 day to 85 years) and 55% were female.
During the same outbreak, 251 participants (173 adults and 78 pediatric participants) with
laboratory- confirmed Orthoebolavirus zairense infection received EBANGA under an expanded
access program, 57% of whom were female. Ages ranged from 6 days to 80 years, with a median
age of 25 years.
Common Adverse Events
Table 2 summarizes the adverse events that were reported in the PALM trial from a pre-defined list of
signs and symptoms that occurred during EBANGA infusion. The evaluation of adverse events in
participants who received EBANGA may have been confounded by the signs and symptoms of the
underlying Orthoebolavirus zairense infection. Twenty nine percent (n=51) of participants who
received EBANGA in the PALM Trial experienced a pre-specified infusion-related adverse event. The
most common pre- specified infusion-related adverse event reported in at least 10% of participants
who received EBANGA was fever (Table 2). The adverse event profile in adult and pediatric
participants treated with EBANGA was similar.
5
Reference ID: 5502671
Table 2:
Adverse Events That Occurred During Infusion in >10% of Adult and
Pediatric Participants in the PALM Trial
Adverse Eventa
EBANGA
(N=173)
%
Controlb
(N=168)
%
Pyrexia
17
58
Tachycardia
9
32
Diarrheac
9
18
Vomitingc
8
23
Hypotension
8
31
Tachypnea
6
28
Chillsd
5
33
Hypoxiac,
3
11
aAdverse events in this table were reported on the day of infusion, and included signs and symptoms that occurred during or immediately after infusion
bInvestigational therapy administered as three separate infusions
cAdverse events that occurred during infusion but were not pre-specified.
dThe term chills includes other similar adverse events including rigors and tremors
The following pre-specified symptoms, which were assessed on a daily basis during admission while
admitted to the treatment unit, were reported in ≥40% of participants who received EBANGA:
diarrhea, pyrexia, abdominal pain, and vomiting. Evaluation of these symptoms may have been
confounded by the underlying Orthoebolavirus zairense infection.
Discontinuation and Infusion Rate Adjustments
Approximately 99% of participants who received EBANGA in the PALM trial were able to complete
their dose within one hour. Two participants who received EBANGA (1%) did not receive their
complete infusion. In eight participants (5%) the EBANGA infusion rate was decreased due to an
AE [see Warnings and Precautions (5.1)].
Selected Laboratory Abnormalities in the PALM Trial
Table 3 presents selected laboratory abnormalities (worsening to Grade 3 or 4 compared to baseline)
in the PALM trial.
6
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Table 3:
Selected Grade 3 and 4 Laboratory Abnormalitiesa, Worsened Grade from
Baseline in the PALM Trial
Laboratory Testa
EBANGA
N=173
%
Control
N=168
%
Sodium, high ≥ 154 mmol/L
5
4
Sodium, low < 125 mmol/L
7
11
Potassium, high ≥ 6.5 mmol/L
15
12
Potassium, low < 2.5 mmol/L
6
8
Creatinine (mg/dL) > 1.8 x ULN or ≥ 1.5 x baseline b
27
23
Alanine aminotransferase (U/L) ≥ 5 x ULNc
12
14
Aspartate aminotransferase (U/L) ≥ 5 x ULNd
13
18
ULN= upper limit of normal
a Graded per Division of AIDS (DAIDS) v2.1
b Based on a ULN of 1.2 mg/dL.
c Based on a ULN of 47 U/L.
d Based on a ULN of 38 U/L.
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity from using ansuvimab-zykl.
There are no data to assess the effects of potential immunogenicity on efficacy and safety in
participants with Orthoebolavirus zairense infection.
7 DRUG INTERACTIONS
7.1 Vaccine Interactions
No vaccine-therapeutic interaction studies have been performed in human participants using
EBANGA. However, because of the potential for EBANGA to inhibit replication of a live vaccine virus
indicated for prevention of Orthoebolavirus zairense infection and possibly reduce the efficacy of the
vaccine, avoid the concurrent administration of a live vaccine during treatment with EBANGA. The
interval between administration of EBANGA therapy and live vaccination should be in accordance
with current vaccination guidelines. The efficacy of EBANGA among participants who reported receipt
of a recombinant live vaccine prior to their enrollment in the PALM trial was similar to participants
who did not report receiving a vaccine prior to enrollment.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Orthoebolavirus zairense infection is life-threatening for both the mother and fetus and treatment
should not be withheld due to pregnancy (see Clinical Considerations). Available data from the PALM
trial in which pregnant women with Orthoebolavirus zairense infection were treated with EBANGA
demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature
regarding the risk associated with underlying maternal Orthoebolavirus zairense infection. These data
are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse
7
Reference ID: 5502671
maternal/fetal outcome.
Animal reproduction studies with ansuvimab-zykl have not been conducted. Monoclonal antibodies,
such as EBANGA, are transported across the placenta; therefore, EBANGA has the potential to be
transferred from the mother to the developing fetus.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Maternal, fetal and neonatal outcomes are poor among pregnant women infected with
Orthoebolavirus zairense. The majority of such pregnancies result in maternal death with
miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.
8.2 Lactation
Risk Summary
The Centers for Disease Control and Prevention recommend that mothers with confirmed
Orthoebolavirus zairense not breastfeed their infants to reduce the risk of postnatal transmission of
Orthoebolavirus zairense infection.
There are no data on the presence of ansuvimab-zykl in human or animal milk, the effects on the
breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk.
The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to
ansuvimab-zykl are unknown.
8.4 Pediatric Use
The safety and effectiveness of EBANGA for the treatment of infection caused by Orthoebolavirus
zairense have been established in pediatric patients from birth to less than 18 years of age. Use of
EBANGA for this indication is supported by evidence from a multi-center, open label, randomized
controlled trial of EBANGA in adults and pediatric participants that included 54 pediatric participants
birth to less than 18 years of age, including neonates born to a mother who is RT-PCR positive for
Orthoebolavirus zairense infection. Of the total number of participants administered EBANGA in the
PALM trial, pediatric participants (1 day to 17 years) accounted for 31% (n=54) of the study
population in the PALM trial. The 28-day mortality and safety in adult and pediatric participants
treated with EBANGA were similar [see Adverse Reactions (6.1), and Clinical Studies (14)]. An
additional 78 (31%) pediatric participants from birth to less than 18 years of age received EBANGA in
an expanded access program.
8.5 Geriatric Use
Clinical trials of EBANGA did not include sufficient numbers of participants aged 65 and over to
determine whether the safety profile of EBANGA is different in this population compared to younger
participants. Of the total number of participants administered EBANGA in the PALM trial, 6
participants (3%) were 65 years or older. The limited clinical experience has not identified
differences in responses between the elderly and younger participants.
11 DESCRIPTION
8
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Ansuvimab-zykl is an Orthoebolavirus zairense (EBOV) glycoprotein 1 (GP1)-directed
recombinant, human IgG1 monoclonal antibody. Ansuvimab-zykl is produced in Chinese Hamster
Ovary (CHO) cells by recombinant DNA technology and has an approximate molecular weight of
147 kDa.
EBANGA (ansuvimab-zykl) for injection is a sterile, preservative-free, off-white to white lyophilized
powder in a single-dose vial for IV use after reconstitution and dilution. Each single-dose vial delivers
400 mg of ansuvimab-zykl, and L-histidine (12.4 mg), L-histidine HCl (16.8 mg), polysorbate 80 (1.6
mg), and sucrose (657 mg). After reconstitution with 7.7 mL of Sterile Water for Injection, USP, each
vial delivers 8 mL of a clear and colorless to slightly yellow solution containing 50 mg/mL of
ansuvimab-zykl, with an approximate pH of 6.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ansuvimab-zykl is a recombinant human monoclonal antibody with antiviral activity against
Orthoebolavirus zairense [see Microbiology (12.4)].
12.2 Pharmacodynamics
Ansuvimab-zykl exposure-response relationship and the time course of pharmacodynamic response
is unknown.
12.3 Pharmacokinetics
Limited data from 18 healthy participants 22 to 56 years of age suggests that the pharmacokinetic
profile of ansuvimab-zykl is consistent with the profile of other IgG1 monoclonal antibodies.
Pharmacokinetic data are not available for Orthoebolavirus zairense infected patients.
Specific Populations
The effect of age, renal impairment or hepatic impairment on the pharmacokinetics of ansuvimab-zykl
is unknown.
12.4 Microbiology
Mechanism of Action
EBANGA (ansuvimab-zykl) is a recombinant, human IgG1κ monoclonal antibody that binds to the
glycan cap and inner chalice of the EBOV GP1 subunit. The epitope to which it binds is located within
the receptor binding domain of EBOV consisting of amino acids LEIKKPDGS (GP residues 111–119).
Ansuvimab-zykl binds EBOV GP without the mucin-like domain with a KD of 0.2 nM at pH 7.4 and 0.6
nM at pH 5.3 as measured by biolayer interferometry. Ansuvimab-zykl blocks binding of EBOV GP1
to the Neiman Pick cell receptor 1 in host cells (half-maximal effective concentration (EC50) value of
0.09 μg/mL), inhibiting virus entry into the host cell. Ansuvimab-zykl exhibited Fc-mediated Antibody
Dependent Cellular Cytotoxicity (ADCC) activity against cells expressing EBOV GP when effector
cells were added.
9
Reference ID: 5502671
Antiviral Activity
In a live virus plaque-reduction neutralization assay performed in Vero E6 cells, ansuvimab-zykl
neutralized Orthoebolavirus zairense Mayinga with an EC50 value of 0.06 µg/mL. In a pseudotyped
EBOV GP lentivirus infectivity assay using HEK293 cells, ansuvimab-zykl inhibited Orthoebolavirus
zairense Mayinga with an EC50 value of 0.09 μg/mL and Orthoebolavirus zairense Makona with an
EC50 value of 0.15 μg/mL. The ADCC activity of ansuvimab-zykl was assessed in EBOV GP
transduced and non-transduced HEK293T target cells in the presence of antibody with effector cells
added at an effector-to-target cell ratio 1:50 and analyzed via flow cytometry. Ansuvimab-zykl
mediated ADCC, with maximal activity observed at mAb concentration of 0.03 μg/mL. Treatment of
Orthoebolavirus zairense infected rhesus macaques with a single IV dose of ansuvimab-zykl (50 mg
per kg) generally protected infected animals from Orthoebolavirus zairense mediated death when
drug was administered 5 days post-infection.
Antiviral Resistance
No in-vivo nonclinical or clinical studies specifically evaluating resistance to ansuvimab-zykl have
been conducted. The possibility of resistance to ansuvimab-zykl should be considered in patients
who either fail to respond to therapy or who develop relapse of disease after an initial period of
responsiveness.
Cell Culture Resistance
Ansuvimab-zykl cell culture resistance studies have been performed using replication competent
recombinant vesicular stomatitis virus expressing the EBOV surface glycoprotein (rVSV-EBOV GP).
The rVSV-EBOV GP virus was sequentially sub-cultured in six experiments for up to 5 passages in
the presence of a concentration range of ansuvimab-zykl (0.08 to 50 µg/mL) to determine if escape
mutants developed via selective pressure. A total of seven different amino acid substitutions in the
EBOV GP were found (Table 4). Three of the seven were detected at less than 1% sequence
frequency and were not within the ansuvimab-zykl GP epitope or within 5Å of the epitope, and
therefore were excluded from further analysis.
Table 4:
Identification of Ebola GP Substitutions in Cell Culture Studies
GP Substitutions
%Frequency of
Sequences with the
Substitutiona
Ansuvimab-zykl Amino Acid Substitutions Induced at
50 µg/mL
R29S
<1
Excluded
P116H
71–94
Resistant
T144M
71–100
Resistant
N228H
<1
Excluded
R299K
71
No Resistance - Equivalent ansuvimab-zykl neutralization to
Kikwit reference GP sequence
N434K
73
No Resistance - Equivalent ansuvimab-zykl neutralization to
Kikwit reference GP sequence
T634A
<1
Excluded
a Frequency range of the sequences in 6 replicate experiments identified at the highest ansuvimab-zykl concentration of 50 µg/mL
The four remaining GP amino acid substitutions (P116H, T144M, R299K and N434K) were further
evaluated in a single-cycle neutralization assay using a replication-defective lentiviral vector not
10
Reference ID: 5502671
expressing envelope pseudotyped with EBOV GP containing each of the substitutions. The P116H
and T144M substitutions exhibited resistance to ansuvimab-zykl based on no neutralization detected
at the highest concentrations assessed (10 µg/mL) resulting in a >56-fold reduction in susceptibility
for each substitution compared to the wild type EBOV GP.
Two additional substitutions within the EBOV GP conserved region (G118E and G118R), which were
not found in the studies described above, have been reported in the literature from similar cell culture
resistance studies and these substitutions were able to confer >29- and >34-fold reductions in
susceptibility to ansuvimab-zykl, respectively.1
Of the four resistant substitutions identified under selective pressure in cell culture (P116H, G118E,
G118R, and T144M), none have been identified in naturally infected Ebola virus disease patients.
In Clinical Studies
A post-hoc detailed analysis of currently available EBOV GP sequences in the public database (as of
November 2022) was performed to identify all amino acid polymorphisms in the ansuvimab-zykl
epitope (GP positions 111-119) and amino acids within 5Å of the epitope. A total of nine sequences
out of 3324 available EBOV genomes had amino acid changes, of which two were within the
ansuvimab-zykl linear epitope (L111I and L111F) and two within 5Å of the epitope compared to the
Kikwit variant (I170L and I170F). Of the nine EBOV GP sequences, six were at the same amino acid
location with the same amino acid substitution (I170L), one was at the same location as the previous
six, but with a different amino acid substitution (I170F). The remaining two were at the same location
but with different amino acid substitutions (L111I and L111F). Overall, four of the nine EBOV GP
sequences expressed distinct amino acid substitutions at only two different positions. Phenotypic
assessments of these amino acid changes inside of, or within 5Å of the ansuvimab-zykl linear
epitope (111-119) using a pseudovirus neutralization assay were performed. The EBOV-GP
pseudotyped viruses with the I170F and I170L substitutions were found to be inactive and unable to
infect target cells. EBOV-GP pseudotyped viruses with the L111I and L111F were fully neutralized by
ansuvimab-zykl with a potency similar to the Ituri wild type variant and historic Mayinga variant EC50
values and therefore none of the four identified amino acid substitutions are expected to be resistant
to ansuvimab-zykl.
PALM Clinical study and MEURI EAP
Samples from a total of 95 participants (79 participants enrolled in the PALM randomized controlled
clinical study and 16 participants from the MEURI EAP) including samples from 40 deceased
participants and from 36 surviving participants with paired samples taken at baseline and after treatment
with ansuvimab-zykl where available for EBOV glycoprotein (GP) sequencing. A total of 147 EBOV (GP)
genome sequences were produced and when compared to the Kikwit or the Ituri reference sequences,
no amino acid changes were found in the ansuvimab-zykl epitope or within 5Å of the ansuvimab-zykl
epitope of EBOV GP. This finding includes EBOV GP sequences from deceased participants and
samples collected after treatment with ansuvimab-zykl. When compared to the Kikwit and the Ituri
variants, 26 and 14 amino acid substitutions, respectively, were found outside of the region of the
ansuvimab-zykl epitope in EBOV GP from PALM participants. These amino acid changes were located
predominantly in the less conserved mucin-like domain of the EBOV GP. None of these amino acid
changes were associated with mortality nor appeared to be driven by ansuvimab-zykl treatment.
The amino acid substitution G118R, which was selected for in cell culture, was detected at 9% to
13% frequency by Next Generation Sequencing (NGS) in 10 participant samples (9 of which were
11
Reference ID: 5502671
survivors) collected prior to treatment with ansuvimab-zykl in the PALM and MEURI EAP; the clinical
significance of this substitution is unknown.
Immune Response
Interaction studies with recombinant live EBOV vaccines and EBANGA have not been conducted
[see Drug Interactions (7.1)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, genotoxicity and fertility studies have not been conducted with ansuvimab-zykl.
14 CLINICAL STUDIES
The efficacy of EBANGA has been evaluated in 174 participants with confirmed Orthoebolavirus
zairense infection in the PALM trial, a multi-center, open-label, randomized, controlled trial
(NCT03719586). The trial was conducted in the North Kivu and Ituri provinces in the Democratic
Republic of Congo, where an outbreak began in August 2018, and enrolled 681 participants of all
ages, including pregnant women, with documented Orthoebolavirus zairense infection and symptoms
of any duration who were receiving oSOC. Eligible participants had a positive reverse transcriptase
polymerase chain reaction (RT-PCR) for the nucleoprotein (NP) gene of Orthoebolavirus zairense
and had not received other investigational treatments (with the exception of experimental vaccines)
within the previous 30 days. Neonates ≤7 days of age were eligible if the mother had documented
infection. Neonates born to a mother who had cleared Orthoebolavirus zairense following a course of
her assigned investigational medication were also eligible to be enrolled at investigator discretion
regarding the likelihood that the neonate was infected. Participants were randomized to receive
EBANGA 50 mg/kg IV as a single infusion, an investigational control 50 mg/kg IV every third day, for
a total of 3 doses, or other investigational drugs. Randomization was stratified by reverse
transcription-PCR cycle threshold calculated using NP targets (CtNP ≤22.0 vs ˃22.0; corresponding
to high and low viral load, respectively) and Ebola Treatment Unit (ETU) site. All participants received
oSOC consisting, at a minimum, of IV fluids, daily clinical laboratory testing, correction of
hypoglycemia and electrolyte imbalances, and broad-spectrum antibiotics and antimalarials, as
indicated.
The primary efficacy endpoint was 28-day mortality. The primary analysis population includes all
participants who were randomized and concurrently eligible to receive either EBANGA or the
investigational control during the same time period of the trial.
The demographics and baseline characteristics are provided in Table 5 below.
12
Reference ID: 5502671
Table 5:
Demographics and Baseline Characteristics in PALM Trial
Parameter
EBANGA
N=174
N (%)
Control
N=168
N (%)
Mean age (years)
27.3
29.9
Age <1 month, n (%)
4 (2)
2 (1)
Age 1 month to <1 year, n (%)
7 (4)
5 (3)
Age 1 year to <6 years, n (%)
15 (9)
12 (7)
Age 6 years to <12 years, n (%)
13 (7)
5 (3)
Age 12 years to <18 years, n (%)
15 (9)
9 (5)
Age 18 years to <50 years, n (%)
93 (53)
114 (68)
Age 50 years to <65 years, n (%)
21 (12)
18 (11)
Age ≥65 years, n (%)
6 (3)
3 (2)
Female, n (%)
98 (56)
87 (52)
Positive result on pregnancy testa, n (%)
5/98 (5)
4/87 (5)
RT-PCR CtNP cycle threshold ≤22, n (%)
73 (42)
70 (42)
Median RT-PCR CtNP (IQR)
23.3 (19.7, 28.5)
23.1 (19.0, 26.5)
Median creatinine (IQR)
0.9 (0.6, 2.4)
1.2 (0.8, 4.3)
Median AST (IQR)
234 (66, 978)
351 (112, 1404)
Median ALT (IQR)
168 (44, 551)
236 (48, 631)
Median days from onset of symptoms to randomization (IQR)
5 (3, 7)
5 (3, 7)
Reported Vaccination with rVSV-ZEBOV vaccine, n (%)
36 (21)
41 (24)
<10 days before ETU admission, n (%)
22/36 (61)
21/41 (51)
≥10 days before ETU admission, n (%)
12/36 (33)
18/41 (44)
Timing unknown, n (%)
2/36 (6)
2/41 (5)
a Pregnancy positive test was calculated based on participants who were pregnant. Denominator for percentages is the
number of females in the treatment group.
CtNP = cycle threshold calculated using NP targets; IQR=interquartile range; AST=Aspartate aminotransferase;
ALT=Alanine aminotransferase; ETU=Ebola treatment unit.
The PALM trial was stopped early on the basis of a pre-specified interim analysis showing a
statistically significant reduction in mortality for EBANGA compared to control assessed at Day 28.
Mortality efficacy results are shown in Table 6 and Figure 1.
13
Reference ID: 5502671
Table 6:
Mortality Rates in PALM Trial
Efficacy Endpoints
EBANGAa
N=174
Controla
N=168
Overall
28-day mortality, n (%)
61 (35%)
83 (49%)
Mortality rate difference relative to control (95% CI)b
-14.3 (-24.7, -3.7)
p-Valuec
0.008
Baseline Viral Load
High viral load (CtNP ≤ 22)d
28-day mortality, n (%)
51/73 (70%)
60/70 (86%)
Mortality rate difference relative to control (95% CI)b
-15.9 (-31.6, 0.9)
Low viral load (CtNP > 22)d
28-day mortality, n (%)
10/101 (10%)
23/97 (24%)
Mortality rate difference relative to control (95% CI)b
-13.8 (-27.3, 0.3)
Age group, 28-day mortality, n/N (%)
Adults (age ≥18 years)
41/120 (34%)
68/135 (50%)
12 to < 18 years of age
5/15 (33%)
5/9 (56%)
6 to < 12 years of age
4/13 (31%)
2/5 (40%)
< 6 years of age
11/26 (42%)
8/19 (42%)
Sex, 28-day mortality, n/N (%)
Male
30/76 (39%)
32/81 (40%)
Female
31/98 (32%)
51/87 (59%)
N=Number of participants in the Concurrent Intention-to-Treat population and treatment group; n=Number of participants with the
28-day outcome. Denominator for percentages is the total number of participants in the specific group.
a Both EBANGA and Control were administered with optimized standard of care
b 95% CI for Difference = 95% confidence intervals were computed by inverting two one-sided exact tests.
c The result is significant according to the interim stopping boundary, p<0.028.
d Cepheid GeneXpert Ebola® Assay used for detection of Orthoebolavirus zairense RNA
14
Reference ID: 5502671
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70
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60
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11.)
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30
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20
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4
7
10
13
16
34
37
40
43
46
49
52
55
19
22
25
28
31
Study Day
--- EBANGA --- Control
58
Figure 1:
Kaplan-Meier Curve for Overall Mortality in PALM Trial
15 REFERENCES
1. Rayaprolu V, Fulton BO, Rafique A, Arturo E, Williams D, Hariharan C, Callaway H, Parvate A, Schendel SL,
Parekh D, Hui S, Shaffer K, Pascal KE, Wloga E, Giordano S, Negron N, Ni M, Copin R, Atwal GS, Franklin M,
Boytz RM, Donahue C, Davey R, Baum A, Kyratsous CA, Saphire EO. Structure of the Inmazeb Cocktail and
Resistance to Ebola Virus Escape. Cell Host Microbe. 2023 Feb 8;31(2):260-272.e7. doi:
10.1016/j.chom.2023.01.002.
16 HOW SUPPLIED / STORAGE AND HANDLING
How Supplied
EBANGA (ansuvimab-zykl) for injection is supplied as a sterile, preservative-free, off-white to white
lyophilized powder in a single-dose vial (NDC 71655-578-01) for reconstitution and further dilution.
One primary carton (NDC 71655-578-02) contains thirty-six 400 mg vials packaged in a box
containing either one primary carton (NDC 71655-578-03), four primary cartons (NDC 71655-578-04),
or eight primary cartons (NDC 71655-578-08).
Storage and Handling
Store refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light. Do not
freeze. Do not shake.
Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to
81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately
upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at ambient
temperature, protected from light, for no more than 24 hours.
After reconstitution, if storage is needed, the entire storage time for the reconstituted solution
in the vial and the diluted solution in the IV bag should be protected from light and limited to 4
hours refrigerated at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.2)].
15
Reference ID: 5502671
. .. ... '
e6anga
17 PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions Including Infusion-Associated Events
Inform patients that hypersensitivity reactions including infusion-associated events have been
reported during and post-infusion with EBANGA and to immediately report if they experience any
symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.1)].
Lactation
Instruct patients with Orthoebolavirus zairense not to breastfeed because of the risk of
passing Orthoebolavirus zairense to the baby [see Use in Specific Populations (8.2)].
Manufactured by:
Emergent Manufacturing Operations Baltimore LLC
5901 East Lombard St.
Baltimore, MD 21224
U.S. Lic. No. 2083
[EBANGA™ is a trademark of Ridgeback Biotherapeutics, LP]
© 2024 Emergent Manufacturing Operations Baltimore LLC. All rights reserved.
Part No. XXXXXXXX
16
Reference ID: 5502671
| custom-source | 2025-02-12T15:48:15.922379 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761172s008lbl.pdf', 'application_number': 761172, 'submission_type': 'SUPPL ', 'submission_number': 8} |
80,756 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ADALIMUMAB-AATY safely and effectively. See full prescribing
information for ADALIMUMAB-AATY.
ADALIMUMAB-AATY injection, for subcutaneous use
Initial U.S. Approval: 2023
This product is YUFLYMA (adalimumab-aaty). YUFLYMA (adalimumab-aaty)
is biosimilar* to HUMIRA (adalimumab).
WARNING: SERIOUS INFECTIONS and MALIGNANCY
See full prescribing information for complete boxed warning.
SERIOUS INFECTIONS (5.1, 6.1):
•
Increased risk of serious infections leading to hospitalization or
death, including tuberculosis (TB), bacterial sepsis, invasive
fungal infections (such as histoplasmosis), and infections due to
other opportunistic pathogens.
•
Discontinue Adalimumab-aaty if a patient develops a serious
infection or sepsis during treatment.
•
Perform test for latent TB; if positive, start treatment for TB
prior to starting Adalimumab-aaty.
•
Monitor all patients for active TB during treatment, even if
initial latent TB test is negative.
MALIGNANCY (5.2):
•
Lymphoma and other malignancies, some fatal, have been
reported in children and adolescent patients treated with TNF
blockers including adalimumab products.
•
Post-marketing cases of hepatosplenic T-cell lymphoma
(HSTCL), a rare type of T-cell lymphoma, have occurred in
adolescent and young adults with inflammatory bowel disease
treated with TNF blockers including adalimumab products.
------------------------RECENT MAJOR CHANGES-----------------------
Indications and Usage, Uveitis (1.9)
08/2024
------------------------INDICATIONS AND USAGE------------------------
Adalimumab-aaty is a tumor necrosis factor (TNF) blocker indicated for:
•
Rheumatoid Arthritis (RA) (1.1): reducing signs and symptoms,
inducing major clinical response, inhibiting the progression of structural
damage, and improving physical function in adult patients with
moderately to severely active RA.
•
Juvenile Idiopathic Arthritis (JIA) (1.2): reducing signs and symptoms
of moderately to severely active polyarticular JIA in patients 2 years of
age and older.
•
Psoriatic Arthritis (PsA) (1.3): reducing signs and symptoms,
inhibiting the progression of structural damage, and improving physical
function in adult patients with active PsA.
•
Ankylosing Spondylitis (AS) (1.4): reducing signs and symptoms in
adult patients with active AS.
•
Crohn’s Disease (CD) (1.5): treatment of moderately to severely active
Crohn’s disease in adults and pediatric patients 6 years of age and older.
•
Ulcerative Colitis (UC) (1.6): treatment of moderately to severely active
ulcerative colitis in adult patients.
Limitations of Use: Effectiveness has not been established in patients
who have lost response to or were intolerant to TNF blockers.
•
Plaque Psoriasis (Ps) (1.7): treatment of adult patients with moderate to
severe chronic plaque psoriasis who are candidates for systemic therapy
or phototherapy, and when other systemic therapies are medically less
appropriate.
•
Hidradenitis Suppurativa (HS) (1.8): treatment of moderate to severe
hidradenitis suppurativa in adult patients.
•
Uveitis (UV) (1.9): treatment of non-infectious intermediate, posterior,
and panuveitis in adult patients.
--------------------DOSAGE AND ADMINISTRATION-------------------
•
Administer by subcutaneous injection (2)
Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.1):
•
Adults: 40 mg every other week.
•
Some patients with RA not receiving methotrexate may benefit
from increasing the dosage to 40 mg every week or 80 mg every
other week.
Juvenile Idiopathic Arthritis (2.2):
Pediatric Weight
2 Years of Age and Older
Recommended Dosage
15 kg (33 lbs) to less than 30 kg
(66 lbs)
20 mg every other week
30 kg (66 lbs) and greater
40 mg every other week
Crohn's Disease (2.3):
•
Adults: 160 mg on Day 1 (given in one day or split over two
consecutive days); 80 mg on Day 15; and 40 mg every other week
starting on Day 29.
•
Pediatric Patients 6 Years of Age and Older:
Reference ID: 5502211
Pediatric Weight
Recommended Dosage
Days 1 and 15
Starting on Day 29
17 kg (37 lbs) to less
than 40 kg (88 lbs)
Day 1: 80 mg
Day 15: 40 mg
20 mg every other week
40 kg (88 lbs) and
greater
Day 1: 160 mg (single
dose or split over two
consecutive days)
Day 15: 80 mg
40 mg every other week
Ulcerative Colitis (2.4):
•
Adults: 160 mg on Day 1 (given in one day or split over two
consecutive days), 80 mg on Day 15 and 40 mg every other week
starting on Day 29. Discontinue in patients without evidence of
clinical remission by eight weeks (Day 57).
Plaque Psoriasis or Adult Uveitis (2.5):
•
Adults: 80 mg initial dose followed by 40 mg every other week
starting one week after initial dose.
Hidradenitis Suppurativa (2.6):
•
Adults:
◦ Day 1: 160 mg (given in one day or split over two consecutive days)
◦ Day 15: 80 mg
◦ Day 29 and subsequent doses: 40 mg every week or 80 mg every
other week
------------------DOSAGE FORMS AND STRENGTHS------------------
Injection:
•
Single-dose prefilled auto-injector (Adalimumab-aaty AI): 80 mg/0.8
mL, 40 mg/0.4 mL (3)
•
Single-dose prefilled syringe with safety guard: 80 mg/0.8 mL, 40
mg/0.4 mL (3)
•
Single-dose prefilled syringe: 80 mg/0.8 mL, 40 mg/0.4 mL, 20 mg/0.2
mL (3)
---------------------------CONTRAINDICATIONS---------------------------
None (4)
---------------------WARNINGS AND PRECAUTIONS--------------------
•
Serious infections: Do not start Adalimumab-aaty during an
active infection. If an infection develops, monitor carefully,
and stop Adalimumab-aaty if infection becomes serious (5.1)
•
Invasive fungal infections: For patients who develop a systemic
illness on Adalimumab-aaty, consider empiric antifungal therapy for
those who reside or travel to regions where mycoses are endemic
(5.1)
•
Malignancies: Incidence of malignancies was greater in
adalimumab-treated patients than in controls (5.2)
•
Anaphylaxis or serious hypersensitivity reactions may occur (5.3)
•
Hepatitis B virus reactivation: Monitor HBV carriers during and
several months after therapy. If reactivation occurs, stop
Adalimumab-aaty and begin anti-viral therapy (5.4)
•
Demyelinating disease: Exacerbation or new onset, may occur (5.5)
•
Cytopenias, pancytopenia: Advise patients to seek immediate
medical attention if symptoms develop, and consider stopping
Adalimumab-aaty (5.6)
•
Heart failure: Worsening or new onset, may occur (5.8)
•
Lupus-like syndrome: Stop Adalimumab-aaty if syndrome develops
(5.9)
---------------------------ADVERSE REACTIONS---------------------------
Most common adverse reactions (> 10%) are: infections (e.g. upper
respiratory, sinusitis), injection site reactions, headache and rash (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
CELLTRION USA Inc., at 1-800-560-9414 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
----------------------------DRUG INTERACTIONS---------------------------
•
Abatacept: Increased risk of serious infection (5.1, 5.11, 7.2)
•
Anakinra: Increased risk of serious infection (5.1, 5.7, 7.2)
•
Live vaccines: Avoid use with Adalimumab-aaty (5.10, 7.3)
See 17 for PATIENT COUNSELING INFORMATION and
Medication Guide.
* Biosimilar means that the biological product is approved based on data
demonstrating that it is highly similar to an FDA-approved biological
product, known as a reference product, and that there are no clinically
meaningful differences between the biosimilar product and the reference
product. Biosimilarity of Adalimumab-aaty has been demonstrated for
the condition(s) of use (e.g. indication(s), dosing regimen(s)),
strength(s), dosage form(s), and route(s) of administration described in
its Full Prescribing Information.
Revised: 12/2024
Reference ID: 5502211
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SERIOUS INFECTIONSandMALIGNANCY
6.3
PostmarketingExperience
1
INDICATIONS AND USAGE
7
DRUGINTERACTIONS
1.1
Rheumatoid Arthritis
7.1
Methotrexate
1.2
Juvenile Idiopathic Arthritis
7.2
Biological Products
1.3
Psoriatic Arthritis
7.3
Live Vaccines
1.4
AnkylosingSpondylitis
7.4
Cytochrome P450 Substrates
1.5
Crohn’s Disease
8
USE IN SPECIFIC POPULATIONS
1.6
Ulcerative Colitis
8.1
Pregnancy
1.7
Plaque Psoriasis
8.2
Lactation
1.8
Hidradenitis Suppurativa
8.4
Pediatric Use
1.9
Uveitis
8.5
Geriatric Use
2
DOSAGE AND ADMINISTRATION
10
OVERDOSAGE
2.1
Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing
11
DESCRIPTION
Spondylitis
12
CLINICAL PHARMACOLOGY
2.2
Juvenile Idiopathic Arthritis
12.1
Mechanism of Action
2.3
Crohn’s Disease
12.2
Pharmacodynamics
2.4
Ulcerative Colitis
12.3
Pharmacokinetics
2.5
Plaque Psoriasis or Adult Uveitis
13
NONCLINICAL TOXICOLOGY
2.6
Hidradenitis Suppurativa
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
2.7
Monitoring to Assess Safety
14
CLINICAL STUDIES
2.8
General Considerations for Administration
14.1
RheumatoidArthritis
3
DOSAGEFORMS AND STRENGTHS
14.2
Juvenile Idiopathic Arthritis
4
CONTRAINDICATIONS
14.3
Psoriatic Arthritis
5
WARNINGSANDPRECAUTIONS
14.4
AnkylosingSpondylitis
5.1
Serious Infections
14.5
Adult Crohn’s Disease
5.2
Malignancies
14.6
Pediatric Crohn’s Disease
5.3
HypersensitivityReactions
14.7
Adult UlcerativeColitis
5.4
Hepatitis B Virus Reactivation
14.8
Plaque Psoriasis
5.5
NeurologicReactions
14.9
Hidradenitis Suppurativa
5.6
HematologicalReactions
14.10 Adult Uveitis
5.7
Increased Risk of Infection when Used with Anakinra
15
REFERENCES
5.8
Heart Failure
16
HOWSUPPLIED/STORAGE AND HANDLING
5.9
Autoimmunity
17
PATIENT COUNSELINGINFORMATION
5.10
Immunizations
5.11
Increased Risk of Infection When Used with Abatacept
6
ADVERSE REACTIONS
*Sections or subsections omitted from the full prescribing information
6.1
Clinical Trials Experience
are not listed.
6.2
Immunogenicity
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FULL PRESCRIBING INFORMATION
WARNING: SERIOUS INFECTIONS and MALIGNANCY
SERIOUS INFECTIONS
Patients treated with adalimumab products including Adalimumab-aaty, are at increased
risk for developing serious infections that may lead to hospitalization or death [see Warnings
and Precautions (5.1)]. Most patients who developed these infections were taking
concomitant immunosuppressants such as methotrexate or corticosteroids.
Discontinue Adalimumab-aaty if a patient develops a serious infection or sepsis.
Reported infections include:
• Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have
frequently presented with disseminated or extrapulmonary disease. Test patients for
latent TB before Adalimumab-aaty use and during therapy. Initiate treatment for
latent TB prior to Adalimumab-aaty use.
• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis,
aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other
invasive fungal infections may present with disseminated, rather than localized, disease.
Antigen and antibody testing for histoplasmosis may be negative in some patients with
active infection. Consider empiric anti-fungal therapy in patients at risk for invasive
fungal infections who develop severe systemic illness.
• Bacterial, viral and other infections due to opportunistic pathogens, including
Legionella and Listeria.
Carefully consider the risks and benefits of treatment with Adalimumab-aaty prior to
initiating therapy in patients with chronic or recurrent infection.
Monitor patients closely for the development of signs and symptoms of infection during and
after treatment with Adalimumab-aaty, including the possible development of TB in patients
who tested negative for latent TB infection prior to initiating therapy [see Warnings and
Precautions (5.1) and Adverse Reactions (6.1)].
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent
patients treated with TNF blockers including adalimumab products [see Warnings and
Precautions (5.2)]. Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare
type of T-cell lymphoma, have been reported in patients treated with TNF blockers including
adalimumab products. These cases have had a very aggressive disease course and have been
fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's
disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost
all these patients had received treatment with azathioprine or 6-mercaptopurine (6–MP)
concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the
occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with
these other immunosuppressants [see Warnings and Precautions (5.2)].
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1 INDICATIONS AND USAGE
1.1 Rheumatoid Arthritis
Adalimumab-aaty is indicated for reducing signs and symptoms, inducing major clinical response,
inhibiting the progression of structural damage, and improving physical function in adult patients with
moderately to severely active rheumatoid arthritis. Adalimumab-aaty can be used alone or in
combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs
(DMARDs).
1.2 Juvenile Idiopathic Arthritis
Adalimumab-aaty is indicated for reducing signs and symptoms of moderately to severely active
polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. Adalimumab-aaty can be
used alone or in combination with methotrexate.
1.3 Psoriatic Arthritis
Adalimumab-aaty is indicated for reducing signs and symptoms, inhibiting the progression of structural
damage, and improving physical function in adult patients with active psoriatic arthritis. Adalimumab
aaty can be used alone or in combination with non-biologic DMARDs.
1.4 Ankylosing Spondylitis
Adalimumab-aaty is indicated for reducing signs and symptoms in adult patients with active
ankylosing spondylitis.
1.5 Crohn’s Disease
Adalimumab-aaty is indicated for the treatment of moderately to severely active Crohn’s disease
in adults and pediatric patients 6 years of age and older.
1.6 Ulcerative Colitis
Adalimumab-aaty is indicated for the treatment of moderately to severely active ulcerative colitis in adult
patients.
Limitations of Use
The effectiveness of adalimumab products has not been established in patients who have lost response to
or were intolerant to TNF blockers [see Clinical Studies (14.7)].
1.7 Plaque Psoriasis
Adalimumab-aaty is indicated for the treatment of adult patients with moderate to severe chronic plaque
psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are
medically less appropriate. Adalimumab-aaty should only be administered to patients who will be closely
monitored and have regular follow-up visits with a physician [see Warnings and Precautions (5)].
1.8 Hidradenitis Suppurativa
Adalimumab-aaty is indicated for the treatment of moderate to severe hidradenitis suppurativa in adult
patients.
1.9 Uveitis
Adalimumab-aaty is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis
in adult patients.
2 DOSAGE AND ADMINISTRATION
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2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis
The recommended subcutaneous dosage of Adalimumab-aaty for adult patients with rheumatoid arthritis
(RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) is 40 mg administered every other week.
Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti- inflammatory
drugs (NSAIDs), and/or analgesics may be continued during treatment with Adalimumab-aaty. In the
treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing
the dosage of Adalimumab-aaty to 40 mg every week or 80 mg every other week.
2.2 Juvenile Idiopathic Arthritis
The recommended subcutaneous dosage of Adalimumab-aaty for patients 2 years of age and older with
polyarticular juvenile
idiopathic arthritis (JIA) is based on weight as shown below. MTX,
glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with Adalimumab-aaty.
Pediatric Weight
(2 years of age and older)
Recommended Dosage
15 kg (33 lbs) to less than 30 kg (66 lbs)
20 mg every other week
30 kg (66 lbs) and greater
40 mg every other week
There is no dosage form for Adalimumab-aaty that allows weight-based dosing for pediatric patients
below 15 kg.
Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or
in patients with a weight below 10 kg.
2.3 Crohn’s Disease
Adults
The recommended subcutaneous dosage of Adalimumab-aaty for adult patients with Crohn’s disease
(CD) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80
mg two weeks later (Day 15). Two weeks later (Day 29) begin a dosage of 40 mg every other week.
Aminosalicylates and/or corticosteroids may be continued during treatment with Adalimumab-aaty.
Azathioprine, 6- mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] or MTX may be
continued during treatment with Adalimumab-aaty if necessary.
Pediatrics
The recommended subcutaneous dosage of Adalimumab-aaty for pediatric patients 6 years of age and
older with Crohn’s disease (CD) is based on body weight as shown below:
Pediatric Weight
Recommended Dosage
Days 1 through 15
Starting on Day 29
17 kg (37 lbs) to less than
40 kg (88 lbs)
Day 1: 80 mg
Day 15: 40 mg
20 mg every other week
40 kg (88 lbs) and greater
Day 1: 160 mg (single dose or split
over two consecutive days)
Day 15: 80 mg
40 mg every other week
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2.4 Ulcerative Colitis
Adults
The recommended subcutaneous dosage of Adalimumab-aaty for adult patients with ulcerative colitis
(UC) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80
mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dosage of 40 mg every other
week.
Discontinue Adalimumab-aaty in adult patients without evidence of clinical remission by eight weeks
(Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with
Adalimumab-aaty. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)]
may be continued during treatment with Adalimumab-aaty if necessary.
2.5 Plaque Psoriasis or Adult Uveitis
The recommended subcutaneous dosage of Adalimumab-aaty for adult patients with plaque psoriasis (Ps)
or Uveitis (UV) is an initial dose of 80 mg, followed by 40 mg given every other week starting one week
after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year
has not been evaluated in controlled clinical studies.
2.6 Hidradenitis Suppurativa
Adults
The recommended subcutaneous dosage of Adalimumab-aaty for adult patients with hidradenitis
suppurativa (HS) is an initial dose of 160 mg (given in one day or split over two consecutive days),
followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly or 80 mg every other week dosing
two weeks later (Day 29).
2.7 Monitoring to Assess Safety
Prior to initiating Adalimumab-aaty and periodically during therapy, evaluate patients for active
tuberculosis and test for latent infection [see Warnings and Precautions (5.1)].
2.8 General Considerations for Administration
Adalimumab-aaty is intended for use under the guidance and supervision of a physician. A patient may
self-inject Adalimumab-aaty or a caregiver may inject Adalimumab-aaty using either the Adalimumab
aaty AI or Adalimumab-aaty prefilled syringe if a physician determines that it is appropriate, and with
medical follow-up, as necessary, after proper training in subcutaneous injection technique.
Adalimumab-aaty can be taken out of the refrigerator for about 15 to 30 minutes before injecting to
allow the liquid to come to room temperature. Do not remove the cap or cover while allowing it to reach
room temperature. Do not shake. Carefully inspect the solution in the Adalimumab-aaty AI or
Adalimumab-aaty prefilled syringe for particulate matter and discoloration prior to subcutaneous
administration. If particulates and discolorations are noted, do not use the product. Adalimumab-aaty
does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe.
Instruct patients using the Adalimumab-aaty AI or Adalimumab-aaty prefilled syringe to inject the full
amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions
for Use].
Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give
injections into areas where the skin is tender, bruised, red or hard.
If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular
scheduled time.
3 DOSAGE FORMS AND STRENGTHS
Adalimumab-aaty is a clear to opalescent, and colorless to pale brown solution available as:
• Auto-injector (Adalimumab-aaty AI)
Injection: 80 mg/0.8 mL in a single-dose auto-injector.
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Injection: 40 mg/0.4 mL in a single-dose auto-injector.
• Prefilled Syringe with Safety Guard
Injection: 80 mg/0.8 mL in a single-dose prefilled syringe with safety guard.
Injection: 40 mg/0.4 mL in a single-dose prefilled syringe with safety guard.
• Prefilled Syringe
Injection: 80 mg/0.8 mL in a single-dose prefilled syringe.
Injection: 40 mg/0.4 mL in a single-dose prefilled syringe.
Injection: 20 mg/0.2 mL in a single-dose prefilled syringe.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Serious Infections
Patients treated with adalimumab products, including Adalimumab-aaty, are at increased risk for
developing serious infections involving various organ systems and sites that may lead to hospitalization
or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or
other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis,
histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF
blockers. Patients have frequently presented with disseminated rather than localized disease.
The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of
serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of
Adalimumab-aaty and these biologic products is not recommended in the treatment of patients with
RA [see Warnings and Precautions (5.7, 5.11) and Drug Interactions (7.2)].
Treatment with Adalimumab-aaty should not be initiated in patients with an active infection, including
localized infections. Patients 65 years of age and older, patients with co-morbid conditions and/or
patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at
greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in
patients:
• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as
histoplasmosis, coccidioidomycosis, or blastomycosis; or
• with underlying conditions that may predispose them to infection.
Tuberculosis
Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients
receiving adalimumab products, including patients who have previously received treatment for latent or
active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated)
tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating
Adalimumab-aaty and periodically during therapy.
Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to
reduce the risk of tuberculosis reactivation during therapy. Prior to initiating Adalimumab-aaty, assess if
treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin
skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Consider anti-tuberculosis therapy prior to initiation of Adalimumab-aaty in patients with a past history
of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for
patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection.
Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in
patients treated with adalimumab products. Consultation with a physician with expertise in the treatment
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of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is
appropriate for an individual patient.
Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during
Adalimumab-aaty treatment, especially in patients who have previously or recently traveled to countries
with a high prevalence of tuberculosis, or who have had close contact with a person with active
tuberculosis.
Monitoring
Closely monitor patients for the development of signs and symptoms of infection during and after
treatment with Adalimumab-aaty, including the development of tuberculosis in patients who tested
negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection
may also be falsely negative while on therapy with Adalimumab-aaty.
Discontinue Adalimumab-aaty if a patient develops a serious infection or sepsis. For a patient who
develops a new infection during treatment with Adalimumab-aaty, closely monitor them, perform a
prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate
appropriate antimicrobial therapy.
Invasive Fungal Infections
If patients develop a serious systemic illness and they reside or travel in regions where mycoses are
endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for
histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric
antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal
therapy, while a diagnostic workup is being performed. To aid in the management of such patients,
consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal
infections.
5.2 Malignancies
Consider the risks and benefits of TNF-blocker treatment including Adalimumab-aaty prior to initiating
therapy in patients with a known malignancy other than a successfully treated non-melanoma skin
cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.
Malignancies in Adults
In the controlled portions of clinical trials of some TNF-blockers, including adalimumab products, more
cases of malignancies have been observed among TNF-blocker-treated adult patients compared to
control-treated adult patients. During the controlled portions of 39 global adalimumab clinical trials in
adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS),
Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and
uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were
observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973
adalimumab-treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-
treated patients (median duration of treatment of 4 months for adalimumab-treated patients and 4 months
for control-treated patients). In 52 global controlled and uncontrolled clinical trials of adalimumab in
adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the most frequently observed malignancies,
other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in
adalimumab-treated patients in the controlled and uncontrolled portions of the studies were similar in
type and number to what would be expected in the general U.S. population according to the SEER
database (adjusted for age, gender, and race).1
In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients
with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s
granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the
control group.
Non-Melanoma Skin Cancer
During the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA,
AS, CD, UC, Ps, HS and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100
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patient-years among adalimumab-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among
control-treated patients. Examine all patients, and in particular patients with a medical history of prior
prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the
presence of NMSC prior to and during treatment with Adalimumab-aaty.
Lymphoma and Leukemia
In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma
have been observed among TNF-blocker-treated patients compared to control-treated patients. In the
controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC,
Ps, HS and UV, 2 lymphomas occurred among 7973 adalimumab-treated patients versus 1 among 4848
control-treated patients. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult
patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration of approximately 0.7
years, including 24,605 patients and over 40,215 patient-years of adalimumab, the observed rate of
lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than
expected in the general U.S. population according to the SEER database (adjusted for age, gender, and
race).1 Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in
clinical trials of other TNF blockers and may not predict the rates observed in a broader patient
population. Patients with RA and other chronic inflammatory diseases, particularly those with highly
active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to
several fold) than the general population for the development of lymphoma, even in the absence of TNF
blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with
TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with
RA may be at a higher risk (approximately 2-fold) than the general population for the development of
leukemia.
Malignancies in Pediatric Patients and Young Adults
Malignancies, some fatal, have been reported among children, adolescents, and young adults who
received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which Adalimumab
aaty is a member. Approximately half the cases were lymphomas, including Hodgkin's and non
Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare
malignancies usually associated with immunosuppression and malignancies that are not usually observed
in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1
to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were
reported post-marketing and are derived from a variety of sources including registries and spontaneous
postmarketing reports.
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have
been reported in patients treated with TNF blockers including adalimumab products. These cases have
had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases
have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent
and young adult males. Almost all of these patients had received treatment with the
immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or
prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or
a TNF blocker in combination with these other immunosuppressants. The potential risk with the
combination of azathioprine or 6-mercaptopurine and Adalimumab-aaty should be carefully considered.
5.3 Hypersensitivity Reactions
Anaphylaxis and angioneurotic edema have been reported following administration of adalimumab
products. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue
administration of Adalimumab-aaty and institute appropriate therapy. In clinical trials of adalimumab,
hypersensitivity reactions (e.g., rash, anaphylactoid reaction, fixed drug reaction, non-specified drug
reaction, urticaria) have been observed.
5.4 Hepatitis B Virus Reactivation
Use of TNF blockers, including Adalimumab-aaty, may increase the risk of reactivation of hepatitis B
virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation
occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have
occurred in patients concomitantly receiving other medications that suppress the immune system, which
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may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence
of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers
for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of
treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy
to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF
blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection
throughout therapy and for several months following termination of therapy. In patients who develop
HBV reactivation, stop Adalimumab-aaty and initiate effective anti-viral therapy with appropriate
supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled
is not known. Therefore, exercise caution when considering resumption of Adalimumab-aaty therapy in
this situation and monitor patients closely.
5.5 Neurologic Reactions
Use of TNF blocking agents, including adalimumab products, has been associated with rare cases of new
onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system
demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating
disease, including Guillain-Barré syndrome. Exercise caution in considering the use of Adalimumab-aaty
in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders;
discontinuation of Adalimumab-aaty should be considered if any of these disorders develop. There is a
known association between intermediate uveitis and central demyelinating disorders.
5.6 Hematological Reactions
Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents.
Adverse reactions of the hematologic system, including medically significant cytopenia (e.g.,
thrombocytopenia, leukopenia) have been infrequently reported with adalimumab products. The causal
relationship of these reports to adalimumab products remains unclear. Advise all patients to seek
immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or
infection (e.g., persistent fever, bruising, bleeding, pallor) while on Adalimumab-aaty. Consider
discontinuation of Adalimumab-aaty therapy in patients with confirmed significant hematologic
abnormalities.
5.7 Increased Risk of Infection when Used with Anakinra
Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a
greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-
blocker alone in patients with RA. Therefore, the combination of Adalimumab-aaty and anakinra is not
recommended [see Drug Interactions (7.2)].
5.8 Heart Failure
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF
blockers. Cases of worsening CHF have also been observed with adalimumab products. Adalimumab
products have not been formally studied in patients with CHF; however, in clinical trials of another TNF
blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when
using Adalimumab-aaty in patients who have heart failure and monitor them carefully.
5.9 Autoimmunity
Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the
development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like
syndrome following treatment with Adalimumab-aaty, discontinue treatment [see Adverse Reactions
(6.1)].
5.10 Immunizations
In a placebo-controlled clinical trial of patients with RA, no difference was detected in
anti-pneumococcal antibody response between adalimumab and placebo treatment groups when the
pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with
adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies
between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens
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were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown.
Patients on Adalimumab-aaty may receive concurrent vaccinations, except for live vaccines. No data are
available on the secondary transmission of infection by live vaccines in patients receiving adalimumab
products.
It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in
agreement with current immunization guidelines prior to initiating Adalimumab-aaty therapy. Patients on
Adalimumab-aaty may receive concurrent vaccinations, except for live vaccines.
The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in
utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live- attenuated)
exposed infants [see Use in Specific Populations (8.1, 8.4)].
5.11 Increased Risk of Infection When Used with Abatacept
In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a
greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy,
compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the
treatment of RA. Therefore, the combination of abatacept with TNF-blockers including Adalimumab-aaty
is not recommended [see Drug Interactions (7.2)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Serious Infections [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.4)]
• Neurologic Reactions [see Warnings and Precautions (5.5)]
• Hematological Reactions [see Warnings and Precautions (5.6)]
• Heart Failure [see Warnings and Precautions (5.8)]
• Autoimmunity [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled
trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/or
itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection
site reactions were described as mild and generally did not necessitate drug discontinuation.
The proportion of patients who discontinued treatment due to adverse reactions during the double-blind,
placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA- II, RA-III and RA-IV)
was 7% for patients taking adalimumab and 4% for placebo-treated patients. The most common adverse
reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction
(0.7%), rash (0.3%) and pneumonia (0.3%).
Infections
In the controlled portions of the 39 global adalimumab clinical trials in adult patients with RA, PsA, AS,
CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973
adalimumab-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients.
Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections,
erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5.1)].
Tuberculosis and Opportunistic Infections
Reference ID: 5502211
In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that
included 24,605 adalimumab-treated patients, the rate of reported active tuberculosis was 0.20 per 100
patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of
10,113 U.S. and Canadian adalimumab-treated patients, the rate of reported active TB was 0.05 per 100
patient-years and the rate of positive PPD conversion was 0.07 per 100 patient- years. These trials
included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred
within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In
these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate
of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see
Warnings and Precautions (5.1)].
Autoantibodies
In the rheumatoid arthritis-controlled trials, 12% of patients treated with adalimumab and 7% of placebo-
treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients
out of 3046 treated with adalimumab developed clinical signs suggestive of new-onset lupus-like
syndrome. The patients improved following discontinuation of therapy. No patients developed lupus
nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab
products on the development of autoimmune diseases is unknown.
Liver Enzyme Elevations
There have been reports of severe hepatic reactions including acute liver failure in patients receiving
TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with
RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥3 x ULN
occurred in 3.5% of adalimumab-treated patients and 1.5% of control- treated patients. Since many of
these patients in these trials were also taking medications that cause liver enzyme elevations (e.g.,
NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear. In a
controlled Phase 3 trial of adalimumab in patients with polyarticular JIA who were 4 to 17 years, ALT
elevations ≥3 x ULN occurred in 4.4% of adalimumab-treated patients and 1.5% of control-treated
patients (ALT more common than AST); liver enzyme test elevations were more frequent among those
treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In
general, these elevations did not lead to discontinuation of adalimumab treatment. No ALT elevations ≥ 3
x ULN occurred in the open-label study of adalimumab in patients with polyarticular JIA who were 2 to
< 4 years.
In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on
Days 1 and 15, respectively, followed by 40 mg every other week) in adult patients with CD with a control
period duration ranging from 4 to 52 weeks, ALT elevations ≥3 x ULN occurred in 0.9% of adalimumab
treated patients and 0.9% of control-treated patients. In the Phase 3 trial of adalimumab in pediatric patients
with CD which evaluated efficacy and safety of two body weight based maintenance dose regimens following
body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6%
(5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these
patients discontinued due to abnormalities in ALT tests. In controlled Phase 3 trials of adalimumab (initial
doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in adult
patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 x ULN
occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase
3 trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with
control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of
adalimumab-treated patients and 1.8% of control-treated patients. In controlled trials of adalimumab
(initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week
4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x
ULN occurred in 0.3% of adalimumab-treated subjects and 0.6% of control-treated subjects. In controlled
trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at
Week 1) in adult patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in adalimumab
treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of
adalimumab-treated patients and 2.4% of control-treated patients.
Other Adverse Reactions
Rheumatoid Arthritis Clinical Studies
Reference ID: 5502211
The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6
months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies
( Studies RA-I, RA-II, RA-III, and RA-IV). Adalimumab was studied primarily in placebo- controlled
trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of
54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid
arthritis. Most patients received 40 mg adalimumab every other week [see Clinical Studies (14.1)].
Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 40 mg
every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the
types and frequencies of adverse reactions in the second year open-label extension were similar to those
observed in the one-year double-blind portion.
Table 1. Adverse Reactions Reported by ≥ 5% of Patients Treated with Adalimumab During
Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV)
Adalimumab
40 mg subcutaneous
Every Other Week
Placebo
(N=705)
(N=690)
Adverse Reaction (Preferred Term)
Respiratory
Upper respiratory infection
17%
13%
Sinusitis
11%
9%
Flu syndrome
7%
6%
Gastrointestinal
Nausea
9%
8%
Abdominal pain
7%
4%
Laboratory Tests*
Laboratory test abnormal
8%
7%
Hypercholesterolemia
6%
4%
Hyperlipidemia
7%
5%
Hematuria
5%
4%
Alkaline phosphatase increased
5%
3%
Other
Headache
12%
8%
Rash
12%
6%
Accidental injury
10%
8%
Injection site reaction **
8%
1%
Back pain
6%
4%
Urinary tract infection
8%
5%
Hypertension
5%
3%
* Laboratory test abnormalities were reported as adverse reactions in European trials
** Does not include injection site erythema, itching, hemorrhage, pain or swelling
Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies
Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse
Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated patients in RA
studies were:
Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain
Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest,
Reference ID: 5502211
hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope,
tachycardia
Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage,
hepatic necrosis, vomiting
Endocrine System: Parathyroid disorder
Hemic And Lymphatic System: Agranulocytosis, polycythemia
Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia,
peripheral edema
Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint
disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder
Neoplasia: Adenoma
Nervous System: Confusion, paresthesia, subdural hematoma, tremor
Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion
Special Senses: Cataract
Thrombosis: Thrombosis leg
Urogenital System: Cystitis, kidney calculus, menstrual disorder
Juvenile Idiopathic Arthritis Clinical Studies
In general, the adverse reactions in the adalimumab-treated patients in the polyarticular juvenile
idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) [see Clinical Studies (14.2)] were similar in
frequency and type to those seen in adult patients [see Warnings and Precautions (5), Adverse Reactions
(6)]. Important findings and differences from adults are discussed in the following paragraphs.
In Study JIA-I, adalimumab was studied in 171 patients who were 4 to 17 years of age, with polyarticular
JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis,
increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. Serious infections
were observed in 4% of patients within approximately 2 years of initiation of treatment with adalimumab
and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.
In Study JIA-I, 45% of patients experienced an infection while receiving adalimumab with or without
concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab
treated patients were generally similar to those commonly seen in polyarticular JIA patients who are not
treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in
this patient population treated with adalimumab were injection site pain and injection site reaction (19%
and 16%, respectively). A less commonly reported adverse event in patients receiving adalimumab was
granuloma annulare which did not lead to discontinuation of adalimumab treatment.
In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in
approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and
allergic rash.
In Study JIA-I, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies
developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity
during the clinical trial.
Approximately 15% of patients treated with adalimumab developed mild-to-moderate elevations of
creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal
were observed in several patients. CPK concentrations decreased or returned to normal in all patients.
Most patients were able to continue adalimumab without interruption.
In Study JIA-II, adalimumab was studied in 32 patients who were 2 to < 4 years of age or 4 years of age
and older weighing < 15 kg with polyarticular JIA. The safety profile for this patient population was
similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA.
In Study JIA-II, 78% of patients experienced an infection while receiving adalimumab. These included
nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to
moderate in severity. Serious infections were observed in 9% of patients receiving adalimumab in the
study and included dental caries, rotavirus gastroenteritis, and varicella.
In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent
Reference ID: 5502211
urticaria and rash, which were all mild in severity.
Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies
Adalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo- controlled
trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-
controlled studies [see Clinical Studies (14.3, 14.4)]. The safety profile for patients with PsA and AS
treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with
RA, adalimumab Studies RA-I through IV.
Crohn’s Disease Clinical Studies
Adults: The safety profile of adalimumab in 1478 adult patients with Crohn’s disease from four
placebo-controlled and two open-label extension studies [see Clinical Studies (14.5)] was similar to
the safety profile seen in patients with RA.
Pediatric Patients 6 Years to 17 Years: The safety profile of adalimumab in 192 pediatric patients
from one double-blind study (Study PCD-I) and one open-label extension study [see Clinical Studies
(14.6)] was similar to the safety profile seen in adult patients with Crohn’s disease.
During the 4-week open label induction phase of Study PCD-I, the most common adverse reactions
occurring in the pediatric population treated with adalimumab were injection site pain and injection
site reaction (6% and 5%, respectively).
A total of 67% of children experienced an infection while receiving adalimumab in Study PCD-I.
These included upper respiratory tract infection and nasopharyngitis.
A total of 5% of children experienced a serious infection while receiving adalimumab in Study PCD
I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and
disseminated histoplasmosis.
In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and
were primarily localized reactions.
Ulcerative Colitis Clinical Studies
Adults: The safety profile of adalimumab in 1010 adult patients with ulcerative colitis (UC) from two
placebo-controlled studies and one open-label extension study [see Clinical Studies (14.7)] was similar
to the safety profile seen in patients with RA.
Plaque Psoriasis Clinical Studies
Adalimumab has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and
open-label extension studies [see Clinical Studies (14.8)]. The safety profile for subjects with Ps treated
with adalimumab was similar to the safety profile seen in subjects with RA with the following
exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, adalimumab-treated
subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%).
Hidradenitis Suppurativa Clinical Studies
Adalimumab has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo-
controlled studies and one open-label extension study [see Clinical Studies (14.9)]. The safety profile
for subjects with HS treated with adalimumab weekly was consistent with the known safety profile of
adalimumab.
Flare of HS, defined as ≥ 25% increase from baseline in abscesses and inflammatory nodule
counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects
who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two
studies.
Uveitis Clinical Studies
Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-
label extension studies [see Clinical Studies (14.10)]. The safety profile for patients with UV treated
with adalimumab was similar to the safety profile seen in patients with RA.
Reference ID: 5502211
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of antibody (including neutralizing antibody) positivity in an assay may be
influenced by several factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons, comparison of the
incidence of antibodies in the studies described below with the incidence of antibodies in other studies
or to other adalimumab products may be misleading.
There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA,
antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2
mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab
concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development
in patients treated with adalimumab are presented in Table 2.
Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in
Patients Treated with Adalimumab
Indications
Study
Duration
Anti-Adalimumab Antibody
Incidence by ELISA (n/N)
Anti-Adalimumab
Antibody Incidence
by ECL Assay
(n/N)
In all patients
who received
adalimumab
In patients with
serum
adalimumab
concentrations
< 2 mcg/mL
Rheumatoid Arthritisa
6 to 12
months
5% (58/1062)
NR
NA
Juvenile
Idiopathic
Arthritis
(JIA)
4 to 17 years of
b
age
48 weeks
16% (27/171)
NR
NA
2 to 4 years of
age or ≥ 4 years
of age and
weighing < 15
kg
24 weeks
7% (1/15)c
NR
NA
Psoriatic Arthritisd
48 weekse
13% (24/178)
NR
NA
Ankylosing Spondylitis
24 weeks
9% (16/185)
NR
NA
Adult Crohn’s Disease
56 weeks
3% (7/269)
8% (7/86)
NA
Pediatric Crohn’s Disease
52 weeks
3% (6/182)
10% (6/58)
NA
Adult Ulcerative Colitis
52 weeks
5% (19/360)
21% (19/92)
NA
Plaque Psoriasisf
Up to 52
weeksg
8% (77/920)
21% (77/372)
NA
Hidradenitis Suppurativa
36 weeks
7% (30/461)
28% (58/207)h
61% (272/445)i
Non-infectious Uveitis
52 weeks
5% (12/249)
21% (12/57)
40% (99/249)j
n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not
performed)
a In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody
was 1% compared to 12% with adalimumab monotherapy
b In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared
to 26% with adalimumab monotherapy
c This patient received concomitant MTX
d In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to
1% in RA
e Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments.
f In plaque psoriasis patients who were on adalimumab monotherapy and subsequently withdrawn from
the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior
Reference ID: 5502211
to withdrawal
g One 12-week Phase 2 study and one 52-week Phase 3 study
h Among subjects in the 2 Phase 3 studies who stopped adalimumab treatment for up to 24 weeks and in
whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total
subjects studied)
i No apparent association between antibody development and safety was observed
j No correlation of antibody development to safety or efficacy outcomes was observed
Rheumatoid Arthritis and Psoriatic Arthritis: Patients in Studies RA-I, RA-II, and RA-III were tested at
multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12-month period. No
apparent correlation of antibody development to adverse reactions was observed. With monotherapy,
patients receiving every other week dosing may develop antibodies more frequently than those receiving
weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy,
the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients.
The long-term immunogenicity of adalimumab products is unknown.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of adalimumab products.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to adalimumab products
exposure.
Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with
diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis
General disorders and administration site conditions: Pyrexia
Hepato-biliary disorders: Liver failure, hepatitis
Immune system disorders: Sarcoidosis
Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma
(neuroendocrine carcinoma of the skin)
Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome),
cerebrovascular accident
Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism
Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or
worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction
Vascular disorders: Systemic vasculitis, deep vein thrombosis
7 DRUG INTERACTIONS
7.1 Methotrexate
Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate
(MTX). Although MTX reduced the apparent clearance of adalimumab, the data do not suggest the need
for dose adjustment of either Adalimumab-aaty or MTX [see Clinical Pharmacology (12.3)].
7.2 Biological Products
In clinical studies in patients with RA, an increased risk of serious infections has been observed with the
combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of
Adalimumab-aaty with abatacept or anakinra is not recommended in patients with RA [see Warnings and
Precautions (5.7, 5.11)]. A higher rate of serious infections has also been observed in patients with RA
treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient
information regarding the concomitant use of Adalimumab-aaty and other biologic products for the
treatment of RA, PsA, AS, CD, UC, PS and HS. Concomitant administration of Adalimumab-aaty with
other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended
based upon the possible increased risk for infections and other potential pharmacological interactions.
Reference ID: 5502211
7.3 Live Vaccines
Avoid the use of live vaccines with Adalimumab-aaty [see Warnings and Precautions (5.10)].
7.4 Cytochrome P450 Substrates
The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g.,
TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such
as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or
discontinuation of Adalimumab-aaty in patients being treated with CYP450 substrates with a narrow
therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or
theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available studies with use of adalimumab during pregnancy do not reliably establish an association
between adalimumab and major birth defects. Clinical data are available from the Organization of
Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with
rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab. Registry results showed a
rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or
CD and a rate of 7.5% for major birth defects in the disease- matched comparison cohort. The lack of
pattern of major birth defects is reassuring and differences between exposure groups may have impacted
the occurrence of birth defects (see Data).
Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may
affect immune response in the in-utero exposed infant (see Clinical Considerations). In an embryo-fetal
perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were
observed with intravenous administration of adalimumab during organogenesis and later in gestation, at
doses that produced exposures up to approximately 373 times the maximum recommended human dose
(MRHD) of 40 mg subcutaneous without methotrexate (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is
unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and embryo/fetal risk
Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory
bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include
preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for
gestational age at birth.
Fetal/Neonatal Adverse Reactions
Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the
largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered
prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero
[see Use in Specific Populations (8.4)].
Data
Human Data
Reference ID: 5502211
A prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. and
Canada between 2004 and 2016 compared the risk of major birth defects in live-born infants of 221
women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32
CD) not treated with adalimumab.
The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated
cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively. The lack of
pattern of major birth defects is reassuring and differences between exposure groups may have impacted
the occurrence of birth defects. This study cannot reliably establish whether there is an association
between adalimumab and major birth defects because of methodological limitations of the registry,
including small sample size, the voluntary nature of the study, and the non-randomized design.
In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab,
adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant
serum (n=8) on the day of birth. The last dose of adalimumab was given between 1 and 56 days prior to
delivery. Adalimumab concentrations were 0.16-19.7 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant
serum, and 0-16.1 mcg/mL in maternal serum. In all but one case, the cord blood concentration of
adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses
the placenta. In addition, one infant had serum concentrations at each of the following: 6 weeks (1.94
mcg/mL), 7 weeks (1.31 mcg/mL), 8 weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/mL), suggesting
adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.
Animal Data
In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab
from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the
MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week).
Adalimumab did not elicit harm to the fetuses or malformations.
8.2 Lactation
Risk Summary
Limited data from case reports in the published literature describe the presence of adalimumab in human
milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggest that the
systemic exposure to a breastfed infant is expected to be low because adalimumab is a large molecule
and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal
tract are unknown. There are no reports of adverse effects of adalimumab products on the breastfed
infant and no effects on milk production. The developmental and health benefits of breastfeeding should
be considered along with the mother’s clinical need for Adalimumab-aaty and any potential adverse
effects on the breastfed child from Adalimumab-aaty or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of Adalimumab-aaty have been established for:
•
reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2
years of age and older.
•
the treatment of moderately to severely active Crohn’s disease in pediatric patients 6 years of age and
older.
Pediatric assessments for Adalimumab-aaty demonstrate that Adalimumab-aaty is safe and effective for
pediatric patients in indications for which Humira (adalimumab) is approved. However, Adalimumab
aaty is not approved for such indications due to marketing exclusivity for Humira (adalimumab).
Due to their inhibition of TNFα, adalimumab products administered during pregnancy could affect
immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to
adalimumab in utero suggest adalimumab crosses the placenta [see Use in Specific Populations (8.1)].
The clinical significance of elevated adalimumab concentrations in infants is unknown. The safety of
administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should
be considered prior to vaccinating (live or live-attenuated) exposed infants.
Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies,
some fatal, have been reported among children, adolescents, and young adults who received treatment
Reference ID: 5502211
with TNF-blockers including adalimumab products [see Warnings and Precautions (5.2)].
Juvenile Idiopathic Arthritis
In Study JIA-I, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in
patients 4 to 17 years of age [see Clinical Studies (14.2)]. In Study JIA-II, the safety profile for patients
2 to < 4 years of age was similar to the safety profile for patients 4 to 17 years of age with polyarticular
JIA [see Adverse Reactions (6.1)]. Adalimumab products have not been studied in patients with
polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.
The safety of adalimumab in patients in the polyarticular JIA trials was generally similar to that observed
in adults with certain exceptions [see Adverse Reactions (6.1)].
The safety and effectiveness of Adalimumab-aaty have not been established in pediatric patients with
JIA less than 2 years of age.
Pediatric Crohn’s Disease
The safety and effectiveness of Adalimumab-aaty for the treatment of moderately to severely active
Crohn’s disease have been established in pediatric patients 6 years of age and older. Use of
Adalimumab-aaty for this indication is supported by Adalimumab-aaty’s approval as a biosimilar to
adalimumab and evidence from adequate and well-controlled studies in adults with additional data of
adalimumab from a randomized, double-blind, 52-week clinical study of two dose concentrations of
adalimumab in 192 pediatric patients (6 years to 17 years of age) [see Adverse Reactions (6.1), Clinical
Pharmacology (12.2, 12.3), Clinical Studies (14.6)]. The adverse reaction profile in patients 6 years to
17 years of age was similar to adults.
The safety and effectiveness of Adalimumab-aaty have not been established in pediatric patients with
Crohn’s disease less than 6 years of age.
8.5 Geriatric Use
A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older,
received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was
observed between these patients and younger patients. The frequency of serious infection and malignancy
among adalimumab treated patients 65 years of age and older was higher than for those less than 65 years
of age. Consider the benefits and risks of Adalimumab-aaty in patients 65 years of age and older. In
patients treated with Adalimumab-aaty, closely monitor for the development of infection or malignancy
[see Warnings and Precautions (5.1, 5.2)].
10 OVERDOSAGE
Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-
limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs
or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted
immediately.
11 DESCRIPTION
Adalimumab-aaty is a tumor necrosis factor blocker. Adalimumab-aaty is a recombinant human IgG1
monoclonal antibody created using phage display technology resulting in an antibody with human
derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab-aaty is
produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary (CHO))
expression system and is purified by a process that includes specific viral inactivation and removal
steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
Adalimumab-aaty injection is supplied as a sterile, preservative-free solution for subcutaneous
administration. The drug product is supplied as either a single-dose, auto-injector (Adalimumab-aaty
AI), as a single-dose, 1 mL prefilled syringe with safety guard, or a single-dose, 1 mL prefilled syringe.
Enclosed within the auto-injector is a single-dose, 1 mL prefilled syringe. The solution of Adalimumab-
Reference ID: 5502211
aaty is clear to opalescent, and colorless to pale brown, with a pH of about 5.2.
Each 80 mg/0.8 mL prefilled syringe or prefilled syringe with safety guard or auto-injector delivers 0.8
mL (80 mg) of drug product. Each 0.8 mL of Adalimumab-aaty contains adalimumab-aaty (80 mg),
acetic acid (0.13 mg), glycine (15.02 mg) polysorbate 80 (0.8 mg), sodium acetate (0.48 mg) and Water
for Injection, USP.
Each 40 mg/0.4 mL prefilled syringe or prefilled syringe with safety guard or auto-injector delivers 0.4
mL (40 mg) of drug product. Each 0.4 mL of Adalimumab-aaty contains adalimumab-aaty (40 mg),
acetic acid (0.06 mg), glycine (7.51 mg) polysorbate 80 (0.4 mg), sodium acetate (0.24 mg) and Water
for Injection, USP.
Each 20 mg/0.2 mL prefilled syringe delivers 0.2 mL (20 mg) of drug product. Each 0.2 mL of
Adalimumab-aaty contains adalimumab-aaty (20 mg), acetic acid (0.03 mg), glycine (3.75 mg)
polysorbate 80 (0.2 mg), sodium acetate (0.12 mg) and Water for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell
surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the
presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF
is a naturally occurring cytokine that is involved in normal inflammatory and immune responses.
Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and
play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of
these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with
Adalimumab-aaty may reduce the epidermal thickness and infiltration of inflammatory cells. The
relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab
products exert their clinical effects is unknown.
Adalimumab products also modulate biological responses that are induced or regulated by TNF,
including changes in the concentrations of adhesion molecules responsible for leukocyte migration
(ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10 M).
12.2 Pharmacodynamics
After treatment with adalimumab, a decrease in concentrations of acute phase reactants of inflammation
(C- reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was
observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP concentrations
was also observed in patients with Crohn’s disease, ulcerative colitis and hidradenitis suppurativa.
Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling
responsible for cartilage destruction were also decreased after adalimumab administration.
12.3 Pharmacokinetics
The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following
administration of a single intravenous dose (adalimumab products are not approved for intravenous use).
Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab
mean serum trough concentrations at steady state increased approximately proportionally with dose in RA
patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across
studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.
Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable
with that in patients treated with 40 mg every week.
Absorption
The average absolute bioavailability of adalimumab following a single 40 mg subcutaneous dose was
64%. The mean time to reach the maximum concentration was 5.5 days (131 ± 56 hours) and the
Reference ID: 5502211
maximum serum concentration was 4.7 ± 1.6 mcg/mL in healthy subjects following a single 40 mg
subcutaneous administration of adalimumab.
Distribution
The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses
ranging from 0.25 to 10 mg/kg in RA patients.
Elimination
The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with
intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is
approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of
changes in clearance over time in RA patients.
Patient Population
Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other
week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9
mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the
synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The
pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough
concentrations were 6 to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant
treatment, respectively.
Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL
during adalimumab 40 mg every other week treatment.
Adult Uveitis: Adalimumab mean steady concentration was approximately 8 to 10 mcg/mL during
adalimumab 40 mg every other week treatment.
Adult Hidradenitis Suppurativa: Adalimumab trough concentrations were approximately 7 to 8 mcg/mL
at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2.
Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11
mcg/mL during adalimumab 40 mg every week treatment.
Adult Crohn’s Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at
Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state
trough concentrations were 7 mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other
week treatment.
Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at
Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state
trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose
of adalimumab 40 mg every other week and 40 mg every week, respectively.
Anti-Drug Antibody Effects on Pharmacokinetics
Rheumatoid Arthritis: A trend toward higher apparent clearance of adalimumab in the presence of anti
adalimumab antibodies was identified.
Hidradenitis Suppurativa: In subjects with moderate to severe HS, antibodies to adalimumab were
associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum
adalimumab concentrations is greater with increasing titers of antibodies to adalimumab.
Specific Populations
Geriatric Patients: A lower clearance with increasing age was observed in patients with RA aged 40 to >
75 years.
Pediatric Patients:
Juvenile Idiopathic Arthritis:
•
4 years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8
mcg/mL and 10.9 mcg/mL in patients weighing < 30 kg receiving 20 mg adalimumab subcutaneously
Reference ID: 5502211
every other week as monotherapy or with concomitant MTX, respectively. The adalimumab mean
steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing ≥ 30 kg
receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX
concomitant treatment, respectively.
•
2 years to < 4 years of age or 4 years of age and older weighing < 15 kg: The adalimumab mean
steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients
receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant
treatment,respectively.
Pediatric Crohn's Disease: Adalimumab mean ± SD concentrations were 15.7±6.5 mcg/mL at Week 4
following 160 mg at Week 0 and 80 mg at Week 2, and 10.5±6.0 mcg/mL at Week 52 following 40 mg
every other week dosing in patients weighing ≥ 40 kg. Adalimumab mean ± SD concentrations were
10.6±6.1 mcg/mL at Week 4 following dosing 80 mg at Week 0 and 40 mg at Week 2, and 6.9±3.6
mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing < 40 kg.
Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction
for a patient’s body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar
adalimumab pharmacokinetics.
Patients with Renal or Hepatic Impairment: No pharmacokinetic data are available in patients with
hepatic or renal impairment.
Rheumatoid factor or CRP concentrations: Minor increases in apparent clearance were predicted in RA
patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid
factor or CRP concentrations. These increases are not likely to be clinically important.
Drug Interaction Studies:
Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and
44% respectively, in patients with RA [see Drug Interactions (7.1)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies of adalimumab products have not been conducted to evaluate the carcinogenic
potential or its effect on fertility.
14 CLINICAL STUDIES
14.1 Rheumatoid Arthritis
The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients
≥ 18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of
Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Adalimumab was
administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA
III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-
rheumatic drugs (DMARDs) (Study RA-IV).
Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four
DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo
were given every other week for 24 weeks.
Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo,
20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.
Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo,
40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of
adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of
inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks,
457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered
every other week for up to 5 years.
Reference ID: 5502211
Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain
on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days.
Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.
Study RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration
who were ≥ 18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to
20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab /MTX combination therapy
for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint
damage. The median disease duration among patients enrolled in the study was 5 months. The median
MTX dose achieved was 20 mg.
Clinical Response
The percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies RA- II and
III are shown in Table 3.
Table 3. ACR Responses in Studies RA-II and RA-III (Percent of Patients)
Study RA-II
Monotherapy
(26 weeks)
Study RA-III
Methotrexate Combination
(24 and 52 weeks)
Response
Placebo
Adalimumab
40 mg every
other week
Adalimumab
40 mg weekly
Placebo/MTX
Adalimumab/MTX
40 mg every
other week
N=110
N=113
N=103
N=200
N=207
ACR20
Month 6
19%
46%*
53%*
30%
63%*
Month 12
NA
NA
NA
24%
59%*
ACR50
Month 6
8%
22%*
35%*
10%
39%*
Month 12
NA
NA
NA
10%
42%*
ACR70
Month 6
2%
12%*
18%*
3%
21%*
Month 12
NA
NA
NA
5%
23%*
* p<0.01, adalimumab vs. placebo
The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every
other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%,
respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p<0.01).
The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in
Table 4. ACR response rates and improvement in all components of ACR response were maintained to
week 104. Over the 2 years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other
week achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month
period. ACR responses were maintained in similar proportions of patients for up to 5 years with
continuous adalimumab treatment in the open- label portion of Study RA-III.
Table 4. Components of ACR Response in Studies RA-II and RA-III
Study RA-II
Study RA-III
Parameter
(median)
Placebo
N=110
Adalimumaba
N=113
Placebo/MTX
N=200
Adalimumaba/MTX
N=207
Baseline Wk 26
Baseline
Wk 26
Baseline Wk 24
Baseline
Wk 24
Number of
tender joints
(0-68)
35
26
31
16*
26
15
24
8*
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------40 mg ewryalher' ¥.leek - - -o- - -Plocebo,
Number of
swollen
joints (0-66)
19
16
18
10*
17
11
18
5*
Physician global
assessmentb
7.0
6.1
6.6
3.7*
6.3
3.5
6.5
2.0*
Patient global
assessmentb
7.5
6.3
7.5
4.5*
5.4
3.9
5.2
2.0*
Painb
7.3
6.1
7.3
4.1*
6.0
3.8
5.8
2.1*
Disability index
(HAQ)c
2.0
1.9
1.9
1.5*
1.5
1.3
1.5
0.8*
CRP (mg/dL)
3.9
4.3
4.6
1.8*
1.0
0.9
1.0
0.4*
a 40 mg adalimumab administered every other week
b Visual analogue scale; 0 = best, 10 = worst
c Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient’s
ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and
maintain daily activity
* p<0.001, adalimumab vs. placebo, based on mean change from baseline
The time course of ACR 20 response for Study RA-III is shown in Figure 1.
In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52
weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar.
Figure 1. Study RA-III ACR 20 Responses over 52 Weeks
In Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care
had an ACR 20 response at week 24 compared to 35% on placebo plus standard of care (p<0.001). No
unique adverse reactions related to the combination of adalimumab and other DMARDs were observed.
In Study RA-V with MTX naïve patients with recent onset RA, the combination treatment with
adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX
monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 (see
Table 5).
Table 5. ACR Response in Study RA-V (Percent of Patients)
Response
MTXb
N=257
Adalimumabc
N=274
Adalimumab/MTX
N=268
ACR20
Week 52
63%
54%
73%
Week 104
56%
49%
69%
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ACR50
Week 52
Week 104
46%
43%
41%
37%
62%
59%
ACR70
Week 52
Week 104
27%
28%
26%
28%
46%
47%
Major Clinical
Responsea
28%
25%
49%
a Major clinical response is defined as achieving an ACR70 response for a continuous six month
period
b p<0.05, adalimumab/MTX vs. MTX for ACR 20
p<0.001, adalimumab/MTX vs. MTX for ACR 50 and 70, and Major Clinical Response
c p<0.001, adalimumab/MTX vs. adalimumab
At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the
adalimumab/MTX group and improvements were maintained to Week 104.
Radiographic Response
In Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total
Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at
month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40
mg every other week groups. The results are shown in Table 6. Adalimumab/MTX treated patients
demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.
Table 6. Radiographic Mean Changes Over 12 Months in Study RA-III
Placebo/MTX
Adalimumab/MTX
40 mg every other week
Placebo/MTX
Adalimumab/MTX
(95% Confidence Interval*)
P-
value**
Total Sharp
score
2.7
0.1
2.6 (1.4, 3.8)
<0.001
Erosion score
1.6
0.0
1.6 (0.9, 2.2)
<0.001
JSN score
1.0
0.1
0.9 (0.3, 1.4)
0.002
* 95% confidence intervals for the differences in change scores between MTX and adalimumab.
** Based on rank analysis
In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of
adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural
damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined
by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg
adalimumab every other week have been evaluated radiographically at 5 years. Patients had continued
inhibition of structural damage with 50% showing no progression of structural damage defined by a
change in the TSS of zero or less.
In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of
radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the
adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy
group at Week 52 as well as at Week 104 (see Table 7).
Table 7. Radiographic Mean Change* in Study RA-V
MTXa
N=257
Adalimumaba,b
N=274
Adalimumab/MTX
N=268
52 Weeks
Total Sharp
score
5.7 (4.2, 7.3)
3.0 (1.7, 4.3)
1.3 (0.5, 2.1)
Erosion score
3.7 (2.7, 4.8)
1.7 (1.0, 2.4)
0.8 (0.4, 1.2)
JSN score
2.0 (1.2, 2.8)
1.3 (0.5, 2.1)
0.5 (0.0, 1.0)
104
Weeks
Total Sharp
score
10.4
(7.7, 13.2)
5.5 (3.6, 7.4)
1.9 (0.9, 2.9)
Reference ID: 5502211
I
I
I
I
I
I
I
I
Erosion score
6.4 (4.6, 8.2)
3.0 (2.0, 4.0)
1.0 (0.4, 1.6)
JSN score
4.1 (2.7, 5.4)
2.6 (1.5, 3.7)
0.9 (0.3, 1.5)
* mean (95% confidence interval)
a p<0.001, adalimumab/MTX vs. MTX at 52 and 104 weeks and for adalimumab/MTX vs.
adalimumab at 104 weeks
b p<0.01, for adalimumab/MTX vs. adalimumab at 52 weeks
Physical Function Response
In studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the
disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and
significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form
Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the
Mental Component Summary (MCS).
In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55,
0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/MTX (p<0.001) patients. Sixty-three
percent of adalimumab -treated patients achieved a 0.5 or greater improvement in HAQ-DI at week 52 in
the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement
through week 104 and a similar proportion of patients maintained this response through week 260 (5
years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of
measurement at week 156 (3 years).
In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement
(p<0.001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or
the adalimumab monotherapy group at Week 52, which was maintained through Week 104.
14.2 Juvenile Idiopathic Arthritis
The safety and efficacy of adalimumab was assessed in two studies (Studies JIA-I and JIA-II) in
patients with active polyarticular juvenile idiopathic arthritis (JIA).
Study JIA-I
The safety and efficacy of adalimumab were assessed in a multicenter, randomized, withdrawal, double-
blind, parallel-group study in 171 patients who were 4 to 17 years of age with polyarticular JIA. In the
study, the patients were stratified into two groups: MTX-treated or non- MTX-treated. All patients had to
show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics,
corticosteroids, or DMARDS. Patients who received prior treatment with any biologic DMARDS were
excluded from the study.
The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind
randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136
weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study,
adalimumab was administered based on body surface area at a dose of 24 mg/m2 up to a maximum total
body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were
treated with 20 mg of adalimumab SC every other week if their weight was less than 30 kg and with 40
mg of adalimumab SC every other week if their weight was 30 kg or greater. Patients remained on stable
doses of NSAIDs and or prednisone (≤ 0.2 mg/kg/day or 10 mg/day maximum).
Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the
double blind (DB) phase of the study and received either adalimumab or placebo every other week for 32
weeks or until disease flare. Disease flare was defined as a worsening of ≥30% from baseline in ≥ 3 of 6
Pediatric ACR core criteria, ≥ 2 active joints, and improvement of > 30% in no more than 1 of the 6
criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the
open-label extension phase based on the BSA regimen (OLE- BSA), before converting to a fixed dose
regimen based on body weight (OLE-FD phase).
Study JIA-I Clinical Response
At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients
in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients
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who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs.
71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show pediatric
ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses
were maintained for up to two years in the OLE phase in patients who received adalimumab throughout
the study.
Study JIA-II
Adalimumab was assessed in an open-label, multicenter study in 32 patients who were 2 to < 4 years of
age or 4 years of age and older weighing < 15 kg with moderately to severely active polyarticular JIA.
Most patients (97%) received at least 24 weeks of adalimumab treatment dosed 24 mg/m2 up to a
maximum of 20 mg every other week as a single SC injection up to a maximum of 120 weeks duration.
During the study, most patients used concomitant MTX, with fewer reporting use of corticosteroids or
NSAIDs. The primary objective of the study was evaluation of safety [see Adverse Reactions (6.1)].
14.3 Psoriatic Arthritis
The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo-controlled
studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients
enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other
week.
Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (> 3 swollen and > 3
tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1)
distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid
nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA
(N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose
of ≤ 30 mg/week for > 1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or
placebo every other week were administered during the 24-week double-blind period of the study.
Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease
activity (see Tables 8 and 9). Among patients with PsA who received adalimumab, the clinical responses
were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88
weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes
of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing
spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant
MTX therapy at baseline.
Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for
Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a
75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group
(N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses
were apparent in some patients at the time of the first visit (two weeks). Responses were similar in
patients who were or were not receiving concomitant MTX therapy at baseline.
Table 8. ACR Response in Study PsA-I (Percent of Patients)
Placebo
N=162
Adalimumab*
N=151
ACR20
Week 12
Week 24
14%
15%
58%
57%
ACR50
Week 12
Week 24
4%
6%
36%
39%
ACR70
Week 12
Week 24
1%
1%
20%
23%
* p<0.001 for all comparisons between adalimumab and placebo
Reference ID: 5502211
Table 9. Components of Disease Activity in Study PsA-I
Placebo
N= 162
Adalimumab*
N=151
Parameter: median
Baseline
24 weeks
Baseline
24 weeks
Number of tender jointsa
23.0
17.0
20.0
5.0
Number of swollen jointsb
11.0
9.0
11.0
3.0
Physician global assessmentc
53.0
49.0
55.0
16.0
Patient global assessmentc
49.5
49.0
48.0
20.0
Painc
49.0
49.0
54.0
20.0
Disability index (HAQ)d
1.0
0.9
1.0
0.4
CRP (mg/dL)e
0.8
0.7
0.8
0.2
* p<0.001 for adalimumab vs. placebo comparisons based on median changes
a Scale 0-78
b Scale 0-76
c Visual analog scale; 0=best, 100=worst
d Disability Index of the Health Assessment Questionnaire; 0=best, 3=worst; measures the patient’s
ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and
maintain daily activity.
e Normal range: 0-0.287 mg/dL
Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic
arthritis who had suboptimal response to DMARD therapy as manifested by ≥ 3 tender joints and
≥ 3 swollen joints at enrollment.
Radiographic Response
Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were
obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or
placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score
(mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid
arthritis), was used by readers blinded to treatment group to assess the radiographs.
Adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to
placebo-treated patients and this effect was maintained at 48 weeks (see Table 10).
Table 10. Change in Modified Total Sharp Score in Psoriatic Arthritis
Placebo
N=141
Adalimumab
N=133
Week 24
Week 24
Week 48
Baseline mean
22.1
23.4
23.4
Mean Change ± SD
0.9 ± 3.1
-0.1 ± 1.7
-0.2 ± 4.9*
* <0.001 for the difference between adalimumab, Week 48 and Placebo, Week 24 (primary analysis)
Physical Function Response
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ
DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed
greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12
and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24
respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from
baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo,
and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function
based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
14.4 Ankylosing Spondylitis
The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in a
randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing
spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate
or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three
Reference ID: 5502211
70
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N u, 30
-« "'
<I: 20
10
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·- -e- - 'Placebo ( =t 71
Adalimumab ( N=208]
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criteria: (1) a Bath AS disease activity index (BASDAI) score ≥ 4 cm, (2) a visual analog score (VAS)
for total back pain ≥ 40 mm, and (3) morning stiffness ≥1 hour. The blinded period was followed by an
open-label period during which patients received adalimumab 40 mg every other week subcutaneously
for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24
weeks as shown in Figure 2 and Table 11.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
Figure 2. ASAS 20 Response By Visit, Study AS-I
At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of
patients receiving adalimumab, compared to 21%, 10%, and 5% respectively, of patients receiving
placebo (p<0.001). Similar responses were seen at Week 24 and were sustained in patients receiving
open-label adalimumab for up to 52 weeks.
A greater proportion of patients treated with adalimumab (22%) achieved a low level of disease activity
at 24 weeks (defined as a value < 20 [on a scale of 0 to 100 mm] in each of the four ASAS response
parameters) compared to patients treated with placebo (6%).
Table 11. Components of Ankylosing Spondylitis Disease Activity
Placebo
N=107
Adalimumab
N=208
Baseline
mean
Week 24
mean
Baseline
mean
Week 24
mean
ASAS 20 Response Criteria*
Patient’s Global Assessment of
Disease Activitya*
65
60
63
38
Total back pain*
67
58
65
37
Inflammationb*
6.7
5.6
6.7
3.6
BASFIc*
56
51
52
34
*
BASDAId score
6.3
5.5
6.3
3.7
*
BASMIe score
4.2
4.1
3.8
3.3
Tragus to wall (cm)
15.9
15.8
15.8
15.4
Lumbar flexion (cm)
4.1
4.0
4.2
4.4
Cervical rotation (degrees)
42.2
42.1
48.4
51.6
Lumbar side flexion (cm)
8.9
9.0
9.7
11.7
Intermalleolar distance (cm)
92.9
94.0
93.5
100.8
CRPf*
2.2
2.0
1.8
0.6
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a Percent of subjects with at least a 20% and 10-unit improvement measured on a Visual Analog
Scale (VAS) with 0 = “none” and 100 = “severe”
b mean of questions 5 and 6 of BASDAI (defined in ‘d’)
c Bath Ankylosing Spondylitis Functional Index
d Bath Ankylosing Spondylitis Disease Activity Index
e Bath Ankylosing Spondylitis Metrology Index
f C-Reactive Protein (mg/dL)
* statistically significant for comparisons between adalimumab and placebo at Week 24
A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing
spondylitis showed similar results.
Patients treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis
Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36)
Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated patients at Week 24.
14.5 Adult Crohn’s Disease
The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately
to severely active Crohn’s disease, CD, (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in
randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates,
corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to
receive at least one of these medications.
Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies. In Study CD-I, 299
TNF-blocker naïve patients were randomized to one of four treatment groups: the placebo group received
placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week
2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg
at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4.
In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to,
previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg
at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.
Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active
disease received open-label adalimumab, 80 mg at week 0 and 40 mg at Week 2. Patients were then
randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or
placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at
Week 4 were stratified and analyzed separately from those not in clinical response at Week 4.
Induction of Clinical Remission
A greater percentage of the patients treated with 160/80 mg adalimumab achieved induction of clinical
remission versus placebo at Week 4 regardless of whether the patients were TNF blocker naïve (CD-I), or
had lost response to or were intolerant to infliximab (CD-II) (see Table 12).
Table 12. Induction of Clinical Remission in Studies CD-I and CD-II (Percent of Patients)
CD-I
CD-II
Placebo
N=74
Adalimumab
160/80 mg
N=76
Placebo
N=166
Adalimumab
160/80 mg
N=159
Week 4
Clinical remission
12%
36%*
7%
21%*
Clinical response
34%
58%**
34%
52%**
Clinical remission is CDAI score < 150; clinical response is decrease in CDAI of at least 70 points.
* p<0.001 for adalimumab vs. placebo pairwise comparison of proportions
** p<0.01 for adalimumab vs. placebo pairwise comparison of proportions
Maintenance of Clinical Remission
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In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the
primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at
Week 4 achieved clinical remission in the adalimumab 40 mg every other week maintenance group
compared to patients in the placebo maintenance group (see Table 13). The group that received
adalimumab therapy every week did not demonstrate significantly higher remission rates compared to the
group that received adalimumab every other week.
Table 13. Maintenance of Clinical Remission in CD-III (Percent of Patients)
Placebo
40 mg Adalimumab
every other week
N=170
N=172
Week 26
Clinical remission
17%
40%*
Clinical response
28%
54%*
Week 56
Clinical remission
12%
36%*
Clinical response
18%
43%*
Clinical remission is CDAI score < 150; clinical response is decrease in CDAI of at least 70 points.
* p<0.001 for adalimumab vs. placebo pairwise comparisons of proportions
Of those in response at Week 4 who attained remission during the study, patients in the adalimumab
every other week group maintained remission for a longer time than patients in the placebo maintenance
group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did
not result in significantly more responses.
14.6 Pediatric Crohn’s Disease
A randomized, double-blind, 52-week clinical study of 2 dose concentrations of adalimumab (Study
PCD-I) was conducted in 192 pediatric patients (6 to 17 years of age) with moderately to severely
active Crohn’s disease (defined as Pediatric Crohn’s Disease Activity Index (PCDAI) score > 30).
Enrolled patients had over the previous two year period an inadequate response to corticosteroids or an
immunomodulator (i.e., azathioprine, 6-mercaptopurine, or methotrexate). Patients who had previously
received a TNF blocker were allowed to enroll if they had previously had loss of response or
intolerance to that TNF blocker.
Patients received open-label induction therapy at a dose based on their body weight (≥ 40 kg and < 40
kg). Patients weighing ≥ 40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Patients weighing
< 40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, patients within each body
weight category (≥ 40 kg and < 40 kg) were randomized 1:1 to one of two maintenance dose regimens
(high dose and low dose). The high dose was 40 mg every other week for patients weighing ≥ 40 kg
and 20 mg every other week for patients weighing < 40 kg. The low dose was 20 mg every other week
for patients weighing ≥ 40 kg and 10 mg every other week for patients weighing < 40 kg.
Concomitant stable dosages of corticosteroids (prednisone dosage ≤ 40 mg/day or equivalent) and
immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the
study.
At Week 12, patients who experienced a disease flare (increase in PCDAI of ≥ 15 from Week 4 and
absolute PCDAI > 30) or who were non-responders (did not achieve a decrease in the PCDAI of ≥ 15
from baseline for 2 consecutive visits at least 2 weeks apart) were allowed to dose-escalate (i.e., switch
from blinded every other week dosing to blinded every week dosing); patients who dose-escalated
were considered treatment failures.
At baseline, 38% of patients were receiving corticosteroids, and 62% of patients were receiving an
immunomodulator. Forty-four percent (44%) of patients had previously lost response or were
intolerant to a TNF blocker. The median baseline PCDAI score was 40.
Of the 192 patients total, 188 patients completed the 4 week induction period, 152 patients completed
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26 weeks of treatment, and 124 patients completed 52 weeks of treatment. Fifty-one percent (51%)
(48/95) of patients in the low maintenance dose group dose-escalated, and 38% (35/93) of patients in
the high maintenance dose group dose-escalated.
At Week 4, 28% (52/188) of patients were in clinical remission (defined as PCDAI ≤ 10).
The proportions of patients in clinical remission (defined as PCDAI ≤ 10) and clinical response
(defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52.
At both Weeks 26 and 52, the proportion of patients in clinical remission and clinical response was
numerically higher in the high dose group compared to the low dose group (Table 14). The
recommended maintenance regimen is 20 mg every other week for patients weighing < 40 kg and 40
mg every other week for patients weighing ≥ 40 kg. Every week dosing is not the recommended
maintenance dosing regimen [see Dosage and Administration (2.3)].
Table 14. Clinical Remission and Clinical Response in Study PCD-I
Low Maintenance Dose†
(20 or 10 mg every other week)
N = 95
High Maintenance Dose#
(40 or 20 mg every other week)
N = 93
Week 26
Clinical Remission‡
28%
39%
Clinical Response§
48%
59%
Week 52
Clinical Remission‡
23%
33%
Clinical Response§
28%
42%
†The low maintenance dose was 20 mg every other week for patients weighing ≥ 40 kg and 10 mg every
other week for patients weighing < 40 kg.
#The high maintenance dose was 40 mg every other week for patients weighing ≥ 40 kg and 20 mg
every other week for patients weighing < 40 kg.
‡Clinical remission defined as PCDAI ≤ 10.
§Clinical response defined as reduction in PCDAI of at least 15 points from baseline.
14.7 Adult Ulcerative Colitis
The safety and efficacy of adalimumab were assessed in adult patients with moderately to severely active
ulcerative colitis (Mayo score 6 to 12 on a 12-point scale, with an endoscopy subscore of 2 to 3 on a scale
of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids,
azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I
and UC-II). Both studies enrolled TNF-blocker naïve patients, but Study UC-II also allowed entry of
patients who lost response to or were intolerant to TNF- blockers. Forty percent (40%) of patients
enrolled in Study UC-II had previously used another TNF-blocker.
Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I
and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6
MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications.
Induction of clinical remission (defined as Mayo score ≤2 with no individual subscores > 1) at Week 8
was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as
clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II.
In Study UC-I, 390 TNF-blocker naïve patients were randomized to one of three treatment groups for the
primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group
received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the
80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, patients in both
adalimumab treatment groups received 40 mg every other week.
In Study UC-II, 518 patients were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at
Week 2, and 40 mg every other week starting at Week 4 through Week 50, or placebo starting at Week 0
and every other week through Week 50. Corticosteroid taper was permitted starting at Week 8.
In both Studies UC-I and UC-II, a greater percentage of the patients treated with 160/80 mg of
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adalimumab compared to patients treated with placebo achieved induction of clinical remission. In Study
UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients
treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52)
(Table 15).
Table 15. Induction of Clinical Remission in Studies UC-I and UC-II and Sustained
Clinical Remission in Study UC-II (Percent of Patients)
Study UC-I
Study UC-II
Placebo
N=130
Adalimumab
160/80 mg
N=130
Treatment
Difference
(95% CI)
Placebo
N=246
Adalimumab
160/80 mg
N=248
Treatment
Difference
(95% CI)
Induction of Clinical
Remission (Clinical
Remission at Week 8)
9.2%
18.5%
9.3%*
(0.9%,
17.6%)
9.3%
16.5%
7.2%*
(1.2%,
12.9%)
Sustained Clinical
Remission (Clinical
Remission at both
Weeks 8 and 52)
N/A
N/A
N/A
4.1%
8.5%
4.4%*
(0.1%, 8.6%)
Clinical remission is defined as Mayo score ≤ 2 with no individual subscores > 1.
CI=Confidence interval
* p<0.05 for adalimumab vs. placebo pairwise comparison of proportions
In Study UC-I, there was no statistically significant difference in clinical remission observed between the
adalimumab 80/40 mg group and the placebo group at Week 8.
In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared
to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%,
14.5%]; p<0.05).
In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for
induction of clinical remission appeared to be lower than that seen in the whole study population, and the
treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be
similar to those seen in the whole study population. The subgroup of patients with prior TNF-blocker use
achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the
placebo group and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101)
in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in
clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group.
14.8 Plaque Psoriasis
The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo- controlled
studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates
for systemic therapy or phototherapy.
Study Ps-I evaluated 1212 subjects with chronic Ps with ≥ 10% body surface area (BSA) involvement,
Physician’s Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and
Severity Index (PASI) ≥ 12 within three treatment periods. In period A, subjects received placebo or
adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting
at Week 1. After 16 weeks of therapy, subjects who achieved at least a PASI 75 response at Week 16,
defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received
open-label 40 mg adalimumab every other week. After 17 weeks of open label therapy, subjects who
maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in
period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for
an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the
baseline Physician’s Global Assessment score ranged from “moderate” (53%) to “severe” (41%) to “very
severe” (6%).
Study Ps-II evaluated 99 subjects randomized to adalimumab and 48 subjects randomized to placebo with
chronic plaque psoriasis with ≥ 10% BSA involvement and PASI ≥ 12. Subjects received placebo, or an
initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for
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16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score
ranged from “moderate” (41%) to “severe” (51%) to “very severe” (8%).
Studies Ps-I and II evaluated the proportion of subjects who achieved “clear” or “minimal” disease on the
6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75%
(PASI 75) from baseline at Week 16 (see Table 16 and 17).
Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of “clear” or
“minimal” disease or a PASI 75 response after Week 33 and on or before Week 52.
Table 16. Efficacy Results at 16 Weeks in Study Ps-I Number of Subjects (%)
Adalimumab 40 mg every other week
Placebo
N = 814
N = 398
PGA: Clear or minimal*
506 (62%)
17 (4%)
PASI 75
578 (71%)
26 (7%)
* Clear = no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red
coloration
Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal
skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration
Table 17. Efficacy Results at 16 Weeks in Study Ps-II Number of Subjects (%)
Adalimumab 40 mg every other week
Placebo
N = 99
N = 48
PGA: Clear or minimal*
70 (71%)
5 (10%)
PASI 75
77 (78%)
9 (19%)
* Clear = no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration
Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal
skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration
Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re- randomized to
adalimumab (N = 250) or placebo (N = 240) at Week 33. After 52 weeks of treatment with adalimumab,
more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized
to placebo based on maintenance of PGA of “clear” or “minimal” disease (68% vs. 28%) or a PASI 75
(79% vs. 43%).
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label
extension study. Median time to relapse (decline to PGA “moderate” or worse) was approximately 5
months. During the withdrawal period, no subject experienced transformation to either pustular or
erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of
adalimumab, then 40 mg every other week beginning at week 1. At week 16, 69% (123/178) of subjects
had a response of PGA “clear” or “minimal”.
A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus
placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least
moderate severity on the PGA scale, fingernail involvement of at least moderate severity on a 5-point
Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) scale, a Modified Nail Psoriasis Severity
Index (mNAPSI) score for the target-fingernail of ≥ 8, and either a BSA involvement of at least 10% or a
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BSA involvement of at least 5% with a total mNAPSI score for all fingernails of ≥ 20. Subjects received
an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the
initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26
weeks. This study evaluated the proportion of subjects who achieved “clear” or “minimal” assessment
with at least a 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at
least a 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26.
At Week 26, a higher proportion of subjects in the adalimumab group than in the placebo group achieved
the PGA-F endpoint. Furthermore, a higher proportion of subjects in the adalimumab group than in the
placebo group achieved mNAPSI 75 at Week 26 (see Table 18).
Table 18. Efficacy Results at 26 Weeks
Endpoint
Adalimumab 40 mg
every other week*
N=109
Placebo
N=108
PGA-F: ≥ 2-grade improvement and
clear or minimal
49%
7%
mNAPSI 75
47%
3%
*Subjects received 80 mg of adalimumab at Week 0, followed by 40 mg every other week starting
at Week 1.
Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III.
14.9 Hidradenitis Suppurativa
Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the
safety and efficacy of adalimumab in a total of 633 adult subjects with moderate to severe
hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses
or inflammatory nodules. In both studies, subjects received placebo or adalimumab at an initial
dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 and
continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral
antibiotic use was allowed in Study HS-II.
Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12.
HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count
with no increase in abscess count and no increase in draining fistula count relative to baseline
(see Table 17). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale
in patients who entered the study with an initial baseline score of 3 or greater on a 11 point
scale.
In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved
HiSCR (see Table 19).
Table 19. Efficacy Results at 12 Weeks in Subjects with Moderate to Severe Hidradenitis
Suppurativa
HS Study I
HS Study II*
Placebo
Adalimumab
40 mg Weekly
Placebo
Adalimumab
40 mg Weekly
Hidradenitis Suppurativa
Clinical Response
(HiSCR)
N = 154
40 (26%)
N = 153
64 (42%)
N=163
45 (28%)
N=163
96 (59%)
*19.3% of subjects in Study HS-II continued baseline oral antibiotic therapy during the study.
In both studies, from Week 12 to Week 35 (Period B), subjects who had received adalimumab
were re-randomized to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab
Reference ID: 5502211
40 mg every other week, or placebo). Subjects who had been randomized to placebo were
assigned to receive adalimumab 40 mg every week (Study HS-I) or placebo (Study HS-II).
During Period B, flare of HS, defined as ≥ 25% increase from baseline in abscesses and
inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in
22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the
primary efficacy timepoint in two studies.
14.10
Adult Uveitis
The safety and efficacy of adalimumab were assessed in adult patients with non-infectious
intermediate, posterior and panuveitis excluding patients with isolated anterior uveitis, in two
randomized, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or
adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week
after the initial dose. The primary efficacy endpoint in both studies was ´time to treatment failure´.
Treatment failure was a multi-component outcome defined as the development of new
inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior
chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity
(BCVA).
Study UV I evaluated 217 patients with active uveitis while being treated with corticosteroids (oral
prednisone at a dose of 10 to 60 mg/day). All patients received a standardized dose of prednisone
60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid
discontinuation by Week 15.
Study UV II evaluated 226 patients with inactive uveitis while being treated with corticosteroids
(oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently
underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19.
Clinical Response
Results from both studies demonstrated statistically significant reduction of the risk of treatment
failure in patients treated with adalimumab versus patients receiving placebo. In both studies, all
components of the primary endpoint contributed cumulatively to the overall difference between
adalimumab and placebo groups (Table 20).
Table 20. Time to Treatment Failure in Studies UV I and UV II
UV I
UV II
Placebo
(N=107
)
Adalimum
ab
(N=110)
HR
[95%
CI]a
Placebo
(N=111
)
Adalimum
ab
(N=115)
HR
[95%
CI]a
Failureb
n(%)
84
(78.5)
60 (54.5)
0.50
[0.36,
0.70]
61
(55.0)
45 (39.1)
0.57
[0.39,
0.84]
Median
Time to
Failure
(Months)
[95% CI]
3.0
[2.7,
3.7]
5.6
[3.9, 9.2]
N/A
8.3
[4.8,
12.0]
NEc
N/A
ª HR of adalimumab versus placebo from proportional hazards regression with treatment as factor.
b Treatment failure at or after Week 6 in Study UV I, or at or after Week 2 in Study UV II, was
counted as event. Subjects who discontinued the study were censored at the time of dropping out.
c NE = not estimable. Fewer than half of at-risk subjects had an event.
Figure 3: Kaplan-Meier Curves Summarizing Time to Treatment Failure on or after Week
6 (Study UV I) or Week 2 (Study UV II)
Reference ID: 5502211
100
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4!4U.2
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2D
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4510
Study UV I
Study UV II
Note: P# = Placebo (Number of Events/Number at Risk); A# = Adalimumab (Number of
Events/Number at Risk).
15 REFERENCES
1. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program.
SEER Incidence Crude Rates, 17 Registries, 2000-2007.
16 HOW SUPPLIED/STORAGE AND HANDLING
Adalimumab-aaty is supplied as a preservative-free, sterile, clear to opalescent, and colorless to pale
brown solution for subcutaneous administration. The following packaging configurations are
available.
• Adalimumab-aaty AI Carton - 40 mg/0.4 mL (1 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and a single-dose prefilled
auto-injector, containing a 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 40
mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-09.
• Adalimumab-aaty AI Carton - 40 mg/0.4 mL (2 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and two single-dose prefilled
auto-injectors, each containing a 1 mL prefilled syringe with a fixed thin wall, ½ inch needle,
providing 40 mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-10.
• Adalimumab-aaty AI Carton - 40 mg/0.4 mL (4 Count)
Adalimumab-aaty is supplied in a carton containing four alcohol preps and four single-dose prefilled
auto-injectors, each containing a 1 mL prefilled syringe with a fixed thin wall, ½ inch needle,
providing 40 mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-11.
Reference ID: 5502211
• Adalimumab-aaty AI Carton - 40 mg/0.4 mL (6 Count)
Adalimumab-aaty is supplied in a carton containing six alcohol preps and six single-dose prefilled
auto-injectors, each containing a 1 mL prefilled syringe with a fixed thin wall, ½ inch needle,
providing 40 mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-12.
• Prefilled Syringe with Safety Guard Carton - 40 mg/0.4 mL (1 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and a single-dose prefilled
syringe with safety guard, 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 40
mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-05.
• Prefilled Syringe with Safety Guard Carton - 40 mg/0.4 mL (2 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and two single-dose prefilled
syringes with safety guard, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch
needle, and 40 mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-06.
• Prefilled Syringe with Safety Guard Carton - 40 mg/0.4 mL (4 Count)
Adalimumab-aaty is supplied in a carton containing four alcohol preps and four single-dose prefilled
syringes with safety guard, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch
needle, and 40 mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-07.
• Prefilled Syringe with Safety Guard Carton - 40 mg/0.4 mL (6 Count)
Adalimumab-aaty is supplied in a carton containing six alcohol preps and six single-dose prefilled
syringes with safety guard, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch
needle, and 40 mg/0.4 mL of Adalimumab-aaty. The NDC number is 72606-022-08.
• Prefilled Syringe Carton - 40 mg/0.4 mL (1 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and a single-dose prefilled
syringe, 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 40 mg/0.4 mL of
Adalimumab-aaty. The NDC number is 72606-022-01.
• Prefilled Syringe Carton - 40 mg/0.4 mL (2 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and two single-dose prefilled
syringes, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, and 40 mg/0.4
mL of Adalimumab-aaty. The NDC number is 72606-022-02.
• Prefilled Syringe Carton - 40 mg/0.4 mL (4 Count)
Adalimumab-aaty is supplied in a carton containing four alcohol preps and four single-dose prefilled
syringes, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, and 40 mg/0.4
mL of Adalimumab-aaty. The NDC number is 72606-022-03.
• Prefilled Syringe Carton - 40 mg/0.4 mL (6 Count)
Adalimumab-aaty is supplied in a carton containing six alcohol preps and six single-dose prefilled
syringes, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, and 40 mg/0.4
mL of Adalimumab-aaty. The NDC number is 72606-022-04.
• Adalimumab-aaty AI Carton - 80 mg/0.8 mL (1 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and a single-dose prefilled auto-
injector, containing a 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 80 mg/0.8
mL of Adalimumab-aaty. The NDC number is 72606-040-04.
• Adalimumab-aaty AI Carton - 80 mg/0.8 mL (2 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and two single-dose prefilled
auto-injectors, each containing a 1 mL prefilled syringe with a fixed thin wall, ½ inch needle,
providing 80 mg/0.8 mL of Adalimumab-aaty. The NDC number is 72606-040-05.
• Prefilled Syringe with Safety Guard Carton - 80 mg/0.8 mL (1 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and a single-dose prefilled
syringe with safety guard, 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 80
Reference ID: 5502211
mg/0.8 mL of Adalimumab-aaty. The NDC number is 72606-040-02.
• Prefilled Syringe with Safety Guard Carton - 80 mg/0.8 mL (2 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and two single-dose prefilled
syringes with safety guard, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch
needle, and 80 mg/0.8 mL of Adalimumab-aaty. The NDC number is 72606-040-03.
• Prefilled Syringe Carton - 80 mg/0.8 mL (1 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and a single-dose prefilled
syringe, 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 80 mg/0.8 mL of
Adalimumab-aaty. The NDC number is 72606-040-01.
• Prefilled Syringe Carton - 20 mg/0.2 mL (2 Count)
Adalimumab-aaty is supplied in a carton containing two alcohol preps and two single-dose prefilled
syringes, each containing 1 mL prefilled syringe with a fixed thin wall, ½ inch needle, and 20 mg/0.2
mL of Adalimumab-aaty. The NDC number is 72606-041-01.
• Adalimumab-aaty AI 80 mg/0.8 mL – Crohn’s Disease, Ulcerative Colitis or Hidradenitis
Suppurativa Starter Package (3 Count)
Adalimumab-aaty is supplied in a carton containing 4 alcohol preps and 3 dose trays (Crohn’s Disease
Starter Package). Each dose tray consists of a single-dose prefilled auto-injectors, each containing a
1 mL prefilled syringe with a fixed thin wall, ½ inch needle, providing 80 mg/0.8 mL of
Adalimumab-aaty. The NDC number is 72606-040-06.
Storage and Stability
Do not use beyond the expiration date on the container. Adalimumab-aaty must be refrigerated at 36°F to
46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed.
Store in original carton until time of administration to protect from light. Do not shake.
If needed, for example when traveling, Adalimumab-aaty may be stored at room temperature up to a
maximum of 77°F (25°C) for a period of up to 31 days, with protection from light. Adalimumab-aaty
should be discarded if not used within the 31-day period. Record the date when Adalimumab-aaty is first
removed from the refrigerator in the spaces provided on the carton and dose pack.
Do not store Adalimumab-aaty in extreme heat or cold.
17 PATIENT COUNSELING INFORMATION
Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and
Instructions for Use).
Infections
Inform patients that Adalimumab-aaty may lower the ability of their immune system to fight infections.
Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection,
including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections [see
Warnings and Precautions (5.1, 5.2, 5.4)].
Malignancies
Counsel patients about the risk of malignancies while receiving Adalimumab-aaty [see Warnings and
Precautions (5.2)].
Hypersensitivity Reactions
Advise patients to seek immediate medical attention if they experience any symptoms of severe
hypersensitivity reactions. [see Warnings and Precautions (5.3)].
Other Medical Conditions
Advise patients to report any signs of new or worsening medical conditions such as congestive heart
Reference ID: 5502211
failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any
symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever [see Warnings and
Precautions (5.5, 5.6, 5.8, 5.9)].
Instructions on Injection Technique
Inform patients that the first injection is to be performed under the supervision of a qualified health care
professional. If a patient or caregiver is to administer Adalimumab-aaty, instruct them in injection
techniques and assess their ability to inject subcutaneously to ensure the proper administration of
Adalimumab-aaty [see Instructions for Use].
For patients who will use the Adalimumab-aaty AI, tell them that they:
• May hear a 1st loud “click” when they place the auto-injector straight on their skin and push the entire
device down firmly. The click means the start of the injection.
• Must keep holding the Adalimumab-aaty AI against their skin until all of the medicine is injected.
• Will know that the injection has finished when the blue plunger rod fills the medication window and
stops moving. Also they may hear a 2nd loud “click” several seconds after starting the injection.
Then, count slowly to 5 to ensure full dose has been given.
Instruct patients to dispose of their used needles and syringes or used auto-injector in a FDA-cleared
sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and
syringes or auto-injector in their household trash. Instruct patients that if they do not have a FDA-
cleared sharps disposal container, they may use a household container that is made of a heavy-duty
plastic, can be closed with a tight-fitting and puncture-resistant lid without sharps being able to come
out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside
the container.
Instruct patients that when their sharps disposal container is almost full, they will need to follow their
community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients
that there may be state or local laws regarding disposal of used needles and syringes. Refer patients to the
FDA’s website at http://www.fda.gov/safesharpsdisposal for more information about safe sharps disposal,
and for specific information about sharps disposal in the state that they live in.
Instruct patients not to dispose of their used sharps disposal container in their household trash unless
their community guidelines permit this. Instruct patients not to recycle their used sharps disposal
container.
Adalimumab-aaty
Manufactured by:
CELLTRION, Inc.
23, Academy-ro, Yeonsu-gu,
Incheon, 22014, Republic of Korea
US License Number 1996
Distributed by:
CELLTRION USA, Inc.
One Evertrust Plaza Suite 1207
Jersey City, NJ 07302
Reference ID: 5502211
MEDICATION GUIDE
Adalimumab-aaty (ada-LIM-u-mab aaty)
injection, for subcutaneous use
This product is YUFLYMA (adalimumab-aaty).
Read the Medication Guide that comes with Adalimumab-aaty before you start taking it and
each time you get a refill. There may be new information. This Medication Guide does not
take the place of talking with your doctor about your medical condition or treatment.
What is the most important information I should know about Adalimumab-aaty?
Adalimumab-aaty is a medicine that affects your immune system. Adalimumab-aaty can
lower the ability of your immune system to fight infections. Serious infections have
happened in people taking adalimumab products. These serious infections include
tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have
spread throughout the body. Some people have died from these infections.
•
Your doctor should test you for TB before starting Adalimumab-aaty.
•
Your doctor should check you closely for signs and symptoms of TB during treatment
with Adalimumab-aaty.
You should not start taking Adalimumab-aaty if you have any kind of infection unless your
doctor says it is okay.
Before starting Adalimumab-aaty, tell your doctor if you:
•
think you have an infection or have symptoms of infection such as:
◦ fever, sweats, or chills
◦ warm, red, or painful skin or sores on
◦ muscle aches
your body
◦ cough
◦ diarrhea or stomach pain
◦ shortness of breath
◦ burning when you urinate or urinate
◦ blood in phlegm
more often than normal
◦ feel very tired
◦ weight loss
•
are being treated for an infection.
•
get a lot of infections or have infections that keep coming back.
•
have diabetes.
•
have TB, or have been in close contact with someone with TB.
•
were born in, lived in, or traveled to countries where there is more risk for getting TB. Ask
your doctor if you are not sure.
•
live or have lived in certain parts of the country (such as the Ohio and Mississippi River
valleys) where there is an increased risk for getting certain kinds of fungal infections
(histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or
become more severe if you use Adalimumab-aaty. Ask your doctor if you do not know if
you have lived in an area where these infections are common.
•
have or have had hepatitis B.
•
use the medicine ORENCIA® (abatacept), KINERET® (anakinra), RITUXAN® (rituximab),
IMURAN® (azathioprine), or PURINETHOL® (6–mercaptopurine, 6-MP).
•
are scheduled to have major surgery.
After starting Adalimumab-aaty, call your doctor right away if you have an infection, or
any sign of an infection.
Adalimumab-aaty can make you more likely to get infections or make any infection that
you may have worse.
Cancer
•
For children and adults taking Tumor Necrosis Factor (TNF)-blockers, including
Adalimumab-aaty, the chances of getting cancer may increase.
•
There have been cases of unusual cancers in children, teenagers, and young adults
using TNF-blockers.
Reference ID: 5502211
•
People with rheumatoid arthritis (RA), especially more serious RA, may have a higher
chance for getting a kind of cancer called lymphoma.
•
If you use TNF blockers including Adalimumab-aaty, your chance of getting two types of
skin cancer may increase (basal cell cancer and squamous cell cancer of the skin).
These types of cancer are generally not life-threatening if treated. Tell your doctor if you
have a bump or open sore that does not heal.
•
Some people receiving TNF blockers including Adalimumab-aaty developed a rare type
of cancer called hepatosplenic T-cell lymphoma. This type of cancer often results in
death. Most of these people were male teenagers or young men. Also, most people
were being treated for Crohn’s disease or ulcerative colitis with another medicine called
IMURAN® (azathioprine) or PURINETHOL® (6-mercaptopurine, 6–MP).
What is Adalimumab-aaty?
Adalimumab-aaty is a medicine called a Tumor Necrosis Factor (TNF) blocker. Adalimumab
aaty is used:
•
To reduce the signs and symptoms of:
◦ moderate to severe RA in adults. Adalimumab-aaty can be used alone, with
methotrexate, or with certain other medicines.
◦ moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children 2
years and older. Adalimumab-aaty can be used alone or with methotrexate.
◦ psoriatic arthritis (PsA) in adults. Adalimumab-aaty can be used alone or with
certain other medicines.
◦ ankylosing spondylitis (AS) in adults.
◦ moderate to severe hidradenitis suppurativa (HS) in adults.
•
To treat moderate to severe Crohn’s disease (CD) in adults and children 6 years of
age and older.
•
To treat moderate to severe ulcerative colitis (UC) in adults. It is not known if
adalimumab products are effective in people who stopped responding to or could not
tolerate TNF-blocker medicines.
•
To treat moderate to severe chronic (lasting a long time) plaque psoriasis (Ps) in
adults who have the condition in many areas of their body and who may benefit from
taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet
light alone or with pills).
•
To treat non-infectious intermediate, posterior, and panuveitis in adults.
What should I tell my doctor before taking Adalimumab-aaty?
Adalimumab-aaty may not be right for you. Before starting Adalimumab-aaty, tell your
doctor about all of your medical conditions, including if you:
•
have an infection. See “What is the most important information I should know about
Adalimumab-aaty?”
•
have or have had cancer.
•
have any numbness or tingling or have a disease that affects your nervous system such
as multiple sclerosis or Guillain-Barré syndrome.
•
have or had heart failure.
•
have recently received or are scheduled to receive a vaccine. You may receive vaccines,
except for live vaccines while using Adalimumab-aaty. Children should be brought up to
date with all vaccines before starting Adalimumab-aaty.
•
are allergic to Adalimumab-aaty or to any of its ingredients. See the end of this Medication
Guide for a list of ingredients in Adalimumab-aaty.
•
are pregnant or plan to become pregnant, breastfeeding or plan to breastfeed. You and
your doctor should decide if you should take Adalimumab-aaty while you are pregnant
or breastfeeding.
•
have a baby and you were using Adalimumab-aaty during your pregnancy. Tell your
baby’s doctor before your baby receives any vaccines.
Tell your doctor about all the medicines you take, including prescription and over-the
counter medicines, vitamins, and herbal supplements.
Especially tell your doctor if you use:
Reference ID: 5502211
•
ORENCIA® (abatacept), KINERET® (anakinra), REMICADE® (infliximab), ENBREL®
(etanercept), CIMZIA® (certolizumab pegol) or SIMPONI® (golimumab), because you
should not use Adalimumab-aaty while you are also using one of these medicines.
•
RITUXAN® (rituximab). Your doctor may not want to give you Adalimumab-aaty if
you have received RITUXAN® (rituximab) recently.
•
IMURAN® (azathioprine) or PURINETHOL® (6–mercaptopurine, 6-MP).
Keep a list of your medicines with you to show your doctor and pharmacist each time
you get a new medicine.
How should I take Adalimumab-aaty?
•
Adalimumab-aaty is given by an injection under the skin. Your doctor will tell you how
often to take an injection of Adalimumab-aaty. This is based on your condition to be
treated. Do not inject Adalimumab-aaty more often than you were prescribed.
•
See the Instructions for Use inside the carton for complete instructions for the right way
to prepare and inject Adalimumab-aaty.
•
Make sure you have been shown how to inject Adalimumab-aaty before you do it
yourself. You can call your doctor or 1-877-888-4231 if you have any questions about
giving yourself an injection. Someone you know can also help you with your injection
after they have been shown how to prepare and inject Adalimumab-aaty.
•
Do not try to inject Adalimumab-aaty yourself until you have been shown the right way
to give the injections. If your doctor decides that you or a caregiver may be able to give
your injections of Adalimumab-aaty at home, you should receive training on the right
way to prepare and inject Adalimumab-aaty.
•
Do not miss any doses of Adalimumab-aaty unless your doctor says it is okay. If you
forget to take Adalimumab-aaty, inject a dose as soon as you remember. Then, take your
next dose at your regular scheduled time. This will put you back on schedule. In case you
are not sure when to inject Adalimumab-aaty, call your doctor or pharmacist.
•
If you take more Adalimumab-aaty than you were told to take, call your doctor.
What are the possible side effects of Adalimumab-aaty?
Adalimumab-aaty can cause serious side effects, including:
See “What is the most important information I should know about Adalimumab-aaty?”
•
Serious Infections.
Your doctor will examine you for TB and perform a test to see if you have TB. If your
doctor feels that you are at risk for TB, you may be treated with medicine for TB before
you begin treatment with Adalimumab-aaty and during treatment with Adalimumab-aaty.
Even if your TB test is negative your doctor should carefully monitor you for TB infections
while you are taking Adalimumab-aaty. People who had a negative TB skin test before
receiving adalimumab products have developed active TB. Tell your doctor if you have
any of the following symptoms while taking or after taking Adalimumab-aaty:
◦ cough that does not go away
◦ weight loss
◦ low grade fever
◦ loss of body fat and muscle (wasting)
•
Hepatitis B infection in people who carry the virus in their blood.
If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus can
become active while you use Adalimumab-aaty. Your doctor should do blood tests before
you start treatment, while you are using Adalimumab-aaty, and for several months after
you stop treatment with Adalimumab-aaty. Tell your doctor if you have any of the
following symptoms of a possible hepatitis B infection:
◦ muscle aches
◦ clay-colored bowel movements
◦ feel very tired
◦ fever
◦ dark urine
◦ chills
◦ skin or eyes look yellow
◦ stomach discomfort
◦ little or no appetite
◦ skin rash
◦ vomiting
Reference ID: 5502211
•
Allergic reactions. Allergic reactions can happen in people who use Adalimumab
aaty. Call your doctor or get medical help right away if you have any of these
symptoms of a serious allergic reaction:
◦ hives
◦ swelling of your face, eyes, lips or mouth
◦ trouble breathing
•
Nervous system problems. Signs and symptoms of a nervous system problem include:
numbness or tingling, problems with your vision, weakness in your arms or legs, and
dizziness.
•
Blood problems. Your body may not make enough of the blood cells that help fight
infections or help to stop bleeding. Symptoms include a fever that does not go away,
bruising or bleeding very easily, or looking very pale.
•
New heart failure or worsening of heart failure you already have. Call your doctor
right away if you get new worsening symptoms of heart failure while taking Adalimumab
aaty, including:
◦ shortness of breath
◦ swelling of your ankles or feet
◦ sudden weight gain
•
Immune reactions including a lupus-like syndrome. Symptoms include chest
discomfort or pain that does not go away, shortness of breath, joint pain, or a rash on
your cheeks or arms that gets worse in the sun. Symptoms may improve when you stop
Adalimumab-aaty.
•
Liver Problems. Liver problems can happen in people who use TNF-blocker medicines.
These problems can lead to liver failure and death. Call your doctor right away if you
have any of these symptoms:
◦ feel very tired
◦ skin or eyes look yellow
◦ poor appetite or vomiting
◦ pain on the right side of your stomach (abdomen)
•
Psoriasis. Some people using adalimumab products had new psoriasis or worsening of
psoriasis they already had. Tell your doctor if you develop red scaly patches or raised
bumps that are filled with pus. Your doctor may decide to stop your treatment with
Adalimumab-aaty.
Call your doctor or get medical care right away if you develop any of the above
symptoms. Your treatment with Adalimumab-aaty may be stopped.
The most common side effects of Adalimumab-aaty include:
•
injection site reactions: redness, rash, swelling, itching, or bruising. These symptoms
usually will go away within a few days. Call your doctor right away if you have pain,
redness or swelling around the injection site that does not go away within a few days or
gets worse.
•
upper respiratory infections (including sinus infections)
•
headaches
•
rash
These are not all the possible side effects with Adalimumab-aaty. Tell your doctor if you have
any side effect that bothers you or that does not go away. Ask your doctor or pharmacist for
more information.
Call your doctor for medical advice about side effects. You may report side effects to the FDA
at 1-800-FDA-1088.
How should I store Adalimumab-aaty?
•
Store Adalimumab-aaty in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC). Store
Adalimumab-aaty in the original carton until use to protect it from light. Do not shake.
•
Do not freeze Adalimumab-aaty. Do not use Adalimumab-aaty if frozen, even if it has been
thawed.
•
Refrigerated Adalimumab-aaty may be used until the expiration date printed on the
Adalimumab-aaty carton, dose pack, auto-injector or prefilled syringe. Do not use
Adalimumab-aaty after the expiration date.
Reference ID: 5502211
•
If needed, for example when you are traveling, you may also store Adalimumab-aaty at
room temperature up to 77°F (25°C) for up to 31 days. Store Adalimumab-aaty in the
original carton until use to protect it from light.
•
Throw away Adalimumab-aaty if it has been kept at room temperature and not been
used within 31 days.
•
Record the date you first remove Adalimumab-aaty from the refrigerator in the spaces
provided on the carton and dose pack.
•
Do not store Adalimumab-aaty in extreme heat or cold.
•
Do not use an auto-injector or prefilled syringe if the liquid is cloudy, discolored, or has
flakes or particles in it.
•
Do not drop or crush Adalimumab-aaty. The prefilled syringe is glass.
Keep Adalimumab-aaty, injection supplies, and all other medicines out of the
reach of children.
General information about the safe and effective use of Adalimumab-aaty.
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use Adalimumab-aaty for a condition for which it was not prescribed. Do
not give Adalimumab-aaty to other people, even if they have the same condition. It may
harm them.
This Medication Guide summarizes the most important information about Adalimumab-aaty. If
you would like more information, talk with your doctor. You can ask your doctor or pharmacist
for information about Adalimumab-aaty that is written for health professionals.
What are the ingredients in Adalimumab-aaty?
Active ingredient: adalimumab-aaty
Adalimumab-aaty AI 40 mg/0.4 mL, Adalimumab-aaty 40 mg/0.4 mL prefilled syringe with
safety guard, and Adalimumab-aaty 40 mg/0.4 mL prefilled syringe, Adalimumab-aaty AI 80
mg/0.8 mL, Adalimumab-aaty 80 mg/0.8 mL prefilled syringe with safety guard, Adalimumab
aaty 80 mg/0.8 mL prefilled syringe, and Adalimumab-aaty 20 mg/0.2 mL prefilled syringe:
Inactive ingredients: acetic acid, glycine, polysorbate 80, sodium acetate, and Water
for Injection, USP.
Manufactured by: CELLTRION, Inc., 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea
US License Number 1996
Distributed by: CELLTRION USA, Inc., One Evertrust Plaza, Suite 1207, Jersey City, NJ 07302, USA
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: 12/2024
Reference ID: 5502211
Capfij Needle
Cover
(Needle Inside)
i=
Stopper
Medicine-
1--Window
Plunger
-
'-
Rod
C
C
Body
=
Before Use
After Use
INSTRUCTIONS FOR USE
Adalimumab-aaty (ada-LIM-u-mab aaty)
injection, for subcutaneous use
80 mg/0.8 mL, 40 mg/0.4 mL
Single-Dose Auto-injector
This product is YUFLYMA (adalimumab-aaty).
For subcutaneous use only
Read and follow the Instructions for Use that come with your Adalimumab-aaty Auto-
injector before you start using it and each time you get a refill. There may be new
information. This information does not take the place of talking to your doctor about
your medical condition or treatment.
Figure A: Parts of Adalimumab-aaty Auto-injector
Important Information
•
Use the Auto-injector only if your doctor has trained you on the right way to
prepare for and to give an injection.
•
Ask your doctor how often you will need to give an injection.
•
Do not shake the Auto-injector at any time.
•
Do not remove the Cap until you are ready to inject.
•
Do not share the Auto-injector with anyone.
How to store the Auto-injector
•
Store the Auto-injector in a refrigerator between 36°F to 46°F (2°C to 8°C).
•
Keep the Auto-injector in the original carton until use to protect it from light.
Reference ID: 5502211
0
•
Do not use an Auto-injector that has been left in direct sunlight.
•
Do not freeze the Auto-injector. If the Auto-injector has been frozen, do not use
the Auto-injector even if it is thawed.
•
If needed, you may store the Auto-injector at room temperature up to 77°F
(25°C) for up to 31 days.
•
After the Auto-injector has reached room temperature, do not put it back in the
refrigerator.
•
Keep the Auto-injector and all medicines out of the reach of children.
Read Instructions on All Pages Before Using the Adalimumab-aaty Auto-
injector
Prepare for Injection
1. Gather the supplies for the injection.
1a. Prepare a clean, flat surface, such as a table or countertop, in a well-lit
area.
1b. Remove 1 Auto-injector from the carton stored in your refrigerator.
1c. Make sure you have the following supplies:
-
Auto-injector
-
1 Alcohol swab
Not included in the carton:
-
1 Cotton ball or gauze
-
1 Adhesive bandage
-
FDA-cleared sharps disposal container
2. Inspect the Auto-injector.
2a. Make sure you have the correct medicine
(Adalimumab-aaty) and dosage.
2b. Check the expiration date on the label of the
Auto-injector (see Figure B).
2c. Look at the Auto-injector and make sure it is
not cracked or damaged.
•
Do not use the Auto-injector if;
- it is cracked or damaged.
- the expiration date has passed.
Figure B
Reference ID: 5502211
15 - 30
minutes
-
= Self-injection
and Caregiver
Figure D
3. Inspect the Medicine.
3a. Look through the Window and make sure that
the liquid is clear, colorless to pale brown, and
free of particles (see Figure C).
•
Do not use the Auto-injector if the liquid is the
discolored (yellow or dark brown), cloudy, or
contains particles in it.
•
You may see air bubbles in the liquid. This is
normal.
4. Wait 15 to 30 minutes.
4a. Leave the Auto-injector at room temperature
68°F to 77°F (20°C to 25°C) for 15 to 30 minutes
to allow it to warm up (see Figure D).
•
Do not warm the Auto-injector using heat
sources such as hot water or a microwave.
Figure C
5. Choose an injection site (see Figure E).
5a. You may inject into:
-
the front of your thighs.
-
your abdomen except for the 2 in (5 cm)
around the belly button (navel).
•
Do not inject into skin that is within 2 in (5 cm)
of your belly button (navel), or is red, hard,
tender, damaged, bruised, or scarred.
•
If you have psoriasis, do not inject directly into
any raised, thick, red or scaly skin patches or
lesions on your skin.
•
Do not inject through your clothes.
5b. Rotate the injection site each time you give
an injection.
•
Do not inject the same injection site each time
you give an injection.
Figure E
•
Each new injection site should be at least 1.2 in (3 cm) away from the injection
site you used before.
Reference ID: 5502211
clean
6. Wash your hands.
6a. Wash your hands with soap and water and
dry them thoroughly (see Figure F).
Figure F
7. Clean the injection site.
7a. Clean the injection site with an alcohol swab
using a circular motion (see Figure G).
7b. Let the skin dry before injecting.
•
Do not blow on or touch the injection site
again before giving the injection.
Figure G
Give the Injection
8. Remove the Cap.
8a. Hold the Auto-injector by the injector body
with the Cap on top using one hand. Gently pull
the Cap straight off with the other hand.
•
Do not recap the Auto-injector.
•
Do not remove the Cap until you are ready to
inject.
•
Do not touch the Needle or Needle Cover.
Doing so may result in a needle stick injury
because the Needle is inside the Needle
Cover.
Figure H
8b. Dispose of the Cap in an FDA cleared sharps container (see Step 12 and
Figure H).
Reference ID: 5502211
art of Inject·
9. Place the Auto-injector on the injection site.
9a. Hold the Auto-injector so that you can see
the Window.
9b. Without pinching or stretching the skin, place
the Auto-injector over the injection site at a 90
degree angle (see Figure I).
Figure I
10. Give the injection (see Figure J).
10a. Press the Auto-injector firmly against the
skin.
•
When the injection starts you will hear the 1st
loud “click” and the blue Plunger Rod will
begin to fill the Window.
10b. Keep holding the Auto-injector firmly
against the skin and listen for the 2nd loud “click.”
This can take up to 10 seconds.
•
Do not change the position of the Auto-
injector after the injection has started.
10c. After you hear the 2nd loud “click” continue
to keep holding the Auto-injector firmly against
the skin and count slowly to 5 to make sure you
inject the full dose.
10d. Look at the Auto-injector and make sure that
the blue Plunger Rod is filling the Window
completely.
Figure J
Reference ID: 5502211
i
Needle
Cover
11. Remove the Auto-injector from your skin.
11a. Remove the Auto-injector from your skin
(see Figure K).
•
After you remove the Auto-injector from the
injection site, the needle will be automatically
covered (see Figure L).
•
If the Window has not turned completely blue
or if the medicine is still injecting, this means
you have not received a full dose. Call your
doctor immediately.
•
You may see grey stopper in the Window.
This is normal.
•
Some bleeding may occur.
•
Do not reuse the Auto-injector.
•
Do not rub the injection site.
After the Injection
12. Dispose of the Auto-injector.
12a. Put the used Auto-injector in a FDA-cleared
sharps disposal container right away after use
(see Figure M).
•
Do not throw away (dispose of) the Auto-
injector in your household trash.
•
If you do not have an FDA-cleared sharps
disposal container, you may use a household
container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-
resistant lid, without sharps being able to
come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of it. There may be
state or local laws about how you should throw away used needles and
syringes. For more information about safe sharps disposal, and for specific
information about sharps disposal in the state that you live in, go to the FDA’s
Reference ID: 5502211
Figure K
Figure L
Figure M
website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your used
sharps disposal container.
13. Care for the injection site.
13a. Treat the injection site by gently pressing, not rubbing, a cotton ball or
gauze to the site and apply an adhesive bandage, if necessary.
Manufactured by: CELLTRION, Inc., 23, Academy-ro, Yeonsu-gu, Incheon, 22014,
Republic of Korea
US License Number 1996
Distributed by: CELLTRION USA, Inc., One Evertrust Plaza Suite 1207, Jersey City, NJ
07302
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: 12/2024
Reference ID: 5502211
Finger
Flange
Viewing
Window
\- ~- Needle Guard -----\,i!,c..J
(body)
le)
L Needle
(BJ
I---- Cap -------IJ
Before
Use
After
Use
INSTRUCTIONS FOR USE
Adalimumab-aaty (ada-LIM-u-mab aaty)
injection, for subcutaneous use
80 mg/0.8 mL, 40 mg/0.4 mL
Single-Dose Prefilled Syringe with Safety Guard
This product is YUFLYMA (adalimumab-aaty).
For subcutaneous use only
Read and follow the Instructions for Use that come with your Adalimumab-aaty
Prefilled Syringe before you start using it and each time you get a refill. There may be
new information. This information does not take the place of talking to your doctor
about your medical condition or treatment.
Figure A: Parts of Adalimumab-aaty Prefilled Syringe with Safety Guard
Important Information
•
Use the Prefilled Syringe with Needle Guard only if your doctor has trained you
on the right way to prepare for and to give an injection.
•
Ask your doctor how often you will need to give an injection.
•
Do not shake the Prefilled Syringe at any time.
•
Do not remove the Cap until you are ready to inject.
•
Do not share the Prefilled Syringe with anyone.
•
Only use each Prefilled Syringe for one injection.
•
Do not pull back on the plunger rod at any time.
How to store the Prefilled Syringe
•
Store the Prefilled Syringe in a refrigerator between 36°F to 46°F (2°C to 8°C).
Reference ID: 5502211
•
Keep the Prefilled Syringe in the original carton to protect it from light.
•
Do not use a Prefilled Syringe that has been left in direct sunlight.
•
Do not freeze the Prefilled Syringe. If the Prefilled Syringe has been frozen, do
not use the Prefilled Syringe even if it is thawed.
•
If needed, you may store the Prefilled Syringe at room temperature up to 77°F
(25°C) for up to 31 days.
•
After the Prefilled Syringe has reached room temperature, do not put it back in
the refrigerator.
•
Keep the Prefilled Syringe and all medicines out of the reach of children.
Read Instructions on All Pages Before Using the Adalimumab-aaty Prefilled
Syringe
Prepare for Injection
1. Gather the supplies for the injection.
1a.Prepare a clean, flat surface, such as a table or countertop, in a well-lit area.
1b. Remove 1 Prefilled Syringe from the carton stored in your refrigerator.
•
Hold the Prefilled Syringe body when removing it from the carton.
Do not touch the plunger rod.
1c. Make sure you have the following supplies:
-
Prefilled Syringe
-
1 Alcohol swab
Not included in the carton:
-
1 Cotton ball or gauze
-
1 Adhesive bandage
-
FDA-cleared sharps disposal container
2. Inspect the Prefilled Syringe.
2a. Make sure you have the correct medicine
(Adalimumab-aaty) and dosage.
2b. Check the expiration date on the label of the
Prefilled Syringe (see Figure B).
2c. Look at the Prefilled Syringe and make sure it
is not cracked or damaged.
•
Do not use the Prefilled Syringe if;
- it is cracked or damaged.
- the expiration date has passed.
Figure B
Reference ID: 5502211
15 -30
minutes
-
= Self-injection
and Caregiver
3. Inspect the Medicine.
3a. Look at the Medicine and confirm that the
liquid is clear, colorless to pale brown, and free of
particles
(see Figure C).
•
Do not use the Prefilled Syringe if the liquid is
the discolored (yellow or dark brown), cloudy,
or contains particles in it.
•
You may see air bubbles in the liquid. This is
normal.
4. Wait 15 to 30 minutes.
4a. Leave the Prefilled Syringe at room
temperature 68°F to 77°F (20°C to 25°C) for 15 to
30 minutes to allow it to warm up (see Figure D).
•
Do not warm the Prefilled Syringe using heat
sources such as hot water or a microwave.
5. Choose an injection site (see Figure E).
5a. You may inject into:
-
the front of your thighs.
-
your abdomen except for the 2 in (5 cm)
around the belly button (navel).
•
Do not inject into skin that is within 2 in (5 cm)
of your belly button (navel), or is red, hard,
tender, damaged, bruised, or scarred.
•
If you have psoriasis, do not inject directly into
any raised, thick, red or scaly skin patches or
lesions on your skin.
•
Do not inject through your clothes.
5b. Rotate the injection site each time you give
an injection. Each new injection site should be
at least 1.2 in (3 cm) away from the injection site
you used before.
Reference ID: 5502211
Figure C
Figure D
Figure E
clean
6. Wash your hands.
6a. Wash your hands with soap and water and
dry them thoroughly (see Figure F).
Figure F
7. Clean the injection site.
7a. Clean the injection site with an alcohol swab
using a circular motion (see Figure G).
7b. Let the skin dry before injecting.
•
Do not blow on or touch the injection site
again before giving the injection.
Figure G
Give the Injection
8. Remove the Cap.
8a. Hold the Prefilled Syringe by the injector body
with the Cap on top using one hand. Gently pull
the Cap straight off with the other hand.
•
Do not pull back on the plunger rod at any
time.
•
Do not recap the Prefilled Syringe.
•
Do not remove the Cap until you are ready to
inject.
•
Do not touch the Needle. Doing so may
result in a needle stick injury.
8b. Dispose of the Cap in an FDA cleared sharps
container (see Step 12 and Figure H).
Reference ID: 5502211
Figure H
9. Insert the Prefilled Syringe into the injection
site.
9a. Gently pinch a fold of skin at the injection site
with one hand.
9b. With a quick and “dart-like” motion, insert the
Needle completely into the fold of the skin at a
45-degree angle (see Figure I).
•
Do not change the position of the Prefilled
Syringe after the injection has started.
Figure I
10.Give the injection.
10a. After the Needle is inserted, release the
pinch.
10b. Slowly push the Plunger all the way down
until all of the liquid is injected and the Syringe is
empty
(see Figure J).
Figure J
Reference ID: 5502211
11.Remove the Prefilled Syringe from the injection
site.
11a. After the Prefilled Syringe is empty, slowly
lift your thumb from the Plunger until Needle is
completely covered by the Needle Guard (see
Figure K).
•
Some bleeding may occur.
•
Do not reuse the Prefilled Syringe.
•
Do not touch or recap the needle.
•
Do not rub the injection site.
Figure K
After the Injection
12.Dispose of the Prefilled Syringe.
12a. Put the used Prefilled Syringe in a FDA-
cleared sharps disposal container right away after
use (see Figure L).
•
Do not throw away (dispose of) the Prefilled
Syringe in your household trash.
•
If you do not have an FDA-cleared sharps
disposal container, you may use a household
container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-
resistant lid, without sharps being able to
come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of it. There may be
state or local laws about how you should throw away used needles and
syringes. For more information about safe sharps disposal, and for specific
information about sharps disposal in the state that you live in, go to the FDA’s
website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your used
Reference ID: 5502211
Figure L
sharps disposal container.
13.Care for the injection site.
13a. Treat the injection site by gently pressing, not rubbing, a cotton ball or
gauze to the site and apply an adhesive bandage, if necessary.
Manufactured by: CELLTRION, Inc., 23, Academy-ro, Yeonsu-gu, Incheon, 22014,
Republic of Korea
US License Number 1996
Distributed by: CELLTRION USA, Inc., One Evertrust Plaza Suite 1207, Jersey City, NJ
07302
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: 12/2024
Reference ID: 5502211
Finger
Fllange
- -- Body -
--------i,,,
Medicine--
B,efore
Use
Cap
A'ft,er
Us,e
INSTRUCTIONS FOR USE
Adalimumab-aaty (ada-LIM-u-mab aaty)
injection, for subcutaneous use
80 mg/0.8 mL, 40 mg/0.4 mL, 20 mg/0.2 mL
Single-Dose Prefilled Syringe
This product is YUFLYMA (adalimumab-aaty).
For subcutaneous use only
Read and follow the Instructions for Use that come with your Adalimumab-aaty
Prefilled Syringe before you start using it and each time you get a refill. There may be
new information. This information does not take the place of talking to your doctor
about your medical condition or treatment.
Figure A: Parts of Adalimumab-aaty Prefilled Syringe
Important Information
•
Use the Prefilled Syringe only if your doctor has trained you on the right way to
prepare for and to give an injection.
•
Ask your doctor how often you will need to give an injection.
•
Do not shake the Prefilled Syringe at any time.
•
Do not remove the Cap until you are ready to inject.
•
Do not share the Prefilled Syringe with anyone.
•
Do not pull back on the plunger rod at any time.
How to store the Prefilled Syringe
•
Store the Prefilled Syringe in a refrigerator between 36°F to 46°F (2°C to 8°C).
Reference ID: 5502211
•
Keep the Prefilled Syringe in the original carton to protect it from light.
•
Do not use a Prefilled Syringe that has been left in direct sunlight.
•
Do not freeze the Prefilled Syringe. If the Prefilled Syringe has been frozen,
do not use the Prefilled Syringe even if it is thawed.
•
If needed, you may store the Prefilled Syringe at room temperature up to 77°F
(25°C) for up to 31 days.
•
After the Prefilled Syringe has reached room temperature, do not put it back in
the refrigerator.
•
Keep the Prefilled Syringe and all medicines out of the reach of children.
Read Instructions on All Pages Before Using the Adalimumab-aaty Prefilled
Syringe
Prepare for Injection
1. Gather the supplies for the injection.
1a. Prepare a clean, flat surface, such as a table or countertop, in a well-lit
area.
1b. Remove 1 Prefilled Syringe from the carton stored in your refrigerator.
•
Hold the Prefilled Syringe body when removing it from the carton.
Do not touch the plunger rod.
1c. Make sure you have the following supplies:
-
Prefilled Syringe
-
1 Alcohol swab
Not included in the carton:
-
1 Cotton ball or gauze
-
1 Adhesive bandage
-
FDA-cleared sharps disposal container
2. Inspect the Prefilled Syringe.
2a. Make sure you have the correct medicine
(Adalimumab-aaty) and dosage.
2b. Check the expiration date on the label of the
Prefilled Syringe (see Figure B)
2c. Look at the Prefilled Syringe and make sure it
is not cracked or damaged.
•
Do not use the Prefilled Syringe if;
- it is cracked or damaged.
Figure B
- the expiration date has passed.
Reference ID: 5502211
15 - 30
minutes
-
= Self-injection
and Caregiver
3. Inspect the Medicine.
3a. Look at the Medicine and confirm that the
liquid is clear, colorless to pale brown, and free
of particles (see Figure C).
•
Do not use the Prefilled Syringe if the liquid
is the discolored (yellow or dark brown),
cloudy, or contains particles in it.
•
You may see air bubbles in the liquid. This
is normal.
4. Wait 15 to 30 minutes.
4a. Leave the Prefilled Syringe at room
temperature 68°F to 77°F (20°C to 25°C) for 15
to 30 minutes to allow it to warm up (see
Figure D).
•
Do not warm the Prefilled Syringe using
heat sources such as hot water or a
microwave.
5. Choose an injection site (see Figure E).
5a. You may inject into:
-
the front of your thighs.
-
your abdomen except for the 2 in (5 cm)
around the belly button (navel).
•
Do not inject into skin that is within 2 in (5 cm)
of your belly button (navel), or is red, hard,
tender, damaged, bruised, or scarred.
•
If you have psoriasis, do not inject directly into
any raised, thick, red or scaly skin patches or
lesions on your skin.
•
Do not inject through your clothes.
5b. Rotate the injection site each time you give
an injection. Each new injection site should be
at least 1.2 in (3 cm) away from the injection
site you used before.
Reference ID: 5502211
Figure C
Figure D
Figure E
clean
Figure G
6. Wash your hands.
6a. Wash your hands with soap and water and
dry them thoroughly (see Figure F).
Figure F
7. Clean the injection site.
7a. Clean the injection site with an alcohol swab
using a circular motion (see Figure G).
7b. Let the skin dry before injecting.
•
Do not blow on or touch the injection site
again before giving the injection.
Give the Injection
8. Remove the Cap.
8a. Hold the Prefilled Syringe by the injector body
with the Cap on top using one hand. Gently pull
the Cap straight off with the other hand.
•
Do not pull back on the plunger rod at any
time.
•
Do not recap the Prefilled Syringe.
•
Do not remove the Cap until you are ready to
inject.
•
Do not touch the Needle. Doing so may
result in a needle stick injury.
8b. Dispose of the Cap in an FDA cleared sharps
container (see Step 12 and Figure H).
Reference ID: 5502211
Figure H
9. Insert the Prefilled Syringe into the injection site.
9a. Gently pinch a fold of skin at the injection site
with one hand.
9b. With a quick and “dart-like” motion, insert the
Needle completely into the fold of the skin at a 45
degree angle (see Figure I).
•
Do not change the position of the Prefilled
Syringe after the injection has started.
Figure I
10.Give the injection.
10a. After the Needle is inserted, release the
pinch.
10b. Slowly push the Plunger all the way down
until all of the liquid is injected and the Syringe is
empty
(see Figure J).
Figure J
Reference ID: 5502211
11.Remove the Prefilled Syringe from the injection
site.
11a. After the Prefilled Syringe is empty, remove
the Prefilled Syringe from your skin (see Figure
K).
•
Some bleeding may occur.
•
Do not reuse the Prefilled Syringe.
•
Do not touch the Needle.
•
Do not rub the injection site.
Figure K
After the Injection
12.Dispose of the Prefilled Syringe.
12a. Put the used Prefilled Syringe in a FDA-
cleared sharps disposal container right away after
use (see Figure L).
•
Do not throw away (dispose of) the Prefilled
Syringe in your household trash.
•
If you do not have an FDA-cleared sharps
disposal container, you may use a household
container that is:
-
made of a heavy-duty plastic,
-
can be closed with a tight-fitting, puncture-
resistant lid, without sharps being able to
come out,
-
upright and stable during use,
-
leak-resistant, and
-
properly labeled to warn of hazardous waste inside the container.
•
When your sharps disposal container is almost full, you will need to follow
your community guidelines for the right way to dispose of it. There may be
state or local laws about how you should throw away used needles and
syringes. For more information about safe sharps disposal, and for specific
information about sharps disposal in the state that you live in, go to the FDA’s
website at: http://www.fda.gov/safesharpsdisposal.
•
Do not dispose of your used sharps disposal container in your household
trash unless your community guidelines permit this. Do not recycle your used
sharps disposal container.
13.Care for the injection site.
13a. Treat the injection site by gently pressing, not rubbing, a cotton ball or
gauze to the site and apply an adhesive bandage, if necessary.
Reference ID: 5502211
Figure L
Manufactured by: CELLTRION, Inc., 23, Academy-ro, Yeonsu-gu, Incheon, 22014,
Republic of Korea
US License Number 1996
Distributed by: CELLTRION USA, Inc., One Evertrust Plaza Suite 1207, Jersey City, NJ
07302
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Issued: 12/2024
Reference ID: 5502211
| custom-source | 2025-02-12T15:48:16.227117 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761219s013lbl.pdf', 'application_number': 761219, 'submission_type': 'SUPPL ', 'submission_number': 13} |
80,772 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
STEGLATRO safely and effectively. See full prescribing
information for STEGLATRO.
STEGLATRO® (ertugliflozin) tablets, for oral use
Initial U.S. Approval: 2017
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.3)
12/2024
Warnings and Precautions (5.2, 5.5)
12/2024
----------------------------INDICATIONS AND USAGE---------------------------
STEGLATRO is a sodium glucose co-transporter 2 (SGLT2) inhibitor
indicated as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus. (1)
Limitations of Use:
Not recommended for use to improve glycemic control in patients with
type 1 diabetes mellitus. (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
• Assess renal function before initiating and as clinically indicated.
(2.1)
• Correct volume depletion before initiating STEGLATRO. (2.1)
• Recommended starting dosage is 5 mg orally once daily, taken in
the morning, with or without food. (2.2)
• Increase dosage to 15 mg orally once daily in those tolerating
STEGLATRO and needing additional glycemic control. (2.2)
• Use is not recommended in patients with an estimated glomerular
filtration rate (eGFR) less than 45 mL/min/1.73 m2. (2.2)
• Withhold STEGLATRO for at least 4 days, if possible, prior to
surgery or procedures associated with prolonged fasting. (2.3)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets: 5 mg and 15 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
• Hypersensitivity to ertugliflozin or any of the excipients in
STEGLATRO. (4)
----------------------- WARNINGS AND PRECAUTIONS-----------------------
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and
Other Ketoacidosis: Consider ketone monitoring in patients at risk
for ketoacidosis, as indicated. Assess for ketoacidosis regardless of
presenting blood glucose levels and discontinue STEGLATRO if
ketoacidosis is suspected. Monitor patients for resolution of
ketoacidosis before restarting. (5.1)
• Lower Limb Amputation: Monitor patients for infections or ulcers of
lower limbs, and discontinue if these occur. (5.2)
• Volume Depletion: May result in acute kidney injury. Before
initiating, assess and correct volume status in patients with renal
impairment or low systolic blood pressure, elderly patients, or
patients on diuretics. Monitor for signs and symptoms during
therapy. (5.3)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and
symptoms of urinary tract infections and treat promptly, if indicated.
(5.4)
• Hypoglycemia: Consider a lower dose of insulin or insulin
secretagogue to reduce risk of hypoglycemia when used in
combination. (5.5)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene):
Serious, life-threatening cases have occurred in both females and
males. Assess patients presenting with pain or tenderness,
erythema, or swelling in the genital or perineal area, along with fever
or malaise. If suspected, institute prompt treatment. (5.6)
• Genital Mycotic Infections: Monitor and treat if indicated. (5.7)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions (incidence ≥ 5%) were female genital
mycotic infections. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck
Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
---------------------------- DRUG INTERACTIONS-------------------------------
See full prescribing information for information on drug interactions and
interference of STEGLATRO with laboratory tests. (7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Advise females of the potential risk to a fetus especially
during the second and third trimesters. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)
• Geriatrics: Higher incidence of adverse reactions related to reduced
intravascular volume. (8.5)
• Renal Impairment: Higher incidence of adverse reactions related to
reduced intravascular volume and renal function. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Prior to Initiation of STEGLATRO
2.2
Recommended Dosage
2.3
Temporary Interruption for Surgery
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Diabetic Ketoacidosis in Patients with Type 1 Diabetes
Mellitus and Other Ketoacidosis
5.2
Lower Limb Amputation
5.3
Volume Depletion
5.4
Urosepsis and Pyelonephritis
5.5
Hypoglycemia with Concomitant Use with Insulin or Insulin
Secretagogues
5.6
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
5.7
Genital Mycotic Infections
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Glycemic Control Trials in Patients with Type 2 Diabetes
Mellitus
14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes
Mellitus and Established Cardiovascular Disease
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
Reference ID: 5502336
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
STEGLATRO® is indicated as an adjunct to diet and exercise to improve glycemic control in adults
with type 2 diabetes mellitus.
Limitations of Use
•
Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus
[see Warnings and Precautions (5.1)].
2
DOSAGE AND ADMINISTRATION
2.1
Prior to Initiation of STEGLATRO
•
Assess renal function before initiating STEGLATRO and as clinically indicated [see Warnings
and Precautions (5.3)].
•
Assess volume status. In patients with volume depletion, correct this condition before initiating
STEGLATRO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].
2.2
Recommended Dosage
•
The recommended starting dosage of STEGLATRO is 5 mg orally once daily, taken in the
morning, with or without food.
•
For additional glycemic control, the dosage may be increased to 15 mg orally once daily in
patients tolerating STEGLATRO.
•
Use of STEGLATRO is not recommended in patients with an estimated glomerular filtration rate
(eGFR) less than 45 mL/min/1.73 m2.
2.3 Temporary Interruption for Surgery
Withhold STEGLATRO for at least 4 days, if possible, prior to surgery or procedures associated with
prolonged fasting. Resume STEGLATRO when the patient is clinically stable and has resumed oral
intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
3
DOSAGE FORMS AND STRENGTHS
•
Tablets: 5 mg, pink, triangular-shaped debossed with “701” on one side and plain on the other
side.
•
Tablets: 15 mg, red, triangular-shaped debossed with “702” on one side and plain on the other
side.
4
CONTRAINDICATIONS
STEGLATRO is contraindicated in patients with hypersensitivity to ertugliflozin or any excipient in
STEGLATRO. Reactions such as angioedema have occurred [see Adverse Reactions (6.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, STEGLATRO significantly increases the risk of diabetic
ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients
with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received
sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may
be greater with higher doses. STEGLATRO is not indicated for glycemic control in patients with type 1
diabetes mellitus.
Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery)
are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis
in patients with type 2 diabetes mellitus using SGLT2 inhibitors.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization
due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic
diet, surgery, volume depletion, and alcohol abuse.
Reference ID: 5502336
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include
nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at
presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL).
Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists
for 4 days after discontinuing STEGLATRO [see Clinical Pharmacology (12.2)]; however, there have been
postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks
after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation.
Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs
and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue
STEGLATRO, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of
ketoacidosis before restarting STEGLATRO.
Withhold STEGLATRO, if possible, in temporary clinical situations that could predispose patients to
ketoacidosis. Resume STEGLATRO when the patient is clinically stable and has resumed oral intake [see
Dosage and Administration (2.3)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue
STEGLATRO and seek medical attention immediately if signs and symptoms occur.
5.2
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2
diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb
amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo,
STEGLATRO 5 mg, and STEGLATRO 15 mg treatment arms, respectively.
Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb
amputations). Some patients had multiple amputations, some involving both lower limbs.
Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating
medical events leading to the need for an amputation. Patients with amputations were more likely to be
male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or
peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.
Across seven STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in
1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%)
patients in the STEGLATRO 15 mg group.
Counsel patients about the importance of routine preventative foot care. Monitor patients receiving
STEGLATRO for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores
or ulcers involving the lower limbs, and discontinue STEGLATRO if these complications occur.
5.3
Volume Depletion
STEGLATRO can cause intravascular volume contraction which may sometimes manifest as
symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There
have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in
patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including STEGLATRO. Patients with
impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly
patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for
volume depletion or hypotension. Before initiating STEGLATRO in patients with one or more of these
characteristics, assess volume status and renal function. In patients with volume depletion, correct this
condition before initiating STEGLATRO. Monitor for signs and symptoms of volume depletion, and renal
function after initiating therapy.
5.4
Urosepsis and Pyelonephritis
There have been postmarketing reports of serious urinary tract infections, including urosepsis and
pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors. Treatment with SGLT2
inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary
tract infections and treat promptly, if indicated [see Adverse Reactions (6.1)].
3
Reference ID: 5502336
5.5
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia.
STEGLATRO may increase the risk of hypoglycemia when used in combination with insulin or an insulin
secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in
the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogues). Inform
patients using these medications concomitantly of this risk and educate them on the signs and symptoms
of hypoglycemia.
5.6
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and
life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in
postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including
STEGLATRO. Cases have been reported in females and males. Serious outcomes have included
hospitalization, multiple surgeries, and death.
Patients treated with STEGLATRO presenting with pain or tenderness, erythema, or swelling in the
genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If
suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical
debridement. Discontinue STEGLATRO, closely monitor blood glucose levels, and provide appropriate
alternative therapy for glycemic control.
5.7
Genital Mycotic Infections
STEGLATRO increases the risk of genital mycotic infections. Patients who have a history of genital
mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections [see
Adverse Reactions (6.1)]. Monitor and treat appropriately.
6
ADVERSE REACTIONS
The following important adverse reactions are described elsewhere in the labeling:
•
Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings
and Precautions (5.1)]
•
Lower Limb Amputation [see Warnings and Precautions (5.2)]
•
Volume Depletion [see Warnings and Precautions (5.3)]
•
Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
•
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and
Precautions (5.5)]
•
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions
(5.6)]
•
Genital Mycotic Infections [see Warnings and Precautions (5.7)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Pool of Placebo-Controlled Trials Evaluating STEGLATRO 5 and 15 mg
The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. STEGLATRO
was used as monotherapy in one trial and as add-on therapy in two trials [see Clinical Studies (14)]. These
data reflect exposure of 1,029 patients to STEGLATRO with a mean exposure duration of approximately
25 weeks. Patients received STEGLATRO 5 mg (N=519), STEGLATRO 15 mg (N=510), or placebo
(N=515) once daily. The mean age of the population was 57 years and 2% were older than 75 years of age.
Fifty-three percent (53%) of the population was male and 73% were White, 15% were Asian, and 7% were
Black or African American. At baseline the population had diabetes for an average of 7.5 years, had a mean
HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline renal
4
Reference ID: 5502336
function (mean eGFR 88.9 mL/min/1.73 m2) was normal or mildly impaired in 97% of patients and
moderately impaired in 3% of patients.
Table 1 shows common adverse reactions associated with the use of STEGLATRO. These adverse
reactions were not present at baseline, occurred more commonly on STEGLATRO than on placebo, and
occurred in at least 2% of patients treated with either STEGLATRO 5 mg or STEGLATRO 15 mg.
Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus Treated
with STEGLATRO* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of
STEGLATRO Monotherapy or Combination Therapy
Number (%) of Patients
Placebo
N = 515
STEGLATRO 5 mg
N = 519
STEGLATRO 15 mg
N = 510
Female genital mycotic infections†
3.0%
9.1%
12.2%
Male genital mycotic infections‡
0.4%
3.7%
4.2%
Urinary tract infections§
3.9%
4.0%
4.1%
Headache
2.3%
3.5%
2.9%
Vaginal pruritus¶
0.4%
2.8%
2.4%
Increased urination#
1.0%
2.7%
2.4%
Nasopharyngitis
2.3%
2.5%
2.0%
Back pain
2.3%
1.7%
2.5%
Weight decreased
1.0%
1.2%
2.4%
ThirstÞ
0.6%
2.7%
1.4%
* The three placebo-controlled studies included one monotherapy trial and two add-on combination trials with metformin HCl or with
metformin HCl and sitagliptin.
† Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic
infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo
(N=235), STEGLATRO 5 mg (N=252), STEGLATRO 15 mg (N=245).
‡ Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number
of male patients in each group as denominator: placebo (N=280), STEGLATRO 5 mg (N=267), STEGLATRO 15 mg (N=265).
§ Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.
¶ Includes: vulvovaginal pruritus and pruritus genital. Percentages calculated with the number of female patients in each group as
denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
# Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
Þ Includes: thirst, dry mouth, polydipsia, and dry throat.
Volume Depletion
STEGLATRO causes an osmotic diuresis, which may lead to intravascular volume contraction and
adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR
less than 60 mL/min/1.73 m2). In patients with moderate renal impairment, adverse reactions related to
volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic
hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, STEGLATRO 5 mg,
and STEGLATRO 15 mg, respectively. STEGLATRO may also increase the risk of hypotension in other
patients at risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].
Hypoglycemia
The incidence of hypoglycemia by study is shown in Table 2.
5
Reference ID: 5502336
Table 2: Incidence of Overall* and Severe† Hypoglycemia in Placebo-Controlled Clinical Studies in
Patients with Type 2 Diabetes Mellitus
Monotherapy (26 weeks)
Placebo
(N = 153)
STEGLATRO
5 mg
(N =156)
STEGLATRO
15 mg
(N = 152)
Overall [N (%)]
Severe [N (%)]
1 (0.7)
0 (0.0)
4 (2.6)
0 (0.0)
4 (2.6)
2 (1.3)
Add-on Combination Therapy with
Metformin HCl (26 weeks)
Placebo
(N = 209)
STEGLATRO
5 mg
(N = 207)
STEGLATRO
15 mg
(N = 205)
Overall [N (%)]
Severe [N (%)]
9 (4.3)
1 (0.5)
15 (7.2)
1 (0.5)
16 (7.8)
0 (0.0)
Add-on Combination Therapy with
Metformin HCl and Sitagliptin
(26 weeks)
Placebo
(N = 153)
STEGLATRO
5 mg
(N = 156)
STEGLATRO
15 mg
(N = 153)
Overall [N (%)]
Severe [N (%)]
5 (3.3)
1 (0.7)
7 (4.5)
1 (0.6)
3 (2.0)
0 (0.0)
In Combination with Insulin and/or an
Insulin Secretagogue in Patients with
Moderate Renal Impairment (26
weeks)
Placebo
(N = 133)
STEGLATRO
5 mg
(N = 148)
STEGLATRO
15 mg
(N = 143)
Overall [N (%)]
Severe [N (%)]
48 (36.1)
3 (2.3)
53 (35.8)
5 (3.4)
39 (27.3)
3 (2.1)
Add-on Combination with Insulin with
or without Metformin HCl (18 weeks)
Placebo
(N = 347)
STEGLATRO
5 mg
(N = 348)
STEGLATRO
15 mg
(N = 370)
Overall [N (%)]
Severe [N (%)]
130 (37.5)
12 (3.5)
137 (39.4)
13 (3.7)
144 (38.9)
19 (5.1)
Add-on Combination with a
Sulfonylurea (18 weeks)
Placebo
(N =48)
STEGLATRO
5 mg
(N =55)
STEGLATRO
15 mg
(N =54)
Overall [N (%)]
Severe [N (%)]
2 (4.2)
0 (0.0)
4 (7.3)
0 (0.0)
5 (9.3)
0 (0.0)
Add-on Combination with Metformin
HCl and a Sulfonylurea (18 weeks)
Placebo
(N = 117)
STEGLATRO
5 mg
(N = 100)
STEGLATRO
15 mg
(N = 113)
Overall [N (%)]
Severe [N (%)]
17 (14.5)
1 (0.9)
20 (20.0)
2 (2.0)
30 (26.5)
2 (1.8)
* Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.
† Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.
6
Reference ID: 5502336
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2
diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb
amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo,
STEGLATRO 5 mg, and STEGLATRO 15 mg treatment arms, respectively.
Across seven STEGLATRO clinical trials, non-traumatic lower limb amputations were reported in
1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the STEGLATRO 5 mg group, and 8 (0.5%)
patients in the STEGLATRO 15 mg group.
Genital Mycotic Infections
In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections
(e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis,
vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females treated with
placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1). In females,
discontinuation due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo
and STEGLATRO, respectively.
In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital
infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo,
STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively (see Table 1). Male genital mycotic infections
occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic
infections occurred in 0% and 0.2% of patients treated with placebo and STEGLATRO, respectively.
Phimosis was reported in 8 of 1729 (0.5%) male ertugliflozin-treated patients, of which four required
circumcision.
Urinary Tract Infections
In VERTIS CV, urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in
10.2%, 12.2% and 12.0% of patients treated with placebo, STEGLATRO 5 mg and STEGLATRO 15 mg,
respectively. The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo,
STEGLATRO 5 mg and STEGLATRO 15 mg, respectively.
Laboratory Tests
Changes in Serum Creatinine and eGFR
Initiation of STEGLATRO causes an increase in serum creatinine and decrease in eGFR within
weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal
impairment, larger mean changes were observed. In a long-term cardiovascular outcomes trial, an initial
increase in serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at
Week 6 eGFR changes of -2.7, -3.8 and -0.4 mL/min/1.73 m2 in the STEGLATRO 5 mg, STEGLATRO
15 mg and placebo arms, respectively). The initial decline was followed by a recovery toward baseline to
Week 52 (eGFR change from baseline of - 0.4, - 1.1 and - 0.2 mL/min/1.73 m2 in STEGLATRO 5 mg,
STEGLATRO 15 mg, and placebo arms, respectively). Acute hemodynamic changes may play a role in the
early renal function changes observed with STEGLATRO since they are reversed after treatment
discontinuation.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in
patients treated with STEGLATRO. Mean percent changes from baseline to Week 26 in LDL-C relative to
placebo were 2.6% and 5.4% with STEGLATRO 5 mg and STEGLATRO 15 mg, respectively. The range
of mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.
Increases in Hemoglobin
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week
26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with STEGLATRO 5 mg, and
0.48 g/dL (3.5%) with STEGLATRO 15 mg. The range of mean baseline hemoglobin was 13.90 to
14.00 g/dL across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with
placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively, had a hemoglobin increase greater
than 2 g/dL and above the upper limit of normal.
Increases in Serum Phosphate
7
Reference ID: 5502336
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum
phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with STEGLATRO 5 mg, and
0.26 mg/dL (8.5%) with STEGLATRO 15 mg. The range of mean baseline serum phosphate was 3.53 to
3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean
changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with
placebo, 0.29 mg/dL (9.7%) with STEGLATRO 5 mg, and 0.24 mg/dL (7.8%) with STEGLATRO 15 mg.
6.2
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of STEGLATRO. Because
these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
•
Infections: necrotizing fasciitis of the perineum (Fournier’s Gangrene)
•
Skin and Subcutaneous Tissue Disorders: angioedema, rash
7
DRUG INTERACTIONS
Table 3: Clinically Significant Drug Interactions with STEGLATRO
Insulin or Insulin Secretagogues
Clinical Impact:
The risk of hypoglycemia is increased when STEGLATRO is used in combination with insulin or an
insulin secretagogue.
Intervention:
A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia
when used in combination with STEGLATRO.
Lithium
Clinical Impact:
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention:
Monitor serum lithium concentration more frequently during STEGLATRO initiation and dosage
changes.
Positive Urine Glucose Test
Clinical Impact:
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention:
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2
inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact:
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2
inhibitors.
Intervention:
Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to
monitor glycemic control.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on animal data showing adverse renal effects, STEGLATRO is not recommended during the
second and third trimesters of pregnancy.
The limited available data with STEGLATRO in pregnant women are not sufficient to determine a
drug-associated risk of adverse developmental outcomes. There are risks to the mother and fetus
associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered
during a period of renal development corresponding to the late second and third trimesters of human
pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule
dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in
rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose
of 15 mg/day when administered during organogenesis (see Data).
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes
with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated
background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
8
Reference ID: 5502336
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre
eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Animal Data
When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney
weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or
equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure
during periods of renal development in rats that correspond to the late second and third trimester of human
renal development, and did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered
orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not
adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately
300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally
toxic dose (250 mg/kg/day) in rats (707 times the clinical dose), was associated with reduced fetal viability,
and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and
post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation
day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at
maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum
clinical dose of 15 mg/day, based on AUC).
8.2
Lactation
Risk Summary
There is no information regarding the presence of STEGLATRO in human milk, the effects on the
breastfed infant, or the effects on milk production. Ertugliflozin is present in the milk of lactating rats (see
Data). Since human kidney maturation occurs in utero and during the first 2 years of life when lactational
exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious
adverse reactions in a breastfed infant, advise women that the use of STEGLATRO is not recommended
while breastfeeding.
Data
The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after
parturition. Ertugliflozin derived radioactivity exposure in milk and plasma were similar, with a milk/plasma
ratio of 1.07, based on AUC. Juvenile rats directly exposed to STEGLATRO during a developmental period
corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent
increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).
8.4
Pediatric Use
Safety and effectiveness of STEGLATRO in pediatric patients under 18 years of age have not been
established.
8.5
Geriatric Use
No dosage adjustment of STEGLATRO is recommended based on age. In STEGLATRO clinical
trials, a total of 876 (25.7%) patients treated with STEGLATRO were 65 years and older, and 152 (4.5%)
patients treated with STEGLATRO were 75 years and older. Patients 65 years and older had a higher
incidence of adverse reactions related to volume depletion compared to younger patients; events were
reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, STEGLATRO 5 mg, and
STEGLATRO 15 mg, respectively [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].
In VERTIS CV, a total of 2780 (50.5%) patients treated with STEGLATRO were 65 years and older,
and 595 (10.8%) patients treated with STEGLATRO were 75 years and older. Safety and efficacy were
generally similar for patients age 65 years and older compared to patients younger than 65.
9
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8.6
Renal Impairment
A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR ≥30
to less than 60 mL/min/1.73 m2) treated with STEGLATRO did not demonstrate improvement in glycemic
control.
In the VERTIS CV study, there were 1370 patients (25%) with an eGFR ≥90 mL/min/1.73 m2, 2929
patients (53%) with an eGFR of ≥60 to less than 90 mL/min/1.73 m2, 879 patients (16%) with an eGFR of
≥45 to less than 60 mL/min/1.73 m2, and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m2 treated
with STEGLATRO. Similar effects on glycemic control at Week 18 were observed in patients treated with
STEGLATRO in each eGFR subgroup and also in the overall patient population.
No dosage adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m2.
8.7
Hepatic Impairment
No dosage adjustment of STEGLATRO is necessary in patients with mild or moderate hepatic
impairment. Ertugliflozin has not been studied in patients with severe hepatic impairment and is not
recommended for use in this patient population [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
In the event of an overdose with STEGLATRO, contact the Poison Help line (1-800-222-1222) or a
medical toxicologist for additional overdosage management recommendations. Employ the usual
supportive measures as dictated by the patient’s clinical status. Removal of ertugliflozin by hemodialysis
has not been studied.
11
DESCRIPTION
STEGLATRO (ertugliflozin) tablets for oral use contain ertugliflozin L-pyroglutamic acid, a SGLT2
inhibitor.
The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4
ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5
oxopyrrolidine-2-carboxylic acid. The molecular formula is C27H32ClNO10 and the molecular weight is
566.00.
The chemical structure is:
Ertugliflozin L-pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and
acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.
STEGLATRO is supplied as film-coated tablets, containing 6.48 or 19.43 mg of ertugliflozin L
pyroglutamic acid, which is equivalent to 5 and 15 mg of ertugliflozin.
Inactive ingredients are microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and
magnesium stearate.
The film coating contains: hypromellose, lactose monohydrate, macrogol, triacetin, titanium dioxide
and iron oxide red.
10
Reference ID: 5502336
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular
filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin
reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby
increases urinary glucose excretion.
12.2 Pharmacodynamics
Urinary Glucose Excretion and Urinary Volume
Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy
subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of
ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal
urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration. UGE
with ertugliflozin also results in increases in urinary volume.
Cardiac Electrophysiology
The effect of STEGLATRO on QTc interval was evaluated in a Phase 1 randomized, placebo- and
positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures
with maximum recommended dose, STEGLATRO does not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes
mellitus. The steady state mean plasma AUC and Cmax were 398 ng∙hr/mL and 81.3 ng/mL, respectively,
with 5 mg ertugliflozin once-daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg
ertugliflozin once-daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with
ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up
to 10-40% following multiple dosing.
Absorption
Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma
concentrations (median Tmax) of ertugliflozin occur at 1 hour postdose under fasted conditions. Plasma Cmax
and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg (0.1
times the lowest recommended dose) to 300 mg (20 times the highest recommended dose) and following
multiple doses from 1 mg (0.2 times the lowest recommended dose) to 100 mg (6.7 times the highest
recommended dose). The absolute oral bioavailability of ertugliflozin following administration of a 15 mg
dose is approximately 100%.
Effect of Food
Administration of STEGLATRO with a high-fat and high-calorie meal decreases ertugliflozin Cmax by
29% and prolongs Tmax by 1 hour, but does not alter AUC as compared with the fasted state. The observed
effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may
be administered with or without food. In Phase 3 clinical trials, STEGLATRO was administered without
regard to meals.
Distribution
The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L.
Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations.
Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood-
to-plasma concentration ratio of ertugliflozin is 0.66.
Elimination
Metabolism
Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway for
ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that are
11
Reference ID: 5502336
pharmacologically inactive at clinically relevant concentrations. CYP-mediated (oxidative) metabolism of
ertugliflozin is minimal (12%).
Excretion
The mean systemic plasma clearance following an intravenous 100 µg dose was 11.2 L/hr. The mean
elimination half-life in type 2 diabetic patients with normal renal function was estimated to be 16.6 hours
based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin
solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was
eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged
ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion
of glucuronide metabolites and subsequent hydrolysis to parent.
Specific Populations
Patients with Renal Impairment
In a clinical pharmacology study in patients with type 2 diabetes mellitus and mild, moderate, or
severe renal impairment (as determined by eGFR), following a single-dose administration of 15 mg
STEGLATRO, the mean increases in AUC of ertugliflozin were 1.6-, 1.7-, and 1.6-fold, respectively, for
mild, moderate and severe renally impaired patients, compared to subjects with normal renal function.
These increases in ertugliflozin AUC are not considered clinically meaningful. The 24-hour urinary glucose
excretion declined with increasing severity of renal impairment [see Warnings and Precautions (5.3) and
Use in Specific Populations (8.6)]. The plasma protein binding of ertugliflozin was unaffected in patients
with renal impairment.
Patients with Hepatic Impairment
Moderate hepatic impairment (based on the Child-Pugh classification) did not result in an increase in
exposure of ertugliflozin. The AUC of ertugliflozin decreased by approximately 13%, and Cmax decreased
by approximately 21% compared to subjects with normal hepatic function. This decrease in ertugliflozin
exposure is not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh
class C (severe) hepatic impairment. The plasma protein binding of ertugliflozin was unaffected in patients
with moderate hepatic impairment [see Use in Specific Populations (8.7)].
Effects of Age, Body Weight, Gender, and Race
Based on a population pharmacokinetic analysis, age, body weight, gender, and race do not have a
clinically meaningful effect on the pharmacokinetics of ertugliflozin.
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit CYP450 isoenzymes
(CYPs) 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin
was not a time-dependent inhibitor of CYP3A in vitro. Ertugliflozin did not inhibit UGT1A6, 1A9, or 2B7 in
vitro and was a weak inhibitor (IC50 >39 µM) of UGT1A1 and 1A4. Ertugliflozin glucuronides did not inhibit
UGT1A1, 1A4, 1A6, 1A9, or 2B7 in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of
drugs eliminated by these enzymes. Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer
resistance protein (BCRP) transporters and is not a substrate of organic anion transporters (OAT1, OAT3),
organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1,
OATP1B3). Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or
OAT3 transporters, or transporting polypeptides OATP1B1 and OATP1B3, at clinically relevant
concentrations. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered
medications that are substrates of these transporters.
In Vivo Assessment of Drug Interactions
No dose adjustment of STEGLATRO is recommended when coadministered with commonly
prescribed
medicinal
products.
Ertugliflozin
pharmacokinetics
were
similar with
and
without
coadministration of metformin, glimepiride, sitagliptin, and simvastatin in healthy subjects (see Figure 1).
Coadministration of ertugliflozin with multiple doses of 600 mg once-daily rifampin (an inducer of UGT and
CYP enzymes) resulted in approximately 39% and 15% mean reductions in ertugliflozin AUC and Cmax,
12
Reference ID: 5502336
Sitagliptin, 100 mg, single dose
AUC
Cmax
Metformin, 1000 mg, single dose
AUC
Cmax
Glimepiride, 1 mg, single dose
AUC
Cmax
Simvastatin, 40 mg, single dose
AUC
Cmax
Rifampin, 600 mg, once daily
AUC
Cmax -
Geometric mean ratio (90% Cl)
1 02.27 (99. 72-1 04.89)
98.18 (91 .20-1 05. 70)
100.34 (97.43-103.34)
97.14 (88.77-1 06.30)
102.11 (97.19-107.27)
98.20 (92.17-1 04.63)
102.40 (99.57-105.31 )
1 05.16 (98.26-112.54)
61.16 (57.22-65.37)
84.62 (74.17-96.53)
50
75
100
125
150
Relative to ertugliflozin alone(%)
All ertugliflozin doses were given as 15 mg single dose
respectively, relative to ertugliflozin administered alone. These changes in exposure are not considered
clinically relevant. Ertugliflozin had no clinically relevant effect on the pharmacokinetics of metformin,
glimepiride, sitagliptin, and simvastatin when coadministered in healthy subjects (see Figure 2).
Physiologically-based PK (PBPK) modeling suggests that coadministration of mefenamic acid (UGT
inhibitor) may increase the AUC and Cmax of ertugliflozin by 1.51- and 1.19-fold, respectively. These
predicted changes in exposure are not considered clinically relevant.
Figure 1: Effects of Other Drugs on the Pharmacokinetics of Ertugliflozin
13
Reference ID: 5502336
Geometric mean ratio (90% Cl)
Sitagliptin , 100 mg, single dose
AUG
·-
1 01 .67 (9B.40-1 05.04)
Gmax
101 .6B (91 .65-112.BO)
Metformin, 1000 mg, single dose
AUG
100.94 (90.62-112.44)
Gmax
-
94.00 (B2.94-106.55)
Glimepiride, 1 mg, single dose
AUG
-
109.BO (9B.14-122.B6)
Gmax
97.39 (71.07-133.46}
Simvastatin, 40 mg, single dose
AUG
-
123.B3 (90.92-16B.66)
Gmax
119.05 (97.22-145.77)
Simvastatin Acid
AUG
130.46 (1 OB.32-157.13}
(Administered as Simvastatin)
Gmax
115.66 (95.74-139.71}
100
150
200
Relative to concomitant medication alone (%)
All ertugliflozin doses were given as 15 mg single dose
Figure 2: Effects of Ertugliflozin on the Pharmacokinetics of Other Drugs
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity was evaluated in CD-1 mice and Sprague-Dawley rats. In the mouse study,
ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day for up to 97 weeks in
males and 102 weeks in females. There were no ertugliflozin-related neoplastic findings at doses up to
40 mg/kg/day (approximately 50 times human exposure at the maximum recommended human dose
[MRHD] of 15 mg/day based on AUC). In the rat study, ertugliflozin was administered by oral gavage at
doses of 1.5, 5, and 15 mg/kg/day for up to 92 weeks in females and 104 weeks in males. Ertugliflozin
related neoplastic findings included an increased incidence of adrenal medullary pheochromocytoma (PCC)
in male rats at 15 mg/kg/day. Although the molecular mechanism remains unknown, this finding may be
related to carbohydrate malabsorption leading to altered calcium homeostasis, which has been associated
with PCC development in rats and has unclear relevancy to human risk. The no-observed-effect level
(NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human exposure at the MRHD of
15 mg/day, based on AUC).
Mutagenesis
Ertugliflozin was not mutagenic or clastogenic with or without metabolic activation in the microbial
reverse mutation, in vitro cytogenetic (human lymphocytes), and in vivo rat micronucleus assays.
Impairment of Fertility
In the rat fertility and embryonic development study, male and female rats were administered
ertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day
(approximately 480 and 570 times male and female human exposures, respectively, at the MRHD of
15 mg/day based on AUC comparison).
14
Reference ID: 5502336
14
CLINICAL STUDIES
14.1 Glycemic Control Trials in Patients with Type 2 Diabetes Mellitus
STEGLATRO has been studied as monotherapy and in combination with metformin HCl, sitagliptin,
a sulfonylurea, insulin (with or without metformin HCl), metformin HCl plus sitagliptin, metformin HCl plus a
sulfonylurea and compared to a sulfonylurea (glimepiride). STEGLATRO has also been studied in patients
with type 2 diabetes mellitus and moderate renal impairment.
In patients with type 2 diabetes mellitus treatment with STEGLATRO reduced hemoglobin A1c
(HbA1c) compared to placebo. Reduction in HbA1c was generally similar across subgroups defined by age,
sex, race, geographic region, baseline body mass index (BMI), and duration of type 2 diabetes mellitus.
Monotherapy
A total of 461 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and
10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, 26-week, placebo-
controlled study (NCT01958671) to evaluate the efficacy and safety of STEGLATRO monotherapy. These
patients, who were either treatment naïve or not receiving any background antihyperglycemic treatment ≥8
weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo,
STEGLATRO 5 mg, or STEGLATRO 15 mg, administered once daily.
At Week 26, treatment with STEGLATRO at 5 mg or 15 mg orally once daily provided statistically
significant reductions in HbA1c compared to placebo. STEGLATRO also resulted in a greater proportion of
patients achieving an HbA1c <7% compared with placebo (see Table 4 and Figure 3).
Table 4: Results at Week 26 from a Placebo-Controlled Monotherapy Study of STEGLATRO in
Patients with Type 2 Diabetes Mellitus*
Placebo
STEGLATRO 5 mg
STEGLATRO 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean †, 95% CI)
N = 153
8.1
-0.2
N = 155
8.2
-0.7
-0.6‡ (-0.8, -0.4)
N = 151
8.4
-0.8
-0.7‡ (-0.9, -0.4)
Patients [N (%)] with HbA1c <7%
26 (16.9)
47 (30.1)
59 (38.8)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 150
180.2
-11.6
N = 151
180.9
-31.0
-19.4‡ (-27.6, -11.2)
N = 149
179.1
-36.4
-24.8‡ (-33.2, -16.4)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary
HbA1c endpoint was missing for 23%, 11%, and 16% of patients, and during the trial, rescue medication was initiated by 25%,
2%, and 3% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 26
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.1%, -0.8%, and -1.0% for placebo,
STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication, and baseline eGFR.
‡
p<0.001 compared to placebo.
The mean baseline body weight was 94.2 kg, 94.0 kg, and 90.6 kg in the placebo, STEGLATRO
5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26
were -1.0 kg, -3.0 kg, and -3.1 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups,
respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -2.0 kg (-2.8, -1.2) and for
STEGLATRO 15 mg was -2.1 kg (-2.9, -1.3).
15
Reference ID: 5502336
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0.1
GI
0.0
C
ai
-0.1
Ill
RS
-0.2
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E
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GI
-0.4
en
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RS
-0.5
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C
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o Placebo
♦ Ertugliflozin 5 mg
'f' Ertugliflozin 15 mg
BL
6
12
18
26
26-MI
Week
Placebo (N)
153
137
124
105
89
Ertugliflozin 5 mg (N)
155
143
140
140
136
Ertugliflozin 15 mg (N)
151
144
142
134
123
Figure 3: HbA1c (%) Change Over Time in a 26-Week Placebo-Controlled Monotherapy Study of
STEGLATRO in Patients with Type 2 Diabetes Mellitus*
* Data to the left of the vertical line are observed means (non-model-based) excluding values occurring post glycemic rescue. Data
to the right of the vertical line represent the final Week 26 data, including all values regardless of use of glycemic rescue medication
and use of study drug, with missing Week 26 values imputed using multiple imputation (26-MI) with a mean equal to the baseline
value of the patient (see Table 4).
Combination Therapy
Add-on Combination Therapy with Metformin HCl
A total of 621 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and
10.5%) on metformin HCl monotherapy (≥1,500 mg/day for≥8 weeks) participated in a randomized, double-
blind, multi-center, 26-week, placebo-controlled study (NCT02033889) to evaluate the efficacy and safety
of STEGLATRO in combination with metformin HCl. Patients entered a 2-week, single-blind, placebo run-
in, and were randomized to placebo, STEGLATRO 5 mg, or STEGLATRO 15 mg administered once daily
in addition to continuation of background metformin HCl therapy.
At Week 26, treatment with STEGLATRO at 5 mg or 15 mg orally once daily provided statistically
significant reductions in HbA1c compared to placebo. STEGLATRO also resulted in a greater proportion of
patients achieving an HbA1c <7% compared to placebo (see Table 5).
16
Reference ID: 5502336
Table 5: Results at Week 26 from a Placebo-Controlled Study for STEGLATRO Used in
Combination with Metformin HCl in Patients with Type 2 Diabetes Mellitus*
Placebo
STEGLATRO 5 mg
STEGLATRO 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 207
8.2
-0.2
N = 205
8.1
-0.7
-0.5‡ (-0.7, -0.4)
N = 201
8.1
-0.9
-0.7‡ (-0.9, -0.5)
Patients [N (%)] with HbA1c <7%
38 (18.4)
74 (36.3)
87 (43.3)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 202
169.1
-8.7
N = 199
168.1
-30.3
-21.6‡ (-27.8, -15.5)
N = 201
167.9
-40.9
-32.3‡ (-38.5, -26.0)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary
HbA1c endpoint was missing for 12%, 6%, and 9% of patients, and during the trial, rescue medication was initiated by 18%,
3%, and 1% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 26
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.7%, and -1.0% for placebo,
STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication, menopausal status and
baseline eGFR.
‡
p<0.001 compared to placebo.
The mean baseline body weight was 84.5 kg, 84.9 kg, and 85.3 kg in the placebo, STEGLATRO
5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26
were -1.4 kg, -3.2 kg, and -3.0 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups,
respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -1.8 kg (-2.4, -1.2) and for
STEGLATRO 15 mg was -1.7 kg (-2.2, -1.1).
The mean baseline systolic blood pressure was 129.3 mmHg, 130.5 mmHg, and 130.2 mmHg in the
placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from
baseline to Week 26 were -1.8 mmHg, -5.1 mmHg, and -5.7 mmHg in the placebo, STEGLATRO 5 mg,
and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO
5 mg was -3.3 mmHg (-5.6, -1.1) and for STEGLATRO 15 mg was -3.8 mmHg (-6.1, -1.5).
Active Controlled Study versus Glimepiride as Add-on Combination Therapy with Metformin HCl
A total of 1,326 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7%
and 9%) on metformin HCl monotherapy participated in a randomized, double-blind, multi-center, 52-week,
active comparator controlled study (NCT01999218) to evaluate the efficacy and safety of STEGLATRO in
combination with metformin HCl. These patients, who were receiving metformin HCl monotherapy
(≥1,500 mg/day for ≥8 weeks), entered a 2-week, single-blind, placebo run-in period and were randomized
to glimepiride, STEGLATRO 5 mg, or STEGLATRO 15 mg administered orally once daily in addition to
continuation of background metformin HCl therapy. Glimepiride was initiated at 1 mg/day and titrated up to
a maximum dose of 6 or 8 mg/day (depending on maximum approved dose in each country) or a maximum
tolerated dose or down-titrated to avoid or manage hypoglycemia. The mean daily dose of glimepiride was
3.0 mg.
STEGLATRO 15 mg was non-inferior to glimepiride after 52 weeks of treatment. (See Table 6.)
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Table 6: Results at Week 52 from an Active-Controlled Study Comparing STEGLATRO to
Glimepiride as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled
on Metformin HCl*
Glimepiride
STEGLATRO 5 mg
STEGLATRO 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from glimepiride (LS mean†, 95% CI)
N = 437
7.8
-0.6
N = 447
7.8
-0.5
0.2‡ (0.0, 0.3)
N = 440
7.8
-0.5
0.1‡ (-0.0, 0.2)
Patients [N (%)] with HbA1c <7%
208 (47.7)
177 (39.5)
186 (42.2)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 52, the primary
HbA1c endpoint was missing for 15%, 20%, and 16% of patients and during the trial, rescue medication was initiated by 3%,
6%, and 4% of patients randomized to glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing
Week 52 measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results
include measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication
and had values measured at 52 weeks, the mean changes from baseline for HbA1c were -0.8%, -0.6%, and -0.7% for
glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR.
‡
Non-inferiority is declared when the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is less
than 0.3%.
The mean baseline body weight was 86.8 kg, 87.9 kg, and 85.6 kg in the glimepiride, STEGLATRO
5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 52 were
0.6 kg, -2.6 kg, and -3.0 kg in the glimepiride, STEGLATRO 5 mg, and STEGLATRO 15 mg groups,
respectively. The difference from glimepiride (95% CI) for STEGLATRO 5 mg was -3.2 kg (-3.7, -2.7) and
for STEGLATRO 15 mg was -3.6 kg (-4.1, -3.1).
In Combination with Sitagliptin versus STEGLATRO Alone and Sitagliptin Alone, as Add-on to Metformin
HCl
A total of 1,233 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c
between 7.5% and 11%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a
randomized, double-blind, 26-week, active controlled study (NCT02099110) to evaluate the efficacy and
safety of STEGLATRO 5 mg or 15 mg orally once daily in combination with sitagliptin 100 mg orally once
daily compared to the individual components. Patients were randomized to one of five treatment arms:
STEGLATRO 5 mg, STEGLATRO 15 mg, sitagliptin 100 mg, STEGLATRO 5 mg + sitagliptin 100 mg, or
STEGLATRO 15 mg + sitagliptin 100 mg.
At Week 26, STEGLATRO 5 mg or 15 mg + sitagliptin 100 mg provided statistically significantly
greater reductions in HbA1c compared to STEGLATRO (5 mg or 15 mg) alone or sitagliptin 100 mg alone.
The mean change from baseline in HbA1c was -1.4% for STEGLATRO 5 mg or 15 mg + sitagliptin 100 mg
versus -1.0%, for STEGLATRO 5 mg, STEGLATRO 15 mg, or sitagliptin 100 mg, respectively. More
patients receiving STEGLATRO 5 mg or 15 mg + sitagliptin 100 mg achieved an HbA1c <7% (53.3% and
50.9%, for STEGLATRO 5 mg or 15 mg, respectively, + sitagliptin 100 mg) compared to the individual
components (29.3%, 33.7%, and 38.5% for STEGLATRO 5 mg, STEGLATRO 15 mg, or sitagliptin 100 mg,
respectively).
Add-on Combination Therapy with Metformin HCl and Sitagliptin
A total of 463 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and
10.5%) on metformin HCl (≥1,500 mg/day for ≥8 weeks) and sitagliptin 100 mg once daily participated in a
randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT02036515) to evaluate the
efficacy and safety of STEGLATRO. Patients entered a 2-week, single-blind, placebo run-in period and
were randomized to placebo, STEGLATRO 5 mg, or STEGLATRO 15 mg orally once daily.
18
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At Week 26, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant
reductions in HbA1c. STEGLATRO also resulted in a higher proportion of patients achieving an HbA1c
<7% compared to placebo (see Table 7).
Table 7: Results at Week 26 from an Add-on Study of STEGLATRO in Combination with Metformin
HCl and Sitagliptin in Patients with Type 2 Diabetes Mellitus*
Placebo
STEGLATRO 5 mg
STEGLATRO 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 152
8.0
-0.2
N = 155
8.1
-0.7
-0.5‡ (-0.7, -0.3)
N = 152
8.0
-0.8
-0.6‡ (-0.8, -0.4)
Patients [N (%)] with HbA1c <7%
31 (20.2)
54 (34.6)
64 (42.3)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 152
169.6
-6.5
N = 156
167.7
-25.7
-19.2‡ (-26.8, -11.6)
N = 152
171.7
-32.1
-25.6‡ (-33.2, -18.0)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary
HbA1c endpoint was missing for 10%, 11%, and 7% of patients and during the trial, rescue medication was initiated by 16%,
1%, and 2% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Missing Week 26
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.8%, and -0.9% for placebo,
STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR.
‡
p<0.001 compared to placebo.
The mean baseline body weight was 86.5 kg, 87.6 kg, and 86.6 kg in the placebo, STEGLATRO
5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 26
were -1.0 kg, -3.0 kg, and -2.8 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups,
respectively. The difference from placebo (95% CI) for STEGLATRO 5 mg was -1.9 kg (-2.6, -1.3) and for
STEGLATRO 15 mg was -1.8 kg (-2.4, -1.2).
The mean baseline systolic blood pressure was 130.2 mmHg, 132.1 mmHg, and 131.6 mmHg in the
placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from
baseline to Week 26 were -0.2 mmHg, -3.8 mmHg, and -4.5 mmHg in the placebo, STEGLATRO 5 mg,
and STEGLATRO 15 mg groups, respectively. The difference from placebo (95% CI) for STEGLATRO
5 mg was -3.7 mmHg (-6.1, -1.2) and for STEGLATRO 15 mg was -4.3 mmHg (-6.7, -1.9).
Initial Combination Therapy with Sitagliptin
A total of 291 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 8% and
10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, placebo-controlled
26-week study (NCT02226003) to evaluate the efficacy and safety of STEGLATRO in combination with
sitagliptin. These patients, who were not receiving any background antihyperglycemic treatment for ≥8
weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo,
STEGLATRO 5 mg or STEGLATRO 15 mg, in combination with sitagliptin (100 mg) orally once daily.
At Week 26, treatment with STEGLATRO 5 mg and 15 mg in combination with sitagliptin at 100 mg
daily provided statistically significant reductions in HbA1c compared to placebo. STEGLATRO 5 mg and
15 mg in combination with sitagliptin at 100 mg daily also resulted in a higher proportion of patients
achieving an HbA1c <7% and greater reductions in FPG compared with placebo.
Add-on Combination Therapy with Insulin (with or without Metformin HCl)
In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of
VERTIS CV (eValuation of ERTugliflozin efficacy and Safety CardioVascular, NCT01986881, study details
see 14.2), a total of 1,065 patients with type 2 diabetes mellitus and established atherosclerotic
19
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cardiovascular disease with inadequate glycemic control (HbA1c between 7% and 10.5%) on background
therapy of insulin ≥20 units/day (59% also on metformin HCl ≥1,500 mg/day) were randomized to placebo,
STEGLATRO 5 mg or STEGLATRO 15 mg orally once daily treatment.
At Week 18, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant
reductions in HbA1c compared to placebo (see Table 8).
Table 8: Results at Week 18 from an Add-on Study of STEGLATRO in Combination with Insulin
(with or without Metformin HCl) in Patients with Type 2 Diabetes Mellitus*
Placebo
STEGLATRO 5 mg
STEGLATRO 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 346
8.4
-0.2 (0.05)
N = 346
8.4
-0.7 (0.05)
-0.5‡ (-0.6, -0.4)
N = 367
8.4
-0.7 (0.05)
-0.5‡ (-0.7, -0.4)
Patients [N (%)] with HbA1c <7%§
37 (10.7)
79 (22.8)
81 (22.1)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean† , SE)
†
Difference from placebo (LS mean , 95% CI)
N = 343
167.4
-6.3 (2.91)
N = 346
173.8
-25.6 (2.90)
-19.2‡ (-26.8, -11.6)
N = 368
175.4
-29.8 (2.86)
-23.4‡ (-30.9, -16.0)
* N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 18, the primary
HbA1c endpoint was missing for 10%, 9%, and 12% of patients and during the trial, rescue medication was initiated by 12%,
7%, and 6% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Results include
measurements collected after initiation of rescue medication. Prior to Week 18, background antidiabetic medication was held
stable. Missing Week 18 measurements were imputed using multiple imputation with a mean equal to the baseline value of the
patient (Return to Baseline analysis).
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, insulin stratum, and baseline eGFR.
‡
p<0.001 compared to placebo.
§
Missing values imputed as not meeting the <7% criterion.
SE: standard error.
The mean baseline body weights were 93.3 kg, 93.8 kg, and 92.1 kg in the placebo, STEGLATRO
5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were
- 0.2 kg, -1.6 kg, and -1.9 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups,
respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg were - 1.4 kg (- 1.9, - 0.9) and
for STEGLATRO 15 mg was -1.6 kg (-2.1, -1.1).
The mean baseline systolic blood pressures were 134.0 mmHg, 135.6 mmHg, and 133.7 mmHg in
the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from
baseline to Week 18 were 0.7 mmHg, -2.2 mmHg, and -1.7 mmHg in the placebo, STEGLATRO 5 mg, and
STEGLATRO 15 mg groups, respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg
was – 2.9 mmHg (-4.9, -1.0) and for STEGLATRO 15 mg were -2.5 mmHg (- 4.4, - 0.5).
Add-on Combination Therapy with Metformin HCl and Sulfonylurea
In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of
VERTIS CV (NCT01986881, study details see 14.2), a total of 330 patients with type 2 diabetes mellitus
and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between
7% and 10.5%) with background therapy of metformin HCl ≥1,500 mg/day and a sulfonylurea (SU) were
randomized to placebo, STEGLATRO 5 mg or STEGLATRO 15 mg orally once daily treatment.
At Week 18, treatment with STEGLATRO at 5 mg or 15 mg daily provided statistically significant
reductions in HbA1c compared to placebo (see Table 9).
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Reference ID: 5502336
Table 9: Results at Week 18 from an Add-on Study of STEGLATRO in Combination with Metformin
HCl and a SU in Patients with Type 2 Diabetes Mellitus*
Placebo
STEGLATRO 5 mg
STEGLATRO 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 116
8.3
-0.3 (0.08)
N = 99
8.4
-0.8 (0.09)
-0.6‡ (-0.8, -0.3)
N = 113
8.3
-0.9 (0.08)
-0.7‡ (-0.9, -0.4)
Patients [N (%)] with HbA1c <7%§
17 (14.7)
39 (39.4)
38 (33.6)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 117
177.3
-3.5 (3.65)
N = 99
183.5
-31.3 (3.87)
-27.9‡ (-37.8, -17.9)
N = 113
174.0
-33.0 (3.67)
-29.5‡ (-39.0, -19.9)
* N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 18, the primary
HbA1c endpoint was missing for 9%, 8%, and 6% of patients and during the trial, rescue medication was initiated by 10%, 7%,
and 3% of patients randomized to placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg, respectively. Results include
measurements collected after initiation of rescue medication. Missing Week 18 measurements were imputed using multiple
imputation with a mean equal to the baseline value of the patient (Return to Baseline analysis).
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value and baseline eGFR.
‡
p<0.001 compared to placebo.
§
Missing values imputed as not meeting the <7% criterion.
SE: standard error
The mean baseline body weights were 90.5 kg, 92.1 kg, and 92.9 kg in the placebo, STEGLATRO
5 mg, and STEGLATRO 15 mg groups, respectively. The mean changes from baseline to Week 18 were
- 0.6 kg, -2.0 kg, and - 2.2 kg in the placebo, STEGLATRO 5 mg, and STEGLATRO 15 mg groups,
respectively. The differences from placebo (95% CI) for STEGLATRO 5 mg were - 1.4 kg (- 2.2, - 0.7) and
for STEGLATRO 15 mg was - 1.6 kg (- 2.3, - 0.9).
Use in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment
26-Week Placebo-Controlled Study
The efficacy of STEGLATRO was assessed in a multicenter, randomized, double-blind, placebo-
controlled study (NCT01986855) of patients with type 2 diabetes mellitus and moderate renal impairment
(468 patients with eGFR ≥30 to <60 mL/min/1.73 m2). In this study, 202 patients exposed to STEGLATRO
(5 mg or 15 mg) had an eGFR between 45 and 60 mL/min/1.73 m2 and 111 patients exposed to
STEGLATRO (5 mg or 15 mg orally once daily) had an eGFR between 30 and 45 mL/min/1.73 m2. The
mean duration of diabetes for the study population was approximately 14 years, and the majority of patients
were receiving background insulin (55.9%) and/or sulfonylurea (40.3%) therapy. Approximately 50% had a
history of cardiovascular disease or heart failure.
STEGLATRO did not show efficacy in this study. The HbA1c reductions from baseline to Week 26
were not significantly different between placebo and STEGLATRO 5 mg or 15 mg [see Use in Specific
Populations (8.6)].
14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Established
Cardiovascular Disease
The effect of STEGLATRO on cardiovascular risk in adult patients with type 2 diabetes and
established atherosclerotic cardiovascular disease
was
evaluated
in
the VERTIS
CV
study
(NCT01986881), a multicenter, multi-national, randomized, double-blind, placebo-controlled, event-driven
trial. The study compared the risk of experiencing a major adverse cardiovascular event (MACE) between
STEGLATRO and placebo when these were added to and used concomitantly with standard of care
treatments for diabetes and atherosclerotic cardiovascular disease.
A total of 8,246 patients were randomized to placebo (N=2,747), oral once daily STEGLATRO 5 mg
(N=2,752) or oral once daily STEGLATRO 15 mg (N=2,747) and followed for a median of 3 years.
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Approximately 88% of the study population was White, 6% Asian, and 3% Black or African American. The
mean age was 64 years and approximately 70% were male.
All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c
greater than or equal to 7%). The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA1c
at baseline was 8.2% and the mean eGFR was 76 mL/min/1.73 m2. At baseline, patients were treated with
one (32%) or more (67%) antidiabetic medications including biguanides (metformin HCl) (76%), insulin
(47%), sulfonylureas (41%) DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%).
Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline
including: a documented history of coronary artery disease (76%), cerebrovascular disease (23%) or
peripheral artery disease (19%). Approximately 24% patients had a history of heart failure (HF). At baseline,
the mean systolic blood pressure was 133 mmHg, the mean diastolic blood pressure was 77 mmHg, the
mean LDL was 89 mg/dL, and the mean HDL was 44 mg/dL. At baseline, approximately 81% of patients
were treated with renin angiotensin system inhibitors, 69% with beta-blockers, 43% with diuretics, 82% with
statins, 4% with ezetimibe, and 89% with antiplatelet agents.
The primary endpoint in VERTIS CV was the time to first occurrence of MACE. A major adverse
cardiovascular event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial
infarction (MI) or a nonfatal stroke. The statistical analysis plan pre-specified that the 5 and 15 mg doses
would be combined for the analysis. A Cox proportional hazards model was used to test for non-inferiority
against the pre-specified risk margin of 1.3 for the hazard ratio of MACE. Type-1 error was controlled across
multiple tests using a hierarchical testing strategy.
The incidence rate of MACE was similar between the STEGLATRO-treated and placebo-treated
patients. The estimated hazard ratio of MACE associated with STEGLATRO relative to placebo was 0.97
with 95.6% confidence interval (0.85, 1.11). The upper bound of this confidence interval excluded a risk
larger than 1.3 (Table 10). Results for the individual 5 mg and 15 mg doses were consistent with results for
the combined dose group.
Table 10: Analysis of MACE and its Components from the VERTIS-CV Study*
Placebo (N=2747)
STEGLATRO (N=5499)
Event Rate
Event Rate
Hazard Ratio vs
Endpoint†
N (%)
N (%)
(per 100
(per 100
Placebo
person-years)
person-years)
(CI) ‡
MACE (CV death, non-fatal MI,
327 (11.9)
4.0
653 (11.9)
3.9
0.97
or non-fatal stroke) Composite
(0.85, 1.11)
Components of Composite Endpoint
Non-fatal MI
148 (5.4)
1.6
310 (5.6)
1.7
1.04
(0.86, 1.27)
Non-fatal Stroke
78 (2.8)
0.8
157 (2.9)
0.8
1.00
(0.76, 1.32)
CV death
184 (6.7)
1.9
341 (6.2)
1.8
0.92
(0.77, 1.11)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction.
* Intent-to-treat analysis set.
† MACE was evaluated in subjects who took at least one dose of study medication and, for subjects who discontinued study medication
prior to the end of the study, censored events that occurred more than 365 days after the last dose of study medication. Other
endpoints were evaluated using all randomized subjects and events that occurred any time after the first dose of study medication
until the last contact date. The total number of first events was analyzed for each endpoint.
‡ HR and CI are based on Cox proportional hazards regression model, stratified by cohorts. For MACE a 95.6% CI is presented, for
other endpoints a 95% CI is presented.
16
HOW SUPPLIED/STORAGE AND HANDLING
STEGLATRO (ertugliflozin) tablets are available as follows:
Strength
Description
How Supplied
NDC
5 mg
tablets
pink, triangular-shaped, biconvex
tablets, with “701” debossed on one
side and plain on the other side
unit-of-use bottles of 30
0006-5363-03
unit-of-use bottles of 90
0006-5363-06
22
Reference ID: 5502336
15 mg
red, triangular-shaped, biconvex
unit-of-use bottles of 30
0006-5364-03
tablets
tablets, with “702” debossed on one
side and plain on the other side
unit-of-use bottles of 90
0006-5364-06
Store at 20°C-25°C (68°F-77°F), excursions permitted between 15°C-30°C (between 59°F-86°F) [see
USP Controlled Room Temperature]. Protect from moisture. Store in a dry place.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Inform patients that STEGLATRO can cause potentially fatal ketoacidosis and that type 2 diabetes
mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.
Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses,
infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms
of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform
patients that blood glucose may be normal even in the presence of ketoacidosis.
Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct
patients to discontinue STEGLATRO and seek medical attention immediately [see Warnings and
Precautions (5.1)].
Lower Limb Amputation
Inform patients of the potential for an increased risk of amputations. Counsel patients about the
importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores
or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or
symptoms develop [see Warnings and Precautions (5.2)].
Volume Depletion
Inform patients that symptomatic hypotension may occur with STEGLATRO and advise them to
contact their doctor if they experience such symptoms [see Warnings and Precautions (5.3)]. Inform
patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.
Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them with
information on the symptoms of urinary tract infections. Advise them to seek medical advice if such
symptoms occur [see Warnings and Precautions (5.4)].
Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogue
Inform patients that the incidence of hypoglycemia may increase when STEGLATRO is used with
insulin or an insulin secretagogue. Educate patients or caregivers on the signs and symptoms of
hypoglycemia [see Warnings and Precautions (5.5)].
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with
SGLT2 inhibitors. Counsel patients to promptly seek medical attention if they develop pain or tenderness,
redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever
above 100.4°F or malaise [see Warnings and Precautions (5.6)].
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with information on
the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek
medical advice [see Warnings and Precautions (5.7)].
Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)
Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur,
especially in uncircumcised males. Provide them with information on the signs and symptoms of balanitis
23
Reference ID: 5502336
and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options
and when to seek medical advice [see Warnings and Precautions (5.7)].
Fetal Toxicity
Advise pregnant patients of the potential risk to a fetus with treatment with STEGLATRO. Instruct
patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see
Use in Specific Populations (8.1)].
Lactation
Advise patients that use of STEGLATRO is not recommended while breastfeeding [see Use in
Specific Populations (8.2)].
Laboratory Tests
Due to its mechanism of action, inform patients that their urine will test positive for glucose while
taking STEGLATRO.
Missed Dose
Instruct patients to take STEGLATRO only as prescribed. If a dose is missed, it should be taken as
soon as the patient remembers. Advise patients not to double their next dose.
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA
For patent information: www.msd.com/research/patent
Copyright © 2017-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved.
uspi-mk8835-t-2412r010
24
Reference ID: 5502336
Medication Guide
STEGLATRO® [steh-GLA-troh]
(ertugliflozin)
tablets, for oral use
Read this Medication Guide carefully before you start taking STEGLATRO and each time you get a
refill. There may be new information. This information does not take the place of talking with your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about STEGLATRO?
STEGLATRO may cause serious side effects, including:
•
Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1
diabetes and other ketoacidosis. STEGLATRO can cause ketoacidosis that can be life-
threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated
in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type
2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis
can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet
high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or
miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume
depletion), or who have surgery. Ketoacidosis can happen even if your blood sugar is less than
250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or
blood.
Stop taking STEGLATRO and call your healthcare provider or get medical help right away
if you get any of the following. If possible, check for ketones in your urine or blood, even
if your blood sugar is less than 250 mg/dL:
o nausea
o tiredness
o vomiting
o
trouble breathing
o stomach-area (abdominal) pain o
ketones in your urine or blood
•
Amputations. STEGLATRO may increase your risk of lower limb amputations.
You may be at a higher risk of lower limb amputation if you:
o have a history of amputation
o have had blocked or narrowed blood vessels, usually in your leg
o have damage to the nerves (neuropathy) in your leg
o have had diabetic foot ulcers or sores
Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers,
or infections in your leg or foot. Your healthcare provider may decide to stop your STEGLATRO
for a while if you have any of these signs or symptoms. Talk to your healthcare provider about proper
foot care.
• Dehydration. STEGLATRO can cause some people to become dehydrated (the loss of body
water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak,
especially when you stand up (orthostatic hypotension). There have been reports of sudden
worsening of kidney function in people who are taking STEGLATRO.
You may be at risk of dehydration if you:
o
take medicines to lower your blood pressure, including water pills (diuretics)
o
are on a low sodium (salt) diet
o
have kidney problems
o
are 65 years of age or older
Talk to your healthcare provider about what you can do to prevent dehydration including how much
fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the
amount of food or liquid you drink, for example if you are sick or cannot eat, or you start to lose liquids
from your body, for example from vomiting, diarrhea or being in the sun too long.
Reference ID: 5502336
• Vaginal yeast infection. Symptoms of a vaginal yeast infection include:
o
vaginal odor
o
white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)
o
vaginal itching
• Yeast infection of the penis (balanitis or balanoposthitis). Swelling of an uncircumcised penis
may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms
of yeast infection of the penis include:
o
redness, itching, or swelling of the penis
o
rash of the penis
o
foul smelling discharge from the penis
o
pain in the skin around your penis
Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the
vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal
medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal
medicine and your symptoms do not go away.
What is STEGLATRO?
• STEGLATRO is a prescription medicine used in adults with type 2 diabetes to improve blood sugar
(glucose) control along with diet and exercise.
• STEGLATRO is not recommended to decrease blood sugar (glucose) in people with type 1
diabetes.
• It is not known if STEGLATRO is safe and effective in children under 18 years of age.
Who should not take STEGLATRO?
Do not take STEGLATRO if you:
•
are allergic to ertugliflozin or any of the ingredients in STEGLATRO. See the end of this
Medication Guide for a list of ingredients in STEGLATRO. Symptoms of a serious allergic
reaction to STEGLATRO may include:
o skin rash
o
raised red patches on your skin (hives)
o
swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or
swallowing
If you have any of these symptoms, stop taking STEGLATRO and call your healthcare provider
right away or go to the nearest hospital emergency room.
Before you take STEGLATRO, tell your healthcare provider about all of your medical
conditions, including if you:
•
have type 1 diabetes or have had diabetic ketoacidosis.
•
have a decrease in your insulin dose.
•
have a serious infection.
•
have a history of infection of the vagina or penis.
•
have a history of amputation.
•
have had blocked or narrowed blood vessels, usually in your leg.
•
have damage to the nerves (neuropathy) in your leg.
•
have had diabetic foot ulcers or sores.
•
have kidney problems.
•
have liver problems.
•
have a history of urinary tract infections or problems with urination.
•
are on a low sodium (salt) diet. Your healthcare provider may change your diet or your dose.
•
are going to have surgery. Your healthcare provider may stop your STEGLATRO before you have
surgery. Talk to your healthcare provider if you are having surgery about when to stop taking
STEGLATRO and when to start it again.
2
Reference ID: 5502336
•
are eating less or there is a change in your diet.
•
are dehydrated.
•
have or have had problems with your pancreas, including pancreatitis or surgery on your
pancreas.
• drink alcohol very often or drink a lot of alcohol in the short term (“binge” drinking).
•
have ever had an allergic reaction to STEGLATRO.
•
are pregnant or plan to become pregnant. STEGLATRO may harm your unborn baby. If you
become pregnant while taking STEGLATRO, your healthcare provider may switch you to a
different medicine to control your blood sugar. Talk to your healthcare provider about the best way
to control your blood sugar if you plan to become pregnant or while you are pregnant.
•
are breastfeeding or plan to breastfeed. It is not known if STEGLATRO passes into your breast
milk. You should not breastfeed if you take STEGLATRO.
Tell your healthcare provider about all of the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
STEGLATRO may affect the way other medicines work, and other medicines may affect how
STEGLATRO works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist
when you get a new medicine.
How should I take STEGLATRO?
•
Take STEGLATRO by mouth 1 time in the morning each day, with or without food, exactly as your
healthcare provider tells you to take it.
•
Your healthcare provider may tell you to take STEGLATRO along with other diabetes medicines.
Low blood sugar can happen more often when STEGLATRO is taken with certain other diabetes
medicines. See “What are the possible side effects of STEGLATRO?”.
•
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip
the missed dose and take the medicine at the next regularly scheduled time. Do not take
2 doses of STEGLATRO at the same time. Talk with your healthcare provider if you have
questions about a missed dose.
•
If you take too much STEGLATRO, call your healthcare provider or go to the nearest hospital
emergency room right away.
•
When your body is under some types of stress, such as fever, trauma (such as a car accident),
infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare
provider right away if you have any of these conditions and follow your healthcare provider’s
instructions.
•
STEGLATRO will cause your urine to test positive for glucose.
•
Your healthcare provider may do certain blood tests before you start STEGLATRO and during
treatment as needed. Your healthcare provider may change your dose of STEGLATRO based on
the results of your blood tests.
What are the possible side effects of STEGLATRO?
STEGLATRO may cause serious side effects, including:
See “What is the most important information I should know about STEGLATRO?”
•
Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization
have happened in people who are taking STEGLATRO. Tell your healthcare provider if you have
any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine,
a need to urinate often, the need to urinate right away, pain in the lower part of your stomach
(pelvis), or blood in the urine. Sometimes people may also have a fever, back pain, nausea, or
vomiting.
3
Reference ID: 5502336
•
Low blood sugar (hypoglycemia). If you take STEGLATRO with another medicine that can
cause low blood sugar such as a sulfonylurea or insulin, your risk of getting low blood sugar is
higher. The dose of your sulfonylurea or insulin may need to be lowered while you take
STEGLATRO. Signs and symptoms of low blood sugar may include:
o headache
o drowsiness
o
weakness
o confusion
o dizziness
o
sweating
o hunger
o
fast heartbeat
o
irritability
o
shaking or feeling jittery
•
A rare but serious bacterial infection that causes damage to the tissue under the skin
(necrotizing fasciitis) in the area between and around the anus and genitals (perineum).
Necrotizing fasciitis of the perineum has happened in women and men who take medicines that
lower blood sugar in the same way as STEGLATRO. Necrotizing fasciitis of the perineum may
lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical
attention immediately if you have fever above 100.4ºF or you are feeling very weak, tired
or uncomfortable (malaise) and you develop any of the following symptoms in the area
between and around your anus and genitals:
o pain or tenderness
o swelling
o
redness of skin (erythema)
•
Serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking
STEGLATRO and call your healthcare provider right away or go to the nearest hospital emergency
room. See “Who should not take STEGLATRO?”. Your healthcare provider may give you a
medicine for your allergic reaction and prescribe a different medicine for your diabetes
The most common side effects of STEGLATRO include:
•
vaginal yeast infections and yeast infections of the penis (See “What is the most important
information I should know about STEGLATRO?”)
•
changes in urination, including urgent need to urinate more often, in larger amounts, or at night
These are not all the possible side effects of STEGLATRO.
Call your healthcare provider for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store STEGLATRO?
•
Store STEGLATRO at room temperature between 68°F to 77°F (20°C to 25°C).
•
Keep STEGLATRO dry.
Keep STEGLATRO and all medicines out of the reach of children.
General information about the safe and effective use of STEGLATRO.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do
not use STEGLATRO for a condition for which it was not prescribed. Do not give STEGLATRO to
other people, even if they have the same symptoms that you have. It may harm them. You can ask
your pharmacist or healthcare provider for information about STEGLATRO that is written for health
professionals.
For more information about STEGLATRO, go to www.steglatro.com or call 1-800-622-4477.
What are the ingredients in STEGLATRO?
Active ingredient: ertugliflozin.
Inactive ingredients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, and
magnesium stearate. The tablet film coating contains the following inactive ingredients:
hypromellose, lactose monohydrate, macrogol, triacetin, titanium dioxide, and iron oxide red.
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA
4
Reference ID: 5502336
For patent information, go to: www.msd.com/research/patent
Copyright © 2017-2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved.
usmg-mk8835-t-2309r006
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 09/2023
5
Reference ID: 5502336
| custom-source | 2025-02-12T15:48:18.340535 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/209803s008lbledt.pdf', 'application_number': 209803, 'submission_type': 'SUPPL ', 'submission_number': 8} |
80,767 |
I
I
I
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WEZLANA™ safely and effectively. See full prescribing information for
WEZLANA.
WEZLANA™ (ustekinumab-auub) injection, for subcutaneous or
intravenous use
Initial U.S. Approval: 2023
WEZLANA™ (ustekinumab-auub) is biosimilar* to STELARA®
(ustekinumab).
------------------RECENT MAJOR CHANGES-----------------
Dosage and Administration (2.4, 2.6)
12/2024
-----------------INDICATIONS AND USAGE------------------
WEZLANA is a human interleukin -12 and -23 antagonist indicated for the
treatment of:
Adult patients with:
•
moderate to severe plaque psoriasis (PsO) who are
candidates for phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
•
moderately to severely active Crohn’s disease (CD). (1.3)
•
moderately to severely active ulcerative colitis. (1.4)
Pediatric patients 6 years and older with:
•
moderate to severe plaque psoriasis, who are candidates
for phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
-------------DOSAGE AND ADMINISTRATION--------------
Psoriasis Adult Subcutaneous Recommended Dosage (2.1):
Weight Range (kilograms) Recommended Dosage
less than or equal to 100 kg
45 mg administered subcutaneously initially
and 4 weeks later, followed by 45 mg
administered subcutaneously every 12 weeks
greater than 100 kg
90 mg administered subcutaneously initially
and 4 weeks later, followed by 90 mg
administered subcutaneously every 12 weeks
Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended
Dosage (2.1):
Weight-based dosing is recommended at the initial dose, 4 weeks later, then
every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
greater than 100 kg
90 mg
Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):
•
The recommended dosage is 45 mg administered subcutaneously
initially and 4 weeks later, followed by 45 mg administered
subcutaneously every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis
weighing greater than 100 kg, the recommended dosage is 90 mg
administered subcutaneously initially and 4 weeks later, followed by
90 mg administered subcutaneously every 12 weeks.
Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended
Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4
weeks later, then every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co-existent
moderate-to-severe plaque psoriasis
90 mg
Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous
Recommended Dosage (2.3):
A single intravenous infusion using weight-based dosing:
Weight Range (kilograms)
Dose
up to 55 kg
260 mg (2 vials)
greater than 55 kg to 85 kg
390 mg (3 vials)
greater than 85 kg
520 mg (4 vials)
Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous
Recommended Dosage (2.3):
A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then
every 8 weeks thereafter.
------------DOSAGE FORMS AND STRENGTHS------------
Subcutaneous Injection (3)
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled
syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled
ConfiPen autoinjector
Intravenous Infusion (3)
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
--------------------CONTRAINDICATIONS---------------------
Clinically significant hypersensitivity to ustekinumab products or to any of the
excipients in WEZLANA. (4)
-------------WARNINGS AND PRECAUTIONS---------------
•
Infections: Serious infections have occurred. Avoid starting WEZLANA
during any clinically important active infection. If a serious infection or
clinically significant infection develops, discontinue WEZLANA until
the infection resolves. (5.1)
•
Theoretical Risk for Particular Infections: Serious infections from
mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG)
vaccinations have been reported in patients genetically deficient in
IL-12/IL-23. Consider diagnostic tests for these infections as dictated by
clinical circumstances. (5.2)
•
Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment
with WEZLANA. Initiate treatment of latent TB before administering
WEZLANA. (5.3)
•
Malignancies: Ustekinumab products may increase risk of malignancy.
The safety of ustekinumab products in patients with a history of or a
known malignancy has not been evaluated. (5.4)
•
Hypersensitivity Reactions: If an anaphylactic or other clinically
significant hypersensitivity reaction occurs, institute appropriate therapy
and discontinue WEZLANA. (5.5)
•
Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is
suspected, treat promptly and discontinue WEZLANA. (5.6)
•
Immunizations: Avoid use of live vaccines in patients during treatment
with WEZLANA. (5.7)
•
Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic
pneumonia and cryptogenic organizing pneumonia have been reported
during post-approval use of ustekinumab products. If diagnosis is
confirmed, discontinue WEZLANA and institute appropriate treatment.
(5.8)
--------------------ADVERSE REACTIONS----------------------
Most common adverse reactions are:
•
Psoriasis (≥ 3%): nasopharyngitis, upper respiratory tract infection,
headache, and fatigue. (6.1)
•
Crohn’s Disease, induction (≥ 3%): vomiting. (6.1)
•
Crohn’s Disease, maintenance (≥ 3%): nasopharyngitis, injection site
erythema, vulvovaginal candidiasis/mycotic infection, bronchitis,
pruritus, urinary tract infection, and sinusitis. (6.1)
•
Ulcerative colitis, induction (≥ 3%): nasopharyngitis. (6.1)
•
Ulcerative colitis, maintenance (≥ 3%): nasopharyngitis, headache,
abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen
Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
1 of 34
Reference ID: 5502917
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
* Biosimilar means that the biological product is approved based on data
demonstrating that it is highly similar to an FDA-approved biological product
known as a reference product, and that there are no clinically meaningful
differences between the biosimilar product and the reference product.
Biosimilarity of WEZLANA has been demonstrated for the condition(s) of use
(e.g., indication(s), dosing regimen(s), strength(s), dosage form(s), and route(s)
of administration described in its Full Prescribing Information.
2 of 34
Reference ID: 5502917
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Plaque Psoriasis (PsO)
1.2 Psoriatic Arthritis (PsA)
1.3 Crohn’s Disease (CD)
1.4 Ulcerative Colitis
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage in Plaque Psoriasis
2.2 Recommended Dosage in Psoriatic Arthritis
2.3 Recommended Dosage in Crohn’s Disease and Ulcerative Colitis
2.4 General Considerations for Administration
2.5 Instructions for Administration of WEZLANA Prefilled Syringes
Equipped with Needle Safety Guard
2.6 Instructions for Administration of WEZLANA Prefilled ConfiPen
Autoinjector
2.7 Preparation and Administration of WEZLANA 130 mg/26 mL
(5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and
Ulcerative Colitis)
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Infections
5.2 Theoretical Risk for Vulnerability to Particular Infections
5.3 Pre-treatment Evaluation for Tuberculosis
5.4 Malignancies
5.5 Hypersensitivity Reactions
5.6 Posterior Reversible Encephalopathy Syndrome (PRES)
5.7 Immunizations
5.8 Noninfectious Pneumonia
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Concomitant Therapies
7.2 CYP450 Substrates
7.3 Allergen Immunotherapy
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Adult Plaque Psoriasis
14.2 Pediatric Plaque Psoriasis
14.3 Psoriatic Arthritis
14.4 Crohn’s Disease
14.5 Ulcerative Colitis
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
3 of 34
Reference ID: 5502917
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1
Plaque Psoriasis (PsO)
WEZLANA is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe
plaque psoriasis who are candidates for phototherapy or systemic therapy.
1.2
Psoriatic Arthritis (PsA)
WEZLANA is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic
arthritis.
1.3
Crohn's Disease (CD)
WEZLANA is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.
1.4
Ulcerative Colitis
WEZLANA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.
2 DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage in Plaque Psoriasis
Subcutaneous Adult Dosage Regimen
•
For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed
by 45 mg every 12 weeks.
•
For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later,
followed by 90 mg every 12 weeks.
In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater
efficacy in these subjects [see Clinical Studies (14)].
Subcutaneous Pediatric Dosage Regimen
Administer WEZLANA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of WEZLANA for pediatric patients (6–17 years old) with plaque psoriasis based on body weight
is shown below (Table 1).
Table 1. Recommended Dose of WEZLANA for Subcutaneous Injection in Pediatric Patients
(6–17 years old) with Plaque Psoriasis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
more than 100 kg
90 mg
For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is
shown in Table 2; withdraw the appropriate volume from the single-dose vial.
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15
20
25
30
35
40
45
50
Table 2. Injection Volumes of WEZLANA 45 mg/0.5 mL Single-dose Vials for Pediatric Patients
(6–17 years old) with Plaque Psoriasis and Pediatric Patients (6-17 years old) with Psoriatic Arthritis* Weighing
Less Than 60 kg
Body Weight (kg) at the
Volume of
time of dosing
Dose (mg)
injection (mL)
11.3
0.12
16
12.0
0.13
17
12.8
0.14
18
13.5
0.15
19
14.3
0.16
15.0
0.17
21
15.8
0.17
22
16.5
0.18
23
17.3
0.19
24
18.0
0.20
18.8
0.21
26
19.5
0.22
27
20.3
0.22
28
21.0
0.23
29
21.8
0.24
22.5
0.25
31
23.3
0.26
32
24.0
0.27
33
24.8
0.27
34
25.5
0.28
26.3
0.29
36
27.0
0.30
37
27.8
0.31
38
28.5
0.32
39
29.3
0.32
30.0
0.33
41
30.8
0.34
42
31.5
0.35
43
32.3
0.36
44
33.0
0.37
33.8
0.37
46
34.5
0.38
47
35.3
0.39
48
36.0
0.40
49
36.8
0.41
37.5
0.42
51
38.3
0.42
52
39.0
0.43
53
39.8
0.44
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Body Weight (kg) at the
Volume of
time of dosing
Dose (mg)
injection (mL)
54
40.5
0.45
55
41.3
0.46
56
42.0
0.46
57
42.8
0.47
58
43.5
0.48
59
44.3
0.49
*
Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen.
2.2
Recommended Dosage in Psoriatic Arthritis
Subcutaneous Adult Dosage Regimen
•
The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the
recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
Subcutaneous Pediatric Dosage Regimen
Administer WEZLANA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of WEZLANA for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body
weight, is shown below (Table 3).
Table 3. Recommended Dose of WEZLANA for Subcutaneous Injection in Pediatric Patients
(6 to 17 years old) with Psoriatic Arthritis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg*
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co-existent moderate-to-severe
90 mg
plaque psoriasis
*
For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is
shown in Table 2; withdraw the appropriate volume from the single-dose vial.
2.3
Recommended Dosage in Crohn's Disease and Ulcerative Colitis
Intravenous Induction Adult Dosage Regimen
A single intravenous infusion dose of WEZLANA using the weight-based dosage regimen specified in Table 4 [see
Instructions for dilution of WEZLANA 130 mg vial for intravenous infusion (2.6)].
Table 4. Initial Intravenous Dosage of WEZLANA
Body Weight of Patient at the
time of dosing
Dose
Number of 130 mg/26 mL
(5 mg/mL) WEZLANA vials
55 kg or less
260 mg
2
more than 55 kg to 85 kg
390 mg
3
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more than 85 kg
520 mg
4
Subcutaneous Maintenance Adult Dosage Regimen
The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous
dose, then every 8 weeks thereafter.
2.4
General Considerations for Administration
•
WEZLANA is intended for use under the guidance and supervision of a healthcare provider. WEZLANA should
only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare
provider. The appropriate dose should be determined by a healthcare provider using the patient's current weight at
the time of dosing. In pediatric patients, it is recommended that WEZLANA be administered by a healthcare
provider. If a healthcare provider determines that it is appropriate, a patient may self-inject, or a caregiver may
inject WEZLANA after proper training in subcutaneous injection technique. Instruct patients to follow the
directions provided in the Medication Guide [see Medication Guide].
•
The needle cap on the prefilled syringe does not contain dry natural rubber (a derivative of latex). The prefilled
ConfiPen autoinjector is not made with natural rubber latex.
•
It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal
regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is
tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 27 gauge,
½ inch needle is recommended.
•
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. WEZLANA is a clear to opalescent and colorless to light
yellow solution. Do not use WEZLANA if it is discolored or cloudy, or if other particulate matter is present.
WEZLANA does not contain preservatives; therefore, discard any unused product remaining in the ConfiPen
autoinjector, vial and/or syringe.
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2.5
Instructions for Administration of WEZLANA Prefilled Syringes Equipped with Needle Safety Guard
Refer to the diagram below for the provided instructions.
To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD CLIPS at any time
during use.
Plunger
Viewing
Plunger
rod
(location may vary)
Body
window
Plunger
head
Needle
guard clips
Finger grip
Label
Needle cap
(needle inside)
•
Hold the BODY and remove the NEEDLE CAP. Do not hold the PLUNGER or PLUNGER HEAD while
removing the NEEDLE CAP or the PLUNGER may move. Do not use the prefilled syringe if it is dropped
without the NEEDLE CAP in place.
Inject WEZLANA subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)].
•
Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the
finger grip. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.
•
After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly
take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is
covered by the needle guard, as shown by the illustration below:
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Used syringes should be placed in a puncture-resistant container.
2.6
Instructions for Administration of WEZLANA Prefilled ConfiPen Autoinjector
The WEZLANA single-dose prefilled ConfiPen autoinjector “Instructions for Use” insert contains detailed instructions on
preparation, injection site selection, administration and disposal.
Expiration
date
Plunger
(may be visible in the window; location
may vary)
Window
Medicine
Yellow safety
guard under cap
(needle inside)
Cap
2.7
Preparation and Administration of WEZLANA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion
(Crohn's Disease and Ulcerative Colitis)
WEZLANA solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using
aseptic technique.
1. Calculate the dose and the number of WEZLANA vials needed based on patient weight (Table 4). Each 26 mL vial of
WEZLANA contains 130 mg of ustekinumab-auub.
2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal
to the volume of WEZLANA to be added (discard 26 mL sodium chloride for each vial of WEZLANA needed, for 2
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vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag
containing 0.45% Sodium Chloride Injection, USP may be used.
3. Withdraw 26 mL of WEZLANA from each vial needed and add it to the 250 mL infusion bag. The final volume in the
infusion bag should be 250 mL. Gently mix.
4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Do not use if visibly opaque particles, discoloration or foreign particles are
observed.
5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely
administered within eight hours of the dilution in the infusion bag.
6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
7. Do not infuse WEZLANA concomitantly in the same intravenous line with other agents.
8. WEZLANA does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining
solution. Dispose any unused medicinal product in accordance with local requirements.
Storage
If necessary, the diluted infusion solution may be kept at room temperature up to 25°C (77°F) for up to 7 hours. Storage
time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within
8 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion
period). Do not freeze. Discard any unused portion of the infusion solution.
3
DOSAGE FORMS AND STRENGTHS
WEZLANA (ustekinumab-auub) is a clear to opalescent and colorless to light yellow solution.
Subcutaneous Injection
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled ConfiPen autoinjector
Intravenous Infusion
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
4
CONTRAINDICATIONS
WEZLANA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of
the excipients in WEZLANA [see Warnings and Precautions (5.5)].
5 WARNINGS AND PRECAUTIONS
5.1
Infections
Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial,
mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse
Reactions (6.1, 6.3)].
Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included
the following:
•
Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral
infections, gastroenteritis and urinary tract infections.
•
Psoriatic arthritis: cholecystitis.
•
Crohn's disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.
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•
Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.
Avoid initiating treatment with WEZLANA in patients with any clinically important active infection until the infection
resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of WEZLANA in
patients with a chronic infection or a history of recurrent infection.
Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with
WEZLANA and discontinue WEZLANA for serious or clinically significant infections until the infection resolves or is
adequately treated.
5.2
Theoretical Risk for Vulnerability to Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria
(including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus
Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products
may be susceptible to these types of infections. Consider appropriate diagnostic testing (e.g., tissue culture, stool culture, as
dictated by clinical circumstances).
5.3
Pre-treatment Evaluation for Tuberculosis
Evaluate patients for tuberculosis infection prior to initiating treatment with WEZLANA.
Avoid administering WEZLANA to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis
prior to administering WEZLANA. Consider anti-tuberculosis therapy prior to initiation of WEZLANA in patients with a
past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor
patients receiving WEZLANA for signs and symptoms of active tuberculosis during and after treatment.
5.4
Malignancies
Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported
among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of
IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)].
The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a
known malignancy.
There have been postmarketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients
receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all
patients receiving WEZLANA for the appearance of non-melanoma skin cancer. Closely follow patients greater than
60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA
treatment [see Adverse Reactions (6.1)].
5.5
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see
Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute
appropriate therapy and discontinue WEZLANA.
5.6
Posterior Reversible Encephalopathy Syndrome (PRES)
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior
Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing
experience in patients with psoriasis, psoriatic arthritis and Crohn's disease. Clinical presentation included headaches,
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seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after
ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care
following withdrawal of ustekinumab products.
Monitor all patients treated with WEZLANA for signs and symptoms of PRES. If PRES is suspected, promptly administer
appropriate treatment, and discontinue WEZLANA.
5.7
Immunizations
Prior to initiating therapy with WEZLANA, patients should receive all age-appropriate immunizations as recommended by
current immunization guidelines. Patients being treated with WEZLANA should avoid receiving live vaccines. Avoid
administering BCG vaccines during treatment with WEZLANA or for one year prior to initiating treatment or one year
following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of
patients receiving WEZLANA because of the potential risk for shedding from the household contact and transmission to
patient.
Non-live vaccinations received during a course of WEZLANA may not elicit an immune response sufficient to prevent
disease.
5.8
Noninfectious Pneumonia
Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during
post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates
following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients
improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed,
discontinue WEZLANA and institute appropriate treatment [see Postmarketing Experience (6.3)].
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the label:
•
Infections [see Warnings and Precautions (5.1)]
•
Malignancies [see Warnings and Precautions (5.4)]
•
Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
•
Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]
•
Noninfectious Pneumonia [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in
practice.
Adult Subjects with Plaque Psoriasis
The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at
least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three
years, 1482 exposed for at least four years and 838 exposed for at least five years.
Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups
during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)].
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Table 5. Adverse Reactions Reported by ≥ 1% of Subjects with Plaque Psoriasis and at Higher Rates in the
Ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2
Ustekinumab
Placebo
45 mg
90 mg
Subjects treated
665
664
666
Nasopharyngitis
51 (8%)
56 (8%)
49 (7%)
Upper respiratory tract infection
30 (5%)
36 (5%)
28 (4%)
Headache
23 (3%)
33 (5%)
32 (5%)
Fatigue
14 (2%)
18 (3%)
17 (3%)
Back pain
8 (1%)
9 (1%)
14 (2%)
Dizziness
8 (1%)
8 (1%)
14 (2%)
Pharyngolaryngeal pain
7 (1%)
9 (1%)
12 (2%)
Pruritus
9 (1%)
10 (2%)
9 (1%)
Injection site erythema
3 (< 1%)
6 (1%)
13 (2%)
Myalgia
4 (1%)
7 (1%)
8 (1%)
Depression
3 (< 1%)
8 (1%)
4 (1%)
Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12
included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration,
hemorrhage, bruising, and irritation).
One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions (5.6)].
Infections
In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of 12.6 weeks for
placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported
infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of
follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per subject-year of follow-up) and in
0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)].
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years),
representing 8998 subject-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per
subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).
Malignancies
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing
8998 subject-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma
skin cancers (0.60 per hundred subject-years of follow-up).
Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred subject-years of
follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma
skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than
non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were
similar in type and number to what would be expected in the general U.S. population according to the SEER database
(adjusted for age, gender and race).1
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Pediatric Subjects with Plaque Psoriasis
The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps
STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety
for up to 56 weeks in 44 pediatric subjects 6 to 11years old. The safety profile in pediatric subjects was similar to the safety
profile from trials in adults with plaque psoriasis.
Psoriatic Arthritis
The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in
adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent
with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections
was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and
3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.
Crohn's Disease
The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn's disease (Crohn's
Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized,
double-blind, placebo-controlled, parallel-group, multicenter trials. These 1407 subjects included 40 subjects who received
a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1
and CD-2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose
and 466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in either trial CD-1
or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or
placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including
aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral
corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn's disease [see Clinical Studies (14.4)].
The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult psoriasis and psoriatic
arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 6 and 7,
respectively.
Table 6. Common Adverse Reactions Through Week 8 in Trials CD-1 and CD-2 Occurring in ≥ 3% of
Ustekinumab-Treated Subjects and Higher Than Placebo
Placebo
Ustekinumab
6 mg/kg single intravenous
induction dose
N = 466
N = 470
Vomiting
3%
4%
Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne
(1% vs 0.4%), and pruritus (2% vs 0.4%).
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Table 7. Common Adverse Reactions Through Week 44 in Trial CD-3 Occurring in ≥ 3% of Ustekinumab-Treated
Subjects and Higher Than Placebo
Ustekinumab
Placebo
90 mg subcutaneous
maintenance dose every
8 weeks
N = 133
N = 131
Nasopharyngitis
Injection site erythema
Vulvovaginal candidiasis/mycotic
infection
8%
0
1%
11%
5%
5%
Bronchitis
3%
5%
Pruritus
2%
4%
Urinary tract infection
Sinusitis
2%
2%
4%
3%
Infections
In subjects with Crohn's disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and
pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one patient each [see Warnings
and Precautions (5.1)].
Malignancies
With up to one year of treatment in the Crohn's disease clinical trials, 0.2% of ustekinumab-treated subjects (0.36 events
per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed
non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated
subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects.
Hypersensitivity Reactions Including Anaphylaxis
In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One patient
experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing)
after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab). In addition, one subject
experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing,
urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving
intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases,
symptoms resolved within an hour.
Ulcerative Colitis
The safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV
induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see
Clinical Studies (14.5)]. The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with
the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated
subjects and at a higher rate than placebo were:
•
Induction (UC-1): nasopharyngitis (7% vs 4%).
•
Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%),
influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and
nausea (3% vs 2%).
Infections
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In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia.
In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions
(5.1)].
Malignancies
With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab-treated subjects (0.48 events
per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient-years) developed
non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated
subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred
patient-years).
6.2
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.
Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies
described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other
ustekinumab products.
Approximately 6 to 12.4% of subjects treated with ustekinumab in plaque psoriasis and psoriatic arthritis clinical trials
developed antibodies to ustekinumab, which were generally low-titer. In plaque psoriasis clinical trials, antibodies to
ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In
plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing
antibodies.
In Crohn's disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, developed antibodies to
ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the
development of antibodies to ustekinumab and the development of injection site reactions was seen.
6.3
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to ustekinumab product exposure.
Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other
hypersensitivity reactions (including rash and urticaria).
Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis).
Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic
organizing pneumonia.
Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.
7
DRUG INTERACTIONS
7.1
Concomitant Therapies
In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive agents or
phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the
safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis induction trials, immunomodulators (6-MP,
AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in
16 of 34
Reference ID: 5502917
approximately 40% and 50% of Crohn's disease and ulcerative colitis subjects, respectively. Use of these concomitant
therapies did not appear to influence the overall safety or efficacy of ustekinumab.
7.2
CYP450 Substrates
The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα,
IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the
formation of CYP450 enzymes. Upon initiation or discontinuation of WEZLANA in patients who are receiving
concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic
effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing
information of specific CYP substrates.
A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology
(12.3)].
7.3
Allergen Immunotherapy
Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab
products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of
an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or
who have received allergen immunotherapy, particularly for anaphylaxis.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab
products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other
adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy
progresses and peaks during the third trimester; therefore, ustekinumab products may be transferred to the developing fetus
[see Clinical Considerations]. In animal reproductive and developmental toxicity studies, no adverse developmental
effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100
times the maximum recommended human dose (MRHD).
The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies
have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits
prior to administering live vaccines to infants exposed to WEZLANA in utero. There are insufficient data regarding
exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in
infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants
exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the
clearance of the product.
Data
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Animal Data
Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or
other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab
subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of
ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously
with 90 mg of ustekinumab weekly for 4 weeks.
In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus
monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the
MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one
monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on
functional, morphological, or immunological development were observed in the neonates from birth through six months of
age.
8.2
Lactation
Risk Summary
Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available
data on the effects of ustekinumab products on milk production. The effects of local gastrointestinal exposure and limited
systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant
causally related to ustekinumab products have been identified in the published literature or postmarketing experience.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for
WEZLANA and any potential adverse effects on the breastfed child from WEZLANA or from the underlying maternal
condition.
8.4
Pediatric Use
Plaque Psoriasis
The safety and effectiveness of WEZLANA have been established for the treatment of moderate to severe plaque psoriasis
in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy.
Use of WEZLANA in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter,
randomized, 60-week trial (Ps STUDY 3) of ustekinumab that included a 12-week, double-blind, placebo-controlled,
parallel-group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies
(14.2)].
Use of WEZLANA in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm,
efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects [see Adverse Reactions (6.1),
Pharmacokinetics (12.3)].
The safety and effectiveness of WEZLANA have not been established in pediatric patients less than 6 years of age with
plaque psoriasis.
Psoriatic Arthritis
The safety and effectiveness of WEZLANA have been established for treatment of psoriatic arthritis in pediatric patients 6
to 17 years old.
Use of WEZLANA in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab
in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and
pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects 6 to
11 years old with psoriasis and 110 pediatric subjects 12 to 17 years old with psoriasis. The observed pre-dose (trough)
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concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric
subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)].
The safety and effectiveness of WEZLANA have not been established in pediatric patients less than 6 years old with
psoriatic arthritis.
Crohn’s Disease and Ulcerative Colitis
The safety and effectiveness of WEZLANA have not been established in pediatric patients with Crohn’s disease or
ulcerative colitis.
8.5
Geriatric Use
Of the 6709 subjects exposed to ustekinumab, a total of 340 were 65 years of age or older (183 subjects with plaque
psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn's disease and 34 subjects with ulcerative colitis), and
40 subjects were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of subjects 65
years of age and older to determine whether they respond differently from younger adult subjects.
10
OVERDOSAGE
Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of
overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate
symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist
for additional overdose management recommendations.
11
DESCRIPTION
Ustekinumab-auub, a human IgG1κ monoclonal antibody, is a human interleukin -12 and -23 antagonist. Using DNA
recombinant technology, ustekinumab-auub is produced in a mammalian cell line (Chinese Hamster Ovary). The
manufacturing process contains steps for the clearance of viruses. Ustekinumab-auub is comprised of 1326 amino acids
and has an estimated molecular mass that ranges from 148 to 150 kDa.
WEZLANA (ustekinumab-auub) injection is a sterile, preservative-free, clear to opalescent and colorless to light yellow
solution with a pH of 6.0.
WEZLANA for Subcutaneous Use
Available as 45 mg of ustekinumab-auub in 0.5 mL and 90 mg of ustekinumab-auub in 1 mL, supplied as a sterile solution
in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and a single-dose prefilled ConfiPen autoinjector,
and as 45 mg of ustekinumab-auub in 0.5 mL in a single-dose Type I glass vial with a coated stopper. The syringe is fitted
with a passive needle guard and a needle cap that does not contain dry natural rubber (a derivative of latex). The prefilled
ConfiPen autoinjector is not made with natural rubber latex.
Each 0.5 mL prefilled syringe, prefilled ConfiPen autoinjector or vial delivers 45 mg ustekinumab-auub, histidine (0.23
mg) and histidine hydrochloride monohydrate (0.36 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg).
Each 1 mL prefilled syringe, or prefilled ConfiPen autoinjector delivers 90 mg ustekinumab-auub, histidine (0.46 mg) and
histidine hydrochloride monohydrate (0.72 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg).
WEZLANA for Intravenous Infusion
Available as 130 mg of ustekinumab-auub in 26 mL, supplied as a single-dose Type I glass vial with a coated stopper.
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Each 26 mL vial delivers 130 mg ustekinumab-auub, edetate disodium (0.47 mg), histidine (20 mg), histidine
hydrochloride monohydrate (27 mg), methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2210 mg).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ustekinumab products are human IgG1κ monoclonal antibodies that bind with specificity to the p40 protein subunit used by
both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and
immune responses, such as natural killer cell activation and CD4+ T -cell differentiation and activation. In in vitro models,
ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the
interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been
implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease and ulcerative colitis.
In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of
ustekinumab products, was shown to be protective.
12.2
Pharmacodynamics
Plaque Psoriasis
In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in
lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with plaque psoriasis.
Ulcerative Colitis
In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed between exposure and
rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached a plateau at the
ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment [see Clinical Studies
(14.5)].
12.3
Pharmacokinetics
Absorption
In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days
and 7 days, respectively, after a single subcutaneous administration of 45 mg (N = 22) and 90 mg (N = 24) of ustekinumab.
In healthy subjects (N = 30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of
ustekinumab was comparable to that observed in subjects with plaque psoriasis.
Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-state serum
concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum ustekinumab
concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and
0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose. There was no apparent accumulation in
serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was
125.2 ± 33.6 mcg/mL in subjects with Crohn's disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis.
Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8
weeks. Steady-state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no
apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ±SD
steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn's disease, and 3.3 ± 2.3 mcg/mL in subjects
with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks.
Distribution
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Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment
was 2.7 L (95% CI: 2.69, 2.78) in subjects with Crohn's disease and 3.0 L (95% CI: 2.96, 3.07) in subjects with ulcerative
colitis. The total volume of distribution at steady-state was 4.6 L in subjects with Crohn's disease and 4.4 L in subjects with
ulcerative colitis.
Elimination
The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials following
subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was
0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohn's disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with
ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohn's disease and
ulcerative colitis) populations.
These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn's disease and
ulcerative colitis.
Metabolism
The metabolic pathway of ustekinumab products has not been characterized. As a human IgG1κ monoclonal antibody,
ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same
manner as endogenous IgG.
Specific Populations
Weight
When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100 kg had lower
median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough
serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were
comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group.
Age: Geriatric Population
A population pharmacokinetic analysis (N = 106/1937 subjects with plaque psoriasis greater than or equal to 65 years old)
was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in
pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
Age: Pediatric Population
Following multiple recommended doses of ustekinumab in pediatric subjects 6 to 17 years of age with plaque psoriasis,
steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean ±SD steady-state
trough serum ustekinumab concentrations were 0.36 ± 0.26 mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric
subjects 6 to 11 years of age and pediatric subjects 12 to 17 years of age.
Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were
within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration
of ustekinumab.
Drug Interaction Studies
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human
hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities
(CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).
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Reference ID: 5502917
No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole
(CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used
concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease [see Drug
Interactions (7.2)].
Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX,
NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects with psoriatic arthritis.
In subjects with Crohn's disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in
ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum
ustekinumab concentrations were not impacted by concomitant use of these medications.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ustekinumab products.
Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained
transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased
host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed
UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental
findings in mouse models for malignancy risk in humans is unknown.
No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous
doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period.
However, fertility and pregnancy outcomes were not evaluated in mated females.
No effects on fertility were observed in female mice that were administered an analogous IL-12/IL- 23p40 antibody by
subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.
13.2
Animal Toxicology and/or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly
for 26 weeks had a bacterial infection.
14
CLINICAL STUDIES
14.1 Adult Plaque Psoriasis
Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2) enrolled a total of
1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%,
and Psoriasis Area and Severity Index (PASI) score ≥ 12, and who were candidates for phototherapy or systemic therapy.
Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the trials.
Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week
28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects
randomized to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects
randomized to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12
and 16.
In both trials, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18.
Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2.
Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional
22 of 34
Reference ID: 5502917
systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and
43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis.
In both trials, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75)
from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The
PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of
psoriasis focusing on plaque thickness/induration, erythema, and scaling.
Clinical Response
The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.
Table 8. Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
Placebo
ustekinumab
Placebo
ustekinumab
45 mg
90 mg
45 mg
90 mg
Subjects
randomized
255
255
256
410
409
411
PASI 75 response
8
(3%)
171
(67%)
170
(66%)
15
(4%)
273
(67 %)
311
(76%)
PGA of Cleared or
10
151
156
18
277
300
Minimal
(4%)
(59%)
(61%)
(4%)
(68%)
(73%)
Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab among these
subgroups.
In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg doses; however,
in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg
dosing (Table 9 below).
Table 9. Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
ustekinumab
ustekinumab
Placebo
45 mg
90 mg
Placebo
45 mg
90 mg
Subjects randomized
255
255
256
410
409
411
PASI 75 response*
≤ 100 kg
4%
74%
65%
4%
73%
78%
6/166
124/168
107/164
12/290
218/297
225/289
> 100 kg
2%
54%
68%
3%
49%
71%
2/89
47/87
63/92
3/120
55/112
86/121
PGA of Cleared or Minimal
≤ 100 kg
4%
64%
63%
5%
74%
75%
7/166
108/168
103/164
14/290
220/297
216/289
> 100 kg
3%
49%
58%
3%
51%
69%
3/89
43/87
53/92
4/120
57/112
84/121
* Subjects were dosed with trial medication at Weeks 0 and 4.
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either
continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week
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Reference ID: 5502917
52, 89% (144/162) of subjects re-randomized to ustekinumab treatment were PASI 75 responders compared with 63%
(100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of
PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
14.2
Pediatric Plaque Psoriasis
A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17
years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater
than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately
controlled by topical therapy.
Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36), or one -half the
recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every
12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg
for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who
received placebo were crossed over to receive ustekinumab at the recommended dose or one -half the recommended dose.
Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and
approximately 11% had prior exposure to biologics.
The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and
PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent.
Clinical Response
The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10.
Table 10. Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3
Ps STUDY 3
Placebo
ustekinumab*
n (%)
n (%)
N
37
36
PGA
PGA of cleared (0) or minimal (1)
2 (5.4%)
25 (69.4%)
PASI
PASI 75 responders
4 (10.8%)
29 (80.6%)
PASI 90 responders
2 (5.4%)
22 (61.1%)
* Using the weight-based dosage regimen specified in Table 1 and Table 2.
14.3
Psoriatic Arthritis
The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n = 615; PsA STUDY 2, n = 312), in
two randomized, double-blind, placebo-controlled trials in adult subjects 18 years of age and older with active PsA (≥ 5
swollen joints and ≥ 5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic
(DMARD) therapy. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA
were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral
arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans
(0.5%). Over 70% and 40% of the subjects, respectively, had enthesitis and dactylitis at baseline.
Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and
4 followed by every 12 weeks (q12w) dosing. Approximately 50% of subjects continued on stable doses of MTX
(≤ 25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24.
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Reference ID: 5502917
60
-;,R_
40
~
.$
c::
a,
~
CL.
20
PsA STUDY 1
24
Weeks
--o-
Placebo (n=206)
__.__ Ustekinumab 45 mg (n=205)
-
Ustekinumab 90 mg (n=204)
In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with
DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed.
In PsA STUDY 2, 58% (n = 180) of the subjects had been previously treated with TNF blocker, of whom over 70% had
discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time.
Clinical Response
In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the ustekinumab 45 mg
and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70 responses were also higher in the ustekinumab
45 mg and 90 mg groups, although the difference was only numerical (p = NS) in STUDY 2. Responses were consistent in
subjects treated with ustekinumab alone or in combination with methotrexate. Responses were similar in subjects
regardless of prior TNFα exposure.
Table 11. ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and
PsA STUDY 2 at Week 24
PsA STUDY 1
PsA STUDY 2
ustekinumab
ustekinumab
Number of subjects
randomized
Placebo
206
45 mg
205
90 mg
204
Placebo
104
45 mg
103
90 mg
105
ACR 20 response, N (%)
ACR 50 response, N (%)
47 (23%)
18 (9%)
87 (42%)
51 (25%)
101
(50%)
57 (28%)
21 (20%)
7 (7%)
45 (44%)
18 (17%)
46 (44%)
24 (23%)
ACR 70 response, N (%)
Number of subjects with
≥ 3% BSAa
5 (2%)
146
25 (12%)
145
29 (14%)
149
3 (3%)
80
7 (7%)
80
9 (9%)
81
PASI 75 response, N (%)
16 (11%)
83 (57%)
93 (62%)
4 (5%)
41 (51%)
45 (56%)
a Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline.
The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1.
Figure 1. Percent of subjects achieving ACR 20 response through Week 24
The results of the components of the ACR response criteria are shown in Table 12.
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Table 12. Mean change from baseline in ACR components at Week 24
PsA STUDY 1
Placebo
ustekinumab
45 mg
90 mg
(N = 206)
(N = 205)
(N = 204)
Number of swollen jointsa
Baseline
15
12
13
Mean Change at Week 24
-3
-5
-6
Number of tender jointsb
Baseline
25
22
23
Mean Change at Week 24
-4
-8
-9
Subjects’ assessment of painc
Baseline
6.1
6.2
6.6
Mean Change at Week 24
-0.5
-2.0
-2.6
Subject global assessmentc
Baseline
6.1
6.3
6.4
Mean Change at Week 24
-0.5
-2.0
-2.5
Physician global assessmentc
Baseline
5.8
5.7
6.1
Mean Change at Week 24
-1.4
-2.6
-3.1
Disability index (HAQ)d
Baseline
1.2
1.2
1.2
Mean Change at Week 24
-0.1
-0.3
-0.4
CRP (mg/dL)e
Baseline
1.6
1.7
1.8
Mean Change at Week 24
0.01
-0.5
-0.8
a Number of swollen joints counted (0–66).
b Number of tender joints counted (0–68).
c Visual analogue scale; 0 = best, 10 = worst.
d Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to
perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
e CRP: (Normal Range 0.0–1.0 mg/dL).
An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared with placebo at
Week 24.
Physical Function
Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated with placebo as
assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ-DI responders (≥ 0.3 improvement in HAQ-DI
score) was greater in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24.
14.4
Crohn's Disease
Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with
moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). There were
two 8-week intravenous induction trials (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal
maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment
with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators
or corticosteroids, but never failed treatment with a TNF blocker.
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Trials CD-1 and CD-2
In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n = 741; CD-2, n = 627) were included in
the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to
100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at
Week 8 were evaluated. In both trials, subjects were randomized to receive a single intravenous administration of
ustekinumab at either approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended).
In trial CD-1, subjects had failed or were intolerant to prior treatment with a TNF blocker: 29% subjects had an inadequate
initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and
36% were intolerant to a TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had
failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving
corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline
CDAI score was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group.
In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one
immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of subjects). Additionally, 69% never received a
TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial,
approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving
immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the
placebo group.
In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended dose of
approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo
(see Table 13 for clinical response and remission rates).
Clinical response and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to
improve through Week 8.
Table 13. Induction of Clinical Response and Remission in CD-1* and CD-2†
CD-1 n = 741
CD-2 n = 627
Treatment
Treatment
Placebo
Ustekinumab‡
difference
Placebo
Ustekinumab‡
difference
N = 247
N = 249
and 95% CI
N = 209
N = 209
and 95% CI
Clinical Response
(100 point), Week 6
53 (21%)
84 (34%)§
12%
(4%, 20%)
60 (29%)
116 (56%)¶
27%
(18%, 36%)
Clinical Remission,
Week 8
18 (7%)
52 (21%)¶
14%
(8%, 20%)
41 (20%)
84 (40%)¶
21%
(12%, 29%)
Clinical Response
(100 point), Week 8
50 (20%)
94 (38%)¶
18%
(10%, 25%)
67 (32%)
121 (58%)¶
26%
(17%, 35%)
70 Point Response,
Week 6
75 (30%)
109 (44%)§
13%
(5%, 22%)
81 (39%)
135 (65%)¶
26%
(17%, 35%)
70 Point Response,
Week 3
67 (27%)
101 (41%)§
13%
(5%, 22%)
66 (32%)
106 (51%)¶
19%
(10%, 28%)
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points
or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points
* Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy.
† Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA,
MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker.
‡ Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
§ 0.001 ≤ p < 0.01.
¶ p < 0.001.
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Trial CD-3
The maintenance trial (CD-3) evaluated 388 subjects who achieved clinical response (≥ 100 point reduction in CDAI
score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2. Subjects were randomized to
receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks (see
Table 14).
Table 14. Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)
90 mg
Placebo*
ustekinumab every
8 weeks
Treatment
difference
N = 131†
N = 128†
and 95% CI
Clinical Remission
47 (36%)
68 (53%)‡
17% (5%,29%)
Clinical Response
58 (44%)
76 (59%)§
15% (3%,27%)
Clinical Remission in subjects
36/79 (46%)
52/78 (67%)‡
21% (6%, 36%)
in remission at the start of
maintenance therapy¶
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction
in CDAI of at least 100 points or being in clinical remission
* The placebo group consisted of subjects who were in response to ustekinumab and were
randomized to receive placebo at the start of maintenance therapy.
† Subjects who achieved clinical response to ustekinumab at the end of the induction trial.
‡ p < 0.01.
§ 0.01≤ p < 0.05.
¶ Subjects in remission at the end of maintenance therapy who were in remission at the start of
maintenance therapy. This does not account for any other time point during maintenance
therapy.
At Week 44, 47% of subjects who received ustekinumab were corticosteroid-free and in clinical remission, compared to
30% of subjects in the placebo group.
At Week 0 of trial CD-3, 34/56 (61%) ustekinumab-treated subjects who previously failed or were intolerant to TNF
blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the
placebo arm, 27/61 (44%) subjects were in clinical remission at Week 0 while 16/61 (26%) of these subjects were in
remission at Week 44.
At Week 0 of trial CD-3, 46/72 (64%) ustekinumab-treated subjects who had previously failed immunomodulator therapy
or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical
remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week 0 while 31/70
(44%) were in remission at Week 44. In the subset of these subjects who were also naïve to TNF blockers, 34/52 (65%) of
ustekinumab-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm.
Subjects who were not in clinical response 8 weeks after ustekinumab induction were not included in the primary efficacy
analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg subcutaneous injection of ustekinumab
upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were
followed for the duration of the trial.
14.5
Ulcerative Colitis
Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2
(NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to
or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The
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8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal
maintenance trial (UC-2) for a total of 52 weeks of therapy.
Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored
from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and
physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo
score of 6 to 12, including a Mayo endoscopy subscore ≥ 2. An endoscopy score of 2 was defined by marked erythema,
absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline,
subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6–10) and 15% having
severe disease (Mayo score 11–12).
Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory
agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).
Trial UC-1
In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab of approximately
6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with
corticosteroids, immunomodulators or at least one biologic. A total of 51% had failed at least one biologic and 17% had
failed both a TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or
immunomodulators but were biologic-naïve and an additional 3% had previously received but had not failed a biologic. At
induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects
were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates.
The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo stool frequency
subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo endoscopy subscore of 0 or 1 (Mayo
endoscopy subscore of 0 defined as normal or inactive disease and Mayo subscore of 1 defined as presence of erythema,
decreased vascular pattern and no friability) is provided in Table 15.
The secondary endpoints were clinical response, endoscopic improvement, and histologic-endoscopic mucosal
improvement. Clinical response with a definition of (≥ 2 points and ≥ 30% decrease in modified Mayo score, defined as
3-component Mayo score without the Physician's Global Assessment, with either a decrease from baseline in the rectal
bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1), endoscopic improvement with a definition of Mayo
endoscopy subscore of 0 or 1, and histologic-endoscopic mucosal improvement with a definition of combined endoscopic
improvement and histologic improvement of the colon tissue [neutrophil infiltration in < 5% of crypts, no crypt
destruction, and no erosions, ulcerations, or granulation tissue] are provided in Table 15.
In UC-1, a significantly greater proportion of subjects treated with ustekinumab (at the recommended dose of
approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and
histologic-endoscopic mucosal improvement compared to placebo (see Table 15).
Table 15. Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1
Endpoint
Placebo
N = 319
Ustekinumab*
N = 322
Treatment difference
and 97.5% CI†
N
%
N
%
Clinical Remission**
22
7%
62
19%
12%
(7%, 18%)§
Bio-naïve¶
14/151
9%
36/147
24%
Prior biologic failure
7/161
4%
24/166
14%
Endoscopic Improvement#
40
13%
80
25%
12%
(6%, 19%)§
Bio-naïve¶
28/151
19%
43/147
29%
Prior biologic failure
11/161
7%
34/166
20%
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Clinical ResponseÞ
99
31%
186
58%
27%
(18%, 35%)§
Bio-naïve¶
55/151
36%
94/147
64%
Prior biologic failure
42/161
26%
86/166
52%
Histologic-Endoscopic
Mucosal Improvement‡
26
8%
54
17%
9%
(3%, 14%)§
Bio-naïve¶
19/151
13%
30/147
20%
Prior biologic failure
6/161
4%
21/166
13%
‡ Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 or 1)
and histologic improvement of the colon tissue (neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions,
ulcerations, or granulation tissue).
* Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
† Adjusted treatment difference (97.5% CI).
** Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy
subscore of 0 or 1 (modified so that 1 does not include friability).
§ p < 0.001.
¶ An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics.
# Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
Þ Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a decrease
from baseline in the rectal bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1.
The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to disease progression and
long-term outcomes was not evaluated during UC-1.
Rectal Bleeding and Stool Frequency Subscores
Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in ustekinumab-treated
subjects.
Trial UC-2
The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following the intravenous
administration of either induction dose of ustekinumab in UC-1. These subjects were randomized to receive a
subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or every 12 weeks (a lower dose than
recommended), or placebo for 44 weeks.
The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included
the proportion of subjects maintaining clinical response at Week 44, the proportion of subjects with endoscopic
improvement at Week 44, the proportion of subjects with corticosteroid-free clinical remission at Week 44, and the
proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission 8 weeks
after induction.
Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the recommended
dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16.
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Table 16. Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose)
Endpoint
Placebo*
N = 175†
90 mg ustekinumab
every 8 weeks
N = 176
Treatment difference and 95% CI
N
%
N
%
Clinical Remission‡
46
26%
79
45%
19%
(9%, 28%)§
Bio-naïve¶
30/84
36%
39/79
49%
Prior biologic failure
16/88
18%
37/91
41%
Maintenance of Clinical
Response at Week 44†
84
48%
130
74%
26%
(16%, 36%)§
Bio-naïve¶
49/84
58%
62/79
78%
Prior biologic failure
35/88
40%
64/91
70%
Endoscopic Improvement#
47
27%
83
47%
20%
(11%, 30%)§
Bio-naïve¶
29/84
35%
42/79
53%
Prior biologic failure
18/88
20%
38/91
42%
Corticosteroid-free Clinical
RemissionÞ
45
26%
76
43%
17%
(8%, 27%)§
Bio-naïve¶
30/84
36%
38/79
48%
Prior biologic failure
15/88
17%
35/91
38%
Maintenance of Clinical
Remission at Week 44 in subjects
who achieved clinical remission
8 weeks after induction
18/50
36%
27/41
66%
31%
(12%, 50%)ß
Bio-naïve¶
12/27
44%
14/20
70%
Prior biologic failure
6/23
26%
12/18
67%
* The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the
start of maintenance therapy.
† Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a
decrease from baseline in the rectal bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1.
‡ Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo
endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
§ p = < 0.001.
¶ An additional 3 subjects on placebo and 6 patients on ustekinumab had been exposed to, but had not failed, biologics.
# Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
Þ Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44.
ß p = 0.004.
Other Endpoints
Week 16 Responders to Ustekinumab Induction
Subjects who were not in clinical response 8 weeks after induction with ustekinumab in UC-1 were not included in the
primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive a 90 mg subcutaneous injection
of ustekinumab at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and
received ustekinumab 90 mg subcutaneously every 8 weeks during the UC-2 trial. At Week 44, there were 97/157 (62%)
subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission.
Histologic-Endoscopic Mucosal Improvement at Week 44
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The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2
was 75/172 (44%) among subjects on ustekinumab and 40/172 (23%) in subjects on placebo at Week 44. The relationship
of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term
outcomes was not evaluated in UC-2.
Endoscopic Normalization
Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At Week 8 in
UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with ustekinumab and 12/319 (4%) of
subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects
treated with ustekinumab and in 32/175 (18%) of subjects in placebo group.
15
REFERENCES
1
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database:
Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973–2007) – Linked To County Attributes - Total U.S.,
1969–2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems
Branch, released April 2010, based on the November 2009 submission.
16
HOW SUPPLIED/STORAGE AND HANDLING
WEZLANA (ustekinumab-auub) injection is a sterile, preservative-free, clear to opalescent and colorless to light yellow
solution. It is supplied as individually packaged, single-dose prefilled syringes, single-dose vials, or single-dose prefilled
ConfiPen autoinjectors.
For Subcutaneous Use
Prefilled Syringes
•
45 mg/0.5 mL (NDC 55513-076-01, NDC 72511-076-01)
•
90 mg/mL
(NDC 55513-089-01, NDC 72511-089-01)
Each prefilled syringe is equipped with a 27 gauge fixed ½ inch needle, a needle safety guard, and a needle cover that does
not contain dry natural rubber.
Single-dose Vial
•
45 mg/0.5 mL (NDC 55513-055-01, NDC 72511-055-01)
Single-dose Prefilled ConfiPen Autoinjector
•
45 mg/0.5 mL (NDC 55513-102-01)
•
90 mg/mL
(NDC 55513-114-01)
The prefilled ConfiPen autoinjector is not made with natural rubber latex.
For Intravenous Infusion
Single-dose Vial
•
130 mg/26 mL (5 mg/mL) (NDC 55513-066-01)
Storage and Stability
Store WEZLANA vials, prefilled syringes and prefilled ConfiPen autoinjectors refrigerated between 2°C to 8°C (36°F to
46°F). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake.
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Reference ID: 5502917
AMGEN
If needed, individual prefilled syringe, 45 mg vial and prefilled ConfiPen autoinjector may be stored at room temperature
up to 30°C (86°F) for a maximum single period of up to 30 days in the original carton to protect from light. Record the
date when the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector is first removed from the refrigerator on
the carton in the space provided. Once the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector has been
stored at room temperature, do not return it to the refrigerator.
Discard the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector if not used within 30 days at room
temperature storage. Do not use WEZLANA after the expiration date on the carton or on the prefilled syringe, on the
45 mg vial or on the prefilled ConfiPen autoinjector.
17
PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for
Use).
Infections
Inform patients that WEZLANA may lower the ability of their immune system to fight infections and to contact their
healthcare provider immediately if they develop any signs or symptoms of infection [see Warnings and Precautions (5.1)].
Malignancies
Inform patients of the risk of developing malignancies while receiving WEZLANA [see Warnings and Precautions (5.4)].
Hypersensitivity Reactions
•
Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious
hypersensitivity reactions and discontinue WEZLANA [see Warnings and Precautions (5.5)].
Posterior Reversible Encephalopathy Syndrome (PRES)
Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may
include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)].
Immunizations
Inform patients that WEZLANA can interfere with the usual response to immunizations and that they should avoid live
vaccines [see Warnings and Precautions (5.7)].
Administration
Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.
WEZLANA™ (ustekinumab-auub)
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Reference ID: 5502917
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
U.S. License Number 1080
AMGEN, WEZLANA and ConfiPen are trademarks owned by Amgen Inc.
STELARA is a trademark of Johnson & Johnson.
© 2023, xxxx Amgen Inc. All rights reserved.
1xxxxxx-vxx
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Reference ID: 5502917
MEDICATION GUIDE
WEZLANA™ (wez-LAH-nah)
(ustekinumab-auub)
injection, for subcutaneous or intravenous use
What is the most important information I should know about WEZLANA?
WEZLANA is a medicine that affects your immune system. WEZLANA can increase your risk of having
serious side effects, including:
Serious infections. WEZLANA may lower the ability of your immune system to fight infections and may
increase your risk of infections. Some people have serious infections while taking ustekinumab products,
including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be
hospitalized for treatment of their infection.
•
Your doctor should check you for TB before starting WEZLANA.
•
If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you
begin treatment with WEZLANA and during treatment with WEZLANA.
•
Your doctor should watch you closely for signs and symptoms of TB while you are being treated with
WEZLANA.
You should not start taking WEZLANA if you have any kind of infection unless your doctor says it is okay.
Before starting WEZLANA, tell your doctor if you:
•
think you have an infection or have symptoms of an infection such as:
o
fever, sweat, or chills
o
weight loss
o
muscle aches
o
warm, red, or painful skin or sores on your body
o
cough
o
diarrhea or stomach pain
o
shortness of breath
o
burning when you urinate or urinate more often
o
blood in phlegm
than normal
o
feel very tired
•
are being treated for an infection or have any open cuts.
•
get a lot of infections or have infections that keep coming back.
•
have TB, or have been in close contact with someone with TB.
After starting WEZLANA, call your doctor right away if you have any symptoms of an infection (see above).
These may be signs of infections such as chest infections, or skin infections or shingles that could have
serious complications. WEZLANA can make you more likely to get infections or make an infection that you
have worse.
People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12)
and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread
throughout the body and cause death. People who take WEZLANA may also be more likely to get these
infections.
Cancers. WEZLANA may decrease the activity of your immune system and increase your risk for certain
types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving
ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers.
During your treatment with WEZLANA, tell your doctor if you develop any new skin growths.
Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain
and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people
recover. Tell your doctor right away if you have any new or worsening medical problems including:
o
headache
o
confusion
o
seizures
o
vision problems
What is WEZLANA?
WEZLANA is a prescription medicine used to treat:
•
adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking
injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).
•
adults and children 6 years and older with active psoriatic arthritis
•
adults 18 years and older with moderately to severely active Crohn’s disease.
•
adults 18 years and older with moderately to severely active ulcerative colitis.
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It is not known if WEZLANA is safe and effective in children less than 6 years of age.
Do not take WEZLANA if you are allergic to ustekinumab products or any of the ingredients in WEZLANA.
See the end of this Medication Guide for a complete list of ingredients in WEZLANA.
Before you receive WEZLANA, tell your doctor about all of your medical conditions, including if you:
•
have any of the conditions or symptoms listed in the section “What is the most important information
I should know about WEZLANA?”
•
ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.
•
have recently received or are scheduled to receive an immunization (vaccine). People who take
WEZLANA should not receive live vaccines. Tell your doctor if anyone in your house needs a live
vaccine. The viruses used in some types of live vaccines can spread to people with a weakened
immune system and can cause serious problems. You should not receive the BCG vaccine during
the one year before receiving WEZLANA or one year after you stop receiving WEZLANA.
•
have any new or changing lesions within psoriasis areas or on normal skin.
•
are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may
not work as well for you during treatment with WEZLANA. WEZLANA may also increase your risk of
having an allergic reaction to an allergy shot.
•
receive or have received phototherapy for your psoriasis.
•
are pregnant or plan to become pregnant. It is not known if WEZLANA can harm your unborn baby. You
and your doctor should decide if you will receive WEZLANA. See “What should I avoid while using
WEZLANA?”
•
received WEZLANA while you were pregnant. It is important that you tell your baby’s healthcare
provider before any vaccinations are given to your baby.
•
are breastfeeding or plan to breastfeed. WEZLANA can pass into your breast milk.
•
Talk to your doctor about the best way to feed your baby if you receive WEZLANA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new
medicine.
How should I use WEZLANA?
•
Use WEZLANA exactly as your doctor tells you to.
•
The needle cover on the WEZLANA prefilled syringe and prefilled ConfiPen™ autoinjector does
not contain latex.
•
Adults with Crohn’s disease and ulcerative colitis will receive the first dose of WEZLANA through a vein
in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour
to receive the full dose of medicine. You will then receive WEZLANA as an injection under the skin
(subcutaneous injection) 8 weeks after the first dose of WEZLANA, as described below.
•
Adults with psoriasis or psoriatic arthritis and children 6 years and older with psoriasis or psoriatic
arthritis will receive WEZLANA as an injection under the skin (subcutaneous injection) as described
below.
•
Injecting WEZLANA under your skin
o
WEZLANA is intended for use under the guidance and supervision of your doctor. In children 6
years and older, it is recommended that WEZLANA be administered by a healthcare provider. If
your doctor decides that you or a caregiver may give your injections of WEZLANA at home, you
should receive training on the right way to prepare and inject WEZLANA. Your doctor will determine
the right dose of WEZLANA for you, the amount for each injection, and how often you should
receive it. Do not try to inject WEZLANA yourself until you or your caregiver have been shown how
to inject WEZLANA by your doctor or nurse.
o
Inject WEZLANA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs
(thighs) or stomach area (abdomen).
o
Do not give an injection in an area of the skin that is tender, bruised, red or hard.
o
Use a different injection site each time you use WEZLANA.
o
If you inject more WEZLANA than prescribed, call your doctor right away.
o
Be sure to keep all of your scheduled follow-up appointments.
Read the detailed Instructions for Use for instructions about how to prepare and inject a dose of
WEZLANA, and how to properly throw away (dispose of) used needles and syringes. The WEZLANA
syringe, needle, vial and ConfiPen autoinjector must never be re-used. After the rubber stopper of
Reference ID: 5502917
the vial is punctured, WEZLANA can become contaminated by harmful bacteria which could cause
an infection if re-used.
Throw away any unused portion of WEZLANA.
What should I avoid while using WEZLANA?
You should not receive a live vaccine while taking WEZLANA. See “Before you receive WEZLANA, tell
your doctor about all of your medical conditions, including if you:”
What are the possible side effects of WEZLANA?
WEZLANA may cause serious side effects, including:
•
See “What is the most important information I should know about WEZLANA?”
•
Serious allergic reactions. Serious allergic reactions can occur with WEZLANA. Stop using WEZLANA
and get medical help right away if you have any of the following symptoms of a serious allergic reaction:
o
feeling faint
o
chest tightness
o
swelling of your face, eyelids, tongue, or
o
skin rash
throat
•
Lung inflammation. Cases of lung inflammation have happened in some people who receive
ustekinumab products, and may be serious. These lung problems may need to be treated in a hospital.
Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during
treatment with WEZLANA.
Common side effects of WEZLANA include:
•
nasal congestion, sore throat, and runny
•
redness at the injection site
nose
•
vaginal yeast infections
•
upper respiratory infections
•
urinary tract infections
•
fever
•
sinus infection
•
headache
•
bronchitis
•
tiredness
•
diarrhea
•
itching
•
stomach pain
•
nausea and vomiting
These are not all of the possible side effects of WEZLANA. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to 1-800-77-AMGEN (1-800-772-6436).
How should I store WEZLANA?
•
Store WEZLANA vials, prefilled syringes and prefilled ConfiPen autoinjector in a refrigerator between
36°F to 46°F (2°C to 8°C).
•
Store WEZLANA in the original carton to protect it from light until time to use it.
•
Do not freeze WEZLANA.
•
Do not shake WEZLANA.
If needed, individual prefilled syringe, 45 mg vial and prefilled ConfiPen autoinjector may also be
stored at room temperature up to 30°C (86°F) for a maximum single period of up to 30 days in the
original carton to protect from light. Record the date when the prefilled syringe, the 45 mg vial or
prefilled ConfiPen autoinjector is first removed from the refrigerator on the carton in the space
provided. Once the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector has been stored
at room temperature, it should not be returned to the refrigerator.
Discard the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector if not used within 30
days at room temperature storage. Do not use WEZLANA after the expiration date on the carton or on
the prefilled syringe, on the 45 mg vial or on the prefilled ConfiPen autoinjector.
Keep WEZLANA and all medicines out of the reach of children.
General information about the safe and effective use of WEZLANA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
WEZLANA for a condition for which it was not prescribed. Do not give WEZLANA to other people, even if
they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for
information about WEZLANA that was written for health professionals.
Reference ID: 5502917
AMGEN
What are the ingredients in WEZLANA?
Active ingredient: ustekinumab-auub
Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains histidine, histidine
hydrochloride monohydrate, Polysorbate 80, and sucrose. Single-dose vial for subcutaneous use
contains histidine, histidine hydrochloride monohydrate, Polysorbate 80 and sucrose. Single-dose prefilled
ConfiPen autoinjector for subcutaneous use contains histidine, histidine hydrochloride monohydrate,
Polysorbate 80, and sucrose. Single-dose vial for intravenous infusion contains edetate disodium,
histidine, histidine hydrochloride monohydrate, methionine, Polysorbate 80, and sucrose.
WEZLANA™(ustekinumab-auub)
Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799 U.S.A.
US License Number 1080
© 2023–YYYY Amgen Inc. All rights reserved.
1xxxxxx – vxx
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
Reference ID: 5502917
INSTRUCTIONS FOR USE
WEZLANA™ [wez-LAH-nah]
(ustekinumab-auub)
injection, for subcutaneous use
single-dose prefilled ConfiPen™ autoinjector
This Instructions for Use contains information on how to inject WEZLANA with an ConfiPen
autoinjector.
The medicine in the WEZLANA autoinjector is for injection under-the-skin (subcutaneous injection).
See the WEZLANA Medication Guide for information about WEZLANA.
Getting to know the prefilled autoinjector
Expiration date
Plunger (may be visible in the window;
location may vary)
Window
Medicine
Yellow safety guard under cap
(needle inside)
Cap
Important Information You Need to Know Before Injecting WEZLANA
Dosing:
•
WEZLANA comes in two different doses: 45 mg and 90 mg. Check the prescription to make
sure you have the correct dose.
•
The label color and window size of the autoinjector will be different for each dose. The amount
of medicine in the autoinjector will also be different for each dose.
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[□~ (Q)
111111
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)
"""~
[□ ~
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1111 II
1
1 )
IU2560 v3
45 mg
90 mg
Important:
•
If the dose is 90 mg, you will receive either one 90 mg autoinjector or two 45 mg
autoinjectors.
−
If you receive two 45 mg autoinjectors for a 90 mg dose, you will need to give a second
injection right after the first.
−
Repeat Steps 1-16 for the second injection using a new autoinjector.
−
Choose a different site for the second injection.
Using your WEZLANA ConfiPen autoinjector:
•
It is important that you do not try to give the injection until you have fully read and understood
this Instructions for Use.
•
If your doctor decides that you or a caregiver can give your WEZLANA injection at home, you
should receive training on the right way to prepare and inject WEZLANA. Do not try to inject
WEZLANA yourself until you have been shown the right way to give the injections by your
doctor or nurse.
•
Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use an
autoinjector under supervision of a parent or caregiver.
•
Do not use the autoinjector if the carton is damaged or the seal is broken.
•
Do not use the autoinjector after the expiration date on the label.
•
Do not shake the autoinjector.
•
Do not remove the cap from the autoinjector until you are ready to inject.
•
Do not use the autoinjector if it has been frozen.
•
Do not use the autoinjector if it has been dropped on a hard surface. Part of the autoinjector may
be broken even if you cannot see the break. Use a new autoinjector, and call 1-800-77-AMGEN
(1-800-772-6436).
•
The autoinjector is not made with natural rubber latex.
Important: Keep the autoinjector and sharps disposal container out of the sight and reach of
children.
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■
minutes
■
Frequently asked questions:
For additional information and answers to frequently asked questions, visit www.WEZLANA.com.
Where to get help:
If you want more information or help using WEZLANA:
•
Contact your healthcare provider,
•
Visit www.WEZLANA.com, or
•
Call 1-800-77-AMGEN (1-800-772-6436).
Storing and Preparing to Inject WEZLANA
Refrigerate in carton until ready to use
1 Refrigerate the autoinjector carton until you are ready to use it.
•
Keep the autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C).
•
Keep the autoinjector in the original carton to protect it from light or physical damage.
•
Do not freeze the autoinjector.
•
Do not store the autoinjector in extreme heat or cold. For example, avoid storing in your
vehicle’s glove box or trunk.
Important: Keep the autoinjector out of the sight and reach of children.
WAIT
2 Wait 30 minutes for the autoinjector to reach room temperature.
•
Remove the number of autoinjectors you need for the injection from the refrigerator.
•
Let the autoinjector warm up naturally.
•
Do not heat the autoinjector with hot water, a microwave, or direct sunlight.
•
Do not put the autoinjector back in the refrigerator once it reaches room temperature.
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■
■
0-0
30
days
•
Do not shake the autoinjector at any time.
•
Using the autoinjector at room temperature ensures the full dose is delivered and allows for a
more comfortable injection.
3 You may keep WEZLANA at room temperature for up to 30 days, if needed.
•
For example, when you are traveling, you may keep WEZLANA at room temperature.
•
Keep it at room temperature between 68°F to 77°F (20°C to 25°C).
•
Do not use if it has been stored above 86°F (30°C).
•
Record the date you removed it from the refrigerator and use within 30 days.
Important: Place the autoinjector in a sharps disposal container if it has reached room
temperature and has not been used within 30 days.
Medicine
4 Inspect the medicine. It should be clear to white like an opal and colorless to light
yellow.
•
It is okay to see air bubbles.
•
Do not use WEZLANA if the medicine is cloudy, discolored, or has particles.
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■
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ox
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Expiration date
5 Check the expiration date (Exp.) and inspect the autoinjector for damage.
•
Do not use the autoinjector if the expiration date has passed.
•
Do not use the autoinjector if:
−
the cap is missing or loose,
−
it has cracks or broken parts, or
−
it has been dropped on a hard surface.
•
Make sure you have the right medicine and dose.
Important: If the medicine is cloudy, discolored, or has particles, or if the autoinjector is
damaged or expired, call 1-800-77-AMGEN (1-800-772-6436).
Getting Ready to Inject WEZLANA
Sharps disposal
container
Alcohol wipe
Adhesive bandage
Cotton ball or gauze pad
6 Gather and place the following items for the injection on a clean, flat, and well-lit
surface:
•
WEZLANA autoinjector (room temperature),
•
Sharps disposal container [see Disposing of WEZLANA and Checking the Injection Site]
•
Alcohol wipe,
•
Adhesive bandage, and
•
Cotton ball or gauze pad.
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■
■
■
7 Select 1 of these injection locations.
•
Select the front of your thigh or
stomach (except for 2 inches around
your belly button).
•
Someone else can inject in your thigh,
stomach, back of your upper arm, or
buttocks.
Important: Avoid areas with scars, stretch marks or where the skin is tender, bruised, red, or hard.
8 Wash your hands thoroughly with soap and water.
9 Clean the injection site with an alcohol wipe.
Reference ID: 5502917
•
Let the skin dry on its own.
•
Do not touch this area again before injecting.
Injecting WEZLANA
Important: Only remove the cap when you can inject right away (within 5 minutes) because the
medicine can dry out. Do not recap.
Window should
be visible
_____
_JI
■
■
10 Pull hard or twist to remove the cap. Never put the cap back on as it may
damage the needle.
•
It is normal to see a drop of medicine come out of the needle or yellow safety guard.
Important: Do not touch or push the yellow safety guard. Do not put your finger inside of the
yellow safety guard.
11 Pinch the skin to create a firm surface at the injection site.
Place the yellow safety guard straight against the pinched skin.
•
Keep the skin pinched until the injection is finished.
•
Make sure you can see the window.
•
Make sure the autoinjector is positioned straight on the injection site (at a 90-degree angle).
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■
■
■
PUSH & HOLD
down to start injection
12 Firmly push the autoinjector down until the yellow safety guard stops moving.
Hold the autoinjector down, do not lift.
•
The needle will insert and the injection begins.
•
You may hear or feel a click.
•
Hold the autoinjector straight and steady on the skin.
WATCH until COMPLETE
window will turn fully yellow
13 Keep pushing down the autoinjector. Wait for the window to turn fully yellow.
•
The injection can take up to 15 seconds to complete. You may hear or feel a click.
•
After the window turns fully yellow, lift the autoinjector away from the skin.
Completing the Injection
CONFIRM
Window is fully yellow
No medicine leaked out (a small
drop is okay)
14 Confirm a full dose of medicine was injected.
•
Do not touch the yellow safety guard.
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======--1
■
■
•
A small amount of liquid on the injection site is okay.
Important: If the window has not turned fully yellow, if it looks like the medicine is still coming
out, or if you see several drops of medicine, a full dose was not injected. Call your healthcare
provider immediately.
15 Check the injection site.
•
Do not rub the injection site.
•
If there is blood, press a cotton ball or gauze pad on the injection site.
•
Apply an adhesive bandage if necessary.
16 Place the used autoinjector and cap in an FDA-cleared sharps disposal container.
Important: Do not throw away the autoinjector in your household trash.
•
Do not reuse the autoinjector.
•
Do not touch the yellow safety guard.
Additional information about your sharps disposal container
If you do not have an FDA-cleared sharps disposal container, you may use a household container
that is:
•
made of a heavy-duty plastic,
•
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
•
upright and stable during use,
•
leak-resistant, and
Reference ID: 5502917
•
properly labeled to warn of hazardous waste inside the container.
Disposing of sharps containers:
When your sharps disposal container is almost full, you will need to follow your community guidelines
for the right way to dispose of your sharps disposal container.
There may be state or local laws about how you should throw away used needles and syringes.
For more information about safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website at:
https://www.fda.gov/safesharpsdisposal
Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this.
Do not recycle your used sharps disposal container.
For more information or help call 1-800-77-AMGEN (1-800-772-6436).
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
US License Number 1080
©YYYY Amgen Inc.
All rights reserved.
Issued 12/2024
Reference ID: 5502917
| custom-source | 2025-02-12T15:48:18.433181 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761285s001,761331s001lbl.pdf', 'application_number': 761331, 'submission_type': 'SUPPL ', 'submission_number': 1} |
80,765 |
I
I
I
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WEZLANA™ safely and effectively. See full prescribing information for
WEZLANA.
WEZLANA™ (ustekinumab-auub) injection, for subcutaneous or
intravenous use
Initial U.S. Approval: 2023
WEZLANA™ (ustekinumab-auub) is biosimilar* to STELARA®
(ustekinumab).
------------------RECENT MAJOR CHANGES-----------------
Dosage and Administration (2.4, 2.6)
12/2024
-----------------INDICATIONS AND USAGE------------------
WEZLANA is a human interleukin -12 and -23 antagonist indicated for the
treatment of:
Adult patients with:
•
moderate to severe plaque psoriasis (PsO) who are
candidates for phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
•
moderately to severely active Crohn’s disease (CD). (1.3)
•
moderately to severely active ulcerative colitis. (1.4)
Pediatric patients 6 years and older with:
•
moderate to severe plaque psoriasis, who are candidates
for phototherapy or systemic therapy. (1.1)
•
active psoriatic arthritis (PsA). (1.2)
-------------DOSAGE AND ADMINISTRATION--------------
Psoriasis Adult Subcutaneous Recommended Dosage (2.1):
Weight Range (kilograms) Recommended Dosage
less than or equal to 100 kg
45 mg administered subcutaneously initially
and 4 weeks later, followed by 45 mg
administered subcutaneously every 12 weeks
greater than 100 kg
90 mg administered subcutaneously initially
and 4 weeks later, followed by 90 mg
administered subcutaneously every 12 weeks
Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended
Dosage (2.1):
Weight-based dosing is recommended at the initial dose, 4 weeks later, then
every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
greater than 100 kg
90 mg
Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2):
•
The recommended dosage is 45 mg administered subcutaneously
initially and 4 weeks later, followed by 45 mg administered
subcutaneously every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis
weighing greater than 100 kg, the recommended dosage is 90 mg
administered subcutaneously initially and 4 weeks later, followed by
90 mg administered subcutaneously every 12 weeks.
Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended
Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4
weeks later, then every 12 weeks thereafter.
Weight Range (kilograms)
Dose
less than 60 kg
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co-existent
moderate-to-severe plaque psoriasis
90 mg
Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous
Recommended Dosage (2.3):
A single intravenous infusion using weight-based dosing:
Weight Range (kilograms)
Dose
up to 55 kg
260 mg (2 vials)
greater than 55 kg to 85 kg
390 mg (3 vials)
greater than 85 kg
520 mg (4 vials)
Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous
Recommended Dosage (2.3):
A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then
every 8 weeks thereafter.
------------DOSAGE FORMS AND STRENGTHS------------
Subcutaneous Injection (3)
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled
syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled
ConfiPen autoinjector
Intravenous Infusion (3)
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
--------------------CONTRAINDICATIONS---------------------
Clinically significant hypersensitivity to ustekinumab products or to any of the
excipients in WEZLANA. (4)
-------------WARNINGS AND PRECAUTIONS---------------
•
Infections: Serious infections have occurred. Avoid starting WEZLANA
during any clinically important active infection. If a serious infection or
clinically significant infection develops, discontinue WEZLANA until
the infection resolves. (5.1)
•
Theoretical Risk for Particular Infections: Serious infections from
mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG)
vaccinations have been reported in patients genetically deficient in
IL-12/IL-23. Consider diagnostic tests for these infections as dictated by
clinical circumstances. (5.2)
•
Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment
with WEZLANA. Initiate treatment of latent TB before administering
WEZLANA. (5.3)
•
Malignancies: Ustekinumab products may increase risk of malignancy.
The safety of ustekinumab products in patients with a history of or a
known malignancy has not been evaluated. (5.4)
•
Hypersensitivity Reactions: If an anaphylactic or other clinically
significant hypersensitivity reaction occurs, institute appropriate therapy
and discontinue WEZLANA. (5.5)
•
Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is
suspected, treat promptly and discontinue WEZLANA. (5.6)
•
Immunizations: Avoid use of live vaccines in patients during treatment
with WEZLANA. (5.7)
•
Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic
pneumonia and cryptogenic organizing pneumonia have been reported
during post-approval use of ustekinumab products. If diagnosis is
confirmed, discontinue WEZLANA and institute appropriate treatment.
(5.8)
--------------------ADVERSE REACTIONS----------------------
Most common adverse reactions are:
•
Psoriasis (≥ 3%): nasopharyngitis, upper respiratory tract infection,
headache, and fatigue. (6.1)
•
Crohn’s Disease, induction (≥ 3%): vomiting. (6.1)
•
Crohn’s Disease, maintenance (≥ 3%): nasopharyngitis, injection site
erythema, vulvovaginal candidiasis/mycotic infection, bronchitis,
pruritus, urinary tract infection, and sinusitis. (6.1)
•
Ulcerative colitis, induction (≥ 3%): nasopharyngitis. (6.1)
•
Ulcerative colitis, maintenance (≥ 3%): nasopharyngitis, headache,
abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen
Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
1 of 34
Reference ID: 5502917
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
* Biosimilar means that the biological product is approved based on data
demonstrating that it is highly similar to an FDA-approved biological product
known as a reference product, and that there are no clinically meaningful
differences between the biosimilar product and the reference product.
Biosimilarity of WEZLANA has been demonstrated for the condition(s) of use
(e.g., indication(s), dosing regimen(s), strength(s), dosage form(s), and route(s)
of administration described in its Full Prescribing Information.
2 of 34
Reference ID: 5502917
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Plaque Psoriasis (PsO)
1.2 Psoriatic Arthritis (PsA)
1.3 Crohn’s Disease (CD)
1.4 Ulcerative Colitis
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage in Plaque Psoriasis
2.2 Recommended Dosage in Psoriatic Arthritis
2.3 Recommended Dosage in Crohn’s Disease and Ulcerative Colitis
2.4 General Considerations for Administration
2.5 Instructions for Administration of WEZLANA Prefilled Syringes
Equipped with Needle Safety Guard
2.6 Instructions for Administration of WEZLANA Prefilled ConfiPen
Autoinjector
2.7 Preparation and Administration of WEZLANA 130 mg/26 mL
(5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and
Ulcerative Colitis)
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Infections
5.2 Theoretical Risk for Vulnerability to Particular Infections
5.3 Pre-treatment Evaluation for Tuberculosis
5.4 Malignancies
5.5 Hypersensitivity Reactions
5.6 Posterior Reversible Encephalopathy Syndrome (PRES)
5.7 Immunizations
5.8 Noninfectious Pneumonia
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Concomitant Therapies
7.2 CYP450 Substrates
7.3 Allergen Immunotherapy
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1 Adult Plaque Psoriasis
14.2 Pediatric Plaque Psoriasis
14.3 Psoriatic Arthritis
14.4 Crohn’s Disease
14.5 Ulcerative Colitis
15
REFERENCES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1
Plaque Psoriasis (PsO)
WEZLANA is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe
plaque psoriasis who are candidates for phototherapy or systemic therapy.
1.2
Psoriatic Arthritis (PsA)
WEZLANA is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic
arthritis.
1.3
Crohn's Disease (CD)
WEZLANA is indicated for the treatment of adult patients with moderately to severely active Crohn's disease.
1.4
Ulcerative Colitis
WEZLANA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis.
2 DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage in Plaque Psoriasis
Subcutaneous Adult Dosage Regimen
•
For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed
by 45 mg every 12 weeks.
•
For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later,
followed by 90 mg every 12 weeks.
In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater
efficacy in these subjects [see Clinical Studies (14)].
Subcutaneous Pediatric Dosage Regimen
Administer WEZLANA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of WEZLANA for pediatric patients (6–17 years old) with plaque psoriasis based on body weight
is shown below (Table 1).
Table 1. Recommended Dose of WEZLANA for Subcutaneous Injection in Pediatric Patients
(6–17 years old) with Plaque Psoriasis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg
0.75 mg/kg
60 kg to 100 kg
45 mg
more than 100 kg
90 mg
For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is
shown in Table 2; withdraw the appropriate volume from the single-dose vial.
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15
20
25
30
35
40
45
50
Table 2. Injection Volumes of WEZLANA 45 mg/0.5 mL Single-dose Vials for Pediatric Patients
(6–17 years old) with Plaque Psoriasis and Pediatric Patients (6-17 years old) with Psoriatic Arthritis* Weighing
Less Than 60 kg
Body Weight (kg) at the
Volume of
time of dosing
Dose (mg)
injection (mL)
11.3
0.12
16
12.0
0.13
17
12.8
0.14
18
13.5
0.15
19
14.3
0.16
15.0
0.17
21
15.8
0.17
22
16.5
0.18
23
17.3
0.19
24
18.0
0.20
18.8
0.21
26
19.5
0.22
27
20.3
0.22
28
21.0
0.23
29
21.8
0.24
22.5
0.25
31
23.3
0.26
32
24.0
0.27
33
24.8
0.27
34
25.5
0.28
26.3
0.29
36
27.0
0.30
37
27.8
0.31
38
28.5
0.32
39
29.3
0.32
30.0
0.33
41
30.8
0.34
42
31.5
0.35
43
32.3
0.36
44
33.0
0.37
33.8
0.37
46
34.5
0.38
47
35.3
0.39
48
36.0
0.40
49
36.8
0.41
37.5
0.42
51
38.3
0.42
52
39.0
0.43
53
39.8
0.44
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Body Weight (kg) at the
Volume of
time of dosing
Dose (mg)
injection (mL)
54
40.5
0.45
55
41.3
0.46
56
42.0
0.46
57
42.8
0.47
58
43.5
0.48
59
44.3
0.49
*
Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen.
2.2
Recommended Dosage in Psoriatic Arthritis
Subcutaneous Adult Dosage Regimen
•
The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
•
For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the
recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
Subcutaneous Pediatric Dosage Regimen
Administer WEZLANA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter.
The recommended dose of WEZLANA for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body
weight, is shown below (Table 3).
Table 3. Recommended Dose of WEZLANA for Subcutaneous Injection in Pediatric Patients
(6 to 17 years old) with Psoriatic Arthritis
Body Weight of Patient at the Time of Dosing
Recommended Dose
less than 60 kg*
0.75 mg/kg
60 kg or more
45 mg
greater than 100 kg with co-existent moderate-to-severe
90 mg
plaque psoriasis
*
For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is
shown in Table 2; withdraw the appropriate volume from the single-dose vial.
2.3
Recommended Dosage in Crohn's Disease and Ulcerative Colitis
Intravenous Induction Adult Dosage Regimen
A single intravenous infusion dose of WEZLANA using the weight-based dosage regimen specified in Table 4 [see
Instructions for dilution of WEZLANA 130 mg vial for intravenous infusion (2.6)].
Table 4. Initial Intravenous Dosage of WEZLANA
Body Weight of Patient at the
time of dosing
Dose
Number of 130 mg/26 mL
(5 mg/mL) WEZLANA vials
55 kg or less
260 mg
2
more than 55 kg to 85 kg
390 mg
3
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more than 85 kg
520 mg
4
Subcutaneous Maintenance Adult Dosage Regimen
The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous
dose, then every 8 weeks thereafter.
2.4
General Considerations for Administration
•
WEZLANA is intended for use under the guidance and supervision of a healthcare provider. WEZLANA should
only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare
provider. The appropriate dose should be determined by a healthcare provider using the patient's current weight at
the time of dosing. In pediatric patients, it is recommended that WEZLANA be administered by a healthcare
provider. If a healthcare provider determines that it is appropriate, a patient may self-inject, or a caregiver may
inject WEZLANA after proper training in subcutaneous injection technique. Instruct patients to follow the
directions provided in the Medication Guide [see Medication Guide].
•
The needle cap on the prefilled syringe does not contain dry natural rubber (a derivative of latex). The prefilled
ConfiPen autoinjector is not made with natural rubber latex.
•
It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal
regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is
tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 27 gauge,
½ inch needle is recommended.
•
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. WEZLANA is a clear to opalescent and colorless to light
yellow solution. Do not use WEZLANA if it is discolored or cloudy, or if other particulate matter is present.
WEZLANA does not contain preservatives; therefore, discard any unused product remaining in the ConfiPen
autoinjector, vial and/or syringe.
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2.5
Instructions for Administration of WEZLANA Prefilled Syringes Equipped with Needle Safety Guard
Refer to the diagram below for the provided instructions.
To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD CLIPS at any time
during use.
Plunger
Viewing
Plunger
rod
(location may vary)
Body
window
Plunger
head
Needle
guard clips
Finger grip
Label
Needle cap
(needle inside)
•
Hold the BODY and remove the NEEDLE CAP. Do not hold the PLUNGER or PLUNGER HEAD while
removing the NEEDLE CAP or the PLUNGER may move. Do not use the prefilled syringe if it is dropped
without the NEEDLE CAP in place.
Inject WEZLANA subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)].
•
Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the
finger grip. Injection of the entire prefilled syringe contents is necessary to activate the needle guard.
•
After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly
take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is
covered by the needle guard, as shown by the illustration below:
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Used syringes should be placed in a puncture-resistant container.
2.6
Instructions for Administration of WEZLANA Prefilled ConfiPen Autoinjector
The WEZLANA single-dose prefilled ConfiPen autoinjector “Instructions for Use” insert contains detailed instructions on
preparation, injection site selection, administration and disposal.
Expiration
date
Plunger
(may be visible in the window; location
may vary)
Window
Medicine
Yellow safety
guard under cap
(needle inside)
Cap
2.7
Preparation and Administration of WEZLANA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion
(Crohn's Disease and Ulcerative Colitis)
WEZLANA solution for intravenous infusion must be diluted, prepared and infused by a healthcare professional using
aseptic technique.
1. Calculate the dose and the number of WEZLANA vials needed based on patient weight (Table 4). Each 26 mL vial of
WEZLANA contains 130 mg of ustekinumab-auub.
2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal
to the volume of WEZLANA to be added (discard 26 mL sodium chloride for each vial of WEZLANA needed, for 2
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vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag
containing 0.45% Sodium Chloride Injection, USP may be used.
3. Withdraw 26 mL of WEZLANA from each vial needed and add it to the 250 mL infusion bag. The final volume in the
infusion bag should be 250 mL. Gently mix.
4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Do not use if visibly opaque particles, discoloration or foreign particles are
observed.
5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely
administered within eight hours of the dilution in the infusion bag.
6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer).
7. Do not infuse WEZLANA concomitantly in the same intravenous line with other agents.
8. WEZLANA does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining
solution. Dispose any unused medicinal product in accordance with local requirements.
Storage
If necessary, the diluted infusion solution may be kept at room temperature up to 25°C (77°F) for up to 7 hours. Storage
time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within
8 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion
period). Do not freeze. Discard any unused portion of the infusion solution.
3
DOSAGE FORMS AND STRENGTHS
WEZLANA (ustekinumab-auub) is a clear to opalescent and colorless to light yellow solution.
Subcutaneous Injection
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe
•
Injection: 45 mg/0.5 mL solution in a single-dose vial
•
Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled ConfiPen autoinjector
Intravenous Infusion
•
Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
4
CONTRAINDICATIONS
WEZLANA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of
the excipients in WEZLANA [see Warnings and Precautions (5.5)].
5 WARNINGS AND PRECAUTIONS
5.1
Infections
Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial,
mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse
Reactions (6.1, 6.3)].
Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included
the following:
•
Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral
infections, gastroenteritis and urinary tract infections.
•
Psoriatic arthritis: cholecystitis.
•
Crohn's disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.
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•
Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis.
Avoid initiating treatment with WEZLANA in patients with any clinically important active infection until the infection
resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of WEZLANA in
patients with a chronic infection or a history of recurrent infection.
Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with
WEZLANA and discontinue WEZLANA for serious or clinically significant infections until the infection resolves or is
adequately treated.
5.2
Theoretical Risk for Vulnerability to Particular Infections
Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria
(including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus
Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.
It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products
may be susceptible to these types of infections. Consider appropriate diagnostic testing (e.g., tissue culture, stool culture, as
dictated by clinical circumstances).
5.3
Pre-treatment Evaluation for Tuberculosis
Evaluate patients for tuberculosis infection prior to initiating treatment with WEZLANA.
Avoid administering WEZLANA to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis
prior to administering WEZLANA. Consider anti-tuberculosis therapy prior to initiation of WEZLANA in patients with a
past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor
patients receiving WEZLANA for signs and symptoms of active tuberculosis during and after treatment.
5.4
Malignancies
Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported
among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of
IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)].
The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a
known malignancy.
There have been postmarketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients
receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all
patients receiving WEZLANA for the appearance of non-melanoma skin cancer. Closely follow patients greater than
60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA
treatment [see Adverse Reactions (6.1)].
5.5
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see
Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute
appropriate therapy and discontinue WEZLANA.
5.6
Posterior Reversible Encephalopathy Syndrome (PRES)
Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior
Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing
experience in patients with psoriasis, psoriatic arthritis and Crohn's disease. Clinical presentation included headaches,
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seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after
ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care
following withdrawal of ustekinumab products.
Monitor all patients treated with WEZLANA for signs and symptoms of PRES. If PRES is suspected, promptly administer
appropriate treatment, and discontinue WEZLANA.
5.7
Immunizations
Prior to initiating therapy with WEZLANA, patients should receive all age-appropriate immunizations as recommended by
current immunization guidelines. Patients being treated with WEZLANA should avoid receiving live vaccines. Avoid
administering BCG vaccines during treatment with WEZLANA or for one year prior to initiating treatment or one year
following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of
patients receiving WEZLANA because of the potential risk for shedding from the household contact and transmission to
patient.
Non-live vaccinations received during a course of WEZLANA may not elicit an immune response sufficient to prevent
disease.
5.8
Noninfectious Pneumonia
Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during
post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates
following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients
improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed,
discontinue WEZLANA and institute appropriate treatment [see Postmarketing Experience (6.3)].
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the label:
•
Infections [see Warnings and Precautions (5.1)]
•
Malignancies [see Warnings and Precautions (5.4)]
•
Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
•
Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)]
•
Noninfectious Pneumonia [see Warnings and Precautions (5.8)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in
practice.
Adult Subjects with Plaque Psoriasis
The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at
least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three
years, 1482 exposed for at least four years and 838 exposed for at least five years.
Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups
during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)].
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Table 5. Adverse Reactions Reported by ≥ 1% of Subjects with Plaque Psoriasis and at Higher Rates in the
Ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2
Ustekinumab
Placebo
45 mg
90 mg
Subjects treated
665
664
666
Nasopharyngitis
51 (8%)
56 (8%)
49 (7%)
Upper respiratory tract infection
30 (5%)
36 (5%)
28 (4%)
Headache
23 (3%)
33 (5%)
32 (5%)
Fatigue
14 (2%)
18 (3%)
17 (3%)
Back pain
8 (1%)
9 (1%)
14 (2%)
Dizziness
8 (1%)
8 (1%)
14 (2%)
Pharyngolaryngeal pain
7 (1%)
9 (1%)
12 (2%)
Pruritus
9 (1%)
10 (2%)
9 (1%)
Injection site erythema
3 (< 1%)
6 (1%)
13 (2%)
Myalgia
4 (1%)
7 (1%)
8 (1%)
Depression
3 (< 1%)
8 (1%)
4 (1%)
Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12
included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration,
hemorrhage, bruising, and irritation).
One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions (5.6)].
Infections
In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow-up of 12.6 weeks for
placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported
infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of
follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per subject-year of follow-up) and in
0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)].
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years),
representing 8998 subject-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per
subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).
Malignancies
In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing
8998 subject-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma
skin cancers (0.60 per hundred subject-years of follow-up).
Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred subject-years of
follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma
skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than
non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were
similar in type and number to what would be expected in the general U.S. population according to the SEER database
(adjusted for age, gender and race).1
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Pediatric Subjects with Plaque Psoriasis
The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps
STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety
for up to 56 weeks in 44 pediatric subjects 6 to 11years old. The safety profile in pediatric subjects was similar to the safety
profile from trials in adults with plaque psoriasis.
Psoriatic Arthritis
The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo-controlled trials in
adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent
with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections
was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and
3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.
Crohn's Disease
The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn's disease (Crohn's
Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized,
double-blind, placebo-controlled, parallel-group, multicenter trials. These 1407 subjects included 40 subjects who received
a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1
and CD-2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose
and 466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in either trial CD-1
or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or
placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including
aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral
corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn's disease [see Clinical Studies (14.4)].
The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult psoriasis and psoriatic
arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 6 and 7,
respectively.
Table 6. Common Adverse Reactions Through Week 8 in Trials CD-1 and CD-2 Occurring in ≥ 3% of
Ustekinumab-Treated Subjects and Higher Than Placebo
Placebo
Ustekinumab
6 mg/kg single intravenous
induction dose
N = 466
N = 470
Vomiting
3%
4%
Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne
(1% vs 0.4%), and pruritus (2% vs 0.4%).
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Table 7. Common Adverse Reactions Through Week 44 in Trial CD-3 Occurring in ≥ 3% of Ustekinumab-Treated
Subjects and Higher Than Placebo
Ustekinumab
Placebo
90 mg subcutaneous
maintenance dose every
8 weeks
N = 133
N = 131
Nasopharyngitis
Injection site erythema
Vulvovaginal candidiasis/mycotic
infection
8%
0
1%
11%
5%
5%
Bronchitis
3%
5%
Pruritus
2%
4%
Urinary tract infection
Sinusitis
2%
2%
4%
3%
Infections
In subjects with Crohn's disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and
pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one patient each [see Warnings
and Precautions (5.1)].
Malignancies
With up to one year of treatment in the Crohn's disease clinical trials, 0.2% of ustekinumab-treated subjects (0.36 events
per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed
non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated
subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects.
Hypersensitivity Reactions Including Anaphylaxis
In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One patient
experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing)
after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab). In addition, one subject
experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing,
urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving
intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases,
symptoms resolved within an hour.
Ulcerative Colitis
The safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV
induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see
Clinical Studies (14.5)]. The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with
the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated
subjects and at a higher rate than placebo were:
•
Induction (UC-1): nasopharyngitis (7% vs 4%).
•
Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%),
influenza (6% vs 5%), fever (5% vs 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and
nausea (3% vs 2%).
Infections
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In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia.
In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions
(5.1)].
Malignancies
With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab-treated subjects (0.48 events
per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient-years) developed
non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated
subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred
patient-years).
6.2
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.
Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies
described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other
ustekinumab products.
Approximately 6 to 12.4% of subjects treated with ustekinumab in plaque psoriasis and psoriatic arthritis clinical trials
developed antibodies to ustekinumab, which were generally low-titer. In plaque psoriasis clinical trials, antibodies to
ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In
plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing
antibodies.
In Crohn's disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, developed antibodies to
ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the
development of antibodies to ustekinumab and the development of injection site reactions was seen.
6.3
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to ustekinumab product exposure.
Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other
hypersensitivity reactions (including rash and urticaria).
Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis).
Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES).
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia and cryptogenic
organizing pneumonia.
Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis.
7
DRUG INTERACTIONS
7.1
Concomitant Therapies
In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive agents or
phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the
safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis induction trials, immunomodulators (6-MP,
AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in
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approximately 40% and 50% of Crohn's disease and ulcerative colitis subjects, respectively. Use of these concomitant
therapies did not appear to influence the overall safety or efficacy of ustekinumab.
7.2
CYP450 Substrates
The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα,
IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the
formation of CYP450 enzymes. Upon initiation or discontinuation of WEZLANA in patients who are receiving
concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic
effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing
information of specific CYP substrates.
A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology
(12.3)].
7.3
Allergen Immunotherapy
Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab
products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of
an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or
who have received allergen immunotherapy, particularly for anaphylaxis.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab
products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other
adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy
progresses and peaks during the third trimester; therefore, ustekinumab products may be transferred to the developing fetus
[see Clinical Considerations]. In animal reproductive and developmental toxicity studies, no adverse developmental
effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100
times the maximum recommended human dose (MRHD).
The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies
have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%,
respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits
prior to administering live vaccines to infants exposed to WEZLANA in utero. There are insufficient data regarding
exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in
infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants
exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the
clearance of the product.
Data
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Animal Data
Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or
other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab
subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of
ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously
with 90 mg of ustekinumab weekly for 4 weeks.
In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus
monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the
MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one
monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on
functional, morphological, or immunological development were observed in the neonates from birth through six months of
age.
8.2
Lactation
Risk Summary
Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available
data on the effects of ustekinumab products on milk production. The effects of local gastrointestinal exposure and limited
systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant
causally related to ustekinumab products have been identified in the published literature or postmarketing experience.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for
WEZLANA and any potential adverse effects on the breastfed child from WEZLANA or from the underlying maternal
condition.
8.4
Pediatric Use
Plaque Psoriasis
The safety and effectiveness of WEZLANA have been established for the treatment of moderate to severe plaque psoriasis
in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy.
Use of WEZLANA in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter,
randomized, 60-week trial (Ps STUDY 3) of ustekinumab that included a 12-week, double-blind, placebo-controlled,
parallel-group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies
(14.2)].
Use of WEZLANA in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm,
efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects [see Adverse Reactions (6.1),
Pharmacokinetics (12.3)].
The safety and effectiveness of WEZLANA have not been established in pediatric patients less than 6 years of age with
plaque psoriasis.
Psoriatic Arthritis
The safety and effectiveness of WEZLANA have been established for treatment of psoriatic arthritis in pediatric patients 6
to 17 years old.
Use of WEZLANA in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab
in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and
pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects 6 to
11 years old with psoriasis and 110 pediatric subjects 12 to 17 years old with psoriasis. The observed pre-dose (trough)
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concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric
subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)].
The safety and effectiveness of WEZLANA have not been established in pediatric patients less than 6 years old with
psoriatic arthritis.
Crohn’s Disease and Ulcerative Colitis
The safety and effectiveness of WEZLANA have not been established in pediatric patients with Crohn’s disease or
ulcerative colitis.
8.5
Geriatric Use
Of the 6709 subjects exposed to ustekinumab, a total of 340 were 65 years of age or older (183 subjects with plaque
psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn's disease and 34 subjects with ulcerative colitis), and
40 subjects were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of subjects 65
years of age and older to determine whether they respond differently from younger adult subjects.
10
OVERDOSAGE
Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose-limiting toxicity. In case of
overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate
symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist
for additional overdose management recommendations.
11
DESCRIPTION
Ustekinumab-auub, a human IgG1κ monoclonal antibody, is a human interleukin -12 and -23 antagonist. Using DNA
recombinant technology, ustekinumab-auub is produced in a mammalian cell line (Chinese Hamster Ovary). The
manufacturing process contains steps for the clearance of viruses. Ustekinumab-auub is comprised of 1326 amino acids
and has an estimated molecular mass that ranges from 148 to 150 kDa.
WEZLANA (ustekinumab-auub) injection is a sterile, preservative-free, clear to opalescent and colorless to light yellow
solution with a pH of 6.0.
WEZLANA for Subcutaneous Use
Available as 45 mg of ustekinumab-auub in 0.5 mL and 90 mg of ustekinumab-auub in 1 mL, supplied as a sterile solution
in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle and a single-dose prefilled ConfiPen autoinjector,
and as 45 mg of ustekinumab-auub in 0.5 mL in a single-dose Type I glass vial with a coated stopper. The syringe is fitted
with a passive needle guard and a needle cap that does not contain dry natural rubber (a derivative of latex). The prefilled
ConfiPen autoinjector is not made with natural rubber latex.
Each 0.5 mL prefilled syringe, prefilled ConfiPen autoinjector or vial delivers 45 mg ustekinumab-auub, histidine (0.23
mg) and histidine hydrochloride monohydrate (0.36 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg).
Each 1 mL prefilled syringe, or prefilled ConfiPen autoinjector delivers 90 mg ustekinumab-auub, histidine (0.46 mg) and
histidine hydrochloride monohydrate (0.72 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg).
WEZLANA for Intravenous Infusion
Available as 130 mg of ustekinumab-auub in 26 mL, supplied as a single-dose Type I glass vial with a coated stopper.
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Each 26 mL vial delivers 130 mg ustekinumab-auub, edetate disodium (0.47 mg), histidine (20 mg), histidine
hydrochloride monohydrate (27 mg), methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2210 mg).
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ustekinumab products are human IgG1κ monoclonal antibodies that bind with specificity to the p40 protein subunit used by
both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and
immune responses, such as natural killer cell activation and CD4+ T -cell differentiation and activation. In in vitro models,
ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the
interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been
implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease and ulcerative colitis.
In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of
ustekinumab products, was shown to be protective.
12.2
Pharmacodynamics
Plaque Psoriasis
In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in
lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with plaque psoriasis.
Ulcerative Colitis
In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed between exposure and
rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached a plateau at the
ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment [see Clinical Studies
(14.5)].
12.3
Pharmacokinetics
Absorption
In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days
and 7 days, respectively, after a single subcutaneous administration of 45 mg (N = 22) and 90 mg (N = 24) of ustekinumab.
In healthy subjects (N = 30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of
ustekinumab was comparable to that observed in subjects with plaque psoriasis.
Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-state serum
concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum ustekinumab
concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and
0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose. There was no apparent accumulation in
serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was
125.2 ± 33.6 mcg/mL in subjects with Crohn's disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis.
Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8
weeks. Steady-state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no
apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ±SD
steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn's disease, and 3.3 ± 2.3 mcg/mL in subjects
with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks.
Distribution
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Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment
was 2.7 L (95% CI: 2.69, 2.78) in subjects with Crohn's disease and 3.0 L (95% CI: 2.96, 3.07) in subjects with ulcerative
colitis. The total volume of distribution at steady-state was 4.6 L in subjects with Crohn's disease and 4.4 L in subjects with
ulcerative colitis.
Elimination
The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials following
subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was
0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohn's disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with
ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohn's disease and
ulcerative colitis) populations.
These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn's disease and
ulcerative colitis.
Metabolism
The metabolic pathway of ustekinumab products has not been characterized. As a human IgG1κ monoclonal antibody,
ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same
manner as endogenous IgG.
Specific Populations
Weight
When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100 kg had lower
median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough
serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were
comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group.
Age: Geriatric Population
A population pharmacokinetic analysis (N = 106/1937 subjects with plaque psoriasis greater than or equal to 65 years old)
was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in
pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
Age: Pediatric Population
Following multiple recommended doses of ustekinumab in pediatric subjects 6 to 17 years of age with plaque psoriasis,
steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean ±SD steady-state
trough serum ustekinumab concentrations were 0.36 ± 0.26 mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric
subjects 6 to 11 years of age and pediatric subjects 12 to 17 years of age.
Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were
within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration
of ustekinumab.
Drug Interaction Studies
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human
hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities
(CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).
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No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole
(CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used
concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease [see Drug
Interactions (7.2)].
Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX,
NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects with psoriatic arthritis.
In subjects with Crohn's disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in
ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum
ustekinumab concentrations were not impacted by concomitant use of these medications.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ustekinumab products.
Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained
transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased
host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed
UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental
findings in mouse models for malignancy risk in humans is unknown.
No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous
doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period.
However, fertility and pregnancy outcomes were not evaluated in mated females.
No effects on fertility were observed in female mice that were administered an analogous IL-12/IL- 23p40 antibody by
subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.
13.2
Animal Toxicology and/or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly
for 26 weeks had a bacterial infection.
14
CLINICAL STUDIES
14.1 Adult Plaque Psoriasis
Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2) enrolled a total of
1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%,
and Psoriasis Area and Severity Index (PASI) score ≥ 12, and who were candidates for phototherapy or systemic therapy.
Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the trials.
Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week
28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects
randomized to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects
randomized to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12
and 16.
In both trials, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18.
Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2.
Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional
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systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and
43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis.
In both trials, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75)
from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The
PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of
psoriasis focusing on plaque thickness/induration, erythema, and scaling.
Clinical Response
The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below.
Table 8. Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
Placebo
ustekinumab
Placebo
ustekinumab
45 mg
90 mg
45 mg
90 mg
Subjects
randomized
255
255
256
410
409
411
PASI 75 response
8
(3%)
171
(67%)
170
(66%)
15
(4%)
273
(67 %)
311
(76%)
PGA of Cleared or
10
151
156
18
277
300
Minimal
(4%)
(59%)
(61%)
(4%)
(68%)
(73%)
Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab among these
subgroups.
In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg doses; however,
in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg
dosing (Table 9 below).
Table 9. Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2
Ps STUDY 1
Ps STUDY 2
ustekinumab
ustekinumab
Placebo
45 mg
90 mg
Placebo
45 mg
90 mg
Subjects randomized
255
255
256
410
409
411
PASI 75 response*
≤ 100 kg
4%
74%
65%
4%
73%
78%
6/166
124/168
107/164
12/290
218/297
225/289
> 100 kg
2%
54%
68%
3%
49%
71%
2/89
47/87
63/92
3/120
55/112
86/121
PGA of Cleared or Minimal
≤ 100 kg
4%
64%
63%
5%
74%
75%
7/166
108/168
103/164
14/290
220/297
216/289
> 100 kg
3%
49%
58%
3%
51%
69%
3/89
43/87
53/92
4/120
57/112
84/121
* Subjects were dosed with trial medication at Weeks 0 and 4.
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either
continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week
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52, 89% (144/162) of subjects re-randomized to ustekinumab treatment were PASI 75 responders compared with 63%
(100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of
PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
14.2
Pediatric Plaque Psoriasis
A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17
years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater
than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately
controlled by topical therapy.
Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36), or one -half the
recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every
12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg
for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who
received placebo were crossed over to receive ustekinumab at the recommended dose or one -half the recommended dose.
Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and
approximately 11% had prior exposure to biologics.
The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and
PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent.
Clinical Response
The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10.
Table 10. Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3
Ps STUDY 3
Placebo
ustekinumab*
n (%)
n (%)
N
37
36
PGA
PGA of cleared (0) or minimal (1)
2 (5.4%)
25 (69.4%)
PASI
PASI 75 responders
4 (10.8%)
29 (80.6%)
PASI 90 responders
2 (5.4%)
22 (61.1%)
* Using the weight-based dosage regimen specified in Table 1 and Table 2.
14.3
Psoriatic Arthritis
The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n = 615; PsA STUDY 2, n = 312), in
two randomized, double-blind, placebo-controlled trials in adult subjects 18 years of age and older with active PsA (≥ 5
swollen joints and ≥ 5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic
(DMARD) therapy. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA
were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral
arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans
(0.5%). Over 70% and 40% of the subjects, respectively, had enthesitis and dactylitis at baseline.
Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and
4 followed by every 12 weeks (q12w) dosing. Approximately 50% of subjects continued on stable doses of MTX
(≤ 25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24.
24 of 34
Reference ID: 5502917
60
-;,R_
40
~
.$
c::
a,
~
CL.
20
PsA STUDY 1
24
Weeks
--o-
Placebo (n=206)
__.__ Ustekinumab 45 mg (n=205)
-
Ustekinumab 90 mg (n=204)
In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with
DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed.
In PsA STUDY 2, 58% (n = 180) of the subjects had been previously treated with TNF blocker, of whom over 70% had
discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time.
Clinical Response
In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the ustekinumab 45 mg
and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70 responses were also higher in the ustekinumab
45 mg and 90 mg groups, although the difference was only numerical (p = NS) in STUDY 2. Responses were consistent in
subjects treated with ustekinumab alone or in combination with methotrexate. Responses were similar in subjects
regardless of prior TNFα exposure.
Table 11. ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and
PsA STUDY 2 at Week 24
PsA STUDY 1
PsA STUDY 2
ustekinumab
ustekinumab
Number of subjects
randomized
Placebo
206
45 mg
205
90 mg
204
Placebo
104
45 mg
103
90 mg
105
ACR 20 response, N (%)
ACR 50 response, N (%)
47 (23%)
18 (9%)
87 (42%)
51 (25%)
101
(50%)
57 (28%)
21 (20%)
7 (7%)
45 (44%)
18 (17%)
46 (44%)
24 (23%)
ACR 70 response, N (%)
Number of subjects with
≥ 3% BSAa
5 (2%)
146
25 (12%)
145
29 (14%)
149
3 (3%)
80
7 (7%)
80
9 (9%)
81
PASI 75 response, N (%)
16 (11%)
83 (57%)
93 (62%)
4 (5%)
41 (51%)
45 (56%)
a Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline.
The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1.
Figure 1. Percent of subjects achieving ACR 20 response through Week 24
The results of the components of the ACR response criteria are shown in Table 12.
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Table 12. Mean change from baseline in ACR components at Week 24
PsA STUDY 1
Placebo
ustekinumab
45 mg
90 mg
(N = 206)
(N = 205)
(N = 204)
Number of swollen jointsa
Baseline
15
12
13
Mean Change at Week 24
-3
-5
-6
Number of tender jointsb
Baseline
25
22
23
Mean Change at Week 24
-4
-8
-9
Subjects’ assessment of painc
Baseline
6.1
6.2
6.6
Mean Change at Week 24
-0.5
-2.0
-2.6
Subject global assessmentc
Baseline
6.1
6.3
6.4
Mean Change at Week 24
-0.5
-2.0
-2.5
Physician global assessmentc
Baseline
5.8
5.7
6.1
Mean Change at Week 24
-1.4
-2.6
-3.1
Disability index (HAQ)d
Baseline
1.2
1.2
1.2
Mean Change at Week 24
-0.1
-0.3
-0.4
CRP (mg/dL)e
Baseline
1.6
1.7
1.8
Mean Change at Week 24
0.01
-0.5
-0.8
a Number of swollen joints counted (0–66).
b Number of tender joints counted (0–68).
c Visual analogue scale; 0 = best, 10 = worst.
d Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to
perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
e CRP: (Normal Range 0.0–1.0 mg/dL).
An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared with placebo at
Week 24.
Physical Function
Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated with placebo as
assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ-DI responders (≥ 0.3 improvement in HAQ-DI
score) was greater in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24.
14.4
Crohn's Disease
Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with
moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). There were
two 8-week intravenous induction trials (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal
maintenance trial (CD-3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment
with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators
or corticosteroids, but never failed treatment with a TNF blocker.
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Trials CD-1 and CD-2
In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n = 741; CD-2, n = 627) were included in
the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to
100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at
Week 8 were evaluated. In both trials, subjects were randomized to receive a single intravenous administration of
ustekinumab at either approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended).
In trial CD-1, subjects had failed or were intolerant to prior treatment with a TNF blocker: 29% subjects had an inadequate
initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and
36% were intolerant to a TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had
failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving
corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline
CDAI score was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group.
In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one
immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of subjects). Additionally, 69% never received a
TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial,
approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving
immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the
placebo group.
In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended dose of
approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo
(see Table 13 for clinical response and remission rates).
Clinical response and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to
improve through Week 8.
Table 13. Induction of Clinical Response and Remission in CD-1* and CD-2†
CD-1 n = 741
CD-2 n = 627
Treatment
Treatment
Placebo
Ustekinumab‡
difference
Placebo
Ustekinumab‡
difference
N = 247
N = 249
and 95% CI
N = 209
N = 209
and 95% CI
Clinical Response
(100 point), Week 6
53 (21%)
84 (34%)§
12%
(4%, 20%)
60 (29%)
116 (56%)¶
27%
(18%, 36%)
Clinical Remission,
Week 8
18 (7%)
52 (21%)¶
14%
(8%, 20%)
41 (20%)
84 (40%)¶
21%
(12%, 29%)
Clinical Response
(100 point), Week 8
50 (20%)
94 (38%)¶
18%
(10%, 25%)
67 (32%)
121 (58%)¶
26%
(17%, 35%)
70 Point Response,
Week 6
75 (30%)
109 (44%)§
13%
(5%, 22%)
81 (39%)
135 (65%)¶
26%
(17%, 35%)
70 Point Response,
Week 3
67 (27%)
101 (41%)§
13%
(5%, 22%)
66 (32%)
106 (51%)¶
19%
(10%, 28%)
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points
or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points
* Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy.
† Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA,
MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker.
‡ Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
§ 0.001 ≤ p < 0.01.
¶ p < 0.001.
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Trial CD-3
The maintenance trial (CD-3) evaluated 388 subjects who achieved clinical response (≥ 100 point reduction in CDAI
score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2. Subjects were randomized to
receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks (see
Table 14).
Table 14. Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose)
90 mg
Placebo*
ustekinumab every
8 weeks
Treatment
difference
N = 131†
N = 128†
and 95% CI
Clinical Remission
47 (36%)
68 (53%)‡
17% (5%,29%)
Clinical Response
58 (44%)
76 (59%)§
15% (3%,27%)
Clinical Remission in subjects
36/79 (46%)
52/78 (67%)‡
21% (6%, 36%)
in remission at the start of
maintenance therapy¶
Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction
in CDAI of at least 100 points or being in clinical remission
* The placebo group consisted of subjects who were in response to ustekinumab and were
randomized to receive placebo at the start of maintenance therapy.
† Subjects who achieved clinical response to ustekinumab at the end of the induction trial.
‡ p < 0.01.
§ 0.01≤ p < 0.05.
¶ Subjects in remission at the end of maintenance therapy who were in remission at the start of
maintenance therapy. This does not account for any other time point during maintenance
therapy.
At Week 44, 47% of subjects who received ustekinumab were corticosteroid-free and in clinical remission, compared to
30% of subjects in the placebo group.
At Week 0 of trial CD-3, 34/56 (61%) ustekinumab-treated subjects who previously failed or were intolerant to TNF
blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the
placebo arm, 27/61 (44%) subjects were in clinical remission at Week 0 while 16/61 (26%) of these subjects were in
remission at Week 44.
At Week 0 of trial CD-3, 46/72 (64%) ustekinumab-treated subjects who had previously failed immunomodulator therapy
or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical
remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week 0 while 31/70
(44%) were in remission at Week 44. In the subset of these subjects who were also naïve to TNF blockers, 34/52 (65%) of
ustekinumab-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm.
Subjects who were not in clinical response 8 weeks after ustekinumab induction were not included in the primary efficacy
analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg subcutaneous injection of ustekinumab
upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were
followed for the duration of the trial.
14.5
Ulcerative Colitis
Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2
(NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to
or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The
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8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal
maintenance trial (UC-2) for a total of 52 weeks of therapy.
Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored
from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and
physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo
score of 6 to 12, including a Mayo endoscopy subscore ≥ 2. An endoscopy score of 2 was defined by marked erythema,
absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline,
subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6–10) and 15% having
severe disease (Mayo score 11–12).
Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory
agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone).
Trial UC-1
In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab of approximately
6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with
corticosteroids, immunomodulators or at least one biologic. A total of 51% had failed at least one biologic and 17% had
failed both a TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or
immunomodulators but were biologic-naïve and an additional 3% had previously received but had not failed a biologic. At
induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects
were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates.
The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo stool frequency
subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo endoscopy subscore of 0 or 1 (Mayo
endoscopy subscore of 0 defined as normal or inactive disease and Mayo subscore of 1 defined as presence of erythema,
decreased vascular pattern and no friability) is provided in Table 15.
The secondary endpoints were clinical response, endoscopic improvement, and histologic-endoscopic mucosal
improvement. Clinical response with a definition of (≥ 2 points and ≥ 30% decrease in modified Mayo score, defined as
3-component Mayo score without the Physician's Global Assessment, with either a decrease from baseline in the rectal
bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1), endoscopic improvement with a definition of Mayo
endoscopy subscore of 0 or 1, and histologic-endoscopic mucosal improvement with a definition of combined endoscopic
improvement and histologic improvement of the colon tissue [neutrophil infiltration in < 5% of crypts, no crypt
destruction, and no erosions, ulcerations, or granulation tissue] are provided in Table 15.
In UC-1, a significantly greater proportion of subjects treated with ustekinumab (at the recommended dose of
approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and
histologic-endoscopic mucosal improvement compared to placebo (see Table 15).
Table 15. Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1
Endpoint
Placebo
N = 319
Ustekinumab*
N = 322
Treatment difference
and 97.5% CI†
N
%
N
%
Clinical Remission**
22
7%
62
19%
12%
(7%, 18%)§
Bio-naïve¶
14/151
9%
36/147
24%
Prior biologic failure
7/161
4%
24/166
14%
Endoscopic Improvement#
40
13%
80
25%
12%
(6%, 19%)§
Bio-naïve¶
28/151
19%
43/147
29%
Prior biologic failure
11/161
7%
34/166
20%
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Clinical ResponseÞ
99
31%
186
58%
27%
(18%, 35%)§
Bio-naïve¶
55/151
36%
94/147
64%
Prior biologic failure
42/161
26%
86/166
52%
Histologic-Endoscopic
Mucosal Improvement‡
26
8%
54
17%
9%
(3%, 14%)§
Bio-naïve¶
19/151
13%
30/147
20%
Prior biologic failure
6/161
4%
21/166
13%
‡ Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 or 1)
and histologic improvement of the colon tissue (neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions,
ulcerations, or granulation tissue).
* Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4.
† Adjusted treatment difference (97.5% CI).
** Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy
subscore of 0 or 1 (modified so that 1 does not include friability).
§ p < 0.001.
¶ An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics.
# Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
Þ Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a decrease
from baseline in the rectal bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1.
The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to disease progression and
long-term outcomes was not evaluated during UC-1.
Rectal Bleeding and Stool Frequency Subscores
Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in ustekinumab-treated
subjects.
Trial UC-2
The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following the intravenous
administration of either induction dose of ustekinumab in UC-1. These subjects were randomized to receive a
subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or every 12 weeks (a lower dose than
recommended), or placebo for 44 weeks.
The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included
the proportion of subjects maintaining clinical response at Week 44, the proportion of subjects with endoscopic
improvement at Week 44, the proportion of subjects with corticosteroid-free clinical remission at Week 44, and the
proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission 8 weeks
after induction.
Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the recommended
dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16.
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Table 16. Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose)
Endpoint
Placebo*
N = 175†
90 mg ustekinumab
every 8 weeks
N = 176
Treatment difference and 95% CI
N
%
N
%
Clinical Remission‡
46
26%
79
45%
19%
(9%, 28%)§
Bio-naïve¶
30/84
36%
39/79
49%
Prior biologic failure
16/88
18%
37/91
41%
Maintenance of Clinical
Response at Week 44†
84
48%
130
74%
26%
(16%, 36%)§
Bio-naïve¶
49/84
58%
62/79
78%
Prior biologic failure
35/88
40%
64/91
70%
Endoscopic Improvement#
47
27%
83
47%
20%
(11%, 30%)§
Bio-naïve¶
29/84
35%
42/79
53%
Prior biologic failure
18/88
20%
38/91
42%
Corticosteroid-free Clinical
RemissionÞ
45
26%
76
43%
17%
(8%, 27%)§
Bio-naïve¶
30/84
36%
38/79
48%
Prior biologic failure
15/88
17%
35/91
38%
Maintenance of Clinical
Remission at Week 44 in subjects
who achieved clinical remission
8 weeks after induction
18/50
36%
27/41
66%
31%
(12%, 50%)ß
Bio-naïve¶
12/27
44%
14/20
70%
Prior biologic failure
6/23
26%
12/18
67%
* The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the
start of maintenance therapy.
† Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥ 30% and ≥ 2 points, with either a
decrease from baseline in the rectal bleeding subscore ≥ 1 or a rectal bleeding subscore of 0 or 1.
‡ Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo
endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
§ p = < 0.001.
¶ An additional 3 subjects on placebo and 6 patients on ustekinumab had been exposed to, but had not failed, biologics.
# Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability).
Þ Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44.
ß p = 0.004.
Other Endpoints
Week 16 Responders to Ustekinumab Induction
Subjects who were not in clinical response 8 weeks after induction with ustekinumab in UC-1 were not included in the
primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive a 90 mg subcutaneous injection
of ustekinumab at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and
received ustekinumab 90 mg subcutaneously every 8 weeks during the UC-2 trial. At Week 44, there were 97/157 (62%)
subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission.
Histologic-Endoscopic Mucosal Improvement at Week 44
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The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2
was 75/172 (44%) among subjects on ustekinumab and 40/172 (23%) in subjects on placebo at Week 44. The relationship
of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term
outcomes was not evaluated in UC-2.
Endoscopic Normalization
Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At Week 8 in
UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with ustekinumab and 12/319 (4%) of
subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects
treated with ustekinumab and in 32/175 (18%) of subjects in placebo group.
15
REFERENCES
1
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database:
Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973–2007) – Linked To County Attributes - Total U.S.,
1969–2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems
Branch, released April 2010, based on the November 2009 submission.
16
HOW SUPPLIED/STORAGE AND HANDLING
WEZLANA (ustekinumab-auub) injection is a sterile, preservative-free, clear to opalescent and colorless to light yellow
solution. It is supplied as individually packaged, single-dose prefilled syringes, single-dose vials, or single-dose prefilled
ConfiPen autoinjectors.
For Subcutaneous Use
Prefilled Syringes
•
45 mg/0.5 mL (NDC 55513-076-01, NDC 72511-076-01)
•
90 mg/mL
(NDC 55513-089-01, NDC 72511-089-01)
Each prefilled syringe is equipped with a 27 gauge fixed ½ inch needle, a needle safety guard, and a needle cover that does
not contain dry natural rubber.
Single-dose Vial
•
45 mg/0.5 mL (NDC 55513-055-01, NDC 72511-055-01)
Single-dose Prefilled ConfiPen Autoinjector
•
45 mg/0.5 mL (NDC 55513-102-01)
•
90 mg/mL
(NDC 55513-114-01)
The prefilled ConfiPen autoinjector is not made with natural rubber latex.
For Intravenous Infusion
Single-dose Vial
•
130 mg/26 mL (5 mg/mL) (NDC 55513-066-01)
Storage and Stability
Store WEZLANA vials, prefilled syringes and prefilled ConfiPen autoinjectors refrigerated between 2°C to 8°C (36°F to
46°F). Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake.
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Reference ID: 5502917
AMGEN
If needed, individual prefilled syringe, 45 mg vial and prefilled ConfiPen autoinjector may be stored at room temperature
up to 30°C (86°F) for a maximum single period of up to 30 days in the original carton to protect from light. Record the
date when the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector is first removed from the refrigerator on
the carton in the space provided. Once the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector has been
stored at room temperature, do not return it to the refrigerator.
Discard the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector if not used within 30 days at room
temperature storage. Do not use WEZLANA after the expiration date on the carton or on the prefilled syringe, on the
45 mg vial or on the prefilled ConfiPen autoinjector.
17
PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for
Use).
Infections
Inform patients that WEZLANA may lower the ability of their immune system to fight infections and to contact their
healthcare provider immediately if they develop any signs or symptoms of infection [see Warnings and Precautions (5.1)].
Malignancies
Inform patients of the risk of developing malignancies while receiving WEZLANA [see Warnings and Precautions (5.4)].
Hypersensitivity Reactions
•
Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious
hypersensitivity reactions and discontinue WEZLANA [see Warnings and Precautions (5.5)].
Posterior Reversible Encephalopathy Syndrome (PRES)
Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may
include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)].
Immunizations
Inform patients that WEZLANA can interfere with the usual response to immunizations and that they should avoid live
vaccines [see Warnings and Precautions (5.7)].
Administration
Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use.
WEZLANA™ (ustekinumab-auub)
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Reference ID: 5502917
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
U.S. License Number 1080
AMGEN, WEZLANA and ConfiPen are trademarks owned by Amgen Inc.
STELARA is a trademark of Johnson & Johnson.
© 2023, xxxx Amgen Inc. All rights reserved.
1xxxxxx-vxx
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Reference ID: 5502917
MEDICATION GUIDE
WEZLANA™ (wez-LAH-nah)
(ustekinumab-auub)
injection, for subcutaneous or intravenous use
What is the most important information I should know about WEZLANA?
WEZLANA is a medicine that affects your immune system. WEZLANA can increase your risk of having
serious side effects, including:
Serious infections. WEZLANA may lower the ability of your immune system to fight infections and may
increase your risk of infections. Some people have serious infections while taking ustekinumab products,
including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be
hospitalized for treatment of their infection.
•
Your doctor should check you for TB before starting WEZLANA.
•
If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you
begin treatment with WEZLANA and during treatment with WEZLANA.
•
Your doctor should watch you closely for signs and symptoms of TB while you are being treated with
WEZLANA.
You should not start taking WEZLANA if you have any kind of infection unless your doctor says it is okay.
Before starting WEZLANA, tell your doctor if you:
•
think you have an infection or have symptoms of an infection such as:
o
fever, sweat, or chills
o
weight loss
o
muscle aches
o
warm, red, or painful skin or sores on your body
o
cough
o
diarrhea or stomach pain
o
shortness of breath
o
burning when you urinate or urinate more often
o
blood in phlegm
than normal
o
feel very tired
•
are being treated for an infection or have any open cuts.
•
get a lot of infections or have infections that keep coming back.
•
have TB, or have been in close contact with someone with TB.
After starting WEZLANA, call your doctor right away if you have any symptoms of an infection (see above).
These may be signs of infections such as chest infections, or skin infections or shingles that could have
serious complications. WEZLANA can make you more likely to get infections or make an infection that you
have worse.
People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12)
and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread
throughout the body and cause death. People who take WEZLANA may also be more likely to get these
infections.
Cancers. WEZLANA may decrease the activity of your immune system and increase your risk for certain
types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving
ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers.
During your treatment with WEZLANA, tell your doctor if you develop any new skin growths.
Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain
and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people
recover. Tell your doctor right away if you have any new or worsening medical problems including:
o
headache
o
confusion
o
seizures
o
vision problems
What is WEZLANA?
WEZLANA is a prescription medicine used to treat:
•
adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking
injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).
•
adults and children 6 years and older with active psoriatic arthritis
•
adults 18 years and older with moderately to severely active Crohn’s disease.
•
adults 18 years and older with moderately to severely active ulcerative colitis.
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It is not known if WEZLANA is safe and effective in children less than 6 years of age.
Do not take WEZLANA if you are allergic to ustekinumab products or any of the ingredients in WEZLANA.
See the end of this Medication Guide for a complete list of ingredients in WEZLANA.
Before you receive WEZLANA, tell your doctor about all of your medical conditions, including if you:
•
have any of the conditions or symptoms listed in the section “What is the most important information
I should know about WEZLANA?”
•
ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure.
•
have recently received or are scheduled to receive an immunization (vaccine). People who take
WEZLANA should not receive live vaccines. Tell your doctor if anyone in your house needs a live
vaccine. The viruses used in some types of live vaccines can spread to people with a weakened
immune system and can cause serious problems. You should not receive the BCG vaccine during
the one year before receiving WEZLANA or one year after you stop receiving WEZLANA.
•
have any new or changing lesions within psoriasis areas or on normal skin.
•
are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may
not work as well for you during treatment with WEZLANA. WEZLANA may also increase your risk of
having an allergic reaction to an allergy shot.
•
receive or have received phototherapy for your psoriasis.
•
are pregnant or plan to become pregnant. It is not known if WEZLANA can harm your unborn baby. You
and your doctor should decide if you will receive WEZLANA. See “What should I avoid while using
WEZLANA?”
•
received WEZLANA while you were pregnant. It is important that you tell your baby’s healthcare
provider before any vaccinations are given to your baby.
•
are breastfeeding or plan to breastfeed. WEZLANA can pass into your breast milk.
•
Talk to your doctor about the best way to feed your baby if you receive WEZLANA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new
medicine.
How should I use WEZLANA?
•
Use WEZLANA exactly as your doctor tells you to.
•
The needle cover on the WEZLANA prefilled syringe and prefilled ConfiPen™ autoinjector does
not contain latex.
•
Adults with Crohn’s disease and ulcerative colitis will receive the first dose of WEZLANA through a vein
in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour
to receive the full dose of medicine. You will then receive WEZLANA as an injection under the skin
(subcutaneous injection) 8 weeks after the first dose of WEZLANA, as described below.
•
Adults with psoriasis or psoriatic arthritis and children 6 years and older with psoriasis or psoriatic
arthritis will receive WEZLANA as an injection under the skin (subcutaneous injection) as described
below.
•
Injecting WEZLANA under your skin
o
WEZLANA is intended for use under the guidance and supervision of your doctor. In children 6
years and older, it is recommended that WEZLANA be administered by a healthcare provider. If
your doctor decides that you or a caregiver may give your injections of WEZLANA at home, you
should receive training on the right way to prepare and inject WEZLANA. Your doctor will determine
the right dose of WEZLANA for you, the amount for each injection, and how often you should
receive it. Do not try to inject WEZLANA yourself until you or your caregiver have been shown how
to inject WEZLANA by your doctor or nurse.
o
Inject WEZLANA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs
(thighs) or stomach area (abdomen).
o
Do not give an injection in an area of the skin that is tender, bruised, red or hard.
o
Use a different injection site each time you use WEZLANA.
o
If you inject more WEZLANA than prescribed, call your doctor right away.
o
Be sure to keep all of your scheduled follow-up appointments.
Read the detailed Instructions for Use for instructions about how to prepare and inject a dose of
WEZLANA, and how to properly throw away (dispose of) used needles and syringes. The WEZLANA
syringe, needle, vial and ConfiPen autoinjector must never be re-used. After the rubber stopper of
Reference ID: 5502917
the vial is punctured, WEZLANA can become contaminated by harmful bacteria which could cause
an infection if re-used.
Throw away any unused portion of WEZLANA.
What should I avoid while using WEZLANA?
You should not receive a live vaccine while taking WEZLANA. See “Before you receive WEZLANA, tell
your doctor about all of your medical conditions, including if you:”
What are the possible side effects of WEZLANA?
WEZLANA may cause serious side effects, including:
•
See “What is the most important information I should know about WEZLANA?”
•
Serious allergic reactions. Serious allergic reactions can occur with WEZLANA. Stop using WEZLANA
and get medical help right away if you have any of the following symptoms of a serious allergic reaction:
o
feeling faint
o
chest tightness
o
swelling of your face, eyelids, tongue, or
o
skin rash
throat
•
Lung inflammation. Cases of lung inflammation have happened in some people who receive
ustekinumab products, and may be serious. These lung problems may need to be treated in a hospital.
Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during
treatment with WEZLANA.
Common side effects of WEZLANA include:
•
nasal congestion, sore throat, and runny
•
redness at the injection site
nose
•
vaginal yeast infections
•
upper respiratory infections
•
urinary tract infections
•
fever
•
sinus infection
•
headache
•
bronchitis
•
tiredness
•
diarrhea
•
itching
•
stomach pain
•
nausea and vomiting
These are not all of the possible side effects of WEZLANA. Call your doctor for medical advice about side
effects. You may report side effects to FDA at 1-800-FDA-1088.
You may also report side effects to 1-800-77-AMGEN (1-800-772-6436).
How should I store WEZLANA?
•
Store WEZLANA vials, prefilled syringes and prefilled ConfiPen autoinjector in a refrigerator between
36°F to 46°F (2°C to 8°C).
•
Store WEZLANA in the original carton to protect it from light until time to use it.
•
Do not freeze WEZLANA.
•
Do not shake WEZLANA.
If needed, individual prefilled syringe, 45 mg vial and prefilled ConfiPen autoinjector may also be
stored at room temperature up to 30°C (86°F) for a maximum single period of up to 30 days in the
original carton to protect from light. Record the date when the prefilled syringe, the 45 mg vial or
prefilled ConfiPen autoinjector is first removed from the refrigerator on the carton in the space
provided. Once the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector has been stored
at room temperature, it should not be returned to the refrigerator.
Discard the prefilled syringe, the 45 mg vial or prefilled ConfiPen autoinjector if not used within 30
days at room temperature storage. Do not use WEZLANA after the expiration date on the carton or on
the prefilled syringe, on the 45 mg vial or on the prefilled ConfiPen autoinjector.
Keep WEZLANA and all medicines out of the reach of children.
General information about the safe and effective use of WEZLANA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
WEZLANA for a condition for which it was not prescribed. Do not give WEZLANA to other people, even if
they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for
information about WEZLANA that was written for health professionals.
Reference ID: 5502917
AMGEN
What are the ingredients in WEZLANA?
Active ingredient: ustekinumab-auub
Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains histidine, histidine
hydrochloride monohydrate, Polysorbate 80, and sucrose. Single-dose vial for subcutaneous use
contains histidine, histidine hydrochloride monohydrate, Polysorbate 80 and sucrose. Single-dose prefilled
ConfiPen autoinjector for subcutaneous use contains histidine, histidine hydrochloride monohydrate,
Polysorbate 80, and sucrose. Single-dose vial for intravenous infusion contains edetate disodium,
histidine, histidine hydrochloride monohydrate, methionine, Polysorbate 80, and sucrose.
WEZLANA™(ustekinumab-auub)
Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799 U.S.A.
US License Number 1080
© 2023–YYYY Amgen Inc. All rights reserved.
1xxxxxx – vxx
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
Reference ID: 5502917
INSTRUCTIONS FOR USE
WEZLANA™ [wez-LAH-nah]
(ustekinumab-auub)
injection, for subcutaneous use
single-dose prefilled ConfiPen™ autoinjector
This Instructions for Use contains information on how to inject WEZLANA with an ConfiPen
autoinjector.
The medicine in the WEZLANA autoinjector is for injection under-the-skin (subcutaneous injection).
See the WEZLANA Medication Guide for information about WEZLANA.
Getting to know the prefilled autoinjector
Expiration date
Plunger (may be visible in the window;
location may vary)
Window
Medicine
Yellow safety guard under cap
(needle inside)
Cap
Important Information You Need to Know Before Injecting WEZLANA
Dosing:
•
WEZLANA comes in two different doses: 45 mg and 90 mg. Check the prescription to make
sure you have the correct dose.
•
The label color and window size of the autoinjector will be different for each dose. The amount
of medicine in the autoinjector will also be different for each dose.
Reference ID: 5502917
[□~ (Q)
111111
-
)
"""~
[□ ~
~
1111 II
1
1 )
IU2560 v3
45 mg
90 mg
Important:
•
If the dose is 90 mg, you will receive either one 90 mg autoinjector or two 45 mg
autoinjectors.
−
If you receive two 45 mg autoinjectors for a 90 mg dose, you will need to give a second
injection right after the first.
−
Repeat Steps 1-16 for the second injection using a new autoinjector.
−
Choose a different site for the second injection.
Using your WEZLANA ConfiPen autoinjector:
•
It is important that you do not try to give the injection until you have fully read and understood
this Instructions for Use.
•
If your doctor decides that you or a caregiver can give your WEZLANA injection at home, you
should receive training on the right way to prepare and inject WEZLANA. Do not try to inject
WEZLANA yourself until you have been shown the right way to give the injections by your
doctor or nurse.
•
Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use an
autoinjector under supervision of a parent or caregiver.
•
Do not use the autoinjector if the carton is damaged or the seal is broken.
•
Do not use the autoinjector after the expiration date on the label.
•
Do not shake the autoinjector.
•
Do not remove the cap from the autoinjector until you are ready to inject.
•
Do not use the autoinjector if it has been frozen.
•
Do not use the autoinjector if it has been dropped on a hard surface. Part of the autoinjector may
be broken even if you cannot see the break. Use a new autoinjector, and call 1-800-77-AMGEN
(1-800-772-6436).
•
The autoinjector is not made with natural rubber latex.
Important: Keep the autoinjector and sharps disposal container out of the sight and reach of
children.
Reference ID: 5502917
■
minutes
■
Frequently asked questions:
For additional information and answers to frequently asked questions, visit www.WEZLANA.com.
Where to get help:
If you want more information or help using WEZLANA:
•
Contact your healthcare provider,
•
Visit www.WEZLANA.com, or
•
Call 1-800-77-AMGEN (1-800-772-6436).
Storing and Preparing to Inject WEZLANA
Refrigerate in carton until ready to use
1 Refrigerate the autoinjector carton until you are ready to use it.
•
Keep the autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C).
•
Keep the autoinjector in the original carton to protect it from light or physical damage.
•
Do not freeze the autoinjector.
•
Do not store the autoinjector in extreme heat or cold. For example, avoid storing in your
vehicle’s glove box or trunk.
Important: Keep the autoinjector out of the sight and reach of children.
WAIT
2 Wait 30 minutes for the autoinjector to reach room temperature.
•
Remove the number of autoinjectors you need for the injection from the refrigerator.
•
Let the autoinjector warm up naturally.
•
Do not heat the autoinjector with hot water, a microwave, or direct sunlight.
•
Do not put the autoinjector back in the refrigerator once it reaches room temperature.
Reference ID: 5502917
■
■
0-0
30
days
•
Do not shake the autoinjector at any time.
•
Using the autoinjector at room temperature ensures the full dose is delivered and allows for a
more comfortable injection.
3 You may keep WEZLANA at room temperature for up to 30 days, if needed.
•
For example, when you are traveling, you may keep WEZLANA at room temperature.
•
Keep it at room temperature between 68°F to 77°F (20°C to 25°C).
•
Do not use if it has been stored above 86°F (30°C).
•
Record the date you removed it from the refrigerator and use within 30 days.
Important: Place the autoinjector in a sharps disposal container if it has reached room
temperature and has not been used within 30 days.
Medicine
4 Inspect the medicine. It should be clear to white like an opal and colorless to light
yellow.
•
It is okay to see air bubbles.
•
Do not use WEZLANA if the medicine is cloudy, discolored, or has particles.
Reference ID: 5502917
■
I
■
...... Cl.
ox
_JW
I
_J
G-
Expiration date
5 Check the expiration date (Exp.) and inspect the autoinjector for damage.
•
Do not use the autoinjector if the expiration date has passed.
•
Do not use the autoinjector if:
−
the cap is missing or loose,
−
it has cracks or broken parts, or
−
it has been dropped on a hard surface.
•
Make sure you have the right medicine and dose.
Important: If the medicine is cloudy, discolored, or has particles, or if the autoinjector is
damaged or expired, call 1-800-77-AMGEN (1-800-772-6436).
Getting Ready to Inject WEZLANA
Sharps disposal
container
Alcohol wipe
Adhesive bandage
Cotton ball or gauze pad
6 Gather and place the following items for the injection on a clean, flat, and well-lit
surface:
•
WEZLANA autoinjector (room temperature),
•
Sharps disposal container [see Disposing of WEZLANA and Checking the Injection Site]
•
Alcohol wipe,
•
Adhesive bandage, and
•
Cotton ball or gauze pad.
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■
■
■
7 Select 1 of these injection locations.
•
Select the front of your thigh or
stomach (except for 2 inches around
your belly button).
•
Someone else can inject in your thigh,
stomach, back of your upper arm, or
buttocks.
Important: Avoid areas with scars, stretch marks or where the skin is tender, bruised, red, or hard.
8 Wash your hands thoroughly with soap and water.
9 Clean the injection site with an alcohol wipe.
Reference ID: 5502917
•
Let the skin dry on its own.
•
Do not touch this area again before injecting.
Injecting WEZLANA
Important: Only remove the cap when you can inject right away (within 5 minutes) because the
medicine can dry out. Do not recap.
Window should
be visible
_____
_JI
■
■
10 Pull hard or twist to remove the cap. Never put the cap back on as it may
damage the needle.
•
It is normal to see a drop of medicine come out of the needle or yellow safety guard.
Important: Do not touch or push the yellow safety guard. Do not put your finger inside of the
yellow safety guard.
11 Pinch the skin to create a firm surface at the injection site.
Place the yellow safety guard straight against the pinched skin.
•
Keep the skin pinched until the injection is finished.
•
Make sure you can see the window.
•
Make sure the autoinjector is positioned straight on the injection site (at a 90-degree angle).
Reference ID: 5502917
■
■
■
PUSH & HOLD
down to start injection
12 Firmly push the autoinjector down until the yellow safety guard stops moving.
Hold the autoinjector down, do not lift.
•
The needle will insert and the injection begins.
•
You may hear or feel a click.
•
Hold the autoinjector straight and steady on the skin.
WATCH until COMPLETE
window will turn fully yellow
13 Keep pushing down the autoinjector. Wait for the window to turn fully yellow.
•
The injection can take up to 15 seconds to complete. You may hear or feel a click.
•
After the window turns fully yellow, lift the autoinjector away from the skin.
Completing the Injection
CONFIRM
Window is fully yellow
No medicine leaked out (a small
drop is okay)
14 Confirm a full dose of medicine was injected.
•
Do not touch the yellow safety guard.
Reference ID: 5502917
======--1
■
■
•
A small amount of liquid on the injection site is okay.
Important: If the window has not turned fully yellow, if it looks like the medicine is still coming
out, or if you see several drops of medicine, a full dose was not injected. Call your healthcare
provider immediately.
15 Check the injection site.
•
Do not rub the injection site.
•
If there is blood, press a cotton ball or gauze pad on the injection site.
•
Apply an adhesive bandage if necessary.
16 Place the used autoinjector and cap in an FDA-cleared sharps disposal container.
Important: Do not throw away the autoinjector in your household trash.
•
Do not reuse the autoinjector.
•
Do not touch the yellow safety guard.
Additional information about your sharps disposal container
If you do not have an FDA-cleared sharps disposal container, you may use a household container
that is:
•
made of a heavy-duty plastic,
•
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
•
upright and stable during use,
•
leak-resistant, and
Reference ID: 5502917
•
properly labeled to warn of hazardous waste inside the container.
Disposing of sharps containers:
When your sharps disposal container is almost full, you will need to follow your community guidelines
for the right way to dispose of your sharps disposal container.
There may be state or local laws about how you should throw away used needles and syringes.
For more information about safe sharps disposal, and for specific information about sharps disposal in
the state that you live in, go to the FDA’s website at:
https://www.fda.gov/safesharpsdisposal
Do not dispose of your used sharps disposal container in your household trash unless your
community guidelines permit this.
Do not recycle your used sharps disposal container.
For more information or help call 1-800-77-AMGEN (1-800-772-6436).
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
US License Number 1080
©YYYY Amgen Inc.
All rights reserved.
Issued 12/2024
Reference ID: 5502917
| custom-source | 2025-02-12T15:48:18.571525 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761285s001,761331s001lbl.pdf', 'application_number': 761285, 'submission_type': 'SUPPL ', 'submission_number': 1} |
80,774 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
STEGLUJAN safely and effectively. See full prescribing
information for STEGLUJAN.
STEGLUJAN® (ertugliflozin and sitagliptin) tablets, for oral use
Initial U.S. Approval: 2017
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.3)
12/2024
Warnings and Precautions (5.3, 5.8)
12/2024
----------------------------INDICATIONS AND USAGE---------------------------
STEGLUJAN is a combination of ertugliflozin, a sodium glucose co-
transporter 2 (SGLT2) inhibitor, and sitagliptin, a dipeptidyl peptidase-4
(DPP-4) inhibitor, is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus.
Limitations of Use:
• Not recommended for use to improve glycemic control in patients
with type 1 diabetes mellitus. (1)
• Has not been studied in patients with a history of pancreatitis. (1,
5.2)
--------------- DOSAGE AND ADMINISTRATION ----------------------
• Assess renal function before initiating and as clinically indicated.
(2.1)
• Correct volume depletion before initiating. (2.1)
• Recommended starting dosage is 5 mg ertugliflozin/100 mg
sitagliptin orally once daily, taken in the morning, with or without
food. (2.2)
• Increase dosage to 15 mg ertugliflozin/100 mg sitagliptin orally once
daily in those tolerating STEGLUJAN and needing additional
glycemic control. (2.2)
• Use is not recommended in patients with an estimated glomerular
filtration rate (eGFR) less than 45 mL/min/1.73 m2. (2.2)
• Withhold STEGLUJAN for at least 4 days, if possible, prior to
surgery or procedures associated with prolonged fasting. (2.3)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets:
• Ertugliflozin 5 mg and sitagliptin 100 mg (3)
• Ertugliflozin 15 mg and sitagliptin 100 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-
stage renal disease, or dialysis. (4)
• Hypersensitivity to sitagliptin, ertugliflozin, or any excipient in
STEGLUJAN. (4, 5.11, 6.2)
----------------------- WARNINGS AND PRECAUTIONS-----------------------
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and
Other Ketoacidosis: Consider ketone monitoring in patients at risk
for ketoacidosis, as indicated. Assess for ketoacidosis regardless of
presenting blood glucose levels and discontinue STEGLUJAN if
ketoacidosis is suspected. Monitor patients for resolution of
ketoacidosis before restarting. (5.1)
• Pancreatitis: There have been postmarketing reports of acute
pancreatitis in patients taking sitagliptin, including fatal and non-fatal
hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected,
promptly discontinue. (5.2)
• Lower Limb Amputation: Monitor patients for infections or ulcers of
lower limbs, and discontinue if these occur. (5.3)
• Acute Renal Failure: There have been postmarketing reports of
acute renal failure in patients taking sitagliptin, sometimes requiring
dialysis. Monitor renal function. (5.4)
• Volume Depletion: May result in acute kidney injury. Before
initiating, assess and correct volume status in patients with renal
impairment, or low systolic blood pressure elderly patients, or
patients on diuretics. Monitor for signs and symptoms during
therapy. (5.5)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and
symptoms of urinary tract infections and treat promptly, if indicated.
(5.6)
• Heart Failure: Heart failure has been observed with two other
members of the DPP-4 inhibitor class. Consider risks and benefits in
patients who have known risk factors for heart failure. Monitor
patients for signs and symptoms. (5.7)
• Hypoglycemia: Consider a lower dose of insulin or insulin
secretagogue to reduce risk of hypoglycemia when used in
combination. (5.8)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene):
Serious, life-threatening cases have occurred in both females and
males. Assess patients presenting with pain or tenderness,
erythema, or swelling in the genital or perineal area, along with fever
or malaise. If suspected, institute prompt treatment. (5.9)
• Genital Mycotic Infections: Monitor and treat if indicated. (5.10)
• Hypersensitivity: There have been postmarketing reports of serious
allergic and hypersensitivity reactions in patients treated with
sitagliptin such as anaphylaxis, angioedema, and exfoliative skin
conditions including Stevens-Johnson syndrome. In such cases,
promptly discontinue, assess for other potential causes, institute
appropriate monitoring and treatment, and initiate alternative
treatment for diabetes. (5.11)
• Severe and Disabling Arthralgia: Severe and disabling arthralgia has
been reported in patients taking DPP-4 inhibitors. Consider as a
possible cause for severe joint pain and discontinue if appropriate.
(5.12)
• Pemphigoid: There have been postmarketing reports of bullous
pemphigoid requiring hospitalization in patients taking DPP-4
inhibitors. Tell patients to report development of blisters or erosions.
If bullous pemphigoid is suspected, discontinue. (5.13)
------------------------------ ADVERSE REACTIONS -----------------------------
• Most common adverse reactions associated with ertugliflozin
(incidence ≥5%): female genital mycotic infections. (6.1)
• Most common adverse reactions associated with sitagliptin
(incidence ≥5%): upper respiratory tract infection, nasopharyngitis
and headache. In the add-on to sulfonylurea and add-on to insulin
studies, hypoglycemia was also more commonly reported in patients
treated with sitagliptin compared to placebo. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck
Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch .
----------------------------- DRUG INTERACTIONS-------------------------------
See full prescribing information for information on drug interactions and
interference of STEGLUJAN with laboratory tests. (7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Advise females of the potential risk to a fetus especially
during the second and third trimesters. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)
• Geriatrics: Higher incidence of adverse reactions related to reduced
intravascular volume. (8.5)
• Renal Impairment: Higher incidence of adverse reactions related to
reduced intravascular volume and renal function. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Prior to Initiation of STEGLUJAN
2.2
Recommended Dosage
2.3
Temporary Interruption for Surgery
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Diabetic Ketoacidosis in Patients with Type 1 Diabetes
Mellitus and Other Ketoacidosis
5.2
Pancreatitis
5.3
Lower Limb Amputation
5.4
Acute Renal Failure
5.5
Volume Depletion
5.6
Urosepsis and Pyelonephritis
5.7
Heart Failure
Reference ID: 5502336
5.8
Hypoglycemia with Concomitant Use with Insulin or Insulin
Secretagogues
5.9
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
5.10 Genital Mycotic Infections
5.11 Hypersensitivity Reactions
5.12 Severe and Disabling Arthralgia
5.13 Bullous Pemphigoid
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Glycemic Control Trials in Patients with Type 2 Diabetes
Mellitus
14.2 Ertugliflozin Cardiovascular Outcomes in Patients with Type
2 Diabetes Mellitus and Established Cardiovascular
Disease
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
2
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
STEGLUJAN® is indicated as an adjunct to diet and exercise to improve glycemic control in adults
with type 2 diabetes mellitus.
Limitations of Use
•
Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus
[see Warnings and Precautions (5.1)].
•
Has not been studied in patients with a history of pancreatitis. It is unknown whether patients with
a history of pancreatitis are at increased risk for the development of pancreatitis while using
STEGLUJAN [see Warnings and Precautions (5.2)].
2
DOSAGE AND ADMINISTRATION
2.1
Prior to Initiation of STEGLUJAN
•
Assess renal function before initiating STEGLUJAN and as clinically indicated [see Warnings and
Precautions (5.4)].
•
Assess volume status. In patients with volume depletion, correct this condition before initiating
STEGLUJAN [see Warnings and Precautions (5.5) and Use in Specific Populations (8.5, 8.6)].
2.2
Recommended Dosage
• The recommended starting dosage of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin orally
once daily, taken in the morning, with or without food.
• For patients treated with ertugliflozin who are being switched to STEGLUJAN, the dosage of
ertugliflozin can be maintained.
• For additional glycemic control, the dosage may be increased to 15 mg ertugliflozin/100 mg
sitagliptin orally once daily in patients tolerating STEGLUJAN.
• Use is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than
45 mL/min/1.73 m2.
• Use of STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than
30 mL/min/1.73 m2), end-stage renal disease (ESRD) or on dialysis [see Contraindications (4)].
2.3
Temporary Interruption for Surgery
Withhold STEGLUJAN for at least 4 days, if possible, prior to surgery or procedures associated with
prolonged fasting. Resume STEGLUJAN when the patient is clinically stable and has resumed oral
intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
3
DOSAGE FORMS AND STRENGTHS
• STEGLUJAN 5 mg/100 mg tablets: contain ertugliflozin 5 mg and sitagliptin 100 mg and are beige,
almond-shaped debossed with “554” on one side and plain on the other side.
• STEGLUJAN 15 mg/100 mg tablets: contain ertugliflozin 15 mg and sitagliptin 100 mg and are
brown, almond-shaped debossed with “555” on one side and plain on the other side.
4
CONTRAINDICATIONS
STEGLUJAN is contraindicated in patients with:
• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease (ESRD),
or on dialysis [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
• Hypersensitivity to sitagliptin, ertugliflozin, or any excipient, in STEGLUJAN. Reactions such as
anaphylaxis or angioedema have occurred [see Warnings and Precautions (5.11) and Adverse
Reactions (6.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, STEGLUJAN significantly increases the risk of diabetic
ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients
3
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with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received
sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may
be greater with higher doses. STEGLUJAN is not indicated for glycemic control in patients with type 1
diabetes mellitus.
Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery)
are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis
in patients with type 2 diabetes mellitus using SGLT2 inhibitors.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization
due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic
diet, surgery, volume depletion, and alcohol abuse.
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include
nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at
presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL).
Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists
for 4 days after discontinuing STEGLUJAN [see Clinical Pharmacology (12.2)]; however, there have been
postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks
after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation.
Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs
and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue
STEGLUJAN, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of
ketoacidosis before restarting STEGLUJAN.
Withhold STEGLUJAN, if possible, in temporary clinical situations that could predispose patients to
ketoacidosis. Resume STEGLUJAN when the patient is clinically stable and has resumed oral intake [see
Dosage and Administration (2.3)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue
STEGLUJAN and seek medical attention immediately if signs and symptoms occur.
5.2
Pancreatitis
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal
hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin, a component of STEGLUJAN. After
initiation of STEGLUJAN, patients should be observed carefully for signs and symptoms of pancreatitis. If
pancreatitis is suspected, STEGLUJAN should promptly be discontinued and appropriate management
should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the
development of pancreatitis while using STEGLUJAN.
5.3
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2
diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb
amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1000 patient-years in the placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.
Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb
amputations). Some patients had multiple amputations, some involving both lower limbs.
Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating
medical events leading to the need for an amputation. Patients with amputations were more likely to be
male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or
peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.
Across seven ertugliflozin clinical trials, non-traumatic lower limb amputations were reported in
1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%)
patients in the ertugliflozin 15 mg group.
Counsel patients about the importance of routine preventative foot care. Monitor patients receiving
STEGLUJAN for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores
or ulcers involving the lower limbs, and discontinue STEGLUJAN if these complications occur.
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5.4
Acute Renal Failure
There have been postmarketing reports with sitagliptin of worsening renal function, including acute
renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal
insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels
of renal insufficiency has been observed with supportive treatment and discontinuation of potentially
causative agents. Consideration can be given to cautiously reinitiating STEGLUJAN if another etiology is
deemed likely to have precipitated the acute worsening of renal function.
Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or
in clinical trials.
5.5
Volume Depletion
STEGLUJAN can cause intravascular volume contraction which may sometimes manifest as
symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There
have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in
patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including STEGLUJAN. Patients with
impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly
patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for
volume depletion or hypotension. Before initiating STEGLUJAN in patients with one or more of these
characteristics, assess volume status and renal function. In patients with volume depletion, correct this
condition before initiating STEGLUJAN. Monitor for signs and symptoms of volume depletion, and renal
function after initiating therapy.
5.6
Urosepsis and Pyelonephritis
There have been postmarketing reports of serious urinary tract infections, including urosepsis and
pyelonephritis, requiring hospitalization in patients receiving medicines containing SGLT2 inhibitors.
Treatment with medicines containing SGLT2 inhibitors increases the risk for urinary tract infections.
Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see
Adverse Reactions (6)].
5.7
Heart Failure
An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been
observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials
evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the
risks and benefits of STEGLUJAN prior to initiating treatment in patients at risk for heart failure, such as
those with a prior history of heart failure and a history of renal impairment, and observe these patients for
signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart
failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according
to current standards of care and consider discontinuation of STEGLUJAN.
5.8
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Ertugliflozin,
may increase the risk of hypoglycemia when used in combination with insulin or an insulin secretagogue
[see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in the dose of
insulin or sulfonylurea (or other concomitantly administered insulin secretagogues). Inform patients using
these medications concomitantly of this risk and educate them on the signs and symptoms of hypoglycemia.
5.9
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-
threatening necrotizing infection requiring urgent surgical intervention, have been identified in
postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including
ertugliflozin. Cases have been reported in females and males. Serious outcomes have included
hospitalization, multiple surgeries, and death.
Patients treated with STEGLUJAN presenting with pain or tenderness, erythema, or swelling in the
genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If
suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical
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debridement. Discontinue STEGLUJAN, closely monitor blood glucose levels, and provide appropriate
alternative therapy for glycemic control.
5.10 Genital Mycotic Infections
Ertugliflozin, increases the risk of genital mycotic infections. Patients who have a history of genital
mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections [see
Adverse Reactions (6.1)]. Monitor and treat appropriately.
5.11 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
sitagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of
treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is
suspected, discontinue STEGLUJAN, assess for other potential causes for the event, and institute
alternative treatment for diabetes [see Adverse Reactions (6.2)].
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution
in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such
patients will be predisposed to angioedema with STEGLUJAN.
5.12 Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4
inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.
Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients
experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
5.13 Bullous Pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP
4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive
treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or
erosions while receiving STEGLUJAN. If bullous pemphigoid is suspected, STEGLUJAN should be
discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
6
ADVERSE REACTIONS
The following important adverse reactions are described elsewhere in the labeling:
•
Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see
Warnings and Precautions (5.1)]
•
Pancreatitis [see Warnings and Precautions (5.2)]
•
Lower Limb Amputation [see Warnings and Precautions (5.3)]
•
Acute Renal Failure [see Warnings and Precautions (5.4)]
•
Volume Depletion [see Warnings and Precautions (5.5)]
•
Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)]
•
Heart Failure [see Warnings and Precautions (5.7)]
•
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings
and Precautions (5.8)]
•
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions
(5.9)]
•
Genital Mycotic Infections [see Warnings and Precautions (5.10)]
•
Hypersensitivity Reactions [see Warnings and Precautions (5.11)]
•
Severe and Disabling Arthralgia [see Warnings and Precautions (5.12)]
•
Bullous Pemphigoid [see Warnings and Precautions (5.13)]
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6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Ertugliflozin and Sitagliptin
The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in
990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of
ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual
components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin
100 mg and metformin HCl once daily, and a placebo-controlled study of initial therapy with ertugliflozin
5 mg or 15 mg once daily in combination with sitagliptin 100 mg once daily [see Clinical Studies (14)]. The
incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen
with ertugliflozin and described below in Table 1.
Ertugliflozin
Pool of Placebo-Controlled Trials
The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. Ertugliflozin
was used as monotherapy in one trial and as add-on therapy in two trials [see Clinical Studies (14)]. These
data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately
25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515)
once daily. The mean age of the population was 57 years and 2% were older than 75 years of age.
Fifty-three percent (53%) of the population was male and 73% were White, 15% were Asian, and 7% were
Black or African American. At baseline the population had diabetes for an average of 7.5 years, had a mean
HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline renal
function (mean eGFR 88.9 mL/min/1.73 m2) was normal or mildly impaired in 97% of patients and
moderately impaired in 3% of patients.
Table 1 shows common adverse reactions associated with the use of ertugliflozin. These adverse
reactions were not present at baseline, occurred more commonly on ertugliflozin than on placebo, and
occurred in at least 2% of patients treated with either ertugliflozin 5 mg or ertugliflozin 15 mg.
Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus
Treated with Ertugliflozin* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies
of Ertugliflozin Monotherapy or Combination Therapy
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Number (%) of Patients
Placebo
N = 515
Ertugliflozin 5 mg
N = 519
Ertugliflozin 15 mg
N = 510
Female genital mycotic infections†
3.0%
9.1%
12.2%
Male genital mycotic infections‡
0.4%
3.7%
4.2%
Urinary tract infections§
3.9%
4.0%
4.1%
Headache
2.3%
3.5%
2.9%
Vaginal pruritus¶
0.4%
2.8%
2.4%
Increased urination#
1.0%
2.7%
2.4%
Nasopharyngitis
2.3%
2.5%
2.0%
Back pain
2.3%
1.7%
2.5%
Weight decreased
1.0%
1.2%
2.4%
ThirstÞ
0.6%
2.7%
1.4%
* The three placebo controlled studies included one monotherapy trial and two add-on combination trials with metformin HCl or with
metformin HCl and sitagliptin.
† Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic
infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo
(N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
‡ Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number
of male patients in each group as denominator: placebo (N=280), ertugliflozin 5 mg (N=267), ertugliflozin 15 mg (N=265).
§ Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.
¶ Includes: vulvovaginal pruritus and pruritus genital. Percentages calculated with the number of female patients in each group as
denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
# Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
Þ Includes: thirst, dry mouth, polydipsia, and dry throat.
Volume Depletion
Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and
adverse reactions related to volume depletion, particularly in patients with impaired renal function (eGFR
less than 60 mL/min/1.73 m2). In patients with moderate renal impairment, adverse reactions related to
volume depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic
hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, ertugliflozin 5 mg, and
ertugliflozin 15 mg, respectively. Ertugliflozin may also increase the risk of hypotension in other patients at
risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].
Hypoglycemia
The incidence of hypoglycemia by study is shown in Table 2.
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Table 2: Incidence of Overall* and Severe† Hypoglycemia in Placebo-Controlled Clinical Studies in
Patients with Type 2 Diabetes Mellitus
Factorial Study with Sitagliptin as
Add-on Combination Therapy with
Metformin HCl (26 weeks)
Ertugliflozin 5 mg
+ Sitagliptin
(N = 243)
Ertugliflozin 15 mg
+ Sitagliptin
(N = 244)
Overall [N (%)]
Severe [N (%)]
13 (5.3)
0 (0.0)
22 (9.0)
1 (0.4)
Add-on Combination Therapy with
Metformin HCl and Sitagliptin
(26 weeks)
Placebo
(N = 153)
Ertugliflozin 5 mg
(N = 156)
Ertugliflozin 15 mg
(N = 153)
Overall [N (%)]
Severe [N (%)]
5 (3.3)
1 (0.7)
7 (4.5)
1 (0.6)
3 (2.0)
0 (0.0)
Initial Combination Therapy with
Sitagliptin (26 weeks)
Placebo
(N = 97)
Ertugliflozin 5 mg
+ Sitagliptin
(N = 98)
Ertugliflozin 15 mg
+ Sitagliptin
(N = 96)
Overall [N (%)]
Severe [N (%)]
1 (1.0)
0 (0.0)
6 (6.1)
0 (0.0)
3 (3.1)
2 (2.1)
* Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.
† Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of
blood glucose.
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2
diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb
amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.
Across seven ertugliflozin clinical trials, non-traumatic lower limb amputations were reported in
1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%)
patients in the ertugliflozin 15 mg group.
Genital Mycotic Infections
In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections
(e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis,
vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2% of females treated with
placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively (see Table 1). In females, discontinuation
due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo and ertugliflozin,
respectively.
In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital
infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo,
ertugliflozin 5 mg, ertugliflozin 15 mg, respectively (see Table 1). Male genital mycotic infections occurred
more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections
occurred in 0% and 0.2% of patients treated with placebo and ertugliflozin, respectively. Phimosis was
reported in 8 of 1,729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision.
Urinary Tract Infections
In VERTIS CV, urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in
10.2%, 12.2% and 12.0% of patients treated with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg,
respectively. The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo,
ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.
Sitagliptin
The following additional adverse reactions have been reported in clinical studies with sitagliptin: upper
respiratory tract infection, nasopharyngitis, headache, abdominal pain, nausea, diarrhea. In addition, in a
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Reference ID: 5502336
study of sitagliptin as add-on combination therapy with metformin HCl and rosiglitazone, peripheral edema
was noted with a higher incidence than placebo.
In a pooled analysis of the two monotherapy studies, the add-on to metformin HCl study, and the
add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in
patients treated with sitagliptin 100 mg and 0.9% in patients treated with placebo. In the add-on to
sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients
treated with sitagliptin compared to placebo. In the add-on to glimepiride (+/- metformin HCl) study, the
overall incidence of hypoglycemia was 12.2% in patients treated with sitagliptin 100 mg and 1.8% in patients
treated with placebo. In the add-on to insulin (+/- metformin HCl) study, the overall incidence of
hypoglycemia was 15.5% in patients treated with sitagliptin 100 mg and 7.8% in patients treated with
placebo. In all studies, adverse reactions of hypoglycemia were based on all reports of symptomatic
hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of
hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL.
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients
randomized to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control
(N=4,817), the incidence of non-adjudicated acute pancreatitis events was 0.1 per 100 patient-years in
each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in
3,942 patient-years for control).
Laboratory Tests
Ertugliflozin
Changes in Serum Creatinine and eGFR
Initiation of ertugliflozin causes an increase in serum creatinine and decrease in eGFR within weeks
of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment,
larger mean changes were observed. In a long-term cardiovascular outcomes trial, an initial increase in
serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR
changes of -2.7, -3.8 and -0.4 mL/min/1.73 m2 in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo
arms, respectively). The initial decline was followed by a recovery toward baseline to Week 52 (eGFR
change from baseline of - 0.4, - 1.1 and - 0.2 mL/min/1.73 m2 in ertugliflozin 5 mg, ertugliflozin 15 mg, and
placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function
changes observed with ertugliflozin since they are reversed after treatment discontinuation.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in
patients treated with ertugliflozin. Mean percent changes from baseline to Week 26 in LDL-C relative to
placebo were 2.6% and 5.4% with ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. The range of
mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.
Increases in Hemoglobin
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week
26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with ertugliflozin 5 mg, and
0.48 g/dL (3.5%) with ertugliflozin 15 mg. The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL
across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and
above the upper limit of normal.
Increases in Serum Phosphate
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum
phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with ertugliflozin 5 mg, and
0.26 mg/dL (8.5%) with ertugliflozin 15 mg. The range of mean baseline serum phosphate was 3.53 to
3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean
changes (percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%) with
placebo, 0.29 mg/dL (9.7%) with ertugliflozin 5 mg, and 0.24 mg/dL (7.8%) with ertugliflozin 15 mg.
Sitagliptin
Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated
with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count
(WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately
200 cells/microL vs. placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC
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count of approximately 6,600 cells/microL) is not considered to be clinically relevant. In a 12-week study of
91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized
to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized
to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin
[0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this
added increase in serum creatinine relative to placebo is not known.
6.2
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of ertugliflozin or
sitagliptin, both components of STEGLUJAN. Because these reactions are reported voluntarily from a
population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Ertugliflozin
•
Infections: necrotizing fasciitis of the perineum (Fournier’s Gangrene)
•
Skin and Subcutaneous Tissue Disorders: angioedema, rash
Sitagliptin
•
Skin and Subcutaneous Tissue Disorders: hypersensitivity reactions including anaphylaxis,
angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, exfoliative skin conditions
including Stevens-Johnson syndrome, and pruritus
•
Investigations: hepatic enzyme elevations
•
Gastrointestinal Disorders: acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing
pancreatitis, constipation; vomiting, mouth ulceration, and stomatitis
•
Renal and Urinary Disorders: worsening renal function, including acute renal failure (sometimes
requiring dialysis), and tubulointerstitial nephritis
•
Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, myalgia, pain in
extremity, back pain, and rhabdomyolysis
•
Nervous System Disorders: headache
7
DRUG INTERACTIONS
Table 3: Clinically Significant Drug Interactions with STEGLUJAN
Insulin or Insulin Secretagogues
Clinical Impact:
The risk of hypoglycemia is increased when STEGLUJAN is used in combination with insulin
or an insulin secretagogue.
Intervention:
A lower dose of insulin or insulin secretagogue may be required to minimize the risk of
hypoglycemia when used in combination with STEGLUJAN.
Lithium
Clinical Impact:
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium
concentrations.
Intervention:
Monitor serum lithium concentration more frequently during STEGLUJAN initiation and dosage
changes.
Positive Urine Glucose Test
Clinical Impact:
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose
tests.
Intervention:
Monitoring glycemic control with urine glucose tests is not recommended in patients taking
SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact:
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking
SGLT2 inhibitors.
Intervention:
Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods
to monitor glycemic control.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on animal data showing adverse renal effects, from ertugliflozin, STEGLUJAN is not
recommended during the second and third trimesters of pregnancy.
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The limited available data with ertugliflozin and sitagliptin use during pregnancy are not sufficient to
determine a drug associated risk of adverse developmental outcomes. There are risks to the mother and
fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered
during a period of renal development corresponding to the late second and third trimesters of human
pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule
dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in
rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose
of 15 mg/day when administered during organogenesis (see Data).
In rats and rabbits, sitagliptin doses of 250 and 125 mg/kg, respectively (approximately 30 and
20 times the human exposure at the maximum recommended human dose) did not adversely affect
development outcomes of either species.
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes
with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated
background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre
eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Animal Data
Ertugliflozin
When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney
weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or
equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure
during periods of renal development in rats that correspond to the late second and third trimester of human
renal development, and did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered
orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not
adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately
300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally
toxic dose (250 mg/kg/day) in rats (707 times the clinical dose) was associated with reduced fetal viability,
and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and
post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation
day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at
maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum
clinical dose of 15 mg/day, based on AUC).
Sitagliptin
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20
(organogenesis) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (rats) and
125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended
human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of
rib malformations in offspring at 1,000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight
in male and female offspring at 1,000 mg/kg. No functional or behavioral toxicity was observed in offspring
of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and
80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was
approximately 66% at 2 hours and 30% at 24 hours.
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8.2
Lactation
Risk Summary
There is no information regarding the presence of STEGLUJAN, in human milk, the effects on the
breastfed infant, or the effects on milk production. Ertugliflozin and sitagliptin are present in the milk of
lactating rats (see Data). Since human kidney maturation occurs in utero and during the first 2 years of life
when lactational exposure may occur, there may be risk to the developing human kidney, based on data
with ertugliflozin. Because of the potential for serious adverse reactions in a breastfed infant, advise women
that the use of STEGLUJAN is not recommended while breastfeeding.
Data
Ertugliflozin
The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after
parturition. Ertugliflozin-derived radioactivity exposure in milk and plasma were similar, with a milk/plasma
ratio of 1.07, based on AUC. Juvenile rats directly exposed to ertugliflozin during a developmental period
corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent
increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).
Sitagliptin
Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.
8.4
Pediatric Use
Safety and effectiveness of STEGLUJAN in pediatric patients under 18 years of age have not been
established.
8.5
Geriatric Use
STEGLUJAN
No dosage adjustment of STEGLUJAN is recommended based on age. Elderly patients are more
likely to have decreased renal function. Because renal function abnormalities can occur after initiating
ertugliflozin, and sitagliptin is known to be substantially excreted by the kidneys, renal function should be
assessed more frequently in elderly patients [see Dosage and Administration (2.1) and Warnings and
Precautions (5.4)].
Ertugliflozin
In ertugliflozin clinical trials, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years
and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and
older had a higher incidence of adverse reactions related to volume depletion compared to younger
patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, ertugliflozin
5 mg, and ertugliflozin 15 mg, respectively [see Warnings and Precautions (5.5) and Adverse Reactions
(6.1)].
In VERTIS CV, a total of 2780 (50.5%) patients treated with ertugliflozin were 65 years and older,
and 595 (10.8%) patients treated with ertugliflozin were 75 years and older. Safety and efficacy were
generally similar for patients age 65 years and older compared to patients younger than 65.
Sitagliptin
Of the total number of subjects (N=3,884) in pre-approval clinical safety and efficacy studies of
sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall
differences in safety or effectiveness were observed between subjects 65 years and over and younger
subjects. While this and other reported clinical experience have not identified differences in responses
between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
8.6
Renal Impairment
A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR ≥30
to less than 60 mL/min/1.73 m2) treated with ertugliflozin did not demonstrate improvement in glycemic
control. In the VERTIS CV study, there were 1370 patients (25%) with an eGFR ≥90 mL/min/1.73 m2, 2929
patients (53%) with an eGFR of ≥60 to less than 90 mL/min/1.73 m2, 879 patients (16%) with an eGFR of
≥45 to less than 60 mL/min/1.73 m2 and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m2 treated
with ertugliflozin. Similar effects on glycemic control at Week 18 were observed in patients treated with
ertugliflozin in each eGFR subgroup and also in the overall patient population.
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STEGLUJAN is contraindicated in patients with severe renal impairment (eGFR less than
30 mL/min/1.73 m2), ESRD, or on dialysis [see Contraindications (4)].
No dosage adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m2.
8.7
Hepatic Impairment
No dosage adjustment of STEGLUJAN is necessary in patients with mild or moderate hepatic
impairment. STEGLUJAN has not been studied in patients with severe hepatic impairment and is not
recommended for use in this patient population [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
STEGLUJAN
In the event of an overdose with STEGLUJAN, contact the Poison Help line (1-800-222-1222) or a
medical toxicologist for additional overdosage management recommendations. Employ the usual
supportive measures as dictated by the patient’s clinical status.
Ertugliflozin
Removal of ertugliflozin by hemodialysis has not been studied.
Sitagliptin
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed
over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically
appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
11
DESCRIPTION
STEGLUJAN (ertugliflozin and sitagliptin) tablet for oral use contains ertugliflozin L-pyroglutamic acid,
a SGLT2 inhibitor, and sitagliptin phosphate, a DPP-4 inhibitor.
Ertugliflozin
The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4
ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5
oxopyrrolidine-2-carboxylic acid. The molecular formula is C27H32ClNO10 and the molecular weight is
566.00.
The chemical structure is:
Ertugliflozin L-pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and
acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.
Sitagliptin
Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5
trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine
phosphate
(1:1)
monohydrate.
The empirical formula is C16H15F6N5O•H3PO4•H2O and the molecular weight is 523.32. The structural
formula is:
14
Reference ID: 5502336
F
F
O
H
NH2
N
N
.
.
N
H3PO4
H2O
F
N
CF3
Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is
soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol,
acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
STEGLUJAN is available for oral use as film-coated tablets containing:
•
6.48 mg ertugliflozin L-pyroglutamic acid equivalent to 5 mg of ertugliflozin and 128.5 mg sitagliptin
phosphate monohydrate equivalent to 100 mg sitagliptin (STEGLUJAN 5/100)
•
19.43 mg ertugliflozin L-pyroglutamic acid equivalent to 15 mg of ertugliflozin and 128.5 mg sitagliptin
phosphate monohydrate equivalent to 100 mg sitagliptin (STEGLUJAN 15/100)
Inactive ingredients are microcrystalline cellulose, dibasic calcium phosphate anhydrous,
croscarmellose sodium, sodium stearyl fumarate, magnesium stearate, and propyl gallate.
The film coating contains: hypromellose, hydroxypropyl cellulose, titanium dioxide, iron oxide red,
iron oxide yellow, ferrosoferric oxide/black iron oxide, and carnauba wax.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
STEGLUJAN
STEGLUJAN combines two antihyperglycemic agents with complementary mechanisms of action to
improve glycemic control in patients with type 2 diabetes mellitus: ertugliflozin, a SGLT2 inhibitor, and
sitagliptin, a DPP-4 inhibitor.
Ertugliflozin
SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular
filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin
reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby
increases urinary glucose excretion.
Sitagliptin
Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes
mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are
increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin
hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide
(GIP), are released by the intestine throughout the day, and levels are increased in response to a meal.
These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous
system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations
are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells
by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from
pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active
incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a
glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or
DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
12.2 Pharmacodynamics
Ertugliflozin
Urinary Glucose Excretion and Urinary Volume
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Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy
subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of
ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal
urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration. UGE
with ertugliflozin also results in increases in urinary volume.
Cardiac Electrophysiology
The effect of ertugliflozin on QTc interval was evaluated in a Phase 1 randomized, placebo- and
positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures
with maximum recommended dose, ertugliflozin does not prolong QTc to any clinically relevant extent.
Sitagliptin
General
In patients with type 2 diabetes mellitus, administration of sitagliptin led to inhibition of DPP-4 enzyme
activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3
fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and
increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin
concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose
concentrations and reduced glucose excursion following an oral glucose load or a meal.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,
whereas metformin alone increased active and total GLP-1 concentrations to similar extents.
Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate
to changes in glycemic control in patients with type 2 diabetes mellitus.
In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.
Cardiac Electrophysiology
In a randomized, placebo controlled crossover study, 79 healthy subjects were administered a single
oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the
recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma
concentration, or at any other time during the study. Following the 800 mg dose, the maximum increase in
the placebo corrected mean change in QTc from baseline was observed at 3 hours postdose and was
8.0 msec. This increase is not considered to be clinically significant. At the 800 mg dose, peak sitagliptin
plasma concentrations were approximately 11 times higher than the peak concentrations following a
100-mg dose.
In patients with type 2 diabetes mellitus administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg
(N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time
of expected peak plasma concentration.
12.3 Pharmacokinetics
General Introduction
Ertugliflozin
The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes
mellitus. The steady state mean plasma AUC and Cmax were 398 ng∙hr/mL and 81.3 ng/mL, respectively,
with 5 mg ertugliflozin once daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg
ertugliflozin once daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with
ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up
to 10-40% following multiple dosing.
Sitagliptin
The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and
patients with type 2 diabetes mellitus. After oral administration of a 100-mg dose to healthy subjects,
sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours
postdose. Plasma AUC of sitagliptin increased in a dose proportional manner. Following a single oral
100-mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 M•hr, Cmax was 950 nM, and
apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14%
following 100-mg doses at steady state compared to the first dose. The intra subject and inter subject
16
Reference ID: 5502336
coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin
was generally similar in healthy subjects and in patients with type 2 diabetes mellitus.
Absorption
STEGLUJAN
The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and sitagliptin when
administered as STEGLUJAN tablets are comparable to those reported for the individual tablets.
Administration of STEGLUJAN with food decreased ertugliflozin Cmax by 29% and had no meaningful effect
on ertugliflozin AUCinf, and on sitagliptin AUCinf and Cmax.
Ertugliflozin
Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma
concentrations of ertugliflozin occur at 1 hour postdose (median Tmax) under fasted conditions. Plasma Cmax
and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg (0.1
times the lowest recommended dose) to 300 mg (20 times the highest recommended dose) and following
multiple doses from 1 mg (0.2 times the lowest recommended dose) to 100 mg (6.7 times the highest
recommended dose). The absolute oral bioavailability of ertugliflozin following administration of a 15 mg
dose is approximately 100%.
Effect of Food
Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by
29% and prolongs Tmax by 1 hour, but does not alter AUC as compared with the fasted state. The observed
effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may
be administered with or without food. In Phase 3 clinical trials, ertugliflozin was administered without regard
to meals.
Sitagliptin
The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high
fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or
without food.
Distribution
Ertugliflozin
The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L.
Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations.
Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood-
to-plasma concentration ratio of ertugliflozin is 0.66.
Sitagliptin
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 L. The fraction of sitagliptin reversibly bound to plasma
proteins is low (38%).
Elimination
Metabolism
Ertugliflozin
Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway for
ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that are
pharmacologically inactive at clinically relevant concentrations. CYP-mediated (oxidative) metabolism of
ertugliflozin is minimal (12%).
Sitagliptin
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor
pathway of elimination.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute
17
Reference ID: 5502336
to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme
responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Excretion
Ertugliflozin
The mean systemic plasma clearance following an intravenous 100 µg dose was 11.2 L/hr. The mean
elimination half-life in type 2 diabetic patients with normal renal function was estimated to be 16.6 hours
based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin
solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was
eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged
ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion
of glucuronide metabolites and subsequent hydrolysis to parent.
Sitagliptin
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of
the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The
apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal
clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the
renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been
established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the
renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal
clearance of sitagliptin.
Specific Populations
Patients with Renal Impairment
STEGLUJAN
Studies characterizing the pharmacokinetics of ertugliflozin and sitagliptin after administration of
STEGLUJAN in renally impaired patients have not been performed [see Dosage and Administration (2.1)].
Ertugliflozin
In a clinical pharmacology study in patients with type 2 diabetes mellitus and mild, moderate, or
severe renal impairment (as determined by eGFR), following a single-dose administration of 15 mg
ertugliflozin, the mean increases in AUC of ertugliflozin were 1.6-, 1.7-, and 1.6-fold, respectively, for mild,
moderate and severe renally-impaired patients, compared to subjects with normal renal function. These
increases in ertugliflozin AUC are not considered clinically meaningful. The 24-hour urinary glucose
excretion declined with increasing severity of renal impairment [see Warnings and Precautions (5.4) and
Use in Specific Populations (8.6)]. The plasma protein binding of ertugliflozin was unaffected in patients
with renal impairment.
Sitagliptin
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with
moderate renal impairment with eGFR of 30 to less than 45 mL/min/1.73 m2, and an approximately 4-fold
increase was observed in patients with severe renal impairment, including patients with ESRD on
hemodialysis, as compared to normal healthy control subjects.
Patients with Hepatic Impairment
Ertugliflozin
Moderate hepatic impairment (based on the Child-Pugh classification) did not result in an increase in
exposure of ertugliflozin. The AUC of ertugliflozin decreased by approximately 13%, and Cmax decreased
by approximately 21% compared to subjects with normal hepatic function. This decrease in ertugliflozin
exposure is not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh
class C (severe) hepatic impairment. The plasma protein binding of ertugliflozin was unaffected in patients
with moderate hepatic impairment [see Use in Specific Populations (8.7)].
18
Reference ID: 5502336
Sitagliptin
In patients with moderate hepatic insufficiency (Child Pugh score 7 to 9), mean AUC and Cmax of
sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls
following administration of a single 100-mg dose of sitagliptin. These differences are not considered to be
clinically meaningful. No dosage adjustment for sitagliptin is necessary for patients with mild or moderate
hepatic insufficiency.
There is no clinical experience in patients with severe hepatic insufficiency (Child Pugh score >9)
[see Use in Specific Populations (8.7)].
Effects of Age, Body Weight/ Body Mass Index (BMI), Gender, and Race
Ertugliflozin
Based on a population pharmacokinetic analysis, age, body weight, gender, and race do not have a
clinically meaningful effect on the pharmacokinetics of ertugliflozin.
Sitagliptin
Based on a population pharmacokinetic analysis or a composite analysis of available
pharmacokinetic data, BMI, gender, and race do not have a clinically meaningful effect on the
pharmacokinetics of sitagliptin. When the effects of age on renal function are taken into account, age alone
did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population
pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma
concentrations of sitagliptin compared to younger subjects.
Drug Interaction Studies
STEGLUJAN
Coadministration of single dose of ertugliflozin (15 mg) and sitagliptin (100 mg) did not meaningfully
alter the pharmacokinetics of either ertugliflozin or metformin in healthy subjects.
Pharmacokinetic drug interaction studies with STEGLUJAN have not been performed; however, such
studies have been conducted with ertugliflozin and sitagliptin, the individual components of STEGLUJAN.
Ertugliflozin
In Vitro Assessment of Drug Interactions
In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit CYP450 isoenzymes
(CYPs) 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin
was not a time-dependent inhibitor of CYP3A in vitro. Ertugliflozin did not inhibit UGT1A6, 1A9, or 2B7 in
vitro and was a weak inhibitor (IC50 >39 µM) of UGT1A1 and 1A4. Ertugliflozin glucuronides did not inhibit
UGT1A1, 1A4, 1A6, 1A9, or 2B7 in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of
drugs eliminated by these enzymes. Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer
resistance protein (BCRP) transporters and is not a substrate of organic anion transporters (OAT1, OAT3),
organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1,
OATP1B3). Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or
OAT3 transporters, or transporting polypeptides OATP1B1 and OATP1B3, at clinically relevant
concentrations. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered
medications that are substrates of these transporters.
In Vivo Assessment of Drug Interactions
No dose adjustment of STEGLUJAN is recommended when coadministered with commonly
prescribed
medicinal
products.
Ertugliflozin
pharmacokinetics
were
similar with
and
without
coadministration of metformin, glimepiride, sitagliptin, and simvastatin in healthy subjects (see Figure 1).
Coadministration of ertugliflozin with multiple doses of 600 mg once daily rifampin (an inducer of UGT and
CYP enzymes) resulted in approximately 39% and 15% mean reductions in ertugliflozin AUC and Cmax,
respectively, relative to ertugliflozin administered alone. These changes in exposure are not considered
clinically relevant. Ertugliflozin had no clinically relevant effect on the pharmacokinetics of metformin,
glimepiride, sitagliptin, and simvastatin when coadministered in healthy subjects (see Figure 2).
Physiologically-based PK (PBPK) modeling suggests that coadministration of mefenamic acid (UGT
inhibitor) may increase the AUC and Cmax of ertugliflozin by 1.51- and 1.19-fold, respectively. These
predicted changes in exposure are not considered clinically relevant.
19
Reference ID: 5502336
Sitagliptin, 100 mg, single dose
AUG
Gmax
Metformin, 1000 mg, single dose
AUG
Gmax
Glimepiride, 1 mg, single dose
AUG
Gmax
Simvastatin, 40 mg, single dose
AUG
Gmax
Rifampin, 600 mg, once daily
AUG
Gmax -
Geometric mean ratio (90% Cl)
102.27 (99.72-104.89}
98.1 8 (91 .20-1 05. 70)
100.34 (97.43-1 03.34)
97.14 (88.77-106.30)
102.11 (97.19-1 07.27)
98.20 (92.17-104.63)
102.40 (99.57-105.31 )
1 05.16 (98.26-112.54}
61.16 (57.22-65.37)
84.62 (74.17-96.53)
50
75
100
125
150
Relative to ertugliflozin alone (%)
All ertugliflozin doses were given as 15 mg single dose
Figure 1: Effects of Other Drugs on the Pharmacokinetics of Ertugliflozin
20
Reference ID: 5502336
Geometric mean ratio (90% Cl)
Sitagliptin , 100 mg, single dose
AUG
·-
1 01 .67 (9B.40-1 05.04)
Gmax
101 .6B (91 .65-11 2.BO)
Metformin, 1000 mg, single dose
AUG
100.94 (90.62-11 2.44)
Gmax
-
94.00 (B2.94-106.55)
Glimepiride, 1 mg, single dose
AUG
-
109.BO (9B.14-1 22.B6)
Gmax
97.39 (71.07-1 33.46}
Simvastatin, 40 mg, single dose
AUG
-
123.B3 (90.92-16B.66)
Gmax
11 9.05 (97.22-145.77)
Simvastatin Acid
AUG
130.46 (1 OB.32-157. 13}
(Administered as Simvastatin)
Gmax
11 5.66 (95.74-1 39.71}
100
150
200
Relative to concomitant medication alone (%)
All ertugliflozin doses were given as 15 mg single dose
Figure 2: Effects of Ertugliflozin on the Pharmacokinetics of Other Drugs
Sitagliptin
In Vitro Assessment of Drug Interactions
Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is
not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein
mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions
with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be
involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is
very low.
In Vivo Assessment of Drug Interactions
Table 4: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin
Coadministered
Dose of
Dose of Sitagliptin*
Drug
Coadministered
Drug*
Geometric Mean Ratio
(ratio with/without coadministered drug)
No Effect = 1.00
AUC†
Cmax
No dosing adjustments required for the following:
Cyclosporine
600 mg once daily
100 mg once daily
Sitagliptin
1.29
1.68
Metformin
1,000 mg‡ twice daily
for 14 days
50 mg‡ twice daily for
7 days
Sitagliptin
1.02§
1.05
21
Reference ID: 5502336
* All doses administered as single dose unless otherwise specified.
† AUC is reported as AUC0-∞ unless otherwise specified.
‡ Multiple dose.
§ AUC0-12hr.
Table 5: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs
Coadministered Drug
Dose of
Coadministered
Drug*
Dose of
Sitagliptin*
Geometric Mean Ratio
(ratio with/without sitagliptin)
No Effect = 1.00
AUC†
Cmax
No dosing adjustments required for the following:
Digoxin
‡
0.25 mg once daily
for 10 days
100 mg‡ once daily
for 10 days
Digoxin
1.11§
1.18
Glyburide
1.25 mg
200 mg‡ once daily
for 6 days
Glyburide
1.09
1.01
Simvastatin
20 mg
‡
200 mg once daily
for 5 days
Simvastatin
0.85¶
0.80
Simvastatin Acid
1.12¶
1.06
Rosiglitazone
4 mg
200 mg‡ once daily
for 5 days
Rosiglitazone
0.98
0.99
Warfarin
30 mg single dose on
day 5
200 mg‡ once daily
for 11 days
S(-) Warfarin
0.95
0.89
R(+) Warfarin
0.99
0.89
Ethinyl estradiol and
norethindrone
21 days once daily of
35 µg ethinyl
200 mg‡ once daily
for 21 days
Ethinyl estradiol
0.99
0.97
estradiol with
norethindrone 0.5 mg
x 7 days, 0.75 mg x 7
days, 1.0 mg x 7
days
Norethindrone
1.03
0.98
Metformin
1,000 mg‡ twice daily
for 14 days
50 mg‡ twice daily
for 7 days
Metformin
1.02#
0.97
*
All doses administered as single dose unless otherwise specified. The 200 mg dose is 2 times the maximum recommended
daily dose of sitagliptin.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
Multiple dose.
§
AUC0-24hr.
¶
AUC0-last.
#
AUC0-12hr.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Ertugliflozin
Carcinogenicity was evaluated in CD-1 mice and Sprague-Dawley rats. In the mouse study,
ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day for up to 97 weeks in
males and 102 weeks in females. There were no ertugliflozin-related neoplastic findings at doses up to
40 mg/kg/day (approximately 50 times human exposure at the maximum recommended human dose
[MRHD] of 15 mg/day based on AUC). In the rat study, ertugliflozin was administered by oral gavage at
doses of 1.5, 5, and 15 mg/kg/day for up to 92 weeks in females and 104 weeks in males. Ertugliflozin
related neoplastic findings included an increased incidence of adrenal medullary pheochromocytoma (PCC)
in male rats at 15 mg/kg/day. Although the molecular mechanism remains unknown, this finding may be
related to carbohydrate malabsorption leading to altered calcium homeostasis, which has been associated
22
Reference ID: 5502336
with PCC development in rats and has unclear relevance to human risk. The no-observed-effect level
(NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human exposure at the MRHD of
15 mg/day, based on AUC).
Sitagliptin
A two year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin
of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma
in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures
approximately 60 times the human exposure at the maximum recommended daily adult human dose
(MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg,
approximately 20 times the human exposure at the MRHD.
A two year carcinogenicity study was conducted in male and female mice given oral doses of
sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any
organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD.
Mutagenesis
Ertugliflozin
Ertugliflozin was not mutagenic or clastogenic with or without metabolic activation in the microbial
reverse mutation, in vitro cytogenetic (human lymphocytes), and in vivo rat micronucleus assays.
Sitagliptin
Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial
mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro
cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo
micronucleus assay.
Impairment of Fertility
Ertugliflozin
In the rat fertility and embryonic development study, male and female rats were administered
ertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day
(approximately 480 and 570 times male and female human exposures, respectively, at the MRHD of
15 mg/day based on AUC comparison).
Sitagliptin
In rat fertility studies with oral gavage doses of 125, 250, and 1,000 mg/kg, males were treated for 4
weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and
females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was
observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on
AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed
(approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
14
CLINICAL STUDIES
14.1 Glycemic Control Trials in Patients with Type 2 Diabetes Mellitus
The efficacy and safety of ertugliflozin in combination with sitagliptin have been studied in 3 multi-
center, randomized, double-blind, placebo- and active comparator-controlled, clinical studies involving
1,985 patients with type 2 diabetes mellitus. These studies included White, Hispanic or Latino, Black or
African American, Asian, and other racial and ethnic groups, and patients with an age range of 21 to
85 years.
In patients with type 2 diabetes mellitus, treatment with ertugliflozin in combination with sitagliptin
reduced HbA1c compared to placebo or active comparator.
In patients with type 2 diabetes mellitus treated with ertugliflozin in combination with sitagliptin, the
change in HbA1c was generally similar across subgroups defined by age, sex, and race.
In Combination with Sitagliptin versus Ertugliflozin Alone and Sitagliptin Alone, as Add-on to Metformin HCl
A total of 1,233 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c
between 7.5% and 11%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a
23
Reference ID: 5502336
randomized, double-blind, 26-week, active controlled study (NCT02099110) to evaluate the efficacy and
safety of ertugliflozin 5 mg or 15 mg administered orally in combination with sitagliptin 100 mg compared
to the individual components. Patients were randomized to one of five treatment arms: ertugliflozin 5 mg,
ertugliflozin 15 mg, sitagliptin 100 mg, ertugliflozin 5 mg + sitagliptin 100 mg, or ertugliflozin 15 mg +
sitagliptin 100 mg.
At Week 26, ertugliflozin 5 mg or 15 mg + sitagliptin 100 mg provided statistically significantly greater
reductions in HbA1c compared to the individual components. More patients achieved an HbA1c < 7% on
the combination as compared to the individual components (see Table 6 and Figure 3).
Table 6: Results at Week 26 from a Factorial Study with Ertugliflozin and Sitagliptin as Add-on
Combination Therapy with Metformin HCl Compared to Individual Components Alone*
Sitagliptin
100 mg
Ertugliflozin
5 mg
Ertugliflozin
15 mg
Ertugliflozin 5 mg
+Sitagliptin 100 mg
Ertugliflozin 15 mg
+ Sitagliptin 100 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from
Sitagliptin
Ertugliflozin 5 mg
Ertugliflozin 15 mg
†
(LS mean , 95% CI)
N = 242
8.5
-1.0
N = 244
8.6
-1.0
N = 247
8.6
-1.0
N = 237
8.6
-1.4
-0.4‡ (-0.6, -0.2)
-0.4‡ (-0.5, -0.2)
N = 241
8.6
-1.4
-0.4‡ (-0.5, -0.2)
-0.4‡ (-0.6, -0.2)
Patients [N (%)] with HbA1c <7%
93 (38.5)
72 (29.3)
83 (33.7)
126 (53.3)
123 (50.9)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from
Sitagliptin
Ertugliflozin 5 mg
Ertugliflozin 15 mg
†
(LS mean , 95% CI)
N = 246
177.4
-24.3
N = 250
184.1
-34.0
N = 247
179.5
-34.6
N = 240
183.8
-41.1
-16.8‡ (-23.2, -10.4)
-7.0§ (-13.3, -0.7)
N = 241
177.2
-44.3
-20.0‡ (-26.4, -13.6)
-9.8§ (-16.1, -3.4)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26 the primary HbA1c
endpoint was missing for 13%, 10%, 11%, 11%, and 12% of patients and during the trial rescue medication was initiated by 6%, 6%,
3%, 2%, and 0% of patients randomized to sitagliptin, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin 5 mg + sitagliptin, and
ertugliflozin 15 mg + sitagliptin, respectively. Missing Week 26 measurements were imputed using multiple imputation with a mean equal
to the baseline value of the patient. Results included measurements collected after initiation of rescue medication. For those subjects
who did not receive rescue medication and had values measured at 26 weeks, the mean change from baseline for HbA1c was -1.1%,
1.1%, -1.1%, -1.5% and -1.6% for sitagliptin, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin 5 mg + sitagliptin, and ertugliflozin 15 mg
+ sitagliptin, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value and baseline eGFR.
‡
p<0.001 compared to control group.
§
p<0.03 compared to control group.
24
Reference ID: 5502336
0.0
-0.1
-0.2
a,
C:
-0.3
"ij
-0.4
Ill
rtl
-0.5
ID
E
-0.6
0 ...
-0.7
-
a,
Cl
-0.8
C:
rtl
-0.9
~
u
-1.0
C:
rtl
-1.1
a,
:::E:
-1.2
~
~ -1.3
u
-1.4
....
<(
•
.c
-1.5
J:
-1.6
-1.7
♦ Ertu 5 mg
T Ertu 15 mg
• Sita 100 mg
-1.8
• Ertu 5 mg+ Sita 100 mg * Ertu 15 mg+ Sita 100 mg
BL
6
12
18
26 26-MI
Week
Ertu 5 mg (N) 244
Ertu 15 mg (N) 247
236
231
223
211
239
232
226
214
Sita 100 mg (N) 242
Ertu 5 mg + Sita 100 mg (N) 237
Ertu 15 mg + Sita 1 00 mg (N) 241
236
226
212
203
227
223
220
212
229
226
225
215
The mean baseline body weight was 89.8 kg, 88.6 kg, 88.0 kg, 89.5 kg, and 87.5 kg in the sitagliptin
100 mg, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin 5 mg + sitagliptin 100 mg, and ertugliflozin
15 mg + sitagliptin 100 mg groups, respectively. The mean changes from baseline to Week 26 were -0.4
kg, -2.6 kg, -3.4 kg, -2.4 kg, and -2.7 kg in the sitagliptin 100 mg, ertugliflozin 5 mg, ertugliflozin 15 mg,
ertugliflozin 5 mg + sitagliptin 100 mg, and ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively. The
difference from sitagliptin 100 mg (95% CI) for ertugliflozin 5 mg + sitagliptin 100 mg was -1.9 kg (-2.6, -1.3)
and for ertugliflozin 15 mg + sitagliptin 100 mg was -2.3 kg (-3.0, -1.6).
The mean baseline systolic blood pressure was 128.4 mmHg, 129.7 mmHg, 128.9 mmHg,
130.2 mmHg, and 129.1 mmHg in the sitagliptin 100 mg, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin
5 mg + sitagliptin 100 mg, and ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively. The mean
changes from baseline to Week 26 were -0.5 mmHg, -4.0 mmHg, -3.6 mmHg, -2.8 mmHg, and -3.4 mmHg
in the sitagliptin 100 mg, ertugliflozin 5 mg, ertugliflozin 15 mg, ertugliflozin 5 mg + sitagliptin 100 mg, and
ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively. The difference from sitagliptin 100 mg (95%
CI) for ertugliflozin 5 mg + sitagliptin 100 mg was -2.3 mmHg (-4.3, -0.4) and for ertugliflozin 15 mg +
sitagliptin 100 mg was -2.9 mmHg (-4.8, -1.0).
Figure 3: HbA1c (%) Change over Time in a Factorial Study with Ertugliflozin and Sitagliptin as
Add-on Combination Therapy with Metformin HCl Compared to Individual Components Alone*
*Data to the left of the vertical line are observed means (non-model-based) excluding values occurring post glycemic rescue.
Data to the right of the vertical line represent the final Week 26 data, including all values regardless of use of glycemic rescue
medication and use of study drug, with missing Week 26 values imputed using multiple imputation (26-MI) with a mean equal
to the baseline value of the patient (see Table 6).
Ertugliflozin as Add-on Combination Therapy with Metformin HCl and Sitagliptin
A total of 463 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and
10.5%) on metformin HCl (≥1,500 mg/day for ≥8 weeks) and sitagliptin 100 mg orally once daily participated
in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT02036515) to evaluate
25
Reference ID: 5502336
the efficacy and safety of ertugliflozin. Patients entered a 2-week, single-blind, placebo run-in period and
were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg.
At Week 26, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant
reductions in in HbA1c. Ertugliflozin also resulted in a higher proportion of patients achieving an HbA1c
<7% compared to placebo (see Table 7).
Table 7: Results at Week 26 from an Add-on Study of Ertugliflozin in Combination with Metformin
HCl and Sitagliptin in Patients with Type 2 Diabetes Mellitus*
Placebo
Ertugliflozin 5 mg
Ertugliflozin 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 152
8.0
-0.2
N = 155
8.1
-0.7
-0.5‡ (-0.7, -0.3)
N = 152
8.0
-0.8
-0.6‡ (-0.8, -0.4)
Patients [N (%)] with HbA1c <7%
31 (20.2)
54 (34.6)
64 (42.3)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 152
169.6
-6.5
N = 156
167.7
-25.7
-19.2‡ (-26.8, -11.6)
N = 152
171.7
-32.1
-25.6‡ (-33.2, -18.0)
* N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary
HbA1c endpoint was missing for 10%, 11%, and 7% of patients and during the trial, rescue medication was initiated by 16%, 1%,
and 2% of patients randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Missing Week 26
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results included
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.8%, and -0.9% for placebo, ertugliflozin
5 mg, and ertugliflozin 15 mg, respectively.
† Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR.
‡ p<0.001 compared to placebo.
The mean baseline body weight was 86.5 kg, 87.6 kg, and 86.6 kg in the placebo, ertugliflozin 5 mg,
and ertugliflozin 15 mg groups, respectively. The mean changes from baseline to Week 26
were -1.0 kg, -3.0 kg, and -2.8 kg in the placebo, ertugliflozin 5 mg and ertugliflozin 15 mg groups,
respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg was -1.9 kg (-2.6, -1.3) and for
ertugliflozin 15 mg was -1.8 kg (-2.4, -1.2).
The mean baseline systolic blood pressure was 130.2 mmHg, 132.1 mmHg, and 131.6 mmHg in the
placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively. The mean changes from baseline
to Week 26 were -0.2 mmHg, -3.8 mmHg, and -4.5 mmHg in the placebo, ertugliflozin 5 mg and ertugliflozin
15 mg groups, respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg was -3.7 mmHg
(-6.1, -1.2) and for ertugliflozin 15 mg was -4.3 mmHg (-6.7, -1.9).
Initial Combination Therapy of Ertugliflozin and Sitagliptin
A total of 291 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 8% and
10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, placebo-controlled
26-week study (NCT02226003) to evaluate the efficacy and safety of ertugliflozin in combination with
sitagliptin. These patients, who were not receiving any background antihyperglycemic treatment for ≥8
weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo, ertugliflozin
5 mg, or ertugliflozin 15 mg, in combination with sitagliptin (100 mg), orally once daily.
At Week 26, treatment with ertugliflozin 5 mg and 15 mg in combination with sitagliptin at 100 mg
daily provided statistically significant reductions in HbA1c compared to placebo. Ertugliflozin 5 mg and
15 mg in combination with sitagliptin at 100 mg daily also resulted in a higher proportion of patients
achieving an HbA1c <7% compared with placebo (see Table 8).
26
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Table 8: Results at Week 26 from an Initial Combination Therapy Study of Ertugliflozin and
Sitagliptin*
Placebo
Ertugliflozin 5 mg
+ Sitagliptin 100 mg
Ertugliflozin 15 mg
+ Sitagliptin 100 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean† and 95% CI)
N = 96
9.0
-0.6
N = 98
8.9
-1.6
-1.0‡ (-1.3, -0.7)
N = 96
9.0
-1.5
-0.9‡ (-1.3, -0.6)
Patients [N (%)] with HbA1c <7%
9 (9.3)
36 (37.1)
32 (32.9)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 96
207.5
-11.8
N = 98
198.0
-47.1
-35.4‡ (-47.3, -23.4)
N = 96
187.7
-50.8
-39.1‡ (-51.4, -26.8)
* N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26 the primary HbA1c
endpoint was missing for 22%, 7% and 10% of patients and during the trial rescue medication was initiated by 32%, 6%, and 0% of
patients randomized to placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. Missing Week 26 measurements were
imputed using multiple imputation with a mean equal to the baseline value of the patient. Results included measurements collected
after initiation of rescue medication. For those subjects who did not receive rescue medication and had values measured at 26
weeks, the mean change from baseline for HbA1c was -0.8%, -1.7%, -1.7% for placebo, ertugliflozin 5 mg and ertugliflozin 15 mg,
respectively.
† Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR.
‡ p<0.001 compared to placebo.
The mean baseline body weight was 95.0 kg, 90.8 kg, and 91.2 kg in the placebo, ertugliflozin 5 mg
+ sitagliptin 100 mg, and ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively. The mean changes
from baseline to Week 26 were -0.5 kg, -2.7 kg, and -2.8 kg in the placebo, ertugliflozin 5 mg + sitagliptin
100 mg, and ertugliflozin 15 mg + sitagliptin 100 mg groups, respectively. The difference from placebo (95%
CI) for ertugliflozin 5 mg + sitagliptin 100 mg was -2.1 kg (-3.1, -1.2) and for ertugliflozin 15 mg + sitagliptin
100 mg was -2.3 kg (-3.3, -1.3).
The mean baseline systolic blood pressure was 127.4 mmHg, 130.7 mmHg, and 129.2 mmHg in the
placebo, ertugliflozin 5 mg + sitagliptin 100 mg, and ertugliflozin 15 mg + sitagliptin 100 mg groups,
respectively. The mean changes from baseline to Week 26 were 1.6 mmHg, -2.4 mmHg, and -3.5 mmHg
in the placebo, ertugliflozin 5 mg + sitagliptin 100 mg, and ertugliflozin 15 mg + sitagliptin 100 mg,
respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg + sitagliptin 100 mg
was -4.0 mmHg (-7.2, -0.8) and for ertugliflozin 15 mg + sitagliptin 100 mg was -5.2 mmHg (-8.4, -1.9).
14.2 Ertugliflozin Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and
Established Cardiovascular Disease
The effect of ertugliflozin on cardiovascular risk in adult patients with type 2 diabetes and established
atherosclerotic cardiovascular disease was evaluated in the VERTIS CV study (NCT01986881), a
multicenter, multi-national, randomized, double-blind, placebo-controlled, event driven trial. The study
compared the risk of experiencing a major adverse cardiovascular event (MACE) between ertugliflozin and
placebo when these were added to and used concomitantly with standard of care treatments for diabetes
and atherosclerotic cardiovascular disease.
A total of 8,246 patients were randomized to placebo (N=2,747), oral once daily ertugliflozin 5 mg
(N=2,752), or oral once daily ertugliflozin 15 mg (N=2,747) and followed for a median of 3 years.
Approximately 88% of the study population was White, 6% Asian, and 3% Black or African American. The
mean age was 64 years and approximately 70% were male.
All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c
greater than or equal to 7%). The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA1c
at baseline was 8.2% and the mean eGFR was 76 mL/min/1.73 m2. At baseline, patients were treated with
one (32%) or more (67%) antidiabetic medications including biguanides (metformin HCl) (76%), insulin
(47%), sulfonylureas (41%), DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%).
Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline
including: a documented history of coronary artery disease (76%), cerebrovascular disease (23%) or
peripheral artery disease (19%). Approximately 24% patients had a history of heart failure (HF). At baseline,
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Reference ID: 5502336
the mean systolic blood pressure was 133 mmHg, the mean diastolic blood pressure was 77 mmHg, the
mean LDL was 89 mg/dL, and the mean HDL was 44 mg/dL. At baseline, approximately 81% of patients
were treated with renin angiotensin system inhibitors, 69% with beta-blockers, 43% with diuretics, 82% with
statins, 4% with ezetimibe, and 89% with antiplatelet agents.
The primary endpoint in VERTIS CV was the time to first occurrence of a Major Adverse Cardiac
Event (MACE). A major adverse cardiovascular event was defined as occurrence of either a cardiovascular
death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan pre-specified
that the 5 and 15 mg doses would be combined for the analysis. A Cox proportional hazards model was
used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE.
Type I error was controlled across multiple tests using a hierarchical testing strategy.
The incidence rate of MACE was similar between the ertugliflozin-treated and placebo-treated
patients. The estimated hazard ratio of MACE associated with ertugliflozin relative to placebo was 0.97 with
95.6% confidence interval (0.85, 1.11). The upper bound of this confidence interval excluded a risk larger
than 1.3. (Table 9). Results for the 5 mg and 15 mg doses were consistent with results for the combined
dose group.
Table 9: Analysis of MACE and its Components from the VERTIS-CV Study*
Placebo (N=2747)
Ertugliflozin (N=5499)
Event Rate
Event Rate
Hazard Ratio vs
Endpoint†
N (%)
N (%)
(per 100
(per 100
Placebo
person-years)
person-years)
(CI) ‡
MACE (CV death, non-fatal MI,
327 (11.9)
4.0
653 (11.9)
3.9
0.97
or non-fatal stroke) Composite
(0.85, 1.11)
Components of Composite Endpoint
Non-fatal MI
148 (5.4)
1.6
310 (5.6)
1.7
1.04
(0.86, 1.27)
Non-fatal Stroke
78 (2.8)
0.8
157 (2.9)
0.8
1.00
(0.76, 1.32)
CV death
184 (6.7)
1.9
341 (6.2)
1.8
0.92
(0.77, 1.11)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction.
* Intent-to-treat analysis set.
† MACE was evaluated in subjects who took at least one dose of study medication and, for subjects who discontinued study medication
prior to the end of the study, censored events that occurred more than 365 days after the last dose of study medication. Other
endpoints were evaluated using all randomized subjects and events that occurred any time after the first dose of study medication
until the last contact date. The total number of first events was analyzed for each endpoint.
‡ HR and CI are based on Cox proportional hazards regression model, stratified by cohorts.
16
HOW SUPPLIED/STORAGE AND HANDLING
STEGLUJAN (ertugliflozin and sitagliptin) tablets are available in the strengths listed below:
Strength
5 mg/100 mg
tablets
Description
beige, almond-shaped, debossed
with “554” on one side and plain
on the other side.
How Supplied
unit-of-use bottles of 30
NDC
0006-5367-03
unit-of-use bottles of 90
0006-5367-06
15 mg/100 mg
tablets
brown, almond-shaped, debossed
with “555” on one side and plain
on the other side.
unit-of-use bottles of 30
0006-5368-03
unit-of-use bottles of 90
0006-5368-06
Store at 20°C-25°C (68°F-77°F), excursions permitted between 15°C-30°C (between 59°F-86°F) [see
USP Controlled Room Temperature]. Protect from moisture. Store in a dry place.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
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Reference ID: 5502336
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Inform patients that STEGLUJAN can cause potentially fatal ketoacidosis and that type 2 diabetes
mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.
Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses,
infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms
of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform
patients that blood glucose may be normal even in the presence of ketoacidosis.
Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur,
instruct patients to discontinue STEGLUJAN and seek medical attention immediately [see Warnings and
Precautions (5.1)].
Pancreatitis
Inform patients that acute pancreatitis has been reported during use of sitagliptin, a component of
STEGLUJAN. Inform patients that persistent severe abdominal pain, sometimes radiating to the back,
which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct
patients to promptly discontinue STEGLUJAN and contact their physician if persistent severe abdominal
pain occurs [see Warnings and Precautions (5.2)].
Lower Limb Amputation
Inform patients of the potential for an increased risk of amputations. Counsel patients about the
importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores
or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or
symptoms develop [see Warnings and Precautions (5.3)].
Volume Depletion
Inform patients that symptomatic hypotension may occur with STEGLUJAN and advise them to
contact their doctor if they experience such symptoms [see Warnings and Precautions (5.5)]. Inform
patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.
Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them with
information on the symptoms of urinary tract infections. Advise them to seek medical advice if such
symptoms occur [see Warnings and Precautions (5.6)].
Heart Failure
Inform patients of the signs and symptoms of heart failure. Instruct patients to contact their health
care provider as soon as possible if they experience symptoms of heart failure, including increasing
shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.7)].
Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogue
Inform patients that the incidence of hypoglycemia may increase when STEGLUJAN is used with
insulin or an insulin secretagogue. Educate patients or caregivers on the signs and symptoms of
hypoglycemia [see Warnings and Precautions (5.8)].
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with
SGLT2 inhibitors. Counsel patients to promptly seek medical attention if they develop pain or tenderness,
redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever
above 100.4°F or malaise [see Warnings and Precautions (5.9)].
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with information on
the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek
medical advice [see Warnings and Precautions (5.10)].
Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)
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Reference ID: 5502336
Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur,
especially in uncircumcised males. Provide them with information on the signs and symptoms of balanitis
and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options
and when to seek medical advice [see Warnings and Precautions (5.10)].
Hypersensitivity Reactions
Inform patients that allergic reactions have been reported during postmarketing use of sitagliptin, a
component of STEGLUJAN. If symptoms of allergic reactions (including rash, hives, and swelling of the
face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, instruct patients
that they must stop taking STEGLUJAN and seek medical advice promptly [see Warnings and Precautions
(5.11)].
Severe and Disabling Arthralgia
Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to
onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint
pain occurs [see Warnings and Precautions (5.12)].
Bullous Pemphigoid
Inform patients that bullous pemphigoid may occur with the DPP-4 class of drugs. Instruct patients to
seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.13)].
Fetal Toxicity
Advise pregnant patients of the potential risk to a fetus with treatment with STEGLUJAN. Instruct
patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see
Use in Specific Populations (8.1)].
Lactation
Advise patients that use of STEGLUJAN is not recommended while breastfeeding [see Use in Specific
Populations (8.2)].
Laboratory Tests
Due to the mechanism of action of ertugliflozin, inform patients that their urine will test positive for
glucose while taking STEGLUJAN.
Missed Dose
Instruct patients to take STEGLUJAN only as prescribed. If a dose is missed, it should be taken as
soon as the patient remembers. Advise patients not to double their next dose.
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA
For patent information: www.msd.com/research/patent
Copyright © 2017-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved.
uspi-mk8835a-t-2412r015
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Reference ID: 5502336
Medication Guide
STEGLUJAN® [STEG-loo-jan]
(ertugliflozin and sitagliptin)
tablets, for oral use
Read this Medication Guide carefully before you start taking STEGLUJAN and each time you get a
refill. There may be new information. This information does not take the place of talking with your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about STEGLUJAN?
STEGLUJAN may cause serious side effects, including:
• Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1
diabetes and other ketoacidosis. STEGLUJAN can cause ketoacidosis that can be life-
threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated
in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with
type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis.
Ketoacidosis can also happen in people who are sick, cannot eat or drink as usual, skip meals,
are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount
of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the
body (volume depletion), or who have surgery. Ketoacidosis can happen even if your blood sugar
is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in
your urine or blood.
Stop taking STEGLUJAN and call your healthcare provider or get medical help right away
if you get any of the following. If possible, check for ketones in your urine or blood, even
if your blood sugar is less than 250 mg/dL:
o nausea
o tiredness
o vomiting
o
trouble breathing
o stomach-area (abdominal) pain o
ketones in your urine or blood
• Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain
medical problems make you more likely to get pancreatitis.
Before you start taking STEGLUJAN, tell your healthcare provider if you have ever had:
•
pancreatitis
•
stones in your gallbladder
•
a history of alcoholism
(gallstones)
•
kidney problems
•
high blood triglyceride levels
Stop taking STEGLUJAN and call your healthcare provider right away if you have pain in your
stomach area (abdomen) that is severe and will not go away. The pain may be felt going from
your abdomen through to your back. The pain may happen with or without vomiting. These may
be symptoms of pancreatitis.
•
Amputations. STEGLUJAN may increase your risk of lower limb amputations.
You may be at a higher risk of lower limb amputation if you:
o have a history of amputation
o have had blocked or narrowed blood vessels, usually in your leg
o have damage to the nerves (neuropathy) in your leg
o have had diabetic foot ulcers or sores
Call your healthcare provider right away if you have new pain or tenderness, any sores,
ulcers, or infections in your leg or foot. Your healthcare provider may decide to stop your
STEGLUJAN for a while if you have any of these signs or symptoms. Talk to your healthcare
provider about proper foot care.
• Dehydration. STEGLUJAN can cause some people to become dehydrated (the loss of
body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or
Reference ID: 5502336
weak, especially when you stand up (orthostatic hypotension). There have been reports
of sudden worsening of kidney function in people who are taking STEGLUJAN.
You may be at risk of dehydration if you:
o
take medicines to lower your blood pressure, including water pills (diuretics)
o
are on a low sodium (salt) diet
o
have kidney problems
o
are 65 years of age or older
Talk to your healthcare provider about what you can do to prevent dehydration including how much
fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the
amount of food or liquid you drink, for example if you are sick or cannot eat, or you start to lose liquids
from your body, for example from vomiting, diarrhea or being in the sun too long.
• Vaginal yeast infection. Symptoms of a vaginal yeast infection include:
o
vaginal odor
o
white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)
o
vaginal itching
• Yeast infection of the penis (balanitis or balanoposthitis). Swelling of an uncircumcised
penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other
symptoms of yeast infection of the penis include:
o
redness, itching, or swelling of the penis
o
rash of the penis
o
foul smelling discharge from the penis
o
pain in the skin around your penis
Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the
vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal
medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal
medicine and your symptoms do not go away.
•
Heart failure. Heart failure means your heart does not pump blood well enough.
Before you start taking STEGLUJAN, tell your healthcare provider if you have ever had heart
failure or have problems with your kidneys. Contact your healthcare provider right away if you
have any of the following symptoms:
o
increasing shortness of breath or trouble breathing, especially when you lie down
o
swelling or fluid retention, especially in the feet, ankles or legs
o
an unusually fast increase in weight
o
unusual tiredness
These may be symptoms of heart failure.
What is STEGLUJAN?
STEGLUJAN contains 2 prescription medicines called ertugliflozin (STEGLATRO®) and
sitagliptin (JANUVIA®). STEGLUJAN is used in adults with type 2 diabetes to improve blood
sugar (glucose) along with diet and exercise.
•
STEGLUJAN is not recommended to decrease blood sugar (glucose) in people with type 1
diabetes.
•
If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you
have a higher chance of getting pancreatitis while you take STEGLUJAN.
•
It is not known if STEGLUJAN is safe and effective in children under 18 years of age.
Who should not take STEGLUJAN?
Do not take STEGLUJAN if you:
•
have severe kidney problems, end stage renal disease (ESRD), or are on dialysis.
•
are allergic to ertugliflozin, sitagliptin, or any of the ingredients in STEGLUJAN. See the end of
this Medication Guide for a list of ingredients in STEGLUJAN. Symptoms of a serious allergic
reaction to STEGLUJAN may include:
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o skin rash
o
raised red patches on your skin (hives)
o
swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or
swallowing
If you have any of these symptoms, stop taking STEGLUJAN and call your healthcare provider
right away or go to the nearest hospital emergency room.
Before you take STEGLUJAN, tell your healthcare provider about all of your medical
conditions, including if you:
•
have type 1 diabetes or have had diabetic ketoacidosis.
•
have a decrease in your insulin dose.
•
have a serious infection.
•
have a history of infection of the vagina or penis.
•
have a history of amputation.
•
have had blocked or narrowed blood vessels, usually in your leg.
•
have damage to the nerves (neuropathy) in your leg.
•
have had diabetic foot ulcers or sores.
•
have kidney problems.
•
have liver problems.
•
have a history of urinary tract infections or problems with urination.
•
are on a low sodium (salt) diet. Your healthcare provider may change your diet or your dose.
•
are going to have surgery. Your healthcare provider may stop your STEGLUJAN before you
have surgery. Talk to your healthcare provider if you are having surgery about when to stop
taking STEGLUJAN and when to start it again.
•
are eating less or there is a change in your diet.
•
are dehydrated.
•
have or have had problems with your pancreas, including pancreatitis or surgery on your
pancreas.
•
drink alcohol very often or drink a lot of alcohol in the short term (“binge” drinking).
•
have ever had an allergic reaction to STEGLUJAN.
•
are pregnant or plan to become pregnant. STEGLUJAN may harm your unborn baby. If you
become pregnant while taking STEGLUJAN, your healthcare provider may switch you to a
different medicine to control your blood sugar. Talk to your healthcare provider about the best
way to control your blood sugar if you plan to become pregnant or while you are pregnant.
•
are breastfeeding or plan to breastfeed. It is not known if STEGLUJAN passes into your breast
milk. You should not breastfeed if you take STEGLUJAN.
Tell your healthcare provider about all of the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
STEGLUJAN may affect the way other medicines work, and other medicines may affect how
STEGLUJAN works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist
when you get a new medicine.
How should I take STEGLUJAN?
•
Take STEGLUJAN by mouth 1 time in the morning each day, with or without food., exactly as
your healthcare provider tells you to take it.
•
Your healthcare provider may tell you to take STEGLUJAN along with other diabetes medicines.
Low blood sugar can happen more often when STEGLUJAN is taken with certain other diabetes
medicines. See “What are the possible side effects of STEGLUJAN?”.
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•
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip
the missed dose and take the medicine at the next regularly scheduled time. Do not take 2
doses of STEGLUJAN at the same time. Talk with your healthcare provider if you have
questions about a missed dose.
•
If you take too much STEGLUJAN, call your healthcare provider or go to the nearest hospital
emergency room right away.
•
When your body is under some types of stress, such as fever, trauma (such as a car accident),
infection, or surgery, the amount of diabetes medicine you need may change. Tell your
healthcare provider right away if you have any of these conditions and follow your healthcare
provider’s instructions.
•
STEGLUJAN will cause your urine to test positive for glucose.
•
Your healthcare provider may do certain blood tests before you start STEGLUJAN and during
treatment as needed. Your healthcare provider may change your dose of STEGLUJAN based on
the results of your blood tests.
What are the possible side effects of STEGLUJAN?
STEGLUJAN may cause serious side effects, including:
See “What is the most important information I should know about STEGLUJAN?”
•
Kidney problems (sometimes requiring dialysis). Sudden kidney injury has happened to
people treated with STEGLUJAN. Talk to your healthcare provider right away if you:
o
reduce the amount of food or liquid you drink, for example, if you are sick or cannot eat or
o
you start to lose liquids from your body, for example, from vomiting, diarrhea or being in the
sun too long
•
Serious urinary tract infections. Serious urinary tract infections that may lead to
hospitalization have happened in people who are taking STEGLUJAN. Tell your healthcare
provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling
when passing urine, a need to urinate often, the need to urinate right away, pain in the lower
part of your stomach (pelvis), or blood in the urine. Sometimes people may also have a fever,
back pain, nausea, or vomiting.
•
Low blood sugar (hypoglycemia). If you take STEGLUJAN with another medicine that can
cause low blood sugar such as a sulfonylurea or insulin, your risk of getting low blood sugar is
higher. The dose of your sulfonylurea or insulin may need to be lowered while you take
STEGLUJAN. Signs and symptoms of low blood sugar may include:
o headache
o drowsiness
o weakness
o confusion
o dizziness
o sweating
o hunger
o
fast heartbeat
o irritability
o
shaking or feeling jittery
•
A rare but serious bacterial infection that causes damage to the tissue under the skin
(necrotizing fasciitis) in the area between and around the anus and genitals (perineum).
Necrotizing fasciitis of the perineum has happened in women and men who take medicines that
lower blood sugar in the same way as one of the medicines in STEGLUJAN. Necrotizing
fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may
lead to death. Seek medical attention immediately if you have fever above 100.4°F or you
are feeling very weak, tired or uncomfortable (malaise) and you develop any of the
following symptoms in the area between and around your anus and genitals:
o pain or tenderness
o swelling
o redness of skin (erythema)
•
Serious allergic reactions. If you have any symptoms of a serious allergic reaction, stop taking
STEGLUJAN and call your healthcare provider right away or go to the nearest hospital
emergency room. See “Who should not take STEGLUJAN?”. Your healthcare provider may
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Reference ID: 5502336
give you a medicine for your allergic reaction and prescribe a different medicine for your
diabetes.
•
Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in
STEGLUJAN, may develop joint pain that can be severe. Call your healthcare provider if you
have severe joint pain.
•
Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines
in STEGLUJAN, may develop a skin reaction called bullous pemphigoid that can require
treatment in a hospital. Tell your healthcare provider right away if you develop blisters or the
breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to
stop taking STEGLUJAN.
The most common side effects of ertugliflozin include:
•
vaginal yeast infections and yeast infections of the penis (See “What is the most important
information I should know about STEGLUJAN?”)
•
changes in urination, including urgent need to urinate more often, in larger amounts, or at night.
The most common side effects of sitagliptin include:
•
upper respiratory infection
•
stuffy or runny nose and sore throat
•
headache
•
stomach upset and diarrhea
STEGLUJAN may have other side effects including swelling of the hands or legs. Swelling of the
hands and legs can happen when sitagliptin, one of the medicines in STEGLUJAN, is used with
rosiglitazone (Avandia®). Rosiglitazone is another type of diabetes medicine.
These are not all the possible side effects of STEGLUJAN.
Call your healthcare provider for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store STEGLUJAN?
•
Store STEGLUJAN at room temperature between 68°F to 77°F (20°C to 25°C).
•
Keep STEGLUJAN dry.
Keep STEGLUJAN and all medicines out of the reach of children.
General information about the safe and effective use of STEGLUJAN.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do
not use STEGLUJAN for a condition for which it was not prescribed. Do not give STEGLUJAN to
other people, even if they have the same symptoms that you have. It may harm them. You can ask
your pharmacist or healthcare provider for information about STEGLUJAN that is written for health
professionals.
For more information about STEGLUJAN, go to www.steglujan.com or call 1-800-622-4477.
What are the ingredients in STEGLUJAN?
Active ingredients: ertugliflozin and sitagliptin.
Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous,
croscarmellose sodium, sodium stearyl fumarate, and magnesium stearate.
The tablet film coating contains the following inactive ingredients: hypromellose, hydroxypropyl
cellulose, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide/black iron oxide,
and carnauba wax.
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA
For patent information, go to: www.msd.com/research/patent
5
Reference ID: 5502336
Copyright © 2017-2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.
usmg-mk8835a-t-2309r009
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 09/2023
6
Reference ID: 5502336
| custom-source | 2025-02-12T15:48:18.777598 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/209805s017lbledt.pdf', 'application_number': 209805, 'submission_type': 'SUPPL ', 'submission_number': 17} |
80,782 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
EXONDYS 51® safely and effectively. See full prescribing information
for EXONDYS 51.
EXONDYS 51 (eteplirsen) injection, for intravenous use
Initial U.S. Approval: 2016
__________________ INDICATIONS AND USAGE _________________
EXONDYS 51 is an antisense oligonucleotide indicated for the treatment of
Duchenne muscular dystrophy (DMD) in patients who have a confirmed
mutation of the DMD gene that is amenable to exon 51 skipping. This
indication is approved under accelerated approval based on an increase in
dystrophin in skeletal muscle observed in some patients treated with
EXONDYS 51 [see Clinical Studies (14)]. Continued approval for this
indication may be contingent upon verification of a clinical benefit in
confirmatory trials. (1)
_______________ DOSAGE AND ADMINISTRATION ______________
•
30 milligrams per kilogram of body weight once weekly (2.1)
•
Administer as an intravenous infusion over 35 to 60 minutes via an in-
line 0.2 micron filter (2.1, 2.3)
•
Dilution required prior to administration (2.2)
______________ DOSAGE FORMS AND STRENGTHS ______________
Injection:
•
100 mg/2 mL (50 mg/mL) in single-dose vial (3)
•
500 mg/10 mL (50 mg/mL) in single-dose vial (3)
___________________ CONTRAINDICATIONS____________________
None (4)
_______________ WARNINGS AND PRECAUTIONS _______________
Hypersensitivity Reactions: Hypersensitivity reactions, including
bronchospasm, chest pain, cough, tachycardia, and urticaria, have occurred in
patients treated with EXONDYS 51. If hypersensitivity reactions occur,
institute appropriate medical treatment and consider slowing the infusion or
interrupting the EXONDYS 51 therapy. (2.3, 5.1)
____________________ ADVERSE REACTIONS ____________________
The most common adverse reactions (incidence ≥35% and higher than
placebo) were balance disorder and vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Sarepta
Therapeutics, Inc. at 1-888-SAREPTA (1-888-727-3782) or FDA at 1-800-
FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dosing Information
2.2
Preparation Instructions
2.3
Administration Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Patients with Renal Impairment
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.6
Immunogenicitiy
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5503515
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients
who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This
indication is approved under accelerated approval based on an increase in dystrophin in skeletal
muscle observed in some patients treated with EXONDYS 51 [see Clinical Studies (14)].
Continued approval for this indication may be contingent upon verification of a clinical benefit
in confirmatory trials.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing Information
The recommended dose of EXONDYS 51 is 30 milligrams per kilogram administered once
weekly as a 35 to 60 minute intravenous infusion via an in-line 0.2 micron filter.
If a dose of EXONDYS 51 is missed, it may be administered as soon as possible after the
scheduled time.
2.2
Preparation Instructions
EXONDYS 51 is supplied in single-dose vials as a preservative-free concentrated solution that
requires dilution prior to administration. Parenteral drug products should be inspected visually
for particulate matter and discoloration prior to administration, whenever solution and container
permit. Use aseptic technique.
a.
Calculate the total dose of EXONDYS 51 to be administered based on the patient’s
weight and the recommended dose of 30 milligrams per kilogram. Determine the
volume of EXONDYS 51 needed and the correct number of vials to supply the full
calculated dose.
b.
Allow vials to warm to room temperature. Mix the contents of each vial by gently
inverting 2 or 3 times. Do not shake.
c.
Visually inspect each vial of EXONDYS 51. EXONDYS 51 is a clear, colorless
solution that may have some opalescence, and may contain trace amounts of small,
white to off-white amorphous particles. Do not use if the solution in the vials is
cloudy, discolored or contains extraneous particulate matter other than trace amounts
of small, white to off-white amorphous particles.
d.
With a syringe fitted with a 21-gauge or smaller non-coring needle, withdraw the
calculated volume of EXONDYS 51 from the appropriate number of vials.
e.
Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to
make a total volume of 100-150 mL. Visually inspect the diluted solution. Do not use
if the solution is cloudy, discolored or contains extraneous particulate matter other
than trace amounts of small, white to off-white amorphous particles.
Reference ID: 5503515
f.
Administer the diluted solution via an in-line 0.2 micron filter.
g.
EXONDYS 51 contains no preservatives and should be administered immediately
after dilution. Complete infusion of diluted EXONDYS 51 solution within 4 hours of
dilution. If immediate use is not possible, the diluted solution may be stored for up to
24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused EXONDYS 51.
2.3
Administration Instructions
Application of a topical anesthetic cream to the infusion site prior to administration of
EXONDYS 51 may be considered.
EXONDYS 51 is administered via intravenous infusion. Flush the intravenous access line with
0.9% Sodium Chloride Injection, USP, prior to and after infusion.
Infuse the diluted EXONDYS 51 solution over 35 to 60 minutes via an in-line 0.2 micron filter.
Do not mix other medications with EXONDYS 51 or infuse other medications concomitantly via
the same intravenous access line.
If a hypersensitivity reaction occurs, consider slowing the infusion or interrupting the
EXONDYS 51 therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
3
DOSAGE FORMS AND STRENGTHS
EXONDYS 51 is a clear and colorless solution that may have some opalescence, and may
contain trace amounts of small, white to off-white amorphous particles, and is available as
follows:
• Injection: 100 mg/2 mL (50 mg/mL) solution in a single-dose vial
• Injection: 500 mg/10 mL (50 mg/mL) solution in a single-dose vial
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Hypersensitivity reactions, including bronchospasm, chest pain, cough, tachycardia, and
urticaria, have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity
reaction occurs, institute appropriate medical treatment and consider slowing the infusion or
interrupting the EXONDYS 51 therapy [see Dosage and Administration (2.3)].
Reference ID: 5503515
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
EXONDYS 51 was studied in a double-blind, placebo-controlled study for 24 weeks (Study 1),
followed by an open-label extension (Study 2). In Study 1, 12 patients were randomized to
receive weekly intravenous infusions of EXONDYS 51 (n=8) or placebo (n=4) for 24 weeks.
All 12 patients continued in Study 2 and received open-label EXONDYS 51 weekly for up to
208 weeks
In Study 1, 4 patients received placebo, 4 patients received EXONDYS 51 30 mg/kg, and 4
patients received EXONDYS 51 50 mg/kg (1.7 times the recommended dosage). In Study 2, 6
patients received EXONDYS 51 30 mg/kg/week and 6 patients received EXONDYS 51
50 mg/kg/week [see Clinical Studies (14)].
Adverse reactions that occurred in 2 or more patients who received EXONDYS 51 and were
more frequent than in the placebo group in Study 1 are presented in Table 1 (the 30 and 50
mg/kg groups are pooled). Because of the small numbers of patients, these represent crude
frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly
dosing regimen of EXONDYS 51 is not recommended [see Dosage and Administration (2.1)].
The most common adverse reactions were balance disorder and vomiting.
Table 1.
Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week1
EXONDYS 51 with Incidence at Least 25% More than Placebo (Study 1)
Adverse Reactions
EXONDYS 51 (N=8)
Placebo (N=4)
%
%
Balance disorder
38
0
Vomiting
38
0
Contact dermatitis
25
0
1 50 mg/kg/week = 1.7 times the recommended dosage
Adverse Reactions from Observational Clinical Studies
The following adverse reactions have been identified during observational studies that were
conducted as part of the clinical development program and continued postapproval.
In open-label observational studies, 163 patients received at least one intravenous dose of
EXONDYS 51, with doses ranging between 0.5 mg/kg (0.017 times the recommended dosage)
and 50 mg/kg (1.7 times the recommended dosage). All patients were male and had genetically
confirmed Duchenne muscular dystrophy. Age at study entry was 6 months to 19 years.
Most (85%) patients were Caucasian.
The most common adverse reactions seen in greater than 10% of the study population were
headache, cough, rash, and vomiting.
Reference ID: 5503515
Hypersensitivity reactions have occurred in patients treated with EXONDYS 51 [see Warnings
and Precautions (5.1)].
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of EXONDYS 51.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Postmarketing adverse reactions that occurred during infusion include bronchospasm, cyanosis
of the lips, and malaise. The following adverse reactions have also been reported in patients
receiving EXONDYS 51: pyrexia, flushing, protein urine present, and dehydration.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no human or animal data available to assess the use of EXONDYS 51 during
pregnancy. In the U.S. general population, major birth defects occur in 2 to 4% and miscarriage
occurs in 15 to 20% of clinically recognized pregnancies.
8.2
Lactation
Risk Summary
There are no human or animal data to assess the effect of EXONDYS 51 on milk production, the
presence of eteplirsen in milk, or the effects of EXONDYS 51 on the breastfed infant.
The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for EXONDYS 51 and any potential adverse effects on the breastfed
infant from EXONDYS 51 or from the underlying maternal condition.
8.4
Pediatric Use
EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients
who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping,
including pediatric patients [see Clinical Studies (14)].
Intravenous administration of eteplirsen (0, 100, 300, or 900 mg/kg) to juvenile male rats once
weekly for 10 weeks beginning on postnatal day 14 resulted in renal tubular necrosis at the
highest dose tested and decreased bone densitometry parameters (mineral density, mineral
content, area) at all doses. The kidney findings were associated with clinical pathology changes
(increased serum urea nitrogen and creatinine, decreased urine creatinine clearance). No effects
were observed on the male reproductive system, neurobehavioral development, or immune
function. An overall no-effect dose was not identified. Plasma eteplirsen exposure (AUC) at the
Reference ID: 5503515
lowest dose tested (100 mg/kg) was similar to that in humans at the recommended human dose
(30 mg/kg).
8.5
Geriatric Use
DMD is largely a disease of children and young adults; therefore, there is no geriatric experience
with EXONDYS 51.
8.6
Patients with Renal Impairment
Renal clearance of eteplirsen is reduced in non-DMD adults with renal impairment based on
estimated creatinine clearance [see Clinical Pharmacology (12.3)]. However, because of the
effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific
dosage adjustment can be recommended for DMD patients with renal impairment.
11
DESCRIPTION
EXONDYS 51 (eteplirsen) injection is a sterile, aqueous, preservative-free, concentrated
solution for dilution prior to intravenous administration. EXONDYS 51 is clear and colorless,
and may have some opalescence, and may contain trace amounts of small, white to off-white
amorphous particles. EXONDYS 51 is supplied in single dose vials containing 100 mg or
500 mg eteplirsen (50 mg/mL). EXONDYS 51 is formulated as an isotonic, phosphate buffered
saline solution with an osmolality of 260 to 320 mOsm and a pH of 7.5. Each milliliter of
EXONDYS 51 contains 50 mg eteplirsen; 0.2 mg potassium chloride, 0.2 mg potassium
phosphate monobasic, 8 mg sodium chloride, and 1.14 mg sodium phosphate dibasic, anhydrous,
in water for injection. The product may contain hydrochloric acid or sodium hydroxide to adjust
pH.
Eteplirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer
(PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings
found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each
morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the
negatively charged phosphate linkage that is present in natural DNA and RNA. Each
phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA
(adenine, cytosine, guanine, or thymine). Eteplirsen contains 30 linked subunits. The molecular
formula of eteplirsen is C364H569N177O122P30 and the molecular weight is 10305.7 daltons.
The structure and base sequence of eteplirsen are:
Reference ID: 5503515
Break D
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
H
G
A
T
C
T
O
O
O
O
O
Break A
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
C
T
A
C
A
A
N
P
N
O
N
O
A
O
Break B
O
O
O
O
O
O
Break B
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
G
A
A
G
G
A
N
P
N
O
N
O
A
O
Break C
O
O
O
O
O
O
N
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
C
T
C
N
P
N
O
N
O
C
Break A
O
O
O
O
O
O
O
O
OH
[ 5' ]
[ 3' ]
N
N
N
N
N
NH
N
NH
N
N
N
N
NH2
O
NH2
O
NH2
O
O
A
C
G
T (m5U)
The sequence of bases from the 5' end to the 3' end is:
CTCCAACATCAAGGAAGATGGCATTTCTAG
Base:
Break C
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
N
P
N
O
O
T
A
C
G
G
T
N
P
N
O
N
O
T
O
O
O
O
O
O
O
Break D
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this
exon during mRNA processing in patients with genetic mutations that are amenable to exon 51
skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin
protein, which was evaluated in Study 2 and Study 3 [see Clinical Studies (14)].
12.2
Pharmacodynamics
All EXONDYS 51-treated patients evaluated (n=36) were found to produce messenger
ribonucleic acid (mRNA) for a truncated dystrophin protein by reverse transcription polymerase
chain reaction.
In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment
with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy
Reference ID: 5503515
subjects). Because of insufficient information on dystrophin protein levels before treatment with
EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to
EXONDYS 51 in Study 1.
In Study 3, the average dystrophin protein level was 0.16% of normal before treatment, and
0.44% of normal after 48 weeks of treatment with EXONDYS 51 [see Clinical Studies (14)].
The median increase in truncated dystrophin in Study 3 was 0.1% [see Clinical Studies (14)].
Dystrophin levels assessed by western blot can be meaningfully influenced by differences in
sample processing, analytical technique, reference materials, and quantitation methodologies.
Therefore, comparing dystrophin results from different assay protocols will require a
standardized reference material and additional bridging studies.
12.3
Pharmacokinetics
Following single or multiple intravenous infusions of EXONDYS 51 in male pediatric DMD
patients, plasma concentration-time profiles of eteplirsen were generally similar and showed
multi-phasic decline. The majority of drug elimination occurred within 24 hours. Approximate
dose-proportionality and linearity in PK properties were observed following multiple-dose
studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the
recommended dosage]). There was no significant drug accumulation following weekly dosing
across this dose range. The inter-subject variability for eteplirsen Cmax and AUC range from 20
to 55%.
Following single or multiple intravenous infusions of EXONDYS 51, the peak plasma
concentrations (Cmax) of eteplirsen occurred near the end of infusion (i.e., 1.1 to 1.2 hours across
a dose range of 0.5 mg/kg/week to 50 mg/kg/week).
Distribution
In vitro investigation suggested that plasma protein binding of eteplirsen in human ranges
between 6 to 17%. The mean apparent volume of distribution (Vss) of eteplirsen was 600 mL/kg
following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg.
Twenty-four hours after the end of the infusion, mean concentrations of eteplirsen were 0.07% of
Cmax. Accumulation of eteplirsen during once weekly dosing has not been observed.
Elimination
The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30
mg/kg/week.
Metabolism
Eteplirsen did not appear to be metabolized by hepatic microsomes of any species tested,
including humans.
Excretion
Renal clearance of eteplirsen accounts for approximately two-thirds of the administered dose
within 24 hours of intravenous administration. Elimination half-life (t1/2) of eteplirsen was 3 to 4
hours.
Reference ID: 5503515
Specific Populations
Age:
The pharmacokinetics of eteplirsen have been evaluated in male pediatric DMD patients. There
is no experience with the use of EXONDYS 51 in patients 65 years of age or older.
Sex:
Sex effects have not been evaluated; EXONDYS 51 has not been studied in female patients.
Race:
Potential impact of race is not known because 89% of the patients in studies were Caucasians.
Patients with Renal Impairment:
The effect of renal impairment on the pharmacokinetics of eteplirsen was evaluated in non-DMD
subjects aged 51 to 75 years with mild (n=8, creatinine clearance ≥60 mL/min and <90 mL/min)
or moderate (n=8, creatinine clearance ≥30 mL/min and <60 mL/min) renal impairment and
matched healthy subjects (n=9, creatinine clearance >90 mL/min). Subjects received a single
30 mg/kg intravenous dose of eteplirsen.
Subjects with mild and moderate renal impairment showed higher eteplirsen exposure compared
to subjects with normal renal function. In subjects with mild and moderate renal impairment,
exposure (AUC) increased approximately 1.4-fold and 2.4-fold, respectively. The effect of
severe renal impairment or end-stage renal disease on eteplirsen pharmacokinetics and safety has
not been studied.
Estimated creatinine clearance values derived from the Cockcroft-Gault equation and the
threshold definitions for mild, moderate, and severe renal impairment in otherwise healthy adults
would not be generalizable to patients with DMD. Therefore, no specific dosage adjustment can
be recommended for patients with renal impairment.
Patients with Hepatic Impairment:
EXONDYS 51 has not been studied in patients with hepatic impairment.
Drug Interaction Studies
In vitro data showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4,
and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole.
Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key
human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP,
MRP2 and BSEP). Based on in vitro data on plasma protein binding, CYP or drug transporter
interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for
drug-drug interactions in humans.
12.6
Immunogenicity
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
Reference ID: 5503515
incidence of ADA in the studies described below with the incidence of ADA in other studies,
including those of eteplirsen.
With administration of 30 mg/kg/week of EXONDYS 51, during the 192-week treatment
duration in three clinical studies, 1 out of 129 patients (0.78%) was positive for anti-eteplirsen
IgG and 3 out of 21 patients with non-missing samples (14.3%) were positive for anti-eteplirsen
IgE. Because of the low occurrence of anti-eteplirsen antibodies, the impact of immunogenicity
status on the dystrophin levels, pharmacokinetics, pharmacodynamics, safety, and/or efficacy of
EXONDYS 51 is unknown.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg)
weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous
injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks
resulted in no increase in neoplasms.
Mutagenesis
Eteplirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in
CHO cells) and in vivo (mouse bone marrow micronucleus) assays.
Impairment of Fertility
Fertility studies in animals were not conducted with eteplirsen. No effects on the male
reproductive system were observed following intravenous administration of eteplirsen (0, 5, 40,
or 320 mg/kg) to male monkeys once weekly for 39 weeks. Plasma eteplirsen exposure (AUC) in
monkeys at the highest dose tested was 20 times that in humans at recommended human dose (30
mg/kg).
14
CLINICAL STUDIES
EXONDYS 51 was evaluated in three clinical studies in patients who have a confirmed mutation
of the DMD gene that is amenable to exon 51 skipping.
In Study 1, patients were randomized to receive weekly infusions of EXONDYS 51 (30 mg/kg,
n=4); EXONDYS 51 (50 mg/kg, n=4), or placebo (n=4) for 24 weeks. The primary endpoint was
dystrophin production; a clinical outcome measure, the 6-minute walk test (6MWT), was also
assessed. The 6MWT measures the distance that a patient can walk on a flat, hard surface in a
period of 6 minutes. Patients had a mean age of 9.4 years, a mean 6-minute walk distance
(6MWD) at baseline of 363 meters, and were on a stable dose of corticosteroids for at least 6
months. There was no significant difference in change in 6MWD between patients treated with
EXONDYS 51 and those treated with placebo.
All 12 patients who participated in Study 1 continued treatment with open-label EXONDYS 51
weekly for an additional 4 years in Study 2. The 4 patients who had been randomized to placebo
Reference ID: 5503515
were re-randomized 1:1 to EXONDYS 51 30 or 50 mg/kg/week such that there were 6 patients
on each dose. Patients who participated in Study 2 were compared to an external control group.
The primary clinical efficacy outcome measure was the 6MWT. Eleven patients in Study 2 had a
muscle biopsy after 180 weeks of treatment with EXONDYS 51, which was analyzed for
dystrophin protein level by Sarepta western blot. Study 2 failed to provide evidence of a clinical
benefit of EXONDYS 51 compared to the external control group. The average dystrophin protein
level after 180 weeks of treatment with EXONDYS 51 was 0.93% of the dystrophin level in
healthy subjects. Because of insufficient information on dystrophin protein levels before
treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in
response to EXONDYS 51 in Study 1.
In Study 3, 13 patients were treated with open-label EXONDYS 51 (30 mg/kg) weekly for 48
weeks and had a muscle biopsy at baseline and after 48 weeks of treatment. Patients had a mean
age of 8.9 years and were on a stable dose of corticosteroids for at least 6 months. Dystrophin
levels in muscle tissue were assessed by Western blot. In the 12 patients with evaluable results,
the pre-treatment dystrophin level was 0.16% ± 0.12% (mean ± standard deviation) of the
dystrophin level in a healthy subject and 0.44% ± 0.43% after 48 weeks of treatment with
EXONDYS 51 (p < 0.05). The median increase after 48 weeks was 0.1%.
Individual patient dystrophin levels from Study 3 are shown in Table 2.
Table 2.
Sarepta Western Blot Results: EXONDYS 51-Treated (Week 48) vs Pre-
treatment Baseline (% Normal Dystrophin) (Study 301)
Patient
Number
Baseline
% normal dystrophin
Week 48
% normal dystrophin
Change from Baseline
% normal dystrophin
1
0.13
0.26
0.13
2
0.35
0.36
0.01
3
0.06
0.37
0.31
4
0.04
0.10
0.06
5
0.17
1.02
0.85
6
0.37
0.30
-0.07
7
0.17
0.42
0.25
8
0.24
1.57
1.33
9
0.11
0.12
0.01
10
0.05
0.47
0.43
11
0.02
0.09
0.07
12
0.18
0.21
0.03
Mean
0.16
0.44
0.28; p=0.008
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
EXONDYS 51 injection is supplied in single-dose vials. The solution is clear and colorless, and
may have some opalescence, and may contain trace amounts of small, white to off-white
amorphous particles.
• Single-dose vials containing 100 mg/2 mL (50 mg/mL) eteplirsen
NDC 60923-363-02
Reference ID: 5503515
• Single-dose vials containing 500 mg/10 mL (50 mg/mL) eteplirsen
NDC 60923-284-10
16.2
Storage and Handling
Store EXONDYS 51 at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light and store
EXONDYS 51 in the original carton until ready for use.
17
PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions
Advise patients and/or caregivers that symptoms of hypersensitivity, including bronchospasm,
chest pain, cough, tachycardia, and urticaria can occur with EXONDYS 51. Instruct them to seek
immediate medical care should they experience signs and symptoms of hypersensitivity [see
Warnings and Precautions (5.1)].
Manufactured for:
Sarepta Therapeutics, Inc.
Cambridge, MA 02142 USA
SAREPTA, SAREPTA THERAPEUTICS, EXONDYS, EXONDYS 51, and the EXONDYS 51
Logo are trademarks of Sarepta Therapeutics, Inc. registered in the U.S. Patent and Trademark
Office and may be registered in various other jurisdictions.
Reference ID: 5503515
| custom-source | 2025-02-12T15:48:19.801657 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/206488s035lbl.pdf', 'application_number': 206488, 'submission_type': 'SUPPL ', 'submission_number': 35} |
80,776 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SEGLUROMET safely and effectively. See full prescribing
information for SEGLUROMET.
SEGLUROMET® (ertugliflozin and metformin hydrochloride)
tablets, for oral use
Initial U.S. Approval: 2017
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Postmarketing cases of metformin-associated lactic acidosis
have resulted in death, hypothermia, hypotension, and resistant
bradyarrhythmias.
Symptoms
included
malaise,
myalgias,
respiratory
distress,
somnolence,
and
abdominal
pain.
Laboratory abnormalities included elevated blood lactate levels,
anion gap acidosis, increased lactate/pyruvate ratio, and
metformin plasma levels generally >5 mcg/mL. (5.1)
• Risk factors include renal impairment, concomitant use of
certain drugs, age ≥65 years old, radiological studies with
contrast,
surgery and other procedures, hypoxic states,
excessive alcohol intake, and hepatic impairment. Steps to
reduce the risk of and manage metformin-associated lactic
acidosis in these high risk groups are provided in the Full
Prescribing Information. (5.1)
• If lactic acidosis is suspected, discontinue SEGLUROMET and
institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.4)
12/2024
Warnings and Precautions (5.3, 5.6)
12/2024
----------------------------INDICATIONS AND USAGE---------------------------
SEGLUROMET is a combination of ertugliflozin, a sodium glucose co-
transporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated
as an adjunct to diet and exercise to improve glycemic control in adults
with type 2 diabetes mellitus. (1)
Limitations of Use:
Not recommended for use to improve glycemic control in patients with
type 1 diabetes mellitus. (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
• Assess renal function prior to initiation and as clinically indicated.
(2.1)
• Correct volume depletion before initiation. (2.1)
• Individualize the starting dosage based on the patient’s current
regimen. (2.2)
• Maximum recommended dosage is 7.5 mg ertugliflozin/1,000 mg
metformin orally twice daily. (2.2)
• Take orally twice daily with meals, with gradual dose escalation.
(2.2)
o Do not use in patients with an estimated glomerular filtration rate
(eGFR) below 30 mL/minute/1.73 m2.
o Use is not recommended in patients with an eGFR less than 45
mL/min/1.73 m2. (2.2)
o Use is contraindicated in patients with severe renal impairment
(eGFR less than 30 mL/min/1.73 m2), end stage-renal disease
(ESRD), or on dialysis. (2.2)
• SEGLUROMET may need to be discontinued at time of, or prior to,
iodinated contrast imaging procedures. (2.3)
• Withhold SEGLUROMET for at least 4 days, if possible, prior to
surgery or procedures associated with prolonged fasting. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets:
• Ertugliflozin 2.5 mg and metformin hydrochloride 500 mg (3)
• Ertugliflozin 2.5 mg and metformin hydrochloride 1,000 mg (3)
• Ertugliflozin 7.5 mg and metformin hydrochloride 500 mg (3)
• Ertugliflozin 7.5 mg and metformin hydrochloride 1,000 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end
stage-renal disease, or patients on dialysis. (4)
• Metabolic acidosis, including diabetic ketoacidosis. (4)
• Hypersensitivity to ertugliflozin, metformin or any excipient. (4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Lactic Acidosis: See boxed warning. (5.1)
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and
Other Ketoacidosis: Consider ketone monitoring in patients at risk
for ketoacidosis, as indicated. Assess for ketoacidosis regardless of
presenting blood glucose levels and discontinue SEGLUROMET if
ketoacidosis is suspected. Monitor patients for resolution of
ketoacidosis before restarting. (5.2)
• Lower Limb Amputation: Monitor patients for infections or ulcers of
lower limbs, and discontinue if these occur. (5.3)
• Volume Depletion: May result in acute kidney injury. Before
initiating, assess and correct volume status in patients with renal
impairment, low systolic blood pressure, elderly patients, or patients
on diuretics. Monitor for signs and symptoms during therapy. (5.4)
• Urosepsis and Pyelonephritis: Evaluate patients for signs and
symptoms of urinary tract infections and treat promptly, if indicated.
(5.5)
• Hypoglycemia: Consider a lower dose of insulin or insulin
secretagogue to reduce risk of hypoglycemia when used in
combination. (5.6)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene):
Serious, life-threatening cases have occurred in both females and
males. Assess patients presenting with pain or tenderness,
erythema, or swelling in the genital or perineal area, along with fever
or malaise. If suspected, institute prompt treatment. (5.7)
• Genital Mycotic Infections: Monitor and treat if indicated. (5.8)
• Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels.
Measure hematological parameters annually. (5.9)
------------------------------ ADVERSE REACTIONS -----------------------------
• Most common adverse reactions associated with ertugliflozin
(incidence ≥5%) were female genital mycotic infections. (6.1)
• Most common adverse reactions associated with metformin
(incidence ≥5%) were diarrhea, nausea, vomiting, flatulence,
abdominal discomfort, indigestion, asthenia, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck
Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch .
-------------------------------DRUG INTERACTIONS------------------------------
• Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis.
Consider more frequent monitoring. (7.2)
• Drugs that Reduce Metformin Clearance: May increase risk of lactic
acidosis. Consider benefits and risks of concomitant use. (7.2)
• See full prescribing information for additional drug interactions and
information on interference of SEGLUROMET with laboratory tests.
(7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
• Pregnancy: Advise females of the potential risk to a fetus, especially
during the second and third trimesters. (8.1)
• Lactation: Breastfeeding not recommended. (8.2)
• Females and Males of Reproductive Potential: Advise
premenopausal females of the potential for an unintended
pregnancy. (8.3)
• Geriatrics: Higher incidence of adverse reactions related to reduced
intravascular volume. (8.5)
• Renal impairment: Higher incidence of adverse reactions related to
reduced intravascular volume and renal function. (8.6)
• Hepatic impairment: Avoid use in patients with hepatic impairment.
(8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
Reference ID: 5502336
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Prior to Initiation of SEGLUROMET
2.2
Recommended Dosage
2.3
Discontinuation for Iodinated Contrast Imaging Procedures
2.4
Temporary Interruption for Surgery
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Lactic Acidosis
5.2
Diabetic Ketoacidosis in Patients with Type 1 Diabetes
Mellitus and Other Ketoacidosis
5.3
Lower Limb Amputation
5.4
Volume Depletion
5.5
Urosepsis and Pyelonephritis
5.6
Hypoglycemia with Concomitant Use with Insulin or Insulin
Secretagogues
5.7
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
5.8
Genital Mycotic Infections
5.9
Vitamin B12 Deficiency
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Glycemic Control Trials in Patients with Type 2 Diabetes
Mellitus
14.2 Ertugliflozin Cardiovascular Outcomes in Patients with Type
2 Diabetes and Established Cardiovascular Disease
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
2
Reference ID: 5502336
FULL PRESCRIBING INFORMATION
WARNING: LACTIC ACIDOSIS
Postmarketing cases of metformin-associated lactic acidosis have resulted in death,
hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated
lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise,
myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic
acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis
(without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin
plasma levels generally >5 mcg/mL [see Warnings and Precautions
(5.1)].
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant
use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or
greater, having a radiological study with contrast, surgery and other procedures, hypoxic states
(e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high
risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2),
Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific
Populations (8.6, 8.7)].
If metformin-associated lactic acidosis is suspected, immediately discontinue SEGLUROMET
and institute general supportive measures in a hospital setting. Prompt hemodialysis is
recommended [see Warnings and Precautions (5.1)].
1
INDICATIONS AND USAGE
SEGLUROMET® is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus.
Limitations of Use
Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see
Warnings and Precautions (5.2)].
2
DOSAGE AND ADMINISTRATION
2.1
Prior to Initiation of SEGLUROMET
•
Assess renal function before initiating SEGLUROMET and as clinically indicated [see Warnings
and Precautions (5.2)].
•
Assess volume status. In patients with volume depletion, correct this condition before initiating
SEGLUROMET [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5, 8.6)].
2.2
Recommended Dosage
•
Individualize the starting dosage of SEGLUROMET, ertugliflozin and metformin hydrochloride
(HCI), based on the patient’s current regimen, while not exceeding the maximum recommended
oral daily dosage of 15 mg ertugliflozin and 2,000 mg metformin HCl:
o
In patients on metformin HCI, switch to SEGLUROMET tablets containing 2.5 mg
ertugliflozin, with a similar total oral daily dosage of metformin HCl.
o
In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin
HCl, with a similar total oral daily dosage of ertugliflozin.
o
In patients already treated with ertugliflozin and metformin HCl, switch to SEGLUROMET
tablets containing the same total oral daily dosage of ertugliflozin and a similar daily dosage
of metformin HCI.
•
Take SEGLUROMET orally twice daily with meals, with gradual dosage escalation for those
initiating metformin HCl to reduce the gastrointestinal side effects due to metformin [see Adverse
Reactions (6.1)].
•
Dosing may be adjusted based on effectiveness and tolerability.
•
Use of SEGLUROMET is not recommended in patients with an estimated glomerular filtration
rate (eGFR) less than 45 mL/min/1.73 m2.
3
Reference ID: 5502336
•
Use of SEGLUROMET is contraindicated in patients with severe renal impairment (eGFR less
than 30 mL/min/1.73 m2), end stage-renal disease (ESRD), or on dialysis [see Contraindications
(4)].
2.3
Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue SEGLUROMET at the time of, or prior to, an iodinated contrast imaging procedure in
patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism
or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR
48 hours after the imaging procedure; restart SEGLUROMET if renal function is stable [see Warnings and
Precautions (5.1)].
2.4
Temporary Interruption for Surgery
Withhold SEGLUROMET for at least 4 days, if possible, prior to surgery or procedures associated
with prolonged fasting. Resume SEGLUROMET when the patient is clinically stable and has resumed
oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
3
DOSAGE FORMS AND STRENGTHS
•
Tablets: ertugliflozin 2.5 mg and metformin HCl 500 mg, pink, oval, debossed with “2.5/500” on
one side and plain on the other side.
•
Tablets: ertugliflozin 2.5 mg and metformin HCl 1,000 mg, pink, oval, debossed with “2.5/1000”
on one side and plain on the other side.
•
Tablets: ertugliflozin 7.5 mg and metformin HCl 500 mg, red, oval, debossed with “7.5/500” on
one side and plain on the other side.
•
Tablets: ertugliflozin 7.5 mg and metformin HCl 1,000 mg, red, oval, debossed with “7.5/1000”
on one side and plain on the other side.
4
CONTRAINDICATIONS
SEGLUROMET is contraindicated in patients with:
•
Hypersensitivity to ertugliflozin, metformin, or any excipient in SEGLUROMET. Reactions such
as angioedema or anaphylaxis have occurred [see Adverse Reactions (6.2)].
•
Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage-renal disease (ESRD),
or on dialysis [see Use in Specific Populations (8.6)].
•
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
5
WARNINGS AND PRECAUTIONS
5.1
Lactic Acidosis
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.
These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,
myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia,
hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated
lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap
acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin
plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate
blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be
instituted promptly in a hospital setting, along with immediate discontinuation of SEGLUROMET. In
SEGLUROMET-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis
is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is
dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis
has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms
occur instruct them to discontinue SEGLUROMET and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis,
recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided
below:
4
Reference ID: 5502336
Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in
patients with significant renal impairment. The risk of metformin accumulation and metformin-associated
lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted
by the kidney [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
•
Before initiating SEGLUROMET, obtain an eGFR.
•
Use of SEGLUROMET is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2.
•
SEGLUROMET is contraindicated in patients with severe renal impairment (an eGFR less than
30 mL/min/1.73 m2), end stage-renal disease (ESRD), or on dialysis.
•
Obtain an eGFR at least annually in all patients taking SEGLUROMET. In patients at increased
risk for the development of renal impairment (e.g., the elderly), renal function should be assessed
more frequently.
Drug Interactions: The concomitant use of SEGLUROMET with specific drugs may increase the risk of
metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic
change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see
Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age
because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than
younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations
(8.5)].
Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in
metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic
acidosis. Stop SEGLUROMET at the time of, or prior to, an iodinated contrast imaging procedure in patients
with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or
heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR
48 hours after the imaging procedure, and restart SEGLUROMET if renal function is stable.
Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may
increase the risk for volume depletion, hypotension and renal impairment. SEGLUROMET should be
temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in
the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and
hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions
associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal
azotemia. When such events occur, discontinue SEGLUROMET.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may
increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake
while receiving SEGLUROMET.
Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic
acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore,
avoid use of SEGLUROMET in patients with clinical or laboratory evidence of hepatic disease.
5.2
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, SEGLUROMET significantly increases the risk of diabetic
ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients
with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received
5
Reference ID: 5502336
sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may
be greater with higher doses. SEGLUROMET is not indicated for glycemic control in patients with type 1
diabetes mellitus.
Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery)
are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis
in patients with type 2 diabetes mellitus using SGLT2 inhibitors.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization
due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic
diet, surgery, volume depletion, and alcohol abuse.
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include
nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at
presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL).
Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists
for 4 days after discontinuing SEGLUROMET [see Clinical Pharmacology (12.2)]; however, there have
been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2
weeks after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation.
Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs
and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue
SEGLUROMET, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of
ketoacidosis before restarting SEGLUROMET.
Withhold SEGLUROMET, if possible, in temporary clinical situations that could predispose patients
to ketoacidosis. Resume SEGLUROMET when the patient is clinically stable and has resumed oral intake
[see Dosage and Administration (2.4)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue
SEGLUROMET and seek medical attention immediately if signs and symptoms occur.
5.3
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2
diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb
amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.
Amputation of the toe and foot were most frequent (81 out of 109 patients with lower limb
amputations). Some patients had multiple amputations, some involving both lower limbs.
Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating
medical events leading to the need for an amputation. Patients with amputations were more likely to be
male, have higher A1C (%) at baseline, have a history of peripheral arterial disease, amputation or
peripheral revascularization procedure, diabetic foot, and to have been taking diuretics or insulin.
Across seven ertugliflozin clinical trials, non-traumatic lower limb amputations were reported in 1
(0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%)
patients in the ertugliflozin 15 mg group.
Monitor patients receiving SEGLUROMET for signs and symptoms of infection (including
osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue
SEGLUROMET if these complications occur.
5.4
Volume Depletion
SEGLUROMET can cause intravascular volume contraction which may sometimes manifest as
symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There
have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in
patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including SEGLUROMET. Patients with
impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in Specific Populations (8.6)], elderly
patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for
volume depletion or hypotension. Before initiating SEGLUROMET in patients with one or more of these
characteristics, assess volume status and renal function. In patients with volume depletion, correct this
condition before initiating SEGLUROMET. Monitor for signs and symptoms of volume depletion, and renal
function after initiating therapy.
6
Reference ID: 5502336
5.5
Urosepsis and Pyelonephritis
There have been postmarketing reports of serious urinary tract infections, including urosepsis and
pyelonephritis, requiring hospitalization in patients receiving medicines containing SGLT2 inhibitors.
Treatment with medicines containing SGLT2 inhibitors increases the risk for urinary tract infections.
Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see
Adverse Reactions (6)].
5.6
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia.
SEGLUROMET may increase the risk of hypoglycemia when used in combination with insulin or an insulin
secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in
the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogues). Inform
patients using these medications concomitantly of this risk and educate them on the signs and symptoms
of hypoglycemia.
5.7
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and
life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in
postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including
ertugliflozin. Cases have been reported in females and males. Serious outcomes have included
hospitalization, multiple surgeries, and death.
Patients treated with SEGLUROMET presenting with pain or tenderness, erythema, or swelling in the
genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If
suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical
debridement. Discontinue SEGLUROMET, closely monitor blood glucose levels, and provide appropriate
alternative therapy for glycemic control.
5.8
Genital Mycotic Infections
Ertugliflozin increases the risk of genital mycotic infections. Patients who have a history of genital
mycotic infections or who are uncircumcised are more likely to develop genital mycotic infections [see
Adverse Reactions (6.1)]. Monitor and treat appropriately.
5.9
Vitamin B12 Deficiency
In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal
serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to
interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but
appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain
individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to
developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin
B12 at 2 to 3 year intervals in patients on metformin and manage any abnormalities [see Adverse Reactions
(6.1)].
6
ADVERSE REACTIONS
The following important adverse reactions are described elsewhere in the labeling:
•
Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
•
Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see
Warnings and Precautions (5.2)]
•
Lower Limb Amputation [see Warnings and Precautions (5.3)]
•
Volume Depletion [see Warnings and Precautions (5.4)]
•
Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
•
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings
and Precautions (5.6)]
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•
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions
(5.7)]
•
Genital Mycotic Infections [see Warnings and Precautions (5.8)]
•
Vitamin B12 Deficiency [see Warnings and Precautions (5.9)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Ertugliflozin and Metformin Hydrochloride
The incidence and type of adverse reactions in the two 26-week, placebo-controlled trials of
ertugliflozin 5 mg and 15 mg added to metformin HCl, representing a majority of data from the three 26
week, placebo-controlled trials, were similar to the adverse reactions described in Table 1.
Ertugliflozin
Pool of Placebo-Controlled Trials
The data in Table 1 are derived from a pool of three 26-week, placebo-controlled trials. Ertugliflozin
was used as monotherapy in one trial and as add-on therapy in two trials [see Clinical Studies (14)]. These
data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately
25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515)
once daily. The mean age of the population was 57 years and 2% were older than 75 years of age.
Fifty-three percent (53%) of the population was male and 73% were White, 15% were Asian, and 7% were
Black or African American. At baseline the population had diabetes for an average of 7.5 years, had a mean
HbA1c of 8.1%, and 19.4% had established microvascular complications of diabetes. Baseline renal
function (mean eGFR 88.9 mL/min/1.73 m2) was normal or mildly impaired in 97% of patients and
moderately impaired in 3% of patients.
Table 1 shows common adverse reactions associated with the use of ertugliflozin. These adverse
reactions were not present at baseline, occurred more commonly on ertugliflozin than on placebo, and
occurred in at least 2% of patients treated with either ertugliflozin 5 mg or ertugliflozin 15 mg.
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Table 1: Adverse Reactions Reported in ≥2% of Patients with Type 2 Diabetes Mellitus
Treated with Ertugliflozin* and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies
of Ertugliflozin Monotherapy or Combination Therapy
Number (%) of Patients
Placebo
N = 515
Ertugliflozin 5 mg
N = 519
Ertugliflozin 15 mg
N = 510
Female genital mycotic
infections†
3.0%
9.1%
12.2%
Male genital mycotic infections‡
0.4%
3.7%
4.2%
Urinary tract infections§
3.9%
4.0%
4.1%
Headache
2.3%
3.5%
2.9%
Vaginal pruritus¶
0.4%
2.8%
2.4%
Increased urination#
1.0%
2.7%
2.4%
Nasopharyngitis
2.3%
2.5%
2.0%
Back pain
2.3%
1.7%
2.5%
Weight decreased
1.0%
1.2%
2.4%
ThirstÞ
0.6%
2.7%
1.4%
* The three placebo-controlled studies included one monotherapy trial and two add-on combination trials with metformin HCl or with
metformin HCl and sitagliptin.
† Includes: genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic
infection, and vulvovaginitis. Percentages calculated with the number of female patients in each group as denominator: placebo
(N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
‡ Includes: balanitis candida, balanoposthitis, genital infection, and genital infection fungal. Percentages calculated with the number
of male patients in each group as denominator: placebo (N=280), ertugliflozin 5 mg (N=267), ertugliflozin 15 mg (N=265).
§ Includes: cystitis, dysuria, streptococcal urinary tract infection, urethritis, urinary tract infection.
¶ Includes: vulvovaginal pruritus and pruritus genital. Percentages calculated with the number of female patients in each group as
denominator: placebo (N=235), ertugliflozin 5 mg (N=252), ertugliflozin 15 mg (N=245).
# Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
Þ Includes: thirst, dry mouth, polydipsia, and dry throat.
Volume Depletion
Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse
reactions related to volume depletion, particularly in patients with impaired renal function (eGFR less than
60 mL/min/1.73 m2). In patients with moderate renal impairment, adverse reactions related to volume
depletion (e.g., dehydration, dizziness postural, presyncope, syncope, hypotension, and orthostatic
hypotension) were reported in 0%, 4.4%, and 1.9% of patients treated with placebo, ertugliflozin 5 mg, and
ertugliflozin 15 mg, respectively. Ertugliflozin may also increase the risk of hypotension in other patients at
risk for volume contraction [see Use in Specific Populations (8.5, 8.6)].
Hypoglycemia
The incidence of hypoglycemia by study is shown in Table 2.
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Table 2: Incidence of Overall* and Severe† Hypoglycemia in Placebo-Controlled Clinical Studies in
Patients with Type 2 Diabetes Mellitus
Add-on Combination Therapy
with Metformin HCl (26 weeks)
Placebo
(N = 209)
Ertugliflozin
5 mg
(N = 207)
Ertugliflozin
15 mg
(N = 205)
Overall [N (%)]
Severe [N (%)]
9 (4.3)
1 (0.5)
15 (7.2)
1 (0.5)
16 (7.8)
0 (0.0)
Add-on Combination Therapy
with Metformin HCl and
Sitagliptin (26 weeks)
Placebo
(N = 153)
Ertugliflozin
5 mg
(N = 156)
Ertugliflozin
15 mg
(N = 153)
Overall [N (%)]
Severe [N (%)]
5 (3.3)
1 (0.7)
7 (4.5)
1 (0.6)
3 (2.0)
0 (0.0)
Add-on Combination with
Insulin with or without
Metformin HCl (18 weeks)
Placebo
(N = 347)
Ertugliflozin
5 mg
(N = 348)
Ertugliflozin
15 mg
(N = 370)
Overall [N (%)]
130 (37.5)
137 (39.4)
144 (38.9)
Severe [N (%)]
12 (3.5)
13 (3.7)
19 (5.1)
Add-on Combination with
Metformin HCl and a
Sulfonylurea (18 weeks)
Placebo
(N = 117)
Ertugliflozin
5 mg
(N = 100)
Ertugliflozin
15 mg
(N = 113)
Overall [N (%)]
17 (14.5)
20 (20.0)
30 (26.5)
Severe [N (%)]
1 (0.9)
2 (2.0)
2 (1.8)
* Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL.
† Severe hypoglycemic events: required assistance, lost consciousness, or experienced a seizure regardless of blood glucose.
Lower Limb Amputation
In a long-term cardiovascular outcomes study [see Clinical Studies (14.2)], in patients with type 2
diabetes mellitus and established cardiovascular disease, the occurrence of non-traumatic lower limb
amputations was reported with event rates of 4.7, 5.7, and 6.0 events per 1,000 patient-years in the placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg treatment arms, respectively.
Across seven ertugliflozin clinical trials, non-traumatic lower limb amputations were reported in
1 (0.1%) patient in the comparator group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%)
patients in the ertugliflozin 15 mg group.
Genital Mycotic Infections
In the pool of three placebo-controlled clinical trials, the incidence of female genital mycotic infections
(e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis,
vulvovaginal mycotic infection, vulvovaginitis) occurred in 3%, 9.1%, and 12.2%, of females treated with
placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively (see Table 1). In females, discontinuation
due to genital mycotic infections occurred in 0% and 0.6% of patients treated with placebo and ertugliflozin,
respectively.
In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital
infection, genital infection fungal) occurred in 0.4%, 3.7%, and 4.2% of males treated with placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Male genital mycotic infections occurred more
commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in
0% and 0.2% of patients treated with placebo and ertugliflozin, respectively. Phimosis was reported in 8 of
1,729 (0.5%) male ertugliflozin-treated patients, of which four required circumcision.
Urinary Tract Infections
In VERTIS CV urinary tract infections (e.g., urinary tract infection, cystitis, dysuria) occurred in 10.2%,
12.2% and 12.0% of patients treated with placebo, ertugliflozin 5 mg and ertugliflozin 15 mg, respectively.
The incidences of serious urinary tract infections were 0.8%, 0.9% and 0.4% with placebo, ertugliflozin 5
mg and ertugliflozin 15 mg, respectively.
Metformin HCl
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The most common (5% or greater incidence) established adverse reactions due to initiation of
metformin HCl therapy are diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion,
asthenia, and headache.
In controlled clinical trials of metformin HCl of 29 weeks duration, a decrease to subnormal levels of
previously normal serum vitamin B12 levels was observed in approximately 7% of patients.
Laboratory Tests
Ertugliflozin
Changes in Serum Creatinine and eGFR
Initiation of ertugliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of
starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment,
larger mean changes were observed. In a long-term cardiovascular outcomes trial, an initial increase in
serum creatinine and a decrease in eGFR within weeks of starting therapy was observed (at Week 6 eGFR
changes of -2.7, -3.8 and -0.4 mL/min/1.73 m2 in the ertugliflozin 5 mg, ertugliflozin 15 mg and placebo
arms, respectively). The initial decline was followed by a recovery toward baseline to Week 52 (eGFR
change from baseline of - 0.4, - 1.1 and - 0.2 mL/min/1.73 m2 in ertugliflozin 5 mg, ertugliflozin 15 mg, and
placebo arms, respectively). Acute hemodynamic changes may play a role in the early renal function
changes observed with ertugliflozin since they are reversed after treatment discontinuation.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
In the pool of three placebo-controlled trials, dose-related increases in LDL-C were observed in
patients treated with ertugliflozin. Mean percent changes from baseline to Week 26 in LDL-C relative to
placebo were 2.6% and 5.4% with ertugliflozin 5 mg and ertugliflozin 15 mg, respectively. The range of
mean baseline LDL-C was 96.6 to 97.7 mg/dL across treatment groups.
Increases in Hemoglobin
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline to Week
26 in hemoglobin were -0.21 g/dL (-1.4%) with placebo, 0.46 g/dL (3.5%) with ertugliflozin 5 mg, and
0.48 g/dL (3.5%) with ertugliflozin 15 mg. The range of mean baseline hemoglobin was 13.90 to 14.00 g/dL
across treatment groups. At the end of treatment, 0.0%, 0.2%, and 0.4% of patients treated with placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, had a hemoglobin increase greater than 2 g/dL and
above the upper limit of normal.
Increases in Serum Phosphate
In the pool of three placebo-controlled trials, mean changes (percent changes) from baseline in serum
phosphate were 0.04 mg/dL (1.9%) with placebo, 0.21 mg/dL (6.8%) with ertugliflozin 5 mg, and
0.26 mg/dL (8.5%) with ertugliflozin 15 mg. The range of mean baseline serum phosphate was 3.53 to
3.54 mg/dL across treatment groups. In a clinical trial of patients with moderate renal impairment, mean
changes (mean percent changes) from baseline at Week 26 in serum phosphate were -0.01 mg/dL (0.8%)
with placebo, 0.29 mg/dL (9.7%) with ertugliflozin 5 mg, and 0.24 mg/dL (7.8%) with ertugliflozin 15 mg.
6.2
Postmarketing Experience
Additional adverse reactions have been identified during post approval use of ertugliflozin, metformin
HCl, both components of SEGLUROMET. Because these reactions are reported voluntarily from a
population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Ertugliflozin
•
Infections: necrotizing fasciitis of the perineum (Fournier’s Gangrene)
•
Skin and Subcutaneous Tissue Disorders: angioedema, rash
Metformin HCl
•
Hepatobiliary Disorders: cholestatic, hepatocellular, and mixed hepatocellular liver injury
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7
DRUG INTERACTIONS
Table 3: Clinically Significant Drug Interactions with SEGLUROMET
Carbonic Anhydrase Inhibitors
Clinical Impact:
The risk of lactic acidosis may increase due to concomitant use of Topiramate or other carbonic
anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) with metformin. These drugs
frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic
acidosis.
Intervention:
more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical Impact:
The risk of lactic acidosis may increase due to concomitant use of drugs that interfere with common renal
tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic
transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib,
dolutegravir, and cimetidine) which increase systemic exposure to metformin
Intervention
Consider the benefits and risks of concomitant use.
Alcohol
Clinical Impact:
Potentiate the effect of metformin on lactate metabolism.
Intervention:
Warn patients against excessive alcohol intake while receiving SEGLUROMET.
Insulin or Insulin Secretagogues
Clinical Impact:
The risk of hypoglycemia is increased when ertugliflozin is used in combination with insulin or an insulin
secretagogue.
Intervention:
A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia
when used in combination with SEGLUROMET.
Drugs that Affect Glycemic Control
Clinical Impact:
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens,
oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and
isoniazid.
Intervention:
When a patient is receiving SEGLUROMET along with such drugs, the patient should be closely
observed to maintain adequate glycemic control.
Lithium
Clinical Impact:
Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.
Intervention:
Monitor serum lithium concentration more frequently during SEGLUROMET initiation and dosage
changes.
Positive Urine Glucose Test
Clinical Impact:
SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention:
Monitoring glycemic control with urine glucose tests is not recommended in patients taking
SEGLUROMET. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact:
Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2
inhibitors.
Intervention:
Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor
glycemic control.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on animal data showing adverse renal effects, from ertugliflozin, SEGLUROMET is not
recommended during the second and third trimesters of pregnancy. Published studies with metformin use
during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage
risk (see Data).
The limited available data with SEGLUROMET in pregnant women are not sufficient to determine a
drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus
associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
In animal studies, adverse renal changes were observed in rats when ertugliflozin was administered
during a period of renal development corresponding to the late second and third trimesters of human
pregnancy. Doses approximately 13 times the maximum clinical dose caused renal pelvic and tubule
dilatations and renal mineralization that were not fully reversible. There was no evidence of fetal harm in
rats or rabbits at exposures of ertugliflozin approximately 300 times higher than the maximal clinical dose
of 15 mg/day when administered during organogenesis (see Data).
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The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes
with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated
background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre
eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human Data
Published data from postmarketing studies have not reported a clear association with metformin and
major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during
pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated
risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data
Ertugliflozin
When ertugliflozin was orally administered to juvenile rats from PND 21 to PND 90, increased kidney
weight, renal tubule and renal pelvis dilatation, and renal mineralization occurred at doses greater than or
equal to 5 mg/kg (13-fold human exposures, based on AUC). These effects occurred with drug exposure
during periods of renal development in rats that correspond to the late second and third trimester of human
renal development, and did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies, ertugliflozin (50, 100 and 250 mg/kg/day) was administered
orally to rats on gestation days 6 to 17 and to rabbits on gestation days 7 to 19. Ertugliflozin did not
adversely affect developmental outcomes in rats and rabbits at maternal exposures that were approximately
300 times the human exposure at the maximum clinical dose of 15 mg/day, based on AUC. A maternally
toxic dose (250 mg/kg/day) in rats (707 times the clinical dose) was associated with reduced fetal viability
and a higher incidence of a visceral malformation (membranous ventricular septal defect). In the pre- and
post-natal development study in pregnant rats, ertugliflozin was administered to the dams from gestation
day 6 through lactation day 21 (weaning). Decreased post-natal growth (weight gain) was observed at
maternal doses ≥100 mg/kg/day (greater than or equal to 331 times the human exposure at the maximum
clinical dose of 15 mg/day, based on AUC).
Metformin HCl
Metformin did not adversely affect development outcomes when administered to rats and rabbits at
doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum
recommended human dose of 2,000 mg based on body surface area comparisons for rats and rabbits,
respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
8.2
Lactation
Risk Summary
There is no information regarding the presence of SEGLUROMET or ertugliflozin in human milk, the
effects on the breastfed infant, or the effects on milk production. Limited published studies report that
metformin is present in human milk (see Data). However, there is insufficient information on the effects of
metformin on the breastfed infant and no available information on the effects of metformin on milk
production. Ertugliflozin (see Data) and metformin are present in the milk of lactating rats. Since human
kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur,
there may be risk to the developing human kidney, based on data with ertugliflozin. Because of the potential
for serious adverse reactions in a breastfed infant, advise women that the use of SEGLUROMET is not
recommended while breastfeeding.
Data
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The lacteal excretion of radiolabeled ertugliflozin in lactating rats was evaluated 10 to 12 days after
parturition. Ertugliflozin derived radioactivity exposure in milk and plasma were similar, with a milk/plasma
ratio of 1.07, based on AUC. Juvenile rats directly exposed to ertugliflozin during a developmental period
corresponding to human kidney maturation were associated with a risk to the developing kidney (persistent
increased organ weight, renal mineralization, and renal pelvic and tubular dilatations).
Published clinical lactation studies report that metformin is present in human milk, which resulted in
infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio
ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use
of metformin during lactation because of small sample size and limited adverse event data collected in
infants.
8.3
Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with
metformin may result in ovulation in some anovulatory women.
8.4
Pediatric Use
Safety and effectiveness of SEGLUROMET in pediatric patients under 18 years of age have not been
established.
8.5
Geriatric Use
SEGLUROMET
No dosage adjustment of SEGLUROMET is recommended based on age. Elderly patients are more
likely to have decreased renal function. Because renal function abnormalities can occur after initiating
ertugliflozin, and metformin is known to be substantially excreted by the kidneys, care should be taken in
dose selection in the elderly. Assess renal function in elderly patients prior to initiating dosing and
periodically thereafter [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.4)].
Ertugliflozin
In ertugliflozin clinical trials, a total of 876 (25.7%) patients treated with ertugliflozin were 65 years
and older, and 152 (4.5%) patients treated with ertugliflozin were 75 years and older. Patients 65 years and
older had a higher incidence of adverse reactions related to volume depletion compared to younger
patients; events were reported in 1.1%, 2.2%, and 2.6% of patients treated with comparator, ertugliflozin
5 mg, and ertugliflozin 15 mg, respectively [see Warnings and Precautions (5.4) and Adverse Reactions
(6.1)].
In VERTIS CV, a total of 2780 (50.5%) patients treated with ertugliflozin were 65 years and older,
and 595 (10.8%) patients treated with ertugliflozin were 75 years and older. Safety and efficacy were
generally similar for patients age 65 years and older compared to patients younger than 65.
Metformin HCl
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to
determine whether they respond differently from younger patients, although other reported clinical
experience has not identified differences in responses between the elderly and young patients. In general,
dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly
patients [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
8.6
Renal Impairment
A 26-week placebo-controlled study of 313 patients with Stage 3 Chronic Kidney Disease (eGFR ≥30
to less than 60 mL/min/1.73 m2) treated with ertugliflozin did not have improvement in glycemic control.
In the VERTIS CV study, there were 1370 patients (25%) with an eGFR ≥90 mL/min/1.73 m2, 2929
patients (53%) with an eGFR of ≥60 to less than 90 mL/min/1.73 m2, 879 patients (16%) with an eGFR of
≥45 to less than 60 mL/min/1.73 m2, and 299 patients (5%) with eGFR of 30 to <45 mL/min/1.73 m2 treated
with ertugliflozin. Similar effects on glycemic control at Week 18 were observed in patients treated with
ertugliflozin in each eGFR subgroup and also in the overall patient population.
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SEGLUROMET is contraindicated in patients with severe renal impairment (eGFR less than
30 mL/min/1.73 m2), ESRD, or on dialysis [see Contraindications (4)].
No dosage adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m2.
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic
acidosis increases with the degree of renal impairment.
8.7
Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic
acidosis. SEGLUROMET is not recommended in patients with hepatic impairment [see Warnings and
Precautions (5.1)].
10
OVERDOSAGE
SEGLUROMET
In the event of an overdose with SEGLUROMET, contact the Poison Help line (1-800-222-1222) or
a medical toxicologist for additional overdosage management recommendations. Employ the usual
supportive measures as dictated by the patient’s clinical status.
Ertugliflozin
Removal of ertugliflozin by hemodialysis has not been studied.
Metformin HCl
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 g
(25 times the maximum recommended daily dose). Hypoglycemia was reported in approximately 10% of
cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has
been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)].
Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.
Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin
overdosage is suspected.
11
DESCRIPTION
SEGLUROMET (ertugliflozin and metformin hydrochloride) tablet for oral use contains ertugliflozin L
pyroglutamic acid, a SGLT2 inhibitor, and metformin HCl, a member of the biguanide class.
Ertugliflozin
The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4
ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5
oxopyrrolidine-2-carboxylic acid. The molecular formula is C27H32ClNO10 and the molecular weight is
566.00.
The chemical structure is:
Ertugliflozin L-pyroglutamic acid is a white to off-white powder that is soluble in ethyl alcohol and
acetone, slightly soluble in ethyl acetate and acetonitrile and very slightly soluble in water.
Metformin HCl
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically
or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula
is as shown:
15
Reference ID: 5502336
Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl
and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically
insoluble in acetone, ether and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution
of metformin hydrochloride is 6.68.
SEGLUROMET is available as film-coated tablets containing:
•
3.24 mg ertugliflozin L-pyroglutamic acid equivalent to 2.5 mg of ertugliflozin and 500 mg metformin
HCl (SEGLUROMET 2.5/500)
•
3.24 mg ertugliflozin L-pyroglutamic acid equivalent to 2.5 mg of ertugliflozin and 1,000 mg metformin
HCl (SEGLUROMET 2.5/1000)
•
9.71 mg ertugliflozin L-pyroglutamic acid equivalent to 7.5 mg of ertugliflozin and 500 mg metformin
HCl (SEGLUROMET 7.5/500)
•
9.71 mg ertugliflozin L-pyroglutamic acid equivalent to 7.5 mg of ertugliflozin and 1,000 mg metformin
HCl (SEGLUROMET 7.5/1000)
Inactive ingredients are povidone, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and
magnesium stearate.
The film coating contains: hypromellose, hydroxypropyl cellulose, titanium dioxide, iron oxide red,
and carnauba wax.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
SEGLUROMET
SEGLUROMET combines two antihyperglycemic agents with complementary mechanisms of action
to improve glycemic control in patients with type 2 diabetes mellitus: ertugliflozin, a SGLT2 inhibitor, and
metformin hydrochloride, a member of the biguanide class.
Ertugliflozin
SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular
filtrate back into the circulation. Ertugliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, ertugliflozin
reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby
increases urinary glucose excretion.
Metformin HCl
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2
diabetes mellitus, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of
action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic
glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by
increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either
patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings
and Precautions (5.5)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion
remains unchanged while fasting insulin levels and day-long plasma insulin response may actually
decrease.
12.2 Pharmacodynamics
16
Reference ID: 5502336
Ertugliflozin
Urinary Glucose Excretion and Urinary Volume
Dose-dependent increases in the amount of glucose excreted in urine were observed in healthy
subjects and in patients with type 2 diabetes mellitus following single- and multiple-dose administration of
ertugliflozin. Dose-response modeling indicates that ertugliflozin 5 mg and 15 mg result in near maximal
urinary glucose excretion (UGE). Enhanced UGE is maintained after multiple-dose administration. UGE
with ertugliflozin also results in increases in urinary volume.
Cardiac Electrophysiology
The effect of ertugliflozin on QTc interval was evaluated in a Phase 1 randomized, placebo- and
positive-controlled 3-period crossover study in 42 healthy subjects. At 6.7 times the therapeutic exposures
with maximum recommended dose, ertugliflozin does not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
General Introduction
Ertugliflozin
The pharmacokinetics of ertugliflozin are similar in healthy subjects and patients with type 2 diabetes
mellitus. The steady state mean plasma AUC and Cmax were 398 ng∙hr/mL and 81.3 ng/mL, respectively,
with 5 mg ertugliflozin once-daily treatment, and 1,193 ng∙hr/mL and 268 ng/mL, respectively, with 15 mg
ertugliflozin once-daily treatment. Steady-state is reached after 4 to 6 days of once-daily dosing with
ertugliflozin. Ertugliflozin does not exhibit time-dependent pharmacokinetics and accumulates in plasma up
to 10-40% following multiple dosing.
Absorption
SEGLUROMET
The effects of a high-fat meal on the pharmacokinetics of ertugliflozin and metformin when
administered as SEGLUROMET tablets are comparable to those reported for the individual tablets. Food
had no meaningful effect on AUCinf of ertugliflozin and metformin, but reduced mean ertugliflozin Cmax by
approximately 41% and metformin Cmax by approximately 29% compared to the fasted condition.
Ertugliflozin
Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, peak plasma
concentrations of ertugliflozin occur at 1 hour postdose (median Tmax) under fasted conditions. Plasma Cmax
and AUC of ertugliflozin increase in a dose-proportional manner following single doses from 0.5 mg (0.1
times the lowest recommended dose) to 300 mg (20 times the highest recommended dose) and following
multiple doses from 1 mg (0.2 times the lowest recommended dose) to 100 mg (6.7 times the highest
recommended dose). The absolute oral bioavailability of ertugliflozin following administration of a 15 mg
dose is approximately 100%.
Effect of Food
Administration of ertugliflozin with a high-fat and high-calorie meal decreases ertugliflozin Cmax by
29% and prolongs Tmax by 1 hour, but does not alter AUC as compared with the fasted state. The observed
effect of food on ertugliflozin pharmacokinetics is not considered clinically relevant, and ertugliflozin may
be administered with or without food. In Phase 3 clinical trials, ertugliflozin was administered without regard
to meals.
Metformin hydrochloride
The absolute bioavailability of a metformin HCl 500-mg tablet given under fasting conditions is
approximately 50-60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to
1,500 mg, and 850 mg to 2,550 mg (approximately 1.3 times the maximum recommended daily dosage),
indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased
absorption rather than an alternation in elimination. Food decreases the extent of and slightly delays the
absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max),
a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation
of time to peak plasma concentration (Tmax) following administration of a single 850-mg tablet of metformin
17
Reference ID: 5502336
with food, compared to the same tablet strength administered fasting. The clinical relevance of these
decreases is unknown.
Distribution
Ertugliflozin
The mean steady-state volume of distribution of ertugliflozin following an intravenous dose is 85.5 L.
Plasma protein binding of ertugliflozin is 93.6% and is independent of ertugliflozin plasma concentrations.
Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood-
to-plasma concentration ratio of ertugliflozin is 0.66.
Metformin
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin
hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in
contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes,
most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride
tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally
<1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed
5 mcg/mL, even at maximum doses.
Elimination
Metabolism
Ertugliflozin
Metabolism is the primary clearance mechanism for ertugliflozin. The major metabolic pathway for
ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation to two glucuronides that are
pharmacologically inactive at clinically relevant concentrations. CYP-mediated (oxidative) metabolism of
ertugliflozin is minimal (12%).
Metformin
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted
unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in
humans) nor biliary excretion.
Excretion
Ertugliflozin
The mean systemic plasma clearance following an intravenous 100 µg dose was 11.2 L/hr. The mean
elimination half-life in type 2 diabetic patients with normal renal function was estimated to be 16.6 hours
based on the population pharmacokinetic analysis. Following administration of an oral [14C]-ertugliflozin
solution to healthy subjects, approximately 40.9% and 50.2% of the drug-related radioactivity was
eliminated in feces and urine, respectively. Only 1.5% of the administered dose was excreted as unchanged
ertugliflozin in urine and 33.8% as unchanged ertugliflozin in feces, which is likely due to biliary excretion
of glucuronide metabolites and subsequent hydrolysis to parent.
Metformin
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that
tubular secretion is the major route of metformin elimination. Following oral administration, approximately
90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination
half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours,
suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Patients with Renal Impairment
SEGLUROMET
Studies characterizing the pharmacokinetics of ertugliflozin and metformin after administration of
SEGLUROMET in renally impaired patients have not been performed [see Dosage and Administration
(2.2)].
18
Reference ID: 5502336
Ertugliflozin
In a clinical pharmacology study in patients with type 2 diabetes mellitus and mild, moderate, or
severe renal impairment (as determined by eGFR), following a single-dose administration of 15 mg
ertugliflozin, the mean increases in AUC of ertugliflozin were 1.6-, 1.7-, and 1.6-fold, respectively, for mild,
moderate, and severe renally-impaired patients compared to subjects with normal renal function. These
increases in ertugliflozin AUC are not considered clinically meaningful. The 24-hour urinary glucose
excretion declined with increasing severity of renal impairment [see Warnings and Precautions (5.2) and
Use in Specific Populations (8.6)]. The plasma protein binding of ertugliflozin was unaffected in patients
with renal impairment.
Metformin
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged
and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].
Patients with Hepatic Impairment
Ertugliflozin
Moderate hepatic impairment (based on the Child-Pugh classification) did not result in an increase in
exposure of ertugliflozin. The AUC of ertugliflozin decreased by approximately 13%, and Cmax decreased
by approximately 21% compared to subjects with normal hepatic function. This decrease in ertugliflozin
exposure is not considered clinically meaningful. There is no clinical experience in patients with Child-Pugh
class C (severe) hepatic impairment. The plasma protein binding of ertugliflozin was unaffected in patients
with moderate hepatic impairment [see Use in Specific Populations (8.7)].
Metformin
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment
[see Use in Specific Populations (8.7)].
Effects of Age, Body Weight, Gender, and Race
Ertugliflozin
Based on a population pharmacokinetic analysis, age, body weight, gender, and race do not have a
clinically meaningful effect on the pharmacokinetics of ertugliflozin.
Metformin
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest
that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased,
compared to healthy young subjects. From these data, it appears that the change in metformin
pharmacokinetics with aging is primarily accounted for by a change in renal function.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and
patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical
studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable
in males and females.
No studies of metformin pharmacokinetic parameters according to race have been performed. In
controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect
was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).
Drug Interaction Studies
SEGLUROMET
Coadministration of single dose of ertugliflozin (15 mg) and metformin (1,000 mg) did not
meaningfully alter the pharmacokinetics of either ertugliflozin or metformin in healthy subjects.
Pharmacokinetic drug interaction studies with SEGLUROMET have not been performed; however,
such studies have been conducted with ertugliflozin and metformin, the individual components of
SEGLUROMET.
Ertugliflozin
In Vitro Assessment of Drug Interactions
19
Reference ID: 5502336
Sitagliptin , 100 mg, single dose
AUC
Gmax
Metformin, 1000 mg, single dose
AUG
Gmax
Glimepiride, 1 mg, single dose
AUG
Gmax
Simvastatin , 40 mg, single dose
AUG
Gmax
Rifampin , 600 mg , once daily
AUG
Gmax -
Geometric mean ratio (90% Cl)
102.27 (99.72-104.89}
98.18 (91.20-105.70}
100.34 (97.43-103.34)
97.14 (88.77-106.30}
102.11 (97.19-107.27)
98.20 (92.17-1 04 63}
102.40 (99.57-105.31)
1 05.1 6 (98.26-11 2.54}
61 .16 (57.22-65.37}
84.62 (74.17-96.53)
50
75
100
125
150
Relative to ertugliflozin alone (%)
All ertugliflozin doses were given as 15 mg single dose
In in vitro studies, ertugliflozin and ertugliflozin glucuronides did not inhibit CYP450 isoenzymes
(CYPs) 1A2, 2C9, 2C19, 2C8, 2B6, 2D6, or 3A4, and did not induce CYPs 1A2, 2B6, or 3A4. Ertugliflozin
was not a time-dependent inhibitor of CYP3A in vitro. Ertugliflozin did not inhibit UGT1A6, 1A9, or 2B7 in
vitro and was a weak inhibitor (IC50 >39 µM) of UGT1A1 and 1A4. Ertugliflozin glucuronides did not inhibit
UGT1A1, 1A4, 1A6, 1A9, or 2B7 in vitro. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of
drugs eliminated by these enzymes. Ertugliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer
resistance protein (BCRP) transporters and is not a substrate of organic anion transporters (OAT1, OAT3),
organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1,
OATP1B3). Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or
OAT3 transporters, or transporting polypeptides OATP1B1 and OATP1B3, at clinically relevant
concentrations. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered
medications that are substrates of these transporters.
In Vivo Assessment of Drug Interactions
No dose adjustment of SEGLUROMET is recommended when coadministered with commonly
prescribed
medicinal
products.
Ertugliflozin
pharmacokinetics
were
similar with
and
without
coadministration of metformin, glimepiride, sitagliptin, and simvastatin in healthy subjects (see Figure 1).
Coadministration of ertugliflozin with multiple doses of 600 mg once-daily rifampin (an inducer of UGT and
CYP enzymes) resulted in approximately 39% and 15% mean reductions in ertugliflozin AUC and Cmax,
respectively, relative to ertugliflozin administered alone. These changes in exposure are not considered
clinically relevant. Ertugliflozin had no clinically relevant effect on the pharmacokinetics of metformin,
glimepiride, sitagliptin, and simvastatin when coadministered in healthy subjects (see Figure 2).
Physiologically-based PK (PBPK) modeling suggests that coadministration of mefenamic acid (UGT
inhibitor) may increase the AUC and Cmax of ertugliflozin by 1.51- and 1.19-fold, respectively. These
predicted changes in exposure are not considered clinically relevant.
Figure 1: Effects of Other Drugs on the Pharmacokinetics of Ertugliflozin
20
Reference ID: 5502336
Geometric mean ratio (90% Cl)
Sitagliptin , 100 mg, single dose
AUG
·-
1 01 .67 (9B.40-1 05.04)
Gmax
101 .6B (91 .65-112.BO)
Metformin, 1000 mg, single dose
AUG
100.94 (90.62-112.44)
Gmax
-
94.00 (B2.94-106.55)
Glimepiride, 1 mg, single dose
AUG
-
109.BO (9B.14-122.B6)
Gmax
97.39 (71.07-133.46}
Simvastatin, 40 mg, single dose
AUG
-
123.B3 (90.92-16B.66)
Gmax
119.05 (97.22-145.77)
Simvastatin Acid
AUG
130.46 (1 OB.32-157.13}
(Administered as Simvastatin)
Gmax
115.66 (95.74-139.71}
100
150
200
Relative to concomitant medication alone (%)
All ertugliflozin doses were given as 15 mg single dose
Figure 2: Effects of Ertugliflozin on the Pharmacokinetics of Other Drugs
Metformin hydrochloride
Table 4: Effect of Metformin HCl on Systemic Exposure of Coadministered Drugs
Coadministered Drug
Dose of
Dose of Metformin
Geometric Mean Ratio
Coadministered
HCl*
(ratio with/without metformin)
Drug*
No Effect = 1.00
AUC†
Cmax
No dosing adjustments required for the following:
Cimetidine
400 mg
850 mg
Cimetidine
0.95‡
1.01
Glyburide
5 mg
§
500 mg
Glyburide
0.78¶
0.63¶
Furosemide
40 mg
850 mg
Furosemide
0.87¶
0.69¶
Nifedipine
10 mg
850 mg
Nifedipine
1.10‡
1.08
Propranolol
40 mg
850 mg
Propranolol
1.01‡
0.94
Ibuprofen
400 mg
850 mg
Ibuprofen
0.97#
1.01#
*
All doses administered as single dose unless otherwise specified.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
AUC0-24hr.
§
Metformin HCl extended-release tablets 500 mg.
¶
Ratio of arithmetic means, p value of difference <0.05.
#
Ratio of arithmetic means.
21
Reference ID: 5502336
Table 5: Effect of Coadministered Drugs on Systemic Exposure of Metformin HCl
Coadministered Drug
Dose of
Coadministered
Drug*
Dose of
Metformin HCl*
Geometric Mean Ratio
(ratio with/without coadministered drug)
No Effect = 1.00
AUC†
Cmax
No dosing adjustments required for the following:
Glyburide
5 mg
‡
500 mg
Metformin‡
0.98§
0.99§
Furosemide
40 mg
850 mg
Metformin
1.09§
1.22§
Nifedipine
10 mg
850 mg
Metformin
1.16
1.21
Propranolol
40 mg
850 mg
Metformin
0.90
0.94
Ibuprofen
400 mg
850 mg
Metformin
1.05§
1.07§
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Warnings
and
Precautions (5.1) and Drug Interactions (7.2)].
Cimetidine
400 mg
850 mg
Metformin
1.40
1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5.1) and Drug
Interactions (7.2)].
¶
¶
Topiramate
100 mg
500 mg
Metformin
1.25¶
1.17
*
All doses administered as single dose unless otherwise specified.
†
AUC is reported as AUC0-∞ unless otherwise specified.
‡
Metformin hydrochloride extended-release tablets 500 mg.
§
Ratio of arithmetic means.
¶
Steady-state 100 mg topiramate every 12 hr + metformin 500 mg every 12 hr AUC = AUC0-12hr.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Ertugliflozin
Carcinogenicity was evaluated in CD-1 mice and Sprague-Dawley rats. In the mouse study,
ertugliflozin was administered by oral gavage at doses of 5, 15, and 40 mg/kg/day for up to 97 weeks in
males and 102 weeks in females. There were no ertugliflozin-related neoplastic findings at doses up to
40 mg/kg/day (approximately 50 times human exposure at the maximum recommended human dose
[MRHD] of 15 mg/day based on AUC). In the rat study, ertugliflozin was administered by oral gavage at
doses of 1.5, 5, and 15 mg/kg/day for up to 92 weeks in females and 104 weeks in males. Ertugliflozin
related neoplastic findings included an increased incidence of adrenal medullary pheochromocytoma (PCC)
in male rats at 15 mg/kg/day. Although the molecular mechanism remains unknown, this finding may be
related to carbohydrate malabsorption leading to altered calcium homeostasis, which has been associated
with PCC development in rats and has unclear relevancy to human risk. The no-observed-effect level
(NOEL) for neoplasia was 5 mg/kg/day (approximately 16 times human exposure at the MRHD of
15 mg/day, based on AUC).
Metformin HCl
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and
mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day,
respectively. These doses are both approximately four times the maximum recommended human daily
dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin
was found in either male or female mice. Similarly, there was no tumorigenic potential observed with
metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in
female rats treated with 900 mg/kg/day.
Mutagenesis
Ertugliflozin
Ertugliflozin was not mutagenic or clastogenic with or without metabolic activation in the microbial
reverse mutation, in vitro cytogenetic (human lymphocytes), and in vivo rat micronucleus assays.
Metformin
22
Reference ID: 5502336
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test
(S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human
lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Impairment of Fertility
Ertugliflozin
In the rat fertility and embryonic development study, male and female rats were administered
ertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day
(approximately 480 and 570 times male and female human exposures, respectively, at the MRHD of
15 mg/day based on AUC comparison).
Metformin HCl
Fertility of male or female rats was unaffected by metformin when administered at doses as high as
600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based
on body surface area comparisons.
14
CLINICAL STUDIES
14.1 Glycemic Control Trials in Patients with Type 2 Diabetes Mellitus
The efficacy and safety of ertugliflozin in combination with metformin HCl have been studied in
4 multicenter, randomized, double-blind, placebo- and active comparator-controlled, clinical studies
involving 3,643 patients with type 2 diabetes mellitus. These studies included White, Hispanic or Latino,
Black or African American, Asian, and other racial and ethnic groups, and patients with an age range of 21
to 86 years.
In VERTIS CV, ertugliflozin has been studied as add on to insulin (with or without metformin HCl)
and as add on to metformin HCl plus a sulfonylurea in substudies.
In patients with type 2 diabetes mellitus, treatment with ertugliflozin in combination with metformin
HCl reduced hemoglobin A1c (HbA1c) compared to placebo.
In patients with type 2 diabetes mellitus treated with ertugliflozin in combination with metformin HCl,
the reduction in HbA1c was generally similar across subgroups defined by age, sex, race, geographic
region, baseline body mass index (BMI), and duration of type 2 diabetes mellitus.
Ertugliflozin as Add-on Combination Therapy with Metformin HCl
A total of 621 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and
10.5%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a randomized, double-
blind, multi-center, 26-week, placebo-controlled study (NCT02033889) to evaluate the efficacy and safety
of ertugliflozin in combination with metformin HCl. Patients entered a 2-week, single-blind, placebo run-in,
and were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg administered orally once daily in
addition to continuation of background metformin HCl therapy.
At Week 26, statistically significant reductions in HbA1c were observed in the ertugliflozin 5 mg and
15 mg groups compared to placebo. Ertugliflozin also resulted in a greater proportion of patients achieving
an HbA1c <7% compared to placebo (see Table 6 and Figure 3).
23
Reference ID: 5502336
Table 6: Results at Week 26 from a Placebo-Controlled Study for Ertugliflozin Used in
Combination with Metformin HCl in Patients with Type 2 Diabetes Mellitus*
Placebo
Ertugliflozin 5 mg
Ertugliflozin 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 207
8.2
-0.2
N = 205
8.1
-0.7
-0.5‡ (-0.7, -0.4)
N = 201
8.1
-0.9
-0.7‡ (-0.9, -0.5)
Patients [N (%)] with HbA1c <7%
38 (18.4)
74 (36.3)
87 (43.3)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 202
169.1
-8.7
N = 199
168.1
-30.3
-21.6‡ (-27.8, -15.5)
N = 201
167.9
-40.9
-32.3‡ (-38.5, -26.0)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary
HbA1c endpoint was missing for 12%, 6%, and 9% of patients, and during the trial, rescue medication was initiated by 18%,
3%, and 1% of patients randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Missing Week 26
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.7%, and -1.0% for placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication, menopausal status and
baseline eGFR.
‡
p<0.001 compared to placebo.
The mean baseline body weight was 84.5 kg, 84.9 kg, and 85.3 kg in the placebo, ertugliflozin 5 mg,
and ertugliflozin 15 mg groups, respectively. The mean changes from baseline to Week 26
were -1.4 kg, -3.2 kg, and -3.0 kg in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups,
respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg was -1.8 kg (-2.4, -1.2) and for
ertugliflozin 15 mg was -1.7 kg (-2.2, -1.1).
The mean baseline systolic blood pressure was 129.3 mmHg, 130.5 mmHg, and 130.2 mmHg in the
placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively. The mean changes from baseline
to Week 26 were -1.8 mmHg, -5.1 mmHg, and -5.7 mmHg in the placebo, ertugliflozin 5 mg, and
ertugliflozin 15 mg groups, respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg
was -3.3 mmHg (-5.6, -1.1) and for ertugliflozin 15 mg was -3.8 mmHg (-6.1, -1.5).
24
Reference ID: 5502336
0.1
0.0
(II
-0.1
C:
°Qi
-0.2
(II
ra
Ill
-0.3
E
0 ...
-0.4
-
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C:
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u
-0.6
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ra
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u
-0.9
....
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l'
.0
J:
-1.0
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o Placebo ♦ Ertugliflozin 5 mg l' Ertugliflozin 15 mg
BL
6
12
18
26
26-MI
Week
Placebo (N)
207
198
195
174
151
Ertugliflozin 5 mg (N)
205
Ertugllflozin 15 mg (N)
201
197
195
193
190
195
192
189
184
Figure 3: HbA1c (%) Change over Time in a 26-Week Placebo-Controlled Study for Ertugliflozin
Used in Combination with Metformin HCl in Patients with Type 2 Diabetes Mellitus*
*
Data to the left of the vertical line are observed means (non-model-based) excluding values occurring post glycemic rescue.
Data to the right of the vertical line represent the final Week 26 data, including all values regardless of use of glycemic rescue
medication and use of study drug, with missing Week 26 values imputed using multiple imputation (26-MI) with a mean equal to the
baseline value of the patient (see Table 6).
In Combination with Sitagliptin versus Ertugliflozin Alone and Sitagliptin Alone, as Add-on to Metformin HCl
A total of 1,233 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c
between 7.5% and 11%) on metformin HCl monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a
randomized, double-blind, 26-week, active controlled study (NCT02099110) to evaluate the efficacy and
safety of ertugliflozin 5 mg or 15 mg administered orally in combination with sitagliptin 100 mg compared
to the individual components. Patients were randomized to one of five treatment arms: ertugliflozin 5 mg,
ertugliflozin 15 mg, sitagliptin 100 mg, ertugliflozin 5 mg + sitagliptin 100 mg, or ertugliflozin 15 mg +
sitagliptin 100 mg.
At Week 26, ertugliflozin 5 mg or 15 mg + sitagliptin 100 mg provided statistically significantly greater
reductions in HbA1c compared to ertugliflozin (5 mg or 15 mg) alone or sitagliptin 100 mg alone. The mean
change from baseline in HbA1c was -1.4% for ertugliflozin 5 mg or 15 mg + sitagliptin 100 mg versus -1.0%,
for ertugliflozin 5 mg, ertugliflozin 15 mg, or sitagliptin 100 mg, respectively. More patients receiving
ertugliflozin 5 mg or 15 mg + sitagliptin 100 mg achieved an HbA1c <7% (53.3% and 50.9%, for ertugliflozin
5 mg or 15 mg, respectively, + sitagliptin 100 mg) compared to the individual components (29.3%, 33.7%,
and 38.5% for ertugliflozin 5 mg, ertugliflozin 15 mg, or sitagliptin 100 mg, respectively).
Ertugliflozin as Add-on Combination Therapy with Metformin HCl and Sitagliptin
A total of 463 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and
10.5%) on metformin HCl (≥1,500 mg/day for ≥8 weeks) and sitagliptin 100 mg orally once daily participated
25
Reference ID: 5502336
in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT02036515) to evaluate
the efficacy and safety of ertugliflozin. Patients entered a 2-week, single-blind, placebo run-in period and
were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg.
At Week 26, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant
reductions in HbA1c. Ertugliflozin also resulted in a higher proportion of patients achieving an HbA1c <7%
compared to placebo (see Table 7).
Table 7: Results at Week 26 from an Add-on Study of Ertugliflozin in Combination with Metformin
HCl and Sitagliptin in Patients with Type 2 Diabetes Mellitus*
Placebo
Ertugliflozin 5 mg
Ertugliflozin 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 152
8.0
-0.2
N = 155
8.1
-0.7
-0.5‡ (-0.7, -0.3)
N = 152
8.0
-0.8
-0.6‡ (-0.8, -0.4)
Patients [N (%)] with HbA1c <7%
31 (20.2)
54 (34.6)
64 (42.3)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean†)
Difference from placebo (LS mean†, 95% CI)
N = 152
169.6
-6.5
N = 156
167.7
-25.7
-19.2‡ (-26.8, -11.6)
N = 152
171.7
-32.1
-25.6‡ (-33.2, -18.0)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 26, the primary
HbA1c endpoint was missing for 10%, 11%, and 7% of patients and during the trial, rescue medication was initiated by 16%,
1%, and 2% of patients randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Missing Week 26
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 26 weeks, the mean changes from baseline for HbA1c were -0.2%, -0.8%, and -0.9% for placebo,
ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR.
‡
p<0.001 compared to placebo.
The mean baseline body weight was 86.5 kg, 87.6 kg, and 86.6 kg in the placebo, ertugliflozin 5 mg,
and ertugliflozin 15 mg groups, respectively. The mean changes from baseline to Week 26
were -1.0 kg, -3.0 kg, and -2.8 kg in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups,
respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg was -1.9 kg (-2.6, -1.3) and for
ertugliflozin 15 mg was -1.8 kg (-2.4, -1.2).
The mean baseline systolic blood pressure was 130.2 mmHg, 132.1 mmHg, and 131.6 mmHg in the
placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively. The mean changes from baseline
to Week 26 were -0.2 mmHg, -3.8 mmHg, and -4.5 mmHg in the placebo, ertugliflozin 5 mg, and
ertugliflozin 15 mg groups, respectively. The difference from placebo (95% CI) for ertugliflozin 5 mg
was -3.7 mmHg (-6.1, -1.2) and for ertugliflozin 15 mg was -4.3 mmHg (-6.7, -1.9).
Active Controlled Study of Ertugliflozin Versus Glimepiride as Add-on Combination Therapy with Metformin
HCl
A total of 1,326 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7%
and 9%) on metformin HCl monotherapy participated in a randomized, double-blind, multi-center, 52-week,
active comparator-controlled study (NCT01999218) to evaluate the efficacy and safety of ertugliflozin in
combination with metformin HCl. These patients, who were receiving metformin HCl monotherapy
(≥1,500 mg/day for ≥8 weeks), entered a 2-week, single-blind, placebo run-in period and were randomized
to glimepiride, ertugliflozin 5 mg, or ertugliflozin 15 mg, administered orally once daily in addition to
continuation of background metformin HCl therapy. Glimepiride was initiated at 1 mg/day and titrated up to
a maximum dose of 6 or 8 mg/day (depending on maximum approved dose in each country) or a maximum
tolerated dose or down-titrated to avoid or manage hypoglycemia. The mean daily dose of glimepiride was
3.0 mg.
Ertugliflozin 15 mg was non-inferior to glimepiride after 52 weeks of treatment. (See Table 8.)
26
Reference ID: 5502336
Table 8: Results at Week 52 from an Active-Controlled Study Comparing Ertugliflozin to
Glimepiride as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled
on Metformin HCl*
Glimepiride
Ertugliflozin 5 mg
Ertugliflozin 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean†)
Difference from glimepiride (LS mean†, 95% CI)
N = 437
7.8
-0.6
N = 447
7.8
-0.5
0.2‡ (0.0, 0.3)
N = 440
7.8
-0.5
0.1‡ (-0.0, 0.2)
Patients [N (%)] with HbA1c <7%
208 (47.7)
177 (39.5)
186 (42.2)
*
N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 52, the primary
HbA1c endpoint was missing for 15%, 20%, and 16% of patients and during the trial, rescue medication was initiated by 3%,
6%, and 4% of patients randomized to glimepiride, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Missing Week 52
measurements were imputed using multiple imputation with a mean equal to the baseline value of the patient. Results include
measurements collected after initiation of rescue medication. For those patients who did not receive rescue medication and had
values measured at 52 weeks, the mean changes from baseline for HbA1c were -0.8%, -0.6%, and -0.7% for glimepiride,
ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively.
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, prior antihyperglycemic medication and baseline eGFR.
‡
Non-inferiority is declared when the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is less
than 0.3%.
The mean baseline body weight was 86.8 kg, 87.9 kg, and 85.6 kg in the glimepiride, ertugliflozin
5 mg, and ertugliflozin 15 mg groups, respectively. The mean changes from baseline to Week 52 were
0.6 kg, -2.6 kg, and -3.0 kg in the glimepiride, ertugliflozin 5 mg, and ertugliflozin 15 mg groups,
respectively. The difference from glimepiride (95% CI) for ertugliflozin 5 mg was -3.2 kg (-3.7, -2.7) and for
ertugliflozin 15 mg was -3.6 kg (-4.1, -3.1).
Ertugliflozin as Add-on Combination Therapy with Insulin (With or Without Metformin HCl)
In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of
VERTIS CV (NCT01986881, study details see 14.2), a total of 1,065 patients with type 2 diabetes mellitus
and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between
7% and 10.5%) on background therapy of insulin ≥20 units/day (59% also on metformin HCl ≥1,500 mg/day)
were randomized to placebo, ertugliflozin 5 mg or ertugliflozin 15 mg oral once daily treatment.
At Week 18, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant
reductions in HbA1c compared to placebo (see Table 9).
Table 9: Results at Week 18 from an Add-on Study of Ertugliflozin in Combination with Insulin
(with or without Metformin HCl) in Patients with Type 2 Diabetes Mellitus*
Placebo
Ertugliflozin 5 mg
Ertugliflozin 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 346
8.4
-0.2 (0.05)
N = 346
8.4
-0.7 (0.05)
-0.5‡ (-0.6, -0.4)
N = 367
8.4
-0.7 (0.05)
-0.5‡ (-0.7, -0.4)
Patients [N (%)] with HbA1c <7%§
37 (10.7)
79 (22.8)
81 (22.1)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 343
167.4
-6.3 (2.91)
N = 346
173.8
-25.6 (2.90)
-19.2‡ (-26.8, -11.6)
N = 368
175.4
-29.8 (2.86)
-23.4‡ (-30.9, -16.0)
* N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 18, the primary
HbA1c endpoint was missing for 10%, 9%, and 12% of patients and during the trial, rescue medication was initiated by 12%,
7%, and 6% of patients randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Results include
27
Reference ID: 5502336
measurements collected after initiation of rescue medication. Prior to Week 18, background antidiabetic medication was held
stable. Missing Week 18 measurements were imputed using multiple imputation with a mean equal to the baseline value of the
patient (Return to Baseline analysis).
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value, insulin stratum, and baseline eGFR.
‡
p<0.001 compared to placebo.
§
Missing values imputed as not meeting the <7% criterion.
SE: standard error.
The mean baseline body weights were 93.3 kg, 93.8 kg, and 92.1 kg in the placebo, ertugliflozin 5 mg,
and ertugliflozin 15 mg groups, respectively. The mean changes from baseline to Week 18 were -0.2 kg,
- 1.6 kg, and -1.9 kg in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively. The
differences from placebo (95% CI) for ertugliflozin 5 mg were - 1.4 kg (- 1.9, - 0.9) and for ertugliflozin 15 mg
was -1.6 kg (-2.1, -1.1).
The mean baseline systolic blood pressures were 134.0 mmHg, 135.6 mmHg, and 133.7 mmHg in the
placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively. The mean changes from baseline
to Week 18 were 0.7 mmHg, -2.2 mmHg, and -1.7 mmHg in the placebo, ertugliflozin 5 mg, and ertugliflozin
15 mg groups, respectively. The differences from placebo (95% CI) for ertugliflozin 5 mg was – 2.9 mmHg
(-4.9, -1.0) and for ertugliflozin 15 mg were -2.5 mmHg (- 4.4, - 0.5).
Add-on Combination Therapy with Metformin HCl and Sulfonylurea
In an 18-week randomized, double-blind, multi-center, placebo-controlled, glycemic sub-study of
VERTIS CV (NCT01986881, study details see 14.2), a total of 330 patients with type 2 diabetes mellitus
and established atherosclerotic cardiovascular disease with inadequate glycemic control (HbA1c between
7% and 10.5%) with background therapy of metformin HCl ≥1,500 mg/day and a sulfonylurea (SU) were
randomized to placebo, ertugliflozin 5 mg or ertugliflozin 15 mg oral once daily treatment.
At Week 18, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant
reductions in HbA1c compared to placebo (see Table 10).
Table 10: Results at Week 18 from an Add-on Study of Ertugliflozin in Combination with Metformin
HCl and a SU in Patients with Type 2 Diabetes Mellitus*
Placebo
Ertugliflozin 5 mg
Ertugliflozin 15 mg
HbA1c (%)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 116
8.3
-0.3 (0.08)
N = 99
8.4
-0.8 (0.09)
-0.6‡ (-0.8, -0.3)
N = 113
8.3
-0.9 (0.08)
-0.7‡ (-0.9, -0.4)
Patients [N (%)] with HbA1c <7%§
17 (14.7)
39 (39.4)
38 (33.6)
FPG (mg/dL)
Baseline (mean)
Change from baseline (LS mean† , SE)
Difference from placebo (LS mean†, 95% CI)
N = 117
177.3
-3.5 (3.65)
N = 99
183.5
-31.3 (3.87)
-27.9‡ (-37.8, -17.9)
N = 113
174.0
-33.0 (3.67)
-29.5‡ (-39.0, -19.9)
* N includes all randomized and treated patients with a baseline measurement of the outcome variable. At Week 18, the primary
HbA1c endpoint was missing for 9%, 8%, and 6% of patients and during the trial, rescue medication was initiated by 10%, 7%,
and 3% of patients randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively. Results include
measurements collected after initiation of rescue medication. Missing Week 18 measurements were imputed using multiple
imputation with a mean equal to the baseline value of the patient (Return to Baseline analysis).
†
Intent-to-treat analysis using ANCOVA adjusted for baseline value and baseline eGFR.
‡
p<0.001 compared to placebo.
§
Missing values imputed as not meeting the <7% criterion.
SE: standard error
The mean baseline body weights were 90.5 kg, 92.1 kg, and 92.9 kg in the placebo, ertugliflozin 5
mg, and ertugliflozin 15 mg groups, respectively. The mean changes from baseline to Week 18 were
- 0.6 kg, -2.0 kg, and - 2.2 kg in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively.
28
Reference ID: 5502336
The differences from placebo (95% CI) for ertugliflozin 5 mg were - 1.4 kg (- 2.2, - 0.7) and for ertugliflozin
15 mg was - 1.6 kg (- 2.3, - 0.9).
14.2 Ertugliflozin Cardiovascular Outcomes in Patients with Type 2 Diabetes and Established
Cardiovascular Disease
The effect of ertugliflozin on cardiovascular risk in adult patients with type 2 diabetes and established
atherosclerotic cardiovascular disease was evaluated in the VERTIS CV study (NCT 01986881), a
multicenter, multi-national, randomized, double-blind, placebo-controlled, event-driven trial. The study
compared the risk of experiencing a major adverse cardiovascular event (MACE) between ertugliflozin and
placebo when these were added to and used concomitantly with standard of care treatments for diabetes
and atherosclerotic cardiovascular disease.
A total of 8,246 patients were randomized to placebo (N=2,747), oral once daily ertugliflozin 5 mg
(N=2,752), or oral once daily ertugliflozin 15 mg (N=2,747) and followed for a median of 3 years.
Approximately 88% of the study population was White, 6% Asian, and 3% Black or African American. The
mean age was 64 years and approximately 70% were male.
All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c
greater than or equal to 7%). The mean duration of type 2 diabetes mellitus was 13 years, the mean HbA1c
at baseline was 8.2% and the mean eGFR was 76 mL/min/1.73 m2. At baseline, patients were treated with
one (32%) or more (67%) antidiabetic medications including biguanides (metformin HCl) (76%), insulin
(47%), sulfonylureas (41%), DPP-4 inhibitors (11%) and GLP-1 receptor agonists (3%).
Almost all patients (99%) had established atherosclerotic cardiovascular disease at baseline
including: a documented history of coronary artery disease (76%), cerebrovascular disease (23%) or
peripheral artery disease (19%). Approximately 24% patients had a history of heart failure (HF). At baseline,
the mean systolic blood pressure was 133 mmHg, the mean diastolic blood pressure was 77 mmHg, the
mean LDL was 89 mg/dL, and the mean HDL was 44 mg/dL. At baseline, approximately 81% of patients
were treated with renin angiotensin system inhibitors, 69% with beta-blockers, 43% with diuretics, 82% with
statins, 4% ezetimibe, and 89% with antiplatelet agents.
The primary endpoint in VERTIS CV was the time to first occurrence of a Major Adverse Cardiac
Event (MACE). A major adverse cardiovascular event was defined as occurrence of either a cardiovascular
death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan pre-specified
that the 5 and 15 mg doses would be combined for the analysis. A Cox proportional hazards model was
used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE.
Type-1 error was controlled across multiple tests using a hierarchical testing strategy.
The incidence rate of MACE was similar between the ertugliflozin-treated and placebo-treated
patients. The estimated hazard ratio of MACE associated with ertugliflozin relative to placebo was 0.97 with
95.6% confidence interval (0.85, 1.11). The upper bound of this confidence interval excluded a risk larger
than 1.3 (Table 11). Results for the 5 mg and 15 mg doses were consistent with results for the combined
dose group.
Table 11: Analysis of MACE and its Components from the VERTIS-CV Study*
Endpoint†
Placebo (N=2747)
ertugliflozin (N=5499)
N (%)
Event Rate
N (%)
(per 100
person-years)
Event Rate
(per 100
person-years)
Hazard Ratio vs
Placebo
(CI) ‡
MACE (CV death, non-fatal MI,
or non-fatal stroke) Composite
327 (11.9)
4.0
653 (11.9)
3.9
0.97
(0.85, 1.11)
Components of Composite Endpoint
Non-fatal MI
148 (5.4)
1.6
310 (5.6)
1.7
1.04
(0.86, 1.27)
Non-fatal Stroke
78 (2.8)
0.8
157 (2.9)
0.8
1.00
(0.76, 1.32)
CV death
184 (6.7)
1.9
341 (6.2)
1.8
0.92
(0.77, 1.11)
N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction.
29
Reference ID: 5502336
* Intent-to-treat analysis set.
† MACE was evaluated in subjects who took at least one dose of study medication and, for subjects who discontinued study medication
prior to the end of the study, censored events that occurred more than 365 days after the last dose of study medication. Other
endpoints were evaluated using all randomized subjects and events that occurred any time after the first dose of study medication
until the last contact date. The total number of first events was analyzed for each endpoint.
‡ HR and CI are based on Cox proportional hazards regression model, stratified by cohorts. For MACE a 95.6% CI is presented, for
other endpoints a 95% CI is presented.
16
HOW SUPPLIED/STORAGE AND HANDLING
SEGLUROMET (ertugliflozin and metformin hydrochloride) tablets are available as follows:
Strength
Description
How Supplied
NDC
ertugliflozin 2.5 mg and
metformin
hydrochloride
500 mg
pink,
oval,
debossed
with “2.5/500” on one
side and plain on the
unit-of-use bottles of 60
0006-5369-03
tablets
ertugliflozin 2.5 mg and
other side
pink,
oval,
debossed
unit-of-use bottles of 180
0006-5369-06
metformin
hydrochloride 1,000 mg
with “2.5/1000” on one
side and plain on the
unit-of-use bottles of 60
0006-5373-03
tablets
ertugliflozin 7.5 mg and
other side
red, oval, debossed with
unit-of-use bottles of 180
0006-5373-06
metformin
hydrochloride
500 mg
“7.5/500” on one side
and plain on the other
unit-of-use bottles of 60
0006-5370-03
tablets
ertugliflozin 7.5 mg and
side
red, oval, debossed with
unit-of-use bottles of 180
0006-5370-06
metformin
hydrochloride 1,000 mg
tablets
“7.5/1000” on one side
and plain on the other
side
unit-of-use bottles of 60
0006-5374-03
unit-of-use bottles of 180
0006-5374-06
Store at 20°C-25°C (68°F-77°F), excursions permitted between 15°C-30°C (between 59°F-86°F) [see
USP Controlled Room Temperature]. Protect from moisture. Store in a dry place.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Lactic Acidosis
Inform patients of the risks of lactic acidosis due to the metformin component, its symptoms, and
conditions that predispose to its development [see Warnings and Precautions (5.1)]. Advise patients to
discontinue SEGLUROMET immediately and to notify their doctor promptly if unexplained hyperventilation,
malaise, myalgia, unusual somnolence, slow or irregular heartbeat, sensation of feeling cold (especially in
the extremities), or other nonspecific symptoms occur. GI symptoms are common during initiation of
metformin treatment and may occur during initiation of SEGLUROMET therapy; however, advise patients
to consult their doctor if they develop unexplained symptoms. Although GI symptoms that occur after
stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to
determine if it may be due to metformin-induced lactic acidosis or other serious disease.
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
Inform patients that SEGLUROMET can cause potentially fatal ketoacidosis and that type 2 diabetes
mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.
Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses,
infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms
of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform
patients that blood glucose may be normal even in the presence of ketoacidosis.
30
Reference ID: 5502336
Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur,
instruct patients to discontinue SEGLUROMET and seek medical attention immediately [see Warnings and
Precautions (5.2)].
Lower Limb Amputation
Inform patients of the potential for an increased risk of amputations. Counsel patients about the
importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores
or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or
symptoms develop [see Warnings and Precautions (5.3)].
Volume Depletion
Inform patients that symptomatic hypotension may occur with SEGLUROMET and advise them to
contact their doctor if they experience such symptoms [see Warnings and Precautions (5.4)]. Inform
patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.
Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them with
information on the symptoms of urinary tract infections. Advise them to seek medical advice if such
symptoms occur [see Warnings and Precautions (5.5)].
Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogue
Inform patients that the incidence of hypoglycemia may increase when SEGLUROMET is used with
insulin or an insulin secretagogue. Educate patients or caregivers on the signs and symptoms of
hypoglycemia [see Warnings and Precautions (5.6)].
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with
SGLT2 inhibitors. Counsel patients to promptly seek medical attention if they develop pain or tenderness,
redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever
above 100.4°F or malaise [see Warnings and Precautions (5.7)].
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with information on
the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek
medical advice [see Warnings and Precautions (5.8)].
Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)
Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur,
especially in uncircumcised males. Provide them with information on the signs and symptoms of balanitis
and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options
and when to seek medical advice [see Warnings and Precautions (5.8)].
Fetal Toxicity
Advise pregnant patients of the potential risk to a fetus with treatment with SEGLUROMET. Instruct
patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see
Use in Specific Populations (8.1)].
Lactation
Advise patients that use of SEGLUROMET is not recommended while breastfeeding [see Use in
Specific Populations (8.2)].
Pregnancy
Inform female patients that treatment with metformin may result in an unintended pregnancy in some
premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].
Laboratory Tests
31
Reference ID: 5502336
Due to the mechanism of action of ertugliflozin, inform patients that their urine will test positive for
glucose while taking SEGLUROMET.
Missed Dose
Instruct patients to take SEGLUROMET only as prescribed. If a dose is missed, it should be taken as
soon as the patient remembers. Advise patients not to double their next dose.
Manufactured for: Merck Sharp & Dohme LLC
Rahway, NJ 07065, USA
For patent information: www.msd.com/research/patent
Copyright © 2017-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates.
All rights reserved.
uspi-mk8835b-t-2412r010
32
Reference ID: 5502336
Medication Guide
SEGLUROMET® [seg-LUR-oh-met]
(ertugliflozin and metformin hydrochloride)
tablets, for oral use
Read this Medication Guide carefully before you start taking SEGLUROMET and each time you get
a refill. There may be new information. This information does not take the place of talking with your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about SEGLUROMET?
SEGLUROMET may cause serious side effects, including:
Lactic Acidosis. Metformin, one of the medicines in SEGLUROMET, can cause a rare but serious
condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis
is a medical emergency and must be treated in the hospital.
Call your healthcare provider right away if you have any of the following symptoms, which
could be signs of lactic acidosis:
• you feel cold in your hands or feet
•
you have a slow or irregular heartbeat
• you feel very weak or tired
•
you have unusual (not normal) muscle pain
• you have trouble breathing
•
you have unusual sleepiness or sleep longer
than usual
• you have stomach pains, nausea or
•
you feel dizzy or lightheaded
vomiting
Most people who have had lactic acidosis had other conditions that, in combination with metformin
use, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because
you have a higher chance for getting lactic acidosis with SEGLUROMET if you:
• have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable
dye.
• have liver problems.
• drink alcohol very often or drink a lot of alcohol in the short term (“binge”) drinking.
• get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever,
vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise
and do not drink enough fluids.
• have surgery.
• have a heart attack, severe infection, or stroke.
The best way to keep from having a problem with lactic acidosis from metformin is to tell your
healthcare provider if you have any of the problems in the list above. Your healthcare provider may
decide to stop your SEGLUROMET for a while if you have any of these things.
•
Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1
diabetes and other ketoacidosis. SEGLUROMET can cause ketoacidosis that can be life-
threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated
in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with
type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis.
Ketoacidosis can also happen in people who are sick, cannot eat or drink as usual, skip meals,
are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount
of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the
body (volume depletion), or who have surgery. Ketoacidosis can happen even if your blood sugar
is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in
your urine or blood.
Stop taking SEGLUROMET and call your healthcare provider or get medical help right away
if you get any of the following. If possible, check for ketones in your urine or blood, even
if your blood sugar is less than 250 mg/dL:
Reference ID: 5502336
o nausea
o tiredness
o vomiting
o
trouble breathing
o stomach-area (abdominal) pain o
ketones in your urine or blood
SEGLUROMET can have other serious side effects. See “What are the possible side effects of
SEGLUROMET?”
What is SEGLUROMET?
• SEGLUROMET contains 2 prescription medicines called ertugliflozin (STEGLATRO®) and
metformin hydrochloride. SEGLUROMET is used in adults with type 2 diabetes to improve blood
sugar (glucose) along with diet and exercise.
• SEGLUROMET is not recommended to decrease blood sugar (glucose) in people with type 1
diabetes. It is not known if SEGLUROMET is safe and effective in children under 18 years of age.
Who should not take SEGLUROMET?
Do not take SEGLUROMET if you:
•
have severe kidney problems, have end stage renal disease (ESRD) or are on dialysis.
•
have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the
blood or urine).
•
are allergic to ertugliflozin, metformin, or any of the ingredients in SEGLUROMET. See the end
of this Medication Guide for a list of ingredients in SEGLUROMET. Symptoms of a serious
allergic reaction to SEGLUROMET may include:
o skin rash
o
raised red patches on your skin (hives)
o
swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or
swallowing
If you have any of these symptoms, stop taking SEGLUROMET and call your healthcare provider
right away or go to the nearest hospital emergency room.
Before you take SEGLUROMET, tell your healthcare provider about all of your medical
conditions, including if you:
•
have type 1 diabetes or have had diabetic ketoacidosis.
•
have a decrease in your insulin dose.
•
have a serious infection.
•
have a history of infection of the vagina or penis.
•
have a history of amputation.
•
have had blocked or narrowed blood vessels, usually in the leg.
•
have damage to the nerves (neuropathy) in your leg.
•
have had diabetic foot ulcers or sores.
•
have kidney problems.
•
have liver problems.
•
have a history of urinary tract infections or problems with urination.
•
are on a low sodium (salt) diet. Your healthcare provider may change your diet or your dose.
•
have heart problems, including congestive heart failure.
•
are going to have surgery. Your healthcare provider may stop your SEGLUROMET before you
have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking
SEGLUROMET and when to start it again.
•
are eating less or there is a change in your diet.
•
are dehydrated.
2
Reference ID: 5502336
•
have or have had problems with your pancreas, including pancreatitis or surgery on your
pancreas.
• drink alcohol very often or drink a lot of alcohol in the short term (“binge” drinking).
•
have ever had an allergic reaction to SEGLUROMET.
•
are going to get an injection of dye or contrast agents for an x-ray procedure. SEGLUROMET
may need to be stopped for a short time. Talk to your healthcare provider about when you should
stop SEGLUROMET and when you should start SEGLUROMET again. See “What is the most
important information I should know about SEGLUROMET?”
•
are pregnant or plan to become pregnant. SEGLUROMET may harm your unborn baby. If you
become pregnant while taking SEGLUROMET, your healthcare provider may switch you to a
different medicine to control your blood sugar. Talk to your healthcare provider about the best
way to control your blood sugar if you plan to become pregnant or while you are pregnant.
• are a premenopausal woman (before the “change of life”), who does not have periods regularly
or at all. Talk to your healthcare provider about birth control choices while taking SEGLUROMET
if you are not planning to become pregnant since SEGLUROMET may increase your chance of
becoming pregnant. Tell your healthcare provider right away if you become pregnant while taking
SEGLUROMET.
•
are breastfeeding or plan to breastfeed. It is not known if SEGLUROMET passes into your breast
milk. You should not breastfeed if you take SEGLUROMET.
Tell your healthcare provider about all of the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
SEGLUROMET may affect the way other medicines work, and other medicines may affect how
SEGLUROMET works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist
when you get a new medicine.
How should I take SEGLUROMET?
•
Take SEGLUROMET by mouth 2 times a day with meals, exactly as your healthcare provider tells
you to take it. Taking SEGLUROMET with meals may lower your chance of having an upset
stomach.
•
Your healthcare provider may tell you to take SEGLUROMET along with other diabetes
medicines. Low blood sugar can happen more often when SEGLUROMET is taken with certain
other diabetes medicines. See “What are the possible side effects of SEGLUROMET?”
•
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip
the missed dose and take the medicine at the next regularly scheduled time. Do not take 2 doses
of SEGLUROMET at the same time. Talk with your healthcare provider if you have questions
about a missed dose.
•
If you take too much SEGLUROMET, call your healthcare provider or go to the nearest hospital
emergency room right away.
•
When your body is under some types of stress, such as fever, trauma (such as a car accident),
infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare
provider right away if you have any of these conditions and follow your healthcare provider’s
instructions.
•
SEGLUROMET will cause your urine to test positive for glucose.
•
Your healthcare provider may do certain blood tests before you start SEGLUROMET and during
treatment as needed. Your healthcare provider may change your dose of SEGLUROMET based
on the results of your blood tests.
What should I avoid while taking SEGLUROMET?
• Avoid drinking alcohol very often or drinking a lot of alcohol in a short period of time (“binge”
drinking). It can increase your chances of getting serious side effects.
3
Reference ID: 5502336
What are the possible side effects of SEGLUROMET?
SEGLUROMET may cause serious side effects, including:
See “What is the most important information I should know about SEGLUROMET?”
•
Amputations. SEGLUROMET may increase your risk of lower limb amputations.
You may be at a higher risk of lower limb amputation if you:
o
have a history of amputation
o
have had blocked or narrowed blood vessels, usually in your leg
o
have damage to the nerves (neuropathy) in your leg
o
have had diabetic foot ulcers or sores
Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers,
or infections in your leg or foot. Your healthcare provider may decide to stop your SEGLUROMET
for a while if you have any of these signs or symptoms. Talk to your healthcare provider about proper
foot care.
•
Dehydration. SEGLUROMET can cause some people to become dehydrated (the loss of
body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak,
especially when you stand up (orthostatic hypotension). There have been reports of
sudden worsening of kidney function in people who are taking SEGLUROMET.
You may be at risk of dehydration if you:
o
take medicines to lower your blood pressure, including water pills (diuretics)
o
are on a low sodium (salt) diet
o have kidney problems
o
are 65 years of age or older
Talk to your healthcare provider about what you can do to prevent dehydration including how much
fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the
amount of food or liquid you drink, for example if you are sick or cannot eat, or you start to lose liquids
from your body, for example from vomiting, diarrhea or being in the sun too long.
•
Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization
have happened in people who are taking SEGLUROMET. Tell your healthcare provider if you
have any signs or symptoms of a urinary tract infection such as a burning feeling when passing
urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach
(pelvis), or blood in the urine. Sometimes people may also have a fever, back pain, nausea, or
vomiting.
• Low blood sugar (hypoglycemia). If you take SEGLUROMET with another medicine that can
cause low blood sugar such as a sulfonylurea or insulin, your risk of getting low blood sugar is
higher. The dose of your sulfonylurea or insulin may need to be lowered while you take
SEGLUROMET. Signs and symptoms of low blood sugar may include:
o headache
o drowsiness
o
weakness
o confusion
o dizziness
o
sweating
o hunger
o
fast heartbeat
o
irritability
o
shaking or feeling jittery
•
A rare but serious bacterial infection that causes damage to the tissue under the skin
(necrotizing fasciitis) in the area between and around the anus and genitals (perineum).
Necrotizing fasciitis of the perineum has happened in women and men who take medicines that
lower blood sugar in the same way as one of the medicines in SEGLUROMET. Necrotizing
fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead
to death. Seek medical attention immediately if you have fever above 100.4ºF or you are
feeling very weak, tired or uncomfortable (malaise) and you develop any of the following
symptoms in the area between and around your anus and genitals:
o pain or tenderness
o
swelling
o
redness of skin (erythema)
• Vaginal yeast infection. Symptoms of a vaginal yeast infection include:
4
Reference ID: 5502336
o vaginal odor
o
white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)
o
vaginal itching
• Yeast infection of the penis (balanitis or balanoposthitis). Swelling of an uncircumcised penis
may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms
of yeast infection of the penis include:
o
redness, itching, or swelling of the penis
o
rash of the penis
o
foul smelling discharge from the penis
o
pain in the skin around your penis
Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the
vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal
medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal
medicine and your symptoms do not go away.
• Low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a
decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12
blood levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels.
•
Serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking
SEGLUROMET and call your healthcare provider right away or go to the nearest hospital
emergency room. See “Who should not take SEGLUROMET?”. Your healthcare provider may
give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes
The most common side effects of ertugliflozin include:
• vaginal yeast infections and yeast infections of the penis (See “What is the most important
information I should know about SEGLUROMET?”)
• changes in urination, including urgent need to urinate more often, in larger amounts, or at night
The most common side effects of metformin hydrochloride include:
o diarrhea
o vomiting
o indigestion
o nausea
o gas
o weakness
o stomach discomfort
o headache
These are not all the possible side effects of SEGLUROMET.
Call your healthcare provider for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store SEGLUROMET?
•
Store SEGLUROMET at room temperature between 68°F to 77°F (20°C to 25°C).
•
Keep SEGLUROMET dry.
Keep SEGLUROMET and all medicines out of the reach of children.
General information about the safe and effective use of SEGLUROMET.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do
not use SEGLUROMET for a condition for which it was not prescribed. Do not give SEGLUROMET
to other people, even if they have the same symptoms that you have. It may harm them. You can ask
your pharmacist or healthcare provider for information about SEGLUROMET that is written for health
professionals.
For more information about SEGLUROMET, go to www.segluromet.com or call 1-800-622-4477.
What are the ingredients in SEGLUROMET?
Active ingredients: ertugliflozin and metformin hydrochloride.
Inactive ingredients: povidone, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and
magnesium stearate.
The tablet film coating contains the following inactive ingredients: hydroxypropyl methylcellulose,
hydroxypropyl cellulose, titanium dioxide, iron oxide red, and carnauba wax.
Manufactured for: Merck Sharp & Dohme LLC
5
Reference ID: 5502336
Rahway, NJ 07065, USA
For patent information, go to: www.msd.com/research/patent
Copyright © 2017-2023 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.
usmg-mk8835b-t-2309r007
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 09/2023
6
Reference ID: 5502336
| custom-source | 2025-02-12T15:48:20.348749 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/209806s011lbledt.pdf', 'application_number': 209806, 'submission_type': 'SUPPL ', 'submission_number': 11} |
80,788 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
•
Urinary outflow obstruction (4)
These highlights do not include all the information needed to use
CYCLOPHOSPHAMIDE INJECTION safely and effectively. See full
prescribing information for CYCLOPHOSPHAMIDE INJECTION.
CYCLOPHOSPHAMIDE injection, for intravenous use
Initial U.S. Approval: 1959
-------------------------- RECENT MAJOR CHANGES -------------------------
Dosage and Administration (2.2)
12/2024
--------------------------- INDICATIONS AND USAGE --------------------------
Cyclophosphamide Injection is an alkylating drug indicated for treatment of
adult patients with:
Malignant Diseases: malignant lymphomas: Hodgkin’s lymphoma,
lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma,
Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides,
neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma.
(1)
Limitations of Use
This cyclophosphamide product is not indicated for use in pediatric patients
due to the alcohol and propylene glycol content in this product. If treatment
with cyclophosphamide is indicated in a pediatric patient, use a different
cyclophosphamide product. (1)
---------------------- DOSAGE AND ADMINISTRATION ---------------------
During or immediately after Cyclophosphamide Injection administration,
administer adequate amounts of fluid to reduce the risk of urinary tract
toxicity (2.1).
Malignant Diseases: Adult Patients (2.2)
•
Intravenous: Initial course for patients with no hematologic deficiency:
40 mg/kg to 50 mg/kg in divided doses over 2 to 5 days. Other regimens
include 10 mg/kg to 15 mg/kg given every 7 to 10 days or 3 mg/kg to 5
mg/kg twice weekly. (2.2)
•
See full prescribing information for instructions on preparation,
handling, and administration. (2.3)
--------------------- DOSAGE FORMS AND STRENGTHS -------------------
Injection: 500 mg/5 mL (100 mg/mL), 1,000 mg/10 mL (100 mg/mL), 2,000
mg/20 mL (100 mg/mL) in multiple-dose vials (3)
------------------------------ CONTRAINDICATIONS ----------------------------
•
Severe hypersensitivity to cyclophosphamide (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------------
•
Myelosuppression, Immunosuppression, Bone Marrow Failure,
and Infections: Severe immunosuppression may lead to serious and
sometimes fatal infections. Close hematological monitoring is
required. (5.1)
•
Urinary Tract and Renal Toxicity: Hemorrhagic cystitis, pyelitis,
ureteritis, and hematuria can occur. Urotoxicity can be fatal.
Exclude or correct any urinary tract obstructions prior to treatment.
(5.2)
•
Cardiotoxicity: Myocarditis, myopericarditis, pericardial effusion,
arrythmias and congestive heart failure, which may be fatal, have
been reported. Monitor patients, especially those with risk factors
for cardiotoxicity or pre-existing cardiac disease. (5.3)
•
Pulmonary Toxicity: Pneumonitis, pulmonary fibrosis and
pulmonary veno-occlusive disease leading to respiratory failure
may occur. Monitor patients for signs and symptoms of
pulmonary toxicity. (5.4)
•
Secondary Malignancies: Have been reported in patients treated
with cyclophosphamide containing regimens. (5.5)
•
Veno-occlusive Liver Disease: Fatal outcome can occur. (5.6)
•
Alcohol Content: This product is not indicated for use in pediatric
patients. The alcohol content in a dose of Cyclophosphamide
Injection may affect the central nervous system. This may include
impairment of a patient's ability to drive or use machines
immediately after infusion. (5.7)
•
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of potential risk to a fetus and to use
effective contraception. Advise males with female partners of
reproductive potential to use effective contraception (5.8, 8.1, 8.3)
------------------------------ ADVERSE REACTIONS ----------------------------
The most common adverse reactions are neutropenia, febrile neutropenia,
fever, alopecia, nausea, vomiting, and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at
1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
•
Lactation: Advise not to breastfeed. (8.2)
•
Renal Impairment: Monitor for toxicity in patients with moderate
and severe renal impairment. (8.6, 12.3)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Information
2.2 Recommended Dosage for Malignant Diseases
2.3 Preparation, Handling and Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and
Infections
5.2 Urinary Tract and Renal Toxicity
5.3 Cardiotoxicity
5.4 Pulmonary Toxicity
5.5 Secondary Malignancies
5.6 Veno-occlusive Liver Disease
5.7 Alcohol Content
5.8 Embryo-Fetal Toxicity
5.9 Infertility
5.10 Impairment of Wound Healing
5.11 Hyponatremia
6 ADVERSE REACTIONS
6.1 Clinical Trials and Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on Cyclophosphamide Exposure
7.2 Drugs that Potentiate Cyclophosphamide Toxicities
7.3 Effect of Cyclophosphamide on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
Reference ID: 5504355
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Malignant Diseases
Cyclophosphamide Injection is indicated for the treatment of adult patients with:
•
malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s lymphoma, lymphocytic
lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma
•
multiple myeloma
•
leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic
crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia
(cyclophosphamide given during remission is effective in prolonging its duration)
•
mycosis fungoides (advanced disease)
•
neuroblastoma (disseminated disease)
•
adenocarcinoma of the ovary
•
retinoblastoma
•
carcinoma of the breast
Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or
sequentially with other antineoplastic drugs.
Limitations of Use
This cyclophosphamide product is not indicated for use in pediatric patients due to the to the alcohol and propylene glycol
content in this product. If treatment with cyclophosphamide is indicated in a pediatric patient, use a different
cyclophosphamide product [see Warnings and Precautions (5.7), Use in Specific Populations (8.4), and Description
(11)].
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Information
During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis
in order to reduce the risk of urinary tract toxicity. Therefore, Cyclophosphamide Injection should be administered in the
morning.
2.2 Recommended Dosage for Malignant Diseases
Intravenous Use
When used as the only oncolytic drug therapy, the recommended dosage for the initial course of Cyclophosphamide
Injection for patients with no hematologic deficiency is 40 mg per kg to 50 mg per kg given intravenously in divided
doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10
days or 3 mg per kg to 5 mg per kg twice weekly.
Adjust the dosage of Cyclophosphamide Injection based on the specific regimen administered, response to treatment,
myelosuppression or other adverse reactions, and patient risk factors [see Warnings and Precautions (5)].
Reference ID: 5504355
2.3 Preparation, Handling and Administration
Cyclophosphamide Injection is a hazardous drug. Follow applicable special handling and disposal procedures1. Caution
should be exercised when handling and preparing Cyclophosphamide Injection. To minimize the risk of dermal exposure,
always wear gloves when handling vials containing Cyclophosphamide Injection.
Cyclophosphamide Injection
Intravenous Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit. Do not use Cyclophosphamide Injection vials if there are signs of particulate
matter.
Cyclophosphamide Injection does not contain any antimicrobial preservative and thus care must be taken to assure the
sterility of prepared solutions. Use aseptic technique.
For Direct Intravenous Injection
Aseptically withdraw the prescribed dose from the vial and dilute to a concentration of 20 mg/mL by using any of the
following diluents:
•
5% Dextrose Injection
•
0.45% Sodium Chloride Injection
•
0.9% Sodium Chloride Injection
For Intravenous Infusion
Aseptically withdraw the prescribed dose from the vial and dilute to a concentration of 2 mg/mL by using any of the
following diluents:
•
0.9% Sodium Chloride Injection
•
0.45% Sodium Chloride Injection
•
5% Dextrose Injection
To reduce the likelihood of adverse reactions that appear to be administration rate dependent (e.g., facial swelling,
headache, nasal congestion, scalp burning), Cyclophosphamide Injection should be injected or infused very slowly.
Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused. Each vial is
recommended for no more than a total of eight (8) dose withdrawals.
Storage of Diluted Cyclophosphamide Injection Solution:
If the diluted solution is not used immediately, store at room temperature at 68°F to 77°F (20°C to 25°C) for up to 24
hours or refrigerated at 36°F to 46°F (2°C to 8°C) for up to 6 days.
Storage of Undiluted Cyclophosphamide Injection Solution:
After first use, the partially used vial should be stored in the refrigerator in the original carton at 2°C to 8°C (36ºF to 46°F)
up to 28 days. Discard unused portion after 28 days.
3 DOSAGE FORMS AND STRENGTHS
Cyclophosphamide Injection is a 100 mg/mL sterile, clear, colorless to pale-yellow solution in a multiple-dose vial
available in the following presentations:
Reference ID: 5504355
•
500 mg/5 mL
•
1,000 mg/10 mL
•
2,000 mg/20 mL
4 CONTRAINDICATIONS
Severe Hypersensitivity
Cyclophosphamide Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to
cyclophosphamide, any of its metabolites, or to other components of the product. Anaphylactic reactions including death
have been reported with cyclophosphamide. Cross-sensitivity with other alkylating agents can occur.
Urinary Outflow Obstruction
Cyclophosphamide Injection is contraindicated in patients with urinary outflow obstruction [see Warnings and
Precautions (5.2)].
5 WARNINGS AND PRECAUTIONS
5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections
Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow
failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and
septic shock. Latent infections can be reactivated [see Adverse Reactions (6.2)].
Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In
case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated.
Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if
needed. Cyclophosphamide Injection should not be administered to patients with neutrophils ≤1,500/mm3 and platelets <
50,000/mm3. Cyclophosphamide Injection treatment may not be indicated, or should be interrupted, or the dose reduced,
in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia
complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be
considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in
leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are
expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may
be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.
5.2 Urinary Tract and Renal Toxicity
Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or
surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue
Cyclophosphamide Injection therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis,
fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy.
Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide.
Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment
should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity.
Cyclophosphamide Injection should be used with caution, if at all, in patients with active urinary tract infections.
Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder
toxicity. Mesna has been used to prevent severe bladder toxicity.
Reference ID: 5504355
5.3 Cardiotoxicity
Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may
be fatal, have been reported with cyclophosphamide therapy.
Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT
prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included
cyclophosphamide.
The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in
patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other
cardiotoxic agents.
Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac
disease.
Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.
5.4 Pulmonary Toxicity
Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to
respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis
(greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis
may develop years after treatment with cyclophosphamide.
Monitor patients for signs and symptoms of pulmonary toxicity.
5.5 Secondary Malignancies
Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1)]. Secondary malignancies (urinary tract cancer,
myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with
cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis.
5.6 Veno-occlusive Liver Disease
Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide
containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of
Cyclophosphamide Injection in combination with whole-body irradiation, busulfan, or other agents has been identified as
a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose
immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include
preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status.
5.7 Alcohol Content
Due to the alcohol and propylene glycol content of this product, this cyclophosphamide product is not indicated for use in
pediatric patients [see Indications and Usage (1) and Use in Specific Populations (8.4)]. If treatment with
cyclophosphamide is indicated for a pediatric patient, use a different cyclophosphamide product.
The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system and should be taken
into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the
alcohol content in Cyclophosphamide Injection on the ability to drive or use machines immediately after the infusion.
Each administration of this cyclophosphamide product at 25 mg/kg/day delivers 146.2 mg/kg of ethanol. For a patient
with a BSA of 70 kg, this would deliver 10.23 grams of ethanol. Other cyclophosphamide products may have a different
amount of alcohol or no alcohol.
Reference ID: 5504355
Monitor patients for signs of alcohol intoxication during and after treatment. Counsel patients about the possible effects of
the alcohol content in this cyclophosphamide product, including possible effects on the central nervous system.
5.8 Embryo-Fetal Toxicity
Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide
Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Clinical
Pharmacology (12.1), and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause
birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic
and embryo-fetal toxic in mice, rats, rabbits, and monkeys.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with
Cyclophosphamide Injection and for up to 1 year after completion of therapy. Advise male patients with female partners
of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4
months after completion of therapy [see Use in Specific Populations (8.1, 8.3)].
5.9 Infertility
Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide
Injection. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.
Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal
function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Advise
patients on the potential risks for infertility [see Use in Specific Populations (8.3, 8.4)].
5.10 Impairment of Wound Healing
Cyclophosphamide may interfere with normal wound healing.
5.11 Hyponatremia
Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH
(syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling.
•
Hypersensitivity [see Contraindications (4)]
•
Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions
(5.1)]
•
Urinary Tract and Renal Toxicity [see Warnings and Precautions (5.2)]
•
Cardiotoxicity [see Warnings and Precautions (5.3)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.4)]
•
Secondary Malignancies [see Warnings and Precautions (5.5)]
•
Veno-occlusive Liver Disease [see Warnings and Precautions (5.6)]
•
Alcohol Content [see Warnings and Precautions (5.7)]
•
Infertility [see Warnings and Precautions (5.9)]
•
Impaired Wound Healing [see Warnings and Precautions (5.10)]
•
Hyponatremia [see Warnings and Precautions (5.11)]
Reference ID: 5504355
6.1 Clinical Trials and Postmarketing Experience
The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or
postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most common adverse reactions were neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and
diarrhea.
Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion
(progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal
outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular
arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.
Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity
(including myelosuppression, gastroenteritis).
Ear and Labyrinth: deafness, hearing impaired, tinnitus.
Endocrine: water intoxication.
Eye: visual impairment, conjunctivitis, lacrimation.
Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid
gland inflammation, nausea, vomiting, diarrhea.
General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like
illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia,
edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache, febrile neutropenia.
Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic
syndrome (with thrombotic microangiopathy).
Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with
hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal,
hepatic enzymes increased.
Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction.
Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by
cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral,
protozoal, and parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), pneumocystis
jiroveci, herpes zoster, strongyloides, sepsis and septic shock.
Investigations: blood lactate dehydrogenase increased, C-reactive protein increased.
Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased.
Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia.
Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer,
bladder cancer, ureteric cancer, thyroid cancer.
Reference ID: 5504355
Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible
posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia,
hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia.
Pregnancy: premature labor.
Psychiatric: confusional state.
Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis,
bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary
bladder epithelial cells.
Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy,
azoospermia, oligospermia.
Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as
manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis
allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural
effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.
Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar
plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus,
erythema, nail disorder, facial swelling, hyperhidrosis, alopecia.
Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and
hyperuricemia in patients with rapidly growing tumors.
Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing,
hot flush.
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on Cyclophosphamide Exposure
Protease Inhibitors
Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites and may enhance the
toxicities of cyclophosphamide, including higher incidence of infections, neutropenia, and mucositis. Monitor for
increased toxicities in patients receiving protease inhibitors.
7.2 Drugs that Potentiate Cyclophosphamide Toxicities
Radiation therapy or drugs with similar toxicities to Cyclophosphamide Injection can potentiate toxicities for
cyclophosphamide. Monitor for increased toxicities in patients receiving radiation therapy or drugs known to cause:
•
Myelosuppression and/or immunosuppression [see Warnings and Precautions (5.1)]
•
Nephrotoxicity including hemorrhagic cystitis [see Warnings and Precautions (5.2)]
•
Cardiotoxicity [see Warnings and Precautions (5.3)]
•
Pulmonary toxicity [see Warnings and Precautions (5.4)]
•
Secondary malignancies [see Warnings and Precautions (5.5)]
•
Hepatotoxicity including liver necrosis and VOD [see Warnings and Precautions (5.6)]
7.3 Effect of Cyclophosphamide on Other Drugs
Reference ID: 5504355
Metronidazole
Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Monitor for
neurologic toxicities in patients receiving metronidazole.
Tamoxifen
Concomitant use of tamoxifen and a cyclophosphamide-containing chemotherapy regimen may increase the risk of
thromboembolic complications. Monitor for signs and symptoms of thromboembolic events in patients receiving
tamoxifen.
Coumarins
Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide.
Monitor anticoagulant activity closely in patients receiving warfarin or other coumarins.
Cyclosporine
Concomitant administration of cyclophosphamide may decrease serum concentrations of cyclosporine. This interaction
may result in an increased incidence of graft-versus-host disease. Monitor for signs and symptoms of graft-versus-host
disease in patients receiving cyclosporine.
Depolarizing muscle relaxants
If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.
Cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with
concurrent depolarizing muscle relaxants (e.g., succinylcholine).
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide
Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and
Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause fetal malformations,
miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. Cyclophosphamide is teratogenic and
embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data]. Advise pregnant women and females of reproductive
potential of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S.
general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of
clinically recognized pregnancies.
Data
Human Data
Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to
cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including
leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure
to cyclophosphamide.
Animal Data
Reference ID: 5504355
Administration of cyclophosphamide to pregnant mice, rats, rabbits, and monkeys during the period of organogenesis at
doses at or below the dose in patients based on body surface area resulted in various malformations, which included
neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal
ossification.
8.2 Lactation
Risk Summary
Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been
reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse
reactions in a breastfed child, advise lactating women not to breastfeed during the treatment and for 1 week after the last
dose.
8.3 Females and Males of Reproductive Potential
Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Injection.
Contraception
Females
Advise female patients of reproductive potential to use effective contraception during treatment with Cyclophosphamide
Injection and for up to 1 year after therapy.
Males
Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of
reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection for 4 months after
therapy [see Nonclinical Toxicology (13.1)].
Infertility
Females
Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in
a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few
months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age.
Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of
cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their
maturation phases. The exact duration of follicular development in humans is not known but may be longer than 12
months [see Nonclinical Toxicology (13.1)].
Males
Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with
increased gonadotropin but normal testosterone secretion.
Reference ID: 5504355
8.4 Pediatric Use
This cyclophosphamide product is not indicated for use in pediatric patients due to the alcohol and propylene glycol
content in this product. If treatment with cyclophosphamide is indicated in a pediatric patient, use a different
cyclophosphamide product. Since propylene glycol and alcohol are both metabolized by the same enzymes, co-
administration of these excipients may raise systemic exposure to alcohol, particularly in pediatric patients. [see
Indications and Usage (1), Warnings and Precautions (5.7), and Description (11)]. Other cyclophosphamide products
may have a different amount of alcohol or no alcohol.
Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have
regular menses. Ovarian fibrosis with apparent complete loss of germ cells after prolonged cyclophosphamide treatment
in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after
completing treatment are at increased risk of developing premature menopause.
Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally but may have
oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur.
Cyclophosphamide induced azoospermia is reversible in some patients, though the reversibility may not occur for several
years after cessation of therapy.
8.5 Geriatric Use
There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to
determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac functioning, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of
cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor
patients with severe renal impairment (CLcr =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.
Cyclophosphamide and its metabolites are dialyzable [see Clinical Pharmacology (12.3)] although there are probably
quantitative differences depending upon the dialysis system being used. Use of a consistent interval between
cyclophosphamide administration and dialysis should be considered in patients requiring dialysis.
8.7 Hepatic Impairment
Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl
metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)].
The alcohol content of Cyclophosphamide Injection should be taken into account when given to patients with hepatic
impairment [see Warnings and Precautions (5.7)].
10 OVERDOSAGE
No specific antidote for cyclophosphamide is known.
Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection,
myelosuppression, or cardiac toxicity should it occur.
Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression,
urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and
Precautions (5.1, 5.2, 5.3 and 5.6)].
Reference ID: 5504355
Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic
toxicity in particular.
Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any
suicidal or accidental overdose or intoxication.
Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide
overdose.
11 DESCRIPTION
Cyclophosphamide is an alkylating drug. It is a synthetic antineoplastic drug chemically related to the nitrogen mustards.
The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
monohydrate, and has the following structural formula:
Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2P•H2O and a molecular weight
of 279.1. Cyclophosphamide is soluble in water and freely soluble in alcohol.
Cyclophosphamide Injection, 100 mg/mL is a sterile ready-to-dilute, clear, colorless to pale-yellow solution in a multiple-
dose vial available as 500 mg/5 mL, 1,000 mg/10 mL, and 2,000 mg/20 mL strengths.
•
500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide, 2.92
g dehydrated alcohol (equivalent to 73.9 % v/v) and 0.96 g propylene glycol.
•
1,000 mg vial contains 1,069 mg cyclophosphamide monohydrate equivalent to 1,000 mg cyclophosphamide,
5.85 g dehydrated alcohol (equivalent to 73.9 % v/v) and 1.92 g propylene glycol.
•
2,000 mg vial contains 2,138 mg cyclophosphamide monohydrate equivalent to 2,000 mg cyclophosphamide,
11.69 g dehydrated alcohol (equivalent to 73.9 % v/v) and 3.84 g propylene glycol.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action has not been fully characterized. However, cross-linking of tumor cell DNA may be involved.
The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating
malignant cells.
12.2 Pharmacodynamics
Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been
fully characterized.
12.3 Pharmacokinetics
Cyclophosphamide is a prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose
range.
Reference ID: 5504355
Distribution
The volume of distribution of cyclophosphamide is 30 to 50 L. Cyclophosphamide is approximately 20% protein bound,
with no dose dependent changes. Some metabolites are greater than 60% protein bound.
Elimination
The elimination half-life (t½) of cyclophosphamide ranges from 3 to 12 hours, and clearance (CL) ranges from 4 to 5.6
L/h.
When cyclophosphamide was administered at 4 g/m2 (approximately 2 times the approved recommended dosage) over a
90-minutes infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal
elimination.
Metabolism
Cyclophosphamide is metabolized by cytochrome P450s including CYP2A6, 2B6, 3A, 2C9, and 2C19.
Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer
aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde
dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively.
Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This
spontaneous conversion can be catalyzed by albumin and other proteins. At high doses, the fraction of parent compound
cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide.
Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in CL, increased
formation of active 4-hydroxycyclophosphamide and shortened t½ following multiple doses administered at 12-to-24
hour interval.
Excretion
Cyclophosphamide and its metabolites are eliminated by hepatic and renal pathways. Cyclophosphamide is primarily
excreted as metabolites. Ten to 20% is excreted unchanged in the urine. A small percentage of cyclophosphamide may be
eliminated unchanged in bile.
Specific Populations
Renal Impairment
Following one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of
25 to 50 mL/min, by 77% in patients with CLcr of 10 to 24 mL/min and by 23% in the hemodialysis group
(CLcr of < 10 mL/min) compared to the control group (CLcr≥ 80 mL/min).
Cyclophosphamide is dialyzable. Dialysis clearance averaged 104 mL/min, which is similar to the metabolic
clearance of 95 mL/min for cyclophosphamide. A mean of 37% of the administered dose of cyclophosphamide
was removed during a 4-hour hemodialysis period. The t½ was 3.3 hours in patients during hemodialysis, a
49% reduction compared to t½ of 6.5 hours in uremic patients.
Hepatic Impairment
Cyclophosphamide CL is decreased by 40% (45 ± 8.6 L/kg) and t½ is prolonged by 64% (12.5 ± 1 hours) in patients with
hepatic impairment with a mean bilirubin 3.5 mg/dL and mean AST 90 IU/L compared to patients with normal hepatic
function (mean bilirubin 0.5 mg/dL, mean AST 10 IU/L).
Reference ID: 5504355
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or
in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant
tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see
Warnings and Precautions (5.5)].
Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.
Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to
cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies,
and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male
reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive
potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when
mated with untreated females [see Use in Specific Populations (8.3)].
15 REFERENCES
1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
16 HOW SUPPLIED/STORAGE AND HANDLING
Cyclophosphamide Injection, 100 mg/mL is a sterile ready-to-dilute, clear, colorless to pale-yellow solution in a multiple-
dose vial available in the following strengths:
Strength
NDC Number
Volume
500 mg/5 mL
0781-3528-10
Carton of one 5 mL Multiple-Dose Vial
1,000 mg/10 mL 0781-3529-10
Carton of one 10 mL Multiple-Dose Vial
2,000 mg/20 mL 0781-3530-10
Carton of one 20 mL Multiple-Dose Vial
Store vials refrigerated at 2°C to 8°C (36°F to 46°F).
Cyclophosphamide is a hazardous product. Follow special handling and disposal procedures.1
17 PATIENT COUNSELING INFORMATION
Advise the patient of the following:
Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections
•
Inform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for
routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any
occurrence of fever [see Warnings and Precautions (5.1)].
Urinary Tract and Renal Toxicity
•
Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color)
and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].
Cardiotoxicity
•
Inform patients of the possibility of cardiotoxicity (which may be fatal).
Reference ID: 5504355
•
Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening
shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours,
dizziness or loss of consciousness [see Warnings and Precautions (5.3)].
Pulmonary Toxicity
•
Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any
new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].
Alcohol Content
•
Explain to patients the possible effects of the alcohol content in Cyclophosphamide Injection, including possible
effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the
alcohol content of Cyclophosphamide Injection. Alcohol could impair their ability to drive or use machines
immediately after infusion [see Warnings and Precautions (5.7)].
Secondary Malignancies
•
Inform patients that there is an increased risk of secondary malignancies with Cyclophosphamide Injection [see
Warnings and Precautions (5.5)].
Embryo-Fetal Toxicity
•
Inform female patients of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their
healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific
Populations (8.1)].
•
Advise females of reproductive potential to use effective contraception during treatment and for up to 1 year after
completion of therapy [see Warning and Precautions (5.8) and Use in Specific Population (8.1,8.3)].
•
Advise male patients with female partners of reproductive potential to use effective contraception during treatment
and for 4 months after completion of therapy [see Warnings and Precautions (5.8) and Use in Specific Populations
(8.1,8.3)].
Lactation
•
Advise women not to breastfeed during treatment and for 1 week after the last dose of Cyclophosphamide Injection
[see Use in Specific Populations (8.2)].
Infertility
•
Advise patients that Cyclophosphamide Injection may impair fertility in males and females of reproductive potential
[see Warnings and Precautions (5.9) and Use in Specific Populations (8.3, 8.4)].
Common Adverse Reactions
•
Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea,
premature menopause, sterility, and hair loss may be associated with cyclophosphamide administration. Other
undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or
use machines [see Adverse Reactions (6.1)].
Hydration and Important Administration Instructions
•
Advise the patients that during or immediately after the administration, adequate amounts of fluid are required to
reduce the risk of urinary tract toxicity [see Dosage and Administration (2.1)].
Manufactured by FAREVA Unterach GmbH for
Sandoz Inc., Princeton, NJ 08540
Reference ID: 5504355
| custom-source | 2025-02-12T15:48:21.149172 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217150s001lbl.pdf', 'application_number': 217150, 'submission_type': 'SUPPL ', 'submission_number': 1} |
80,790 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
REZUROCK safely and effectively. See full prescribing information for
REZUROCK.
REZUROCK® (belumosudil) tablets, for oral use
Initial U.S. Approval: 2021
----------------------------INDICATIONS AND USAGE--------------------------
REZUROCK is a kinase inhibitor indicated for the treatment of adult and
pediatric patients 12 years and older with chronic graft-versus-host disease
(chronic GVHD) after failure of at least two prior lines of systemic therapy.
(1)
----------------------DOSAGE AND ADMINISTRATION----------------------
Recommended Dosage: 200 mg taken orally once daily with food. (2.1)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Tablet: 200 mg. (3)
---------------------------CONTRAINDICATIONS---------------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential of the potential risk to a fetus and to use effective
contraception. (5.1, 8.1, 8.3)
------------------------------ADVERSE REACTIONS------------------------------
The most common (≥20%) adverse reactions, including laboratory
abnormalities, are infections, asthenia, nausea, diarrhea, dyspnea, cough,
edema, hemorrhage, abdominal pain, musculoskeletal pain, headache,
phosphate decreased, gamma glutamyl transferase increased, lymphocytes
decreased, and hypertension. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Kadmon
Pharmaceuticals, LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
Strong CYP3A Inducers: Increase REZUROCK dosage to 200 mg twice
daily. (7.1, 2.3)
Proton Pump Inhibitors: Increase REZUROCK dosage to 200 mg twice
daily. (7.1, 2.3)
Certain P-gp, OATP1B1, BCRP, and UGT1A1 substrates: Avoid
concomitant use with these substrates for which minimal concentration
changes may lead to serious toxicities. If coadministration cannot be
avoided, decrease the substrates dosage(s) in accordance with the
respective Prescribing Information. (7.2)
----------------------USE IN SPECIFIC POPULATIONS----------------------
Lactation: Advise not to breastfeed. (8.2)
Moderate or Severe Hepatic Impairment: Avoid use of REZUROCK in
patients with moderate or severe hepatic impairment. (2.4, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2
Dosage Modifications for Adverse Reactions
2.3
Dosage Modification Due to Drug Interactions
2.4
Recommended Dosage in Patients with Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
7
DRUG INTERACTIONS
7.1
Effect of Other Drugs on REZUROCK
7.2
Effect of REZUROCK on Other Drugs
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6
Renal Impairment
8.7 Hepatic Impairment
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1 Chronic Graft versus Host Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
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1
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
REZUROCK is indicated for the treatment of adult and pediatric patients 12 years and older with
chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of
systemic therapy.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
The recommended dose of REZUROCK is 200 mg given orally once daily until progression of
chronic GVHD that requires new systemic therapy.
Instruct the patient on the following:
Swallow REZUROCK tablets whole. Do not cut, crush, or chew tablets.
Take REZUROCK with a meal at approximately the same time each day [see Clinical
Pharmacology (12.3)].
If a dose of REZUROCK is missed, instruct the patient to not take extra doses to make up
the missed dose.
Treatment with REZUROCK has not been studied in patients with pre-existing severe renal
impairment. For patients with pre-existing severe renal impairment, consider the risks and
potential benefits before initiating treatment with REZUROCK [see Clinical Pharmacology
(12.3)].
2.2
Dosage Modifications for Adverse Reactions
Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at
least monthly.
Modify the REZUROCK dosage for adverse reactions as per Table 1.
Table 1: Recommended Dosage Modifications for REZUROCK for Adverse Reactions
Adverse Reaction
Severity*
REZUROCK Dosage Modifications
Hepatotoxicity [see
Adverse Reactions
(6.1)]
Grade 3 AST or ALT (5x to
20x ULN) or
Grade 2 bilirubin (1.5x to 3x
ULN)
Hold REZUROCK until recovery of
bilirubin, AST and ALT to Grade 0-1,
then resume REZUROCK at the
recommended dose.
Grade 4 AST or ALT (more
than 20x ULN) or
Grade ≥3 bilirubin (more
than 3x ULN)
Discontinue REZUROCK
permanently.
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Adverse Reaction
Severity*
REZUROCK Dosage Modifications
Other adverse
reactions [see
Adverse Reactions
(6.1)]
Grade 3
Hold REZUROCK until recovery to
Grade 0-1, then resume REZUROCK
at the recommended dose level.
Grade 4
Discontinue REZUROCK
permanently.
*Based on CTCAE v 4.03
2.3
Dosage Modification Due to Drug Interactions
Strong CYP3A Inducers
Increase the dosage of REZUROCK to 200 mg twice daily when coadministered with strong
CYP3A inducers [see Drug Interactions (7.1)].
Proton Pump Inhibitors
Increase the dosage of REZUROCK to 200 mg twice daily when coadministered with proton
pump inhibitors [see Drug Interactions (7.1)].
2.4
Recommended Dosage in Patients with Hepatic Impairment
Avoid use in patients with moderate hepatic impairment (Child-Pugh B) or severe hepatic
impairment (Child-Pugh C) without liver GVHD [see Use in Specific Populations (8.7), Clinical
Pharmacology (12.3)].
No dosage adjustment is recommended when administering REZUROCK to patients with mild
hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Each 200 mg belumosudil tablet is a pale yellow film-coated oblong tablet debossed with
"KDM" on one side and "200" on the other side.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Embryo-Fetal Toxicity
Based on findings in animals and its mechanism of action, REZUROCK can cause fetal harm
when administered to a pregnant woman. In animal reproduction studies, administration of
belumosudil to pregnant rats and rabbits during the period of organogenesis caused adverse
developmental outcomes including embryo-fetal mortality and malformations at maternal
exposures (AUC) less than those in patients at the recommended dose. Advise pregnant women
of the potential risk to a fetus. Advise females of reproductive potential and males with female
partners of reproductive potential to use effective contraception during treatment with
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3
REZUROCK and for one week after the last dose [see Use in Specific Populations (8.1, 8.3),
Nonclinical Toxicology (13.1)].
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
Because clinical trials are conducted under widely variable conditions, adverse reaction rates
observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
another drug and may not reflect the rates observed in practice.
Chronic Graft versus Host Disease
In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic
GVHD were treated with REZUROCK 200 mg once daily [see Clinical Studies (14.1)]. The
median duration of treatment was 9.2 months (range 0.5 to 44.7 months).
Fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea and
multi-organ failure.
Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients.
The adverse reactions which resulted in permanent discontinuation of REZUROCK in >3% of
patients included nausea (4%). Adverse reactions leading to dose interruption occurred in 29% of
patients. The adverse reactions leading to dose interruption in ≥2% were infections (11%),
diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, liver function test abnormal,
nausea, pyrexia, edema, and renal failure with (2% each).
The most common (≥20%) adverse reactions, including laboratory abnormalities, were
infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain,
musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased,
lymphocytes decreased, and hypertension.
Table 2 summarizes the nonlaboratory adverse reactions.
Table 2: Nonlaboratory Adverse Reactions in ≥10% Patients with Chronic GVHD Treated
with REZUROCK
Adverse Reaction
REZUROCK
200 mg once daily
(N=83)
All Grades (%)
Grades 3-4 (%)
Infections and infestations
Infection (pathogen not specified)*
53
16
Viral infection†
19
4
Bacterial infection‡
16
4
General disorders and administration site conditions
Asthenia§
46
4
Edema¶
27
1
Pyrexia
18
1
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Adverse Reaction
REZUROCK
200 mg once daily
(N=83)
All Grades (%)
Grades 3-4 (%)
Gastrointestinal
Nausea#
42
4
Diarrhea
35
5
Abdominal painÞ
22
1
Dysphagia
16
0
Respiratory, thoracic and mediastinal
Dyspneaß
33
5
Coughà
30
0
Nasal congestion
12
0
Vascular
Hemorrhageè
23
5
Hypertension
21
7
Musculoskeletal and connective tissue
Musculoskeletal painð
22
4
Muscle spasm
17
0
Arthralgia
15
2
Nervous system
Headacheø
21
0
Metabolism and nutrition
Decreased appetite
17
1
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Adverse Reaction
REZUROCK
200 mg once daily
(N=83)
All Grades (%)
Grades 3-4 (%)
Skin and subcutaneous
Rashý
12
0
Pruritus£
11
0
* infection with an unspecified pathogen includes acute sinusitis, device related infection, ear infection, folliculitis, gastroenteritis,
gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, tooth infection, urinary tract infection, wound
infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, septic
shock.
† includes influenza, rhinovirus infection, gastroenteritis viral, viral upper respiratory tract infection, bronchitis viral, Epstein-Barr
viremia, Epstein-Barr virus infection, parainfluenzae virus infection, Varicella zoster virus infection, viral infection.
‡ includes cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia
urinary tract infection, gastroenteritis Escherichia coli, Pseudomonas infection, urinary tract infection bacterial.
§ includes fatigue, asthenia, malaise.
¶ includes edema peripheral, generalized edema, face edema, localized edema, edema.
# includes nausea, vomiting.
Þ includes abdominal pain, abdominal pain upper, abdominal pain lower.
ß includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome.
à includes cough, productive cough.
è includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage,
catheter site hemorrhage, hematuria, hemothorax, purpura.
ð includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain.
ø includes headache, migraine.
ý includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative.
£ includes pruritus, pruritus generalized.
Table 3 summarizes the laboratory abnormalities in REZUROCK.
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Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with
REZUROCK
REZUROCK
200 mg once daily
Grade 0‐1
Baseline
Grade 2‐4
Max Post
Grade 3‐4
Max Post
Parameter
(N)
(%)
(%)
Chemistry
Phosphate decreased
76
28
7
Gamma Glutamyl Transferase increased
47
21
11
Calcium decreased
82
12
1
Alkaline Phosphatase increased
80
9
0
Potassium increased
82
7
1
Alanine Aminotransferase increased
83
7
2
Creatinine increased
83
4
0
Hematology
Lymphocytes decreased
62
29
13
Hemoglobin decreased
79
11
1
Platelets decreased
82
10
5
Neutrophil Count decreased
83
8
4
7
DRUG INTERACTIONS
7.1
Effect of Other Drugs on REZUROCK
Strong CYP3A Inducers
Coadministration of REZUROCK with strong CYP3A inducers decreases belumosudil exposure
[see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. Increase
the dosage of REZUROCK when coadministered with strong CYP3A inducers [see Dosage and
Administration (2.3)].
Proton Pump Inhibitors
Coadministration of REZUROCK with proton pump inhibitors decreases belumosudil exposure
[see Clinical Pharmacology (12.3)], which may reduce the efficacy of REZUROCK. Increase
the dosage of REZUROCK when coadministered with proton pump inhibitors [see Dosage and
Administration (2.3)].
7.2
Effect of REZUROCK on Other Drugs
Certain UGT1A1 substrates
Avoid coadministration of REZUROCK with UGT1A1 substrates, for which minimal
concentration changes may lead to serious toxicities. If coadministration cannot be avoided,
Reference ID: 5503992
7
decrease the UGT1A1 substrates dosage(s) in accordance with the respective Prescribing
Information.
REZUROCK is an inhibitor of UGT1A1. Coadministration of REZUROCK with a UGT1A1
substrate decreased plasma concentrations of the glucuronide metabolite [see Clinical
Pharmacology (12.3)], which may increase the risk of adverse reactions related to sensitive
substrates of UGT1A1.
Certain P-gp, OATP1B1, and BCRP substrates
Avoid coadministration of REZUROCK with P-gp, OATP1B1, and BCRP substrates, for which
minimal concentration changes may lead to serious toxicities. If coadministration cannot be
avoided, decrease the P-gp, OATP1B1, and BCRP substrates dosage(s) in accordance with the
respective Prescribing Information.
REZUROCK is an inhibitor of P-gp, OATP1B1, and BCRP. Coadministration of REZUROCK
with P-gp, OATP1B1, and BCRP substrates increased their plasma concentrations [see Clinical
Pharmacology (12.3)], which may increase the risk of adverse reactions related to these
substrates.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on findings from animal studies and the mechanism of action [see Clinical Pharmacology
(12.1)], REZUROCK can cause fetal harm when administered to pregnant women. There are no
available human data on REZUROCK use in pregnant women to evaluate for a drug-associated
risk. In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits
during the period of organogenesis resulted in adverse developmental outcomes, including
alterations to growth, embryo-fetal mortality, and embryo-fetal malformations at maternal
exposures (AUC) approximately ≥1.4 (rat) and ≥0.08 (rabbit) times the human exposure (AUC)
at the recommended dose (see Data). Advise pregnant women and females of reproductive
potential of the potential risk to the fetus.
In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal data
Embryo-fetal development studies were conducted in rats with administration of belumosudil to
pregnant animals during the period of organogenesis at oral doses of 25, 50, 150, and 300
mg/kg/day in a pilot study and doses of 15, 50, and 150 mg/kg/day in a pivotal study. In the pilot
study, maternal toxicity and embryo-fetal developmental effects were observed. Maternal
toxicity (reduced body weight gain) occurred at 150 and 300 mg/kg/day doses. Increased post-
implantation loss occurred at 50 and 300 mg/kg/day. Fetal-malformations were observed at ≥50
mg/kg/day and included absence of anus and tail, omphalocele, and dome shaped head. The
exposure (AUC) at 50 mg/kg/day in rats is approximately 1.4 times the human exposure at the
recommended dose of 200 mg.
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In an embryo-fetal developmental study in rabbits, pregnant animals administered oral doses of
belumosudil at 50, 125, and 225 mg/kg/day during the period of organogenesis resulted in
maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (body weight loss
and mortality) was observed at doses ≥125 mg/kg/day. Embryo-fetal effects were observed at
doses ≥50 mg/kg/day and included spontaneous abortion, increased post-implantation loss,
decreased percentage of live fetuses, malformations, and decreased fetal body weight.
Malformations included those in the tail (short), ribs (branched, fused or deformed), sternebrae
(fused), and neural arches (fused, misaligned, and deformed). The exposure (AUC) at 50
mg/kg/day in rabbits is approximately 0.08 times the human exposure at the recommended dose
of 200 mg.
8.2
Lactation
Risk Summary
There are no data available on the presence of belumosudil or its metabolites in human milk or
the effects on the breastfed child, or milk production. Because of the potential for serious adverse
reactions from belumosudil in the breastfed child, advise lactating women not to breastfeed
during treatment with REZUROCK and for one week after the last dose.
8.3
Females and Males of Reproductive Potential
REZUROCK can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with
REZUROCK.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with
REZUROCK and for one week after the last dose of REZUROCK. If this drug is used during
pregnancy or if the patient becomes pregnant while taking this drug, the patient should be
informed of the potential hazard to a fetus.
Males
Advise males with female partners of reproductive potential to use effective contraception during
treatment with REZUROCK and for one week after the last dose of REZUROCK.
Infertility
Females
Based on findings from rats, REZUROCK may impair female fertility [see Nonclinical
Toxicology (13.1)].
Males
Based on findings from rats and dogs, REZUROCK may impair male fertility [see Nonclinical
Toxicology (13.1)].
8.4
Pediatric Use
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The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years
and older. Use of REZUROCK in this age group is supported by evidence from adequate and
well-controlled studies of REZUROCK in adults with additional population pharmacokinetic
data demonstrating that age and body weight had no clinically meaningful effect on the
pharmacokinetics of drug substance, that the exposure of drug substance is expected to be similar
between adults and pediatric patients age 12 years and older, and that the course of disease is
sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to
pediatric patients.
The safety and effectiveness of REZUROCK in pediatric patients less than 12 years old have not
been established.
8.5
Geriatric Use
Of the 186 patients with chronic GVHD in clinical studies of REZUROCK, 26% were 65 years
and older. No clinically meaningful differences in safety or effectiveness of REZUROCK were
observed in comparison to younger patients.
8.6
Renal Impairment
Treatment with REZUROCK has not been studied in patients with pre-existing severe renal
impairment. For patients with pre-existing severe renal impairment, consider the risks and
potential benefits before initiating treatment with REZUROCK [see Dosage and Administration
(2.1) and Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
Avoid use in patients with moderate hepatic impairment (Child-Pugh B) or severe hepatic
impairment (Child-Pugh C) without liver GVHD [see Dosage and Administration (2.4), Clinical
Pharmacology (12.3)].
No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh
A) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
11
DESCRIPTION
Belumosudil is a kinase inhibitor. The active pharmaceutical ingredient is belumosudil mesylate
with the molecular formula C27H28N6O5S and the molecular weight is 548.62 g/mol. The
chemical name for belumosudil mesylate is 2-{3-[4-(1H-indazol-5-ylamino)-2
quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide methanesulfonate (1:1). The chemical
structure is as follows:
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Belumosudil mesylate is a yellow powder that is practically insoluble in water, slightly soluble in
methanol and DMF and soluble in DMSO.
REZUROCK tablets are for oral administration. Each tablet contains 200 mg of the free base
equivalent to 242.5 mg of belumosudil mesylate. The tablet also contains the following inactive
ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate,
and microcrystalline cellulose.
The tablet film consists of polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and
yellow iron oxide.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Belumosudil is an inhibitor of rho-associated, coiled-coil containing protein kinase (ROCK)
which inhibits ROCK2 and ROCK1 with IC50 values of approximately 100 nM and 3 µM,
respectively. Belumosudil down-regulated proinflammatory responses via regulation of
STAT3/STAT5 phosphorylation and shifting Th17/Treg balance in ex-vivo or in vitro-human T
cell assays. Belumosudil also inhibited aberrant pro-fibrotic signaling, in vitro. In vivo,
belumosudil demonstrated activity in animal models of chronic GVHD.
12.2 Pharmacodynamics
Belumosudil exposure-response relationships and the time course of pharmacodynamic response
are not established.
Cardiac Electrophysiology
At 2.4 times the maximum exposure for approved recommended dose, REZUROCK does not
prolong the QT interval to any clinically relevant extent.
12.3 Pharmacokinetics
The following pharmacokinetic parameters are presented for chronic GVHD patients
administered belumosudil 200 mg once daily, unless otherwise specified. The mean (%
coefficient of variation, %CV) steady-state AUC and Cmax of belumosudil was 22,700 (48%)
h•ng/mL and 2390 (44%) ng/mL, respectively. Belumosudil Cmax and AUC increased in an
approximately proportional manner over a dosage range of 200 and 400 mg (1 to 2 times once
daily recommended dosage). The accumulation ratio of belumosudil was 1.4.
Absorption
Median Tmax of belumosudil at steady state was 1.26 to 2.53 hours following administration of
200 mg once daily or twice daily in patients. The mean (%CV) bioavailability was 64% (17%)
following a single belumosudil dose in healthy subjects.
Effect of food
Belumosudil Cmax and AUC increased 2.2 times and 2 times, respectively, following
administration of a single belumosudil dose with a high-fat and high-calorie meal (800 to 1,000
calories with approximately 50% of total caloric content of the meal from fat) compared to the
fasted state in healthy subjects. Median Tmax was delayed 0.5 hours.
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Distribution
The geometric mean volume of distribution after a single dose of belumosudil in healthy subjects
was 184 L (geo CV% 67.7%).
Belumosudil binding to human serum albumin and human 1-acid glycoprotein was 99.9% and
98.6%, respectively, in vitro.
Elimination
The mean (%CV) elimination half-life of belumosudil was 19 hours (39%), and clearance was
9.83 L/hours (46%) in patients.
Metabolism
Belumosudil is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6,
and UGT1A9, in vitro.
Excretion
Following a single oral dose of radiolabeled belumosudil in healthy subjects, 85% of
radioactivity was recovered in feces (30% as unchanged) and less than 5% in urine.
Specific Populations
No clinically significant differences in belumosudil pharmacokinetics were observed with regard
to age (18 to 77 years), sex, weight (38.6 to 143 kg), or mild to moderate renal impairment
(eGFR ≥60 and <90 mL/min/1.72m2 to eGFR ≥30 and <60 mL/min/1.72m2). The effect of
severe renal impairment on the pharmacokinetics of belumosudil has not been studied.
Patients with Hepatic Impairment
Following a single 200 mg dose of belumosudil, changes in belumosudil exposure in subjects
with varying degrees of hepatic impairment based on Child-Pugh score without liver GVHD
relative to subjects with normal hepatic function is shown in Table 4.
Table 4: Effect of Varying Degrees of Hepatic Impairment on Belumosudil Exposure
Hepatic Impairment
Category
Changes in Belumosudil Exposure in Subjects with Hepatic
Impairment Compared to Subjects with Normal Hepatic
Function
Total (Free + Bound)
Concentrations
Free Concentrations
Cmax
AUC
Cmax
AUC
Mild (Child-Pugh A)
1.2-fold
increase
1.4-fold
increase
14% decrease
19% decrease
Moderate (Child-Pugh B)
6% decrease
1.5-fold
increase
12% decrease
1.4-fold
increase
Severe (Child-Pugh C)
1.3-fold
increase
4.2-fold
increase
5.4-fold
increase
16-fold
increase
Drug Interaction Studies
Reference ID: 5503992
12
Clinical studies and model-informed approaches
Effects of other drugs on Belumosudil
Strong Cytochrome P450 (CYP) 3A Inhibitors: There was no clinically meaningful effect on
belumosudil exposure when coadministered with itraconazole in healthy subjects.
Strong CYP3A Inducers: Coadministration of rifampin decreased belumosudil Cmax by 59% and
AUC by 72% in healthy subjects.
Moderate CYP3A Inducers: Coadministration of efavirenz is predicted to decrease belumosudil
Cmax by 19% and AUC by 35% in healthy subjects.
Proton Pump Inhibitors: Coadministration of rabeprazole decreased belumosudil Cmax by 87%
and AUC by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in
healthy subjects.
Effects of Belumosudil on other drugs
CYP3A Substrates: Coadministration of belumosudil is predicted to increase midazolam (a
sensitive CYP3A substrate) Cmax and AUC approximately 1.3- and 1.5-fold, respectively.
CYP2C9 Substrates: Coadministration of belumosudil is not expected to have clinically
meaningful effect on the exposure of CYP2C9 substrates (such as warfarin).
CYP2C8 Substrates: Coadministration of belumosudil is not expected to have clinically
meaningful effect on the exposure of CYP2C8 substrates that are not an OATP1B1 substrate.
UGT1A1 Substrates: Coadministration of belumosudil decreased raltegravir glucuronide
(metabolite formed via the UGT1A1 pathway) Cmax by 42% and AUC by 40%.
Transporter systems
OATP1B1/BCRP Substrates: Coadministration of belumosudil increased rosuvastatin
(OATP1B1 and BCRP substrate) Cmax and AUC by 3.6- and 4.6-fold, respectively.
P-glycoprotein (P-gp) Substrates: Coadministration of belumosudil increased dabigatran (P-gp
substrate) Cmax and AUC by 2-fold.
In Vitro studies
Transporter Systems: Belumosudil is a substrate of P-gp. Belumosudil inhibits BCRP, P-gp, and
OATP1B1 at clinically relevant concentrations.
Enzymes Systems: Belumosudil is an inhibitor of CYP1A2, CYP2C19, CYP2D6, UGT1A1 and
UGT1A9.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Belumosudil did not result in any carcinogenic effect in a 6-month CByB6F1-Tg (HRAS)2Jic
hemizygous mouse study at oral doses up to 15 mg/kg/day in female and 30 mg/kg/day in male
mice.
Mutagenesis
Reference ID: 5503992
13
Belumosudil was not genotoxic in an in vitro bacterial mutagenicity (Ames) assay, in vitro
chromosome aberration assay in human peripheral blood lymphocytes (HPBL) or an in vivo rat
bone marrow micronucleus assay.
Impairment of Fertility
In a combined male and female rat fertility and early embryonic development study,
belumosudil-treated male animals were mated with untreated females, or untreated males were
mated with belumosudil-treated females. Belumosudil was administered orally at doses of 50,
150 or 275 mg/kg/day to male rats 70 days prior to and throughout the mating period, and to
female rats 14 days prior to mating and up to Gestation Day 7. At the dose of 275 mg/kg/day,
adverse findings in female rats (treated with belumosudil or untreated but mated with treated
males) regarding early embryonic development included increased pre- or post-implantation loss
and decreased number of viable embryos. Administration of belumosudil to male rats at a dose of
275 mg/kg/day resulted in abnormal sperm findings (reduced motility, reduced count, and
increased percentage of abnormal sperm), and testes/epididymis organ changes (reduced weight
and degeneration). Fertility was reduced in both treated males or females at the 275 mg/kg/day
dose and reached statistical significance in males. Adverse changes in male and female
reproductive organs also occurred in general 3-month and 6-month toxicology studies. In males,
findings included spermatozoa degeneration at a belumosudil dose of 50 mg/kg/day in rats and
35 mg/kg/day in dogs. The exposure (AUC) at the doses of 50 mg/kg/day in male rats and 35
mg/kg/day in male dogs is approximately equivalent to the clinical exposure at the recommended
dose of 200 mg/day. Changes were reversible in dogs but not fully reversible in rats. In female
rats, changes included decreased follicular development in ovaries and lower uterine weights that
correlated with uterine/cervical hypoplasia at 275 mg/kg/day [corresponding to 9 times exposure
in patients at the recommended dose of 200 mg/day]. Changes were fully reversed during the 4
week recovery period.
14
CLINICAL STUDIES
14.1 Chronic Graft versus Host Disease
Study KD025-213 (NCT03640481) was a randomized, open-label, multicenter study of
REZUROCK for treatment of patients with chronic GVHD who had received 2 to 5 prior lines of
systemic therapy and required additional treatment. Patients were excluded from the studies if
platelets were <50 × 109/L; absolute neutrophil count <1.5 × 109/L; AST or ALT >3 × ULN;
total bilirubin >1.5 × ULN; QTc(F) >480 ms; eGFR <30 mL/min/1.73 m2; or FEV1 ≤39%. There
were 66 patients treated with REZUROCK 200 mg taken orally once daily. Concomitant
treatment with supportive care therapies for chronic GVHD was permitted. Concomitant
treatment with GVHD prophylaxis and standard care systemic chronic GVHD therapies was
permitted as long as the subject has been on a stable dose for at least 2 weeks prior to study.
Initiation of new systemic chronic GVHD therapy while on study was not permitted.
Demographics and baseline characteristics are summarized in Table 5.
Table 5: Demographics and Baseline Characteristics of Patients with Chronic GVHD
Reference ID: 5503992
14
REZUROCK
200 mg once daily
(N=65)
Age, Median, Years (minimum, maximum)
53 (21, 77)
Age ≥65 Years, n (%)
17 (26)
Male, n (%)
42 (65)
Race, n (%)
White
54 (83)
Black
6 (9)
Other or Not Reported
5 (8)
Median (range) time (months) from Chronic GVHD Diagnosis
25.3 (1.9, 162.4)
≥4 Organs Involved, n (%)
31 (48)
Median (range) Number of Prior Lines of Therapy
3 (2, 6)
Number of Prior Lines of Therapy, n (%)
2
23 (35)
3
12 (19)
4
15 (23)
≥5
15 (23)
Prior chronic GVHD treatment with ibrutinib, n (%)
21 (32)
Prior chronic GVHD treatment with ruxolitinib, n (%)
20 (31)
Refractory to Last Therapy, n (%*)
43/55 (78)
Severe chronic GVHD, n (%)
46 (71)
Median (range) Global Severity Rating
7 (2, 9)
Median (range) Lee Symptom Scale Score at baseline
27 (7, 56)
Median (range) Corticosteroid dose at baseline (PE/kg)†
0.19 (0.03, 0.95)
* Denominator excludes patients with unknown status
† Prednisone equivalents/kilogram
The efficacy of REZUROCK was based on overall response rate (ORR) through Cycle 7 Day 1
where overall response included complete response or partial response according to the 2014
NIH Response Criteria. The ORR results are presented in Table 6. The ORR was 75% (95% CI:
63, 85). The median duration of response, calculated from first response to progression, death, or
new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). The median time
to first response was 1.8 months (95% CI: 1.0, 1.9). In patients who achieved response, no death
Reference ID: 5503992
15
or new systemic therapy initiation occurred in 62% (95% CI: 46, 74) of patients for at least 12
months since response.
Table 6: Overall Response Rate through Cycle 7 Day 1 for Patients with Chronic GVHD in
Study KD025-213
REZUROCK
200 mg once daily
(N=65)
Overall Response Rate (ORR)
49 (75%)
95% Confidence Interval*
(63%, 85%)
Complete Response
4 (6%)
Partial Response
45 (69%)
* Estimated using Clopper-Pearson method
ORR results were supported by exploratory analyses of patient-reported symptom bother which
showed at least a 7-point decrease in the Lee Symptom Scale summary score through Cycle 7
Day 1 in 52% (95% CI: 40, 65) of patients.
16
HOW SUPPLIED/STORAGE AND HANDLING
REZUROCK 200 mg tablets are supplied as pale yellow film-coated oblong tablets containing
200 mg of belumosudil (equivalent to 242.5 mg belumosudil mesylate). Each tablet is debossed
with "KDM" on one side and "200" on the other side and is packaged as follows:
200 mg tablets in 30 count bottle: NDC 79802-200-30
Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to
30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Dispense to patient in original container only. Store in original container to protect from
moisture. Replace cap securely each time after opening. Do not discard desiccant.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Embryo-fetal Toxicity:
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known or
suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1,
8.3)].
Advise females of reproductive potential to use effective contraceptive during treatment with
REZUROCK and for one week after the last dose [see Warnings and Precautions (5.1)].
Advise males with female partners of reproductive potential to use effective contraceptive
during treatment with REZUROCK and for one week after the last dose [see Use in Specific
Populations (8.3)].
Reference ID: 5503992
16
Lactation
Advise women not to breastfeed during treatment with REZUROCK and for one week after
the last dose [see Use in Specific Populations (8.2)].
Infertility
Advise males and females of reproductive potential that REZUROCK may impair fertility
[see Use in Specific Populations (8.3)].
Administration
Inform patients to take REZUROCK orally once daily with food according to their
physician's instructions and that the oral dosage (tablets) should be swallowed whole with a
glass of water, without cutting, crushing or chewing the tablets approximately the same time
each day [see Dosage and Administration (2.1)].
Advise patients that in the event of a missed daily dose of REZUROCK, it should be taken as
soon as possible on the same day with a return to the normal schedule the following day.
Patients should not take extra doses to make up the missed dose [see Dosage and
Administration (2.1)].
Drug Interactions
Advise patients to inform their health care providers of all concomitant medications,
including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see
Drug Interactions (7)].
Distributed and marketed by:
Kadmon Pharmaceuticals, LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
1-800-633-1610
REZUROCK® is a registered trademark of Kadmon Pharmaceuticals, LLC.
© 2024 Kadmon Pharmaceuticals, LLC. All rights reserved.
For patent information: https://www.sanofi.us/en/products-and-resources/patents
Reference ID: 5503992
17
PATIENT INFORMATION
REZUROCK (REZ-ur-ok)
(belumosudil)
tablets
What is REZUROCK?
REZUROCK is a prescription medicine used to treat adults and children 12 years of age and older with chronic graft
versus-host disease (chronic GVHD) after you have received at least 2 prior treatments (systemic therapy) and they did
not work.
It is not known if REZUROCK is safe and effective in children less than 12 years old.
Before taking REZUROCK, tell your healthcare provider about all of your medical conditions, including if you:
have kidney or liver problems.
are pregnant or plan to become pregnant. REZUROCK can harm your unborn baby. If you are able to become
pregnant, your healthcare provider will do a pregnancy test before starting treatment with REZUROCK. Tell your
healthcare provider if you become pregnant or think you may be pregnant during treatment with REZUROCK.
o
Females who can become pregnant should use effective birth control during treatment with REZUROCK and
for 1 week after the last dose.
o
Males with female partners who can become pregnant should use effective birth control during treatment with
REZUROCK and for 1 week after the last dose.
are breastfeeding or plan to breastfeed. It is not known if REZUROCK passes into breast milk. Do not breastfeed
during treatment with REZUROCK and for 1 week after the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. REZUROCK may affect the way other medicines work, and other
medicines may affect the way REZUROCK works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a
new medicine.
How should I take REZUROCK?
Take REZUROCK exactly as your healthcare provider tells you to take it.
Do not change your dose or stop taking REZUROCK without first talking to your healthcare provider.
Take REZUROCK 1 time a day with a meal.
Take REZUROCK at about the same time each day.
Swallow REZUROCK tablets whole with a glass of water.
Do not cut, crush, or chew REZUROCK tablets.
Your healthcare provider will do blood tests to check your liver at least 1 time a month during treatment with
REZUROCK.
If you miss a dose of REZUROCK, take it as soon as you remember on the same day. Take your next dose of
REZUROCK at your regular time on the next day. Do not take extra doses of REZUROCK to make up for a missed
dose.
If you take too much REZUROCK, call your healthcare provider or go to the nearest hospital emergency room right
away.
What are the possible side effects of REZUROCK?
The most common side effects of REZUROCK include:
infections
swelling
tiredness or weakness
bleeding
nausea
stomach (abdominal) pain
diarrhea
muscle or bone pain
shortness of breath
headache
cough
high blood pressure
Your healthcare provider may change your dose of REZUROCK, temporarily stop, or permanently stop
treatment with REZUROCK if you have certain side effects.
REZUROCK may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.
These are not all the possible side effects of REZUROCK.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You
may also report side effects to Kadmon Pharmaceuticals, LLC at 1-800-633-1610.
How should I store REZUROCK?
Store REZUROCK at room temperature between 68°F to 77°F (20°C to 25°C).
Keep REZUROCK in its original container. The REZUROCK bottle contains a desiccant packet to help keep your
tablets dry (protect from moisture). Keep the desiccant in the bottle.
Reference ID: 5503992
Tightly close the REZUROCK bottle after you take your dose.
Keep REZUROCK and all medicines out of the reach of children.
General information about the safe and effective use of REZUROCK.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
REZUROCK for a condition for which it was not prescribed. Do not give REZUROCK to other people, even if they have
the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for
information about REZUROCK that is written for health professionals.
What are the ingredients in REZUROCK?
Active ingredient: belumosudil mesylate
Inactive ingredients:
Tablet core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, and microcrystalline
cellulose.
Tablet coating: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and yellow iron oxide.
Distributed and marketed by Kadmon Pharmaceuticals, LLC, Bridgewater, NJ 08807, A SANOFI COMPANY
REZUROCK® is a registered trademark of Kadmon Pharmaceuticals, LLC
© 202x Kadmon Pharmaceuticals, LLC.
All rights reserved.
For more information, call 1-800-633-1610 or go to www.REZUROCK.com.
This Patient Information has been approved by the U.S. Food and Drug Administration
Issued: 12/2024
Reference ID: 5503992
| custom-source | 2025-02-12T15:48:22.395522 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/214783s007lbl.pdf', 'application_number': 214783, 'submission_type': 'SUPPL ', 'submission_number': 7} |
80,791 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LUMIZYME safely and effectively. See full prescribing information for
LUMIZYME.
LUMIZYME® (alglucosidase alfa), for injection, for intravenous use
Initial U.S. Approval: 2010
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING
ANAPHYLAXIS, IMMUNE-MEDIATED REACTIONS, and RISK
OF ACUTE CARDIORESPIRATORY FAILURE
See full prescribing information for complete boxed warning.
Hypersensitivity Reactions Including Anaphylaxis
Anaphylaxis has occurred during the early course of enzyme
replacement therapy and after extended duration of therapy. Initiate
LUMIZYME in a healthcare setting with appropriate medical
monitoring and support measures, including access to
cardiopulmonary resuscitation equipment. If a severe hypersensitivity
reaction (e.g., anaphylaxis) occurs, discontinue LUMIZYME and
immediately initiate appropriate medical treatment, including use of
epinephrine. (5.1)
Immune-Mediated Reactions
Immune-mediated reactions presenting as proteinuria, nephrotic
syndrome, and necrotizing skin lesions have occurred in some patients
following LUMIZYME treatment. Monitor patients for the
development of systemic immune-mediated reactions involving skin
and other organs while receiving LUMIZYME. (5.3)
Risk of Acute Cardiorespiratory Failure
Infantile-onset Pompe disease (IOPD) patients with compromised
cardiac or respiratory function may be at risk of serious acute
exacerbation of their cardiac or respiratory compromise due to fluid
overload and require additional monitoring. (5.4)
---------------------------RECENT MAJOR CHANGES--------------------------
Boxed Warning
3/2024, 12/2024
Dosage and Administration (2.1, 2.2)
3/2024, 12/2024
Warnings and Precautions (5.1, 5.2, 5.6)
3/2024, 12/2024
Warnings and Precautions, Monitoring (5.7)
Removed 12/2024
----------------------------INDICATIONS AND USAGE--------------------------
LUMIZYME® is a hydrolytic lysosomal glycogen-specific enzyme indicated
for patients with Pompe disease (GAA deficiency). (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
• Administration of LUMIZYME should be supervised by a healthcare
provider knowledgeable in the management of hypersensitivity reactions
including anaphylaxis. (2.1)
• Recommended dosage is 20 mg/per kg body weight administered every 2
weeks as an intravenous infusion. The initial infusion rate should be no
more than 1 mg/kg/hour (2.2)
• Reconstitute and dilute LUMIZYME prior to use. (2.3)
• See full prescribing information for storage of the reconstituted and diluted
product and administration instructions (2.4, 2.5)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
For injection: 50 mg of LUMIZYME as lyophilized powder in a single-dose
vial for reconstitution. (3)
------------------------------CONTRAINDICATIONS------------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
• Infusion-Associated Reactions (IARs): If an IAR occurs, decreasing the
infusion rate, temporarily stopping the infusion, and/or administration of
antihistamines and/or antipyretics may ameliorate the symptoms. (5.2)
• Risk of Cardiac Arrhythmia and Sudden Cardiac Death during General
Anesthesia for Central Venous Catheter Placement: Caution should be used
when administering general anesthesia for the placement of a central
venous catheter intended for LUMIZYME infusion. (5.5)
• Risk of Developing Anti-alglucosidase Alfa Antibodies: Patients with
IOPD should have a cross-reactive immunologic material (CRIM)
assessment early in their disease course and be managed by a clinical
specialist knowledgeable in immune tolerance induction in Pompe disease.
(5.6)
------------------------------ADVERSE REACTIONS------------------------------
The most frequently reported adverse reactions (≥5%) in clinical trials were
hypersensitivity reactions and included: anaphylaxis, rash, pyrexia,
flushing/feeling hot, urticaria, headache, hyperhidrosis, nausea, cough,
decreased oxygen saturation, tachycardia, tachypnea, chest discomfort,
dizziness, muscle twitching, agitation, cyanosis, erythema,
hypertension/increased blood pressure, pallor, rigors, tremor, vomiting,
fatigue, and myalgia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at
1-800-633-1610, option 1 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING
ANAPHYLAXIS, IMMUNE-MEDIATED REACTIONS, and RISK OF
ACUTE CARDIORESPIRATORY FAILURE
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommendations prior to LUMIZYME Treatment
2.2
Recommended Dosage and Administration
2.3
Reconstitution and Dilution Instructions
2.4
Storage Instructions for the Reconstituted and Diluted Product
2.5
Administration Instructions
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions Including Anaphylaxis
5.2
Infusion-Associated Reactions
5.3
Immune-Mediated Reactions
5.4
Risk of Acute Cardiorespiratory Failure
5.5
Risk of Cardiac Arrhythmia and Sudden Cardiac Death during
General Anesthesia for Central Venous Catheter Placement
5.6
Risk of Developing Anti-alglucosidase Alfa Antibodies
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 Immunogenicity
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Clinical Trials in Infantile-Onset Pompe Disease
14.2 Clinical Trials in Late-Onset Pompe Disease
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5502619
1
FULL PRESCRIBING INFORMATION
WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS,
IMMUNE-MEDIATED REACTIONS, and RISK OF ACUTE
CARDIORESPIRATORY FAILURE
Hypersensitivity Reactions Including Anaphylaxis
Patients treated with enzyme replacement therapies have experienced life-threatening
hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the
early course of enzyme replacement therapy and after extended duration of therapy.
Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and
support measures, including access to cardiopulmonary resuscitation equipment. If a
severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue LUMIZYME
and immediately initiate appropriate medical treatment, including use of epinephrine.
Inform patients of the symptoms of life-threatening hypersensitivity reactions,
including anaphylaxis and to seek immediate medical care should symptoms occur [see
Warnings and Precautions (5.1)].
Immune-Mediated Reactions
Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and
necrotizing skin lesions have occurred in some patients following LUMIZYME
treatment. Monitor patients for the development of systemic immune-mediated
reactions involving skin and other organs while receiving LUMIZYME [see Warnings
and Precautions (5.3)].
Risk of Acute Cardiorespiratory Failure
Infantile-onset Pompe disease (IOPD) patients with compromised cardiac or
respiratory function may be at risk of serious acute exacerbation of their cardiac or
respiratory compromise due to fluid overload and require additional monitoring [see
Warnings and Precautions (5.4)].
1
INDICATIONS AND USAGE
LUMIZYME® is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with
Pompe disease (acid α-glucosidase [GAA] deficiency).
2
DOSAGE AND ADMINISTRATION
2.1
Recommendations prior to LUMIZYME Treatment
• Administration of LUMIZYME should be supervised by a healthcare provider
knowledgeable in the management of hypersensitivity reactions including anaphylaxis
[see Warnings and Precautions (5.1)].
• Initiate LUMIZYME in a healthcare setting with appropriate medical monitoring and
support measures, including access to cardiopulmonary resuscitation equipment [see
Warnings and Precautions (5.1)].
• Prior to LUMIZYME administration, consider pretreating with antihistamines,
antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1, 5.2)].
Reference ID: 5502619
2
• LUMIZYME must be reconstituted and diluted prior to use [see Dosage and
Administration (2.3)].
• Appropriate medical monitoring and support measures, including cardiopulmonary
resuscitation equipment, should be readily available during LUMIZYME administration
[see Warnings and Precautions (5.1)].
2.2
Recommended Dosage and Administration
• The recommended dosage of LUMIZYME is 20 mg/kg body weight administered every
2 weeks as an intravenous infusion. The initial infusion rate should be no more than 1
mg/kg/hour [see Dosage and Administration (2.5)].
Missed Dose
If one or more doses are missed, restart LUMIZYME treatment as soon as possible, maintaining
the 2-week interval between infusions thereafter.
2.3
Reconstitution and Dilution Instructions
Reconstitute and dilute LUMIZYME in the following manner.
Use aseptic technique during preparation. Do not use filter needles during preparation.
Reconstitute the Lyophilized Powder
• Determine the number of LUMIZYME vials to be reconstituted based on the actual body
weight in kg and the recommended dose of 20 mg/kg. Round the number of vials up to
the next whole number.
• Remove the required number of LUMIZYME vials from the refrigerator and allow the
vials to sit for approximately 30 minutes at room temperature 20°C to 25°C (68°F to
77°F) prior to reconstitution.
• Reconstitute each vial by slowly injecting 10.3 mL of Sterile Water for Injection, down
the inside wall of each vial. Avoid adding the Sterile Water for Injection to the vial
forcefully or directly onto the lyophilized powder to minimize foaming.
• Gently tilt and roll each vial. Do not invert, swirl, or shake the vial. Each vial will yield a
concentration of 5 mg/mL of LUMIZYME. The total extractable dose per vial is 50 mg
per 10 mL.
• Visually inspect the reconstituted solution in the vials for particulate matter and
discoloration. Discard if particles are present or the solution is discolored. The
reconstituted solution may occasionally contain some LUMIZYME particles (typically
less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to
the initial inspection. This may also happen following dilution for infusion. These
particles have been shown to contain LUMIZYME and may appear after the initial
reconstitution step and increase over time. Studies have shown that these particles are
removed via in-line filtration without having a detectable effect on the purity or strength.
Reference ID: 5502619
3
Dilute the Reconstituted Solution
• Select and prepare an appropriate size 0.9% Sodium Chloride for Injection infusion bag
with quantity sufficient of 0.9% Sodium Chloride for Injection to obtain the
recommended total infusion volume per table 1 based on patient weight and dilute.
• Slowly withdraw the required volume of reconstituted solution from the LUMIZYME
vial(s). Avoid foaming in the syringe. Discard any unused reconstituted solution
remaining in the vial.
• Remove airspace from the prepared 0.9% Sodium Chloride for Injection infusion bag to
minimize particle formation due to the sensitivity of LUMIZYME to air-liquid interfaces.
• Inject the LUMIZYME reconstituted solution slowly and directly into the port of the
prepared 0.9% Sodium Chloride for Injection infusion bag. Avoid foaming and
introducing air in the infusion bag.
• Gently invert or massage the infusion bag to mix the solution. Do not shake. After
dilution, the solution will have a final concentration of 0.5 to 4 mg/mL of LUMIZYME.
2.4
Storage Instructions for the Reconstituted and Diluted Product
• The reconstituted and diluted solution should be administered without delay. Storage of
the reconstituted solution at room temperature is not recommended.
• If immediate use is not possible, the reconstituted and diluted solution is stable for up to
24 hours refrigerated at 2°C to 8°C (36°F to 46°F).
• The reconstituted and diluted LUMIZYME solution should be protected from light.
• Do not freeze or shake.
2.5
Administration Instructions
• The total volume of infusion is determined by the patient’s body weight and should be
administered over approximately 4 hours.
• Administer LUMIZYME using an in-line low protein binding 0.2-micron filter.
• Infusions should be administered in a step-wise manner using an infusion pump. The
initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be
increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is
established, until a maximum rate of 7 mg/kg/hr is reached.
• Vital signs should be obtained at the end of each step. If the patient is stable,
LUMIZYME may be administered at the maximum rate of 7 mg/kg/hr until the infusion
is completed.
• The infusion rate may be slowed or temporarily stopped in the event of mild to moderate
hypersensitivity reactions. In the event of anaphylaxis or severe hypersensitivity reaction,
immediately discontinue administration of LUMIZYME and initiate appropriate medical
treatment. See Table 1 below for the rate of infusion at each step, expressed as mL/hr
based on the recommended infusion volume by patient weight.
Reference ID: 5502619
4
• Do not infuse LUMIZYME in the same intravenous line with other products. Discard any
unused product.
Table 1: Recommended LUMIZYME Infusion Volumes and Incremental Rate Steps by
Patient Weight
Patient Weight
Range
Total infusion
volume
Step 1
1 mg/kg/hr
Step 2
3 mg/kg/hr
Step 3
5 mg/kg/hr
Step 4
7 mg/kg/hr
Infusion Rate in mL/hr
1.25 to 2.5 kg
25 mL
1.25
3.75
6.25
6.6
2.6 to 10 kg
50 mL
3
8
13
18
10.1 to 20 kg
100 mL
5
15
25
35
20.1 to 30 kg
150 mL
8
23
38
53
30.1 to 35 kg
200 mL
10
30
50
70
35.1 to 50 kg
250 mL
13
38
63
88
50.1 to 60 kg
300 mL
15
45
75
105
60.1 to 100 kg
500 mL
25
75
125
175
100.1 to 120 kg
600 mL
30
90
150
210
120.1 to 140 kg
700 mL
35
105
175
245
140.1 to 160 kg
800 mL
40
120
200
280
160.1 to 180 kg
900 mL
45
135
225
315
180.1 to 200 kg
1,000 mL
50
150
250
350
3
DOSAGE FORMS AND STRENGTHS
For injection: 50 mg of LUMIZYME is supplied as a sterile, nonpyrogenic, white to off-white,
lyophilized cake or powder in a single-dose vial for reconstitution. After reconstitution, the
resultant solution concentration is 5 mg/mL.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions Including Anaphylaxis
Hypersensitivity Reactions Including Anaphylaxis
Hypersensitivity reactions including anaphylaxis have been observed in patients during and up to
3 hours after a LUMIZYME infusion. Some of the hypersensitivity reactions were life-
threatening and included anaphylactic shock, cardiac arrest, respiratory arrest, respiratory
distress, hypoxia, apnea, dyspnea, bradycardia, tachycardia, bronchospasm, throat tightness,
hypotension, angioedema (including tongue or lip swelling, periorbital edema, and face edema),
and urticaria. Other accompanying reactions included chest discomfort/pain, wheezing,
tachypnea, cyanosis, decreased oxygen saturation, convulsions, pruritus, rash, hyperhidrosis,
nausea, dizziness, hypertension/increased blood pressure, flushing/feeling hot, erythema,
pyrexia, pallor, peripheral coldness, restlessness, nervousness, headache, back pain, and
paresthesia. Some of these reactions were IgE-mediated.
Reference ID: 5502619
5
In clinical trials, hypersensitivity reactions including anaphylaxis were managed with infusion
interruption; decreased infusion rate; and administration of antihistamines, corticosteroids,
intravenous fluids, and/or oxygen. In some cases of anaphylaxis, epinephrine was administered.
Some LUMIZYME-treated patients who experienced a hypersensitivity reaction and who tested
positive for alglucosidase alfa-specific IgE antibodies were successfully rechallenged with a
slower infusion rate at a lower dosage of LUMIZYME and continued to receive LUMIZYME
under close clinical supervision. Because LUMIZYME-treated patients who develop anti-IgE
alglucosidase alfa antibodies appear to be at a higher risk for developing hypersensitivity
reactions including anaphylaxis, these patients should be monitored more closely during
LUMIZYME administration.
Recommendations to Prevent, Mitigate, and Monitor for Hypersensitivity Reactions
Prior to LUMIZYME administration, consider pretreating with antihistamines, antipyretics,
and/or corticosteroids. Administration of LUMIZYME should be supervised by a healthcare
provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis.
Anaphylaxis has occurred during the early course of enzyme replacement therapy and after
extended duration of therapy. Initiate LUMIZYME in a healthcare setting with appropriate
medical monitoring and support measures, including access to cardiopulmonary resuscitation
equipment.
• If a severehypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue
LUMIZYME and immediately initiate appropriate medical treatment, including use
of epinephrine.
• If a mild or moderate hypersensitivity reaction occurs, consider temporarily holding
the LUMIZYME infusion or slowing the infusion rate.
Consider the risks and benefits of readministering LUMIZYME following a hypersensitivity
reaction including anaphylaxis. Patients may be rechallenged using slower infusion rates at a
lower dosage than the recommended dosage [see Adverse Reactions (6.2)]. Inform patients of
the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and
recommend they seek immediate medical care should these symptoms occur.
5.2
Infusion-Associated Reactions
Infusion-associated reactions (IARs) such as pyrexia, chills, flu-like illness, myalgia, arthralgia,
pain, fatigue, urticaria, rash, pruritus, erythema, dyspnea, tachycardia, flushing, nausea, headache
and syncope occurred in LUMIZYME-treated patients [see Adverse Reactions (6.2)].
If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or
administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor
patients who have experienced IARs when re-administering LUMIZYME.
5.3
Immune-Mediated Reactions
Immune-mediated cutaneous reactions have been reported with LUMIZYME including
necrotizing skin lesions [see Adverse Reactions (6.2)]. Systemic immune-mediated reactions,
including possible type III immune-mediated reactions have been observed with LUMIZYME.
These reactions occurred several weeks to 3 years after initiation of LUMIZYME infusions. Skin
biopsy in one patient demonstrated deposition of anti-rhGAA antibodies in the lesion. Another
patient developed severe inflammatory arthropathy in association with pyrexia and elevated
Reference ID: 5502619
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erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous
glomerulonephritis was observed in some LUMIZYME-treated patients with Pompe disease who
had persistently positive anti-rhGAA IgG antibody titers. In these patients, renal biopsy was
consistent with immune complex deposition. Patients improved following LUMIZYME
treatment interruption [see Adverse Reactions (6.2)].
LUMIZYME treated patients should be monitored for the development of systemic immune-
mediated reactions involving skin and other organs including periodic urinalysis. If immune-
mediated reactions occur, consider discontinuing the LUMIZYME administration, and initiating
appropriate medical treatment. The risks and benefits of readministering LUMIZYME following
an immune-mediated reaction should be considered. Some patients have been able to be
rechallenged and have continued to receive LUMIZYME under close clinical supervision.
Immune tolerance induction administered in conjunction with LUMIZYME may also aide
tolerability of LUMIZYME under the management of a clinical specialist knowledgeable in
immune tolerance induction in pediatric patients with IOPD or LOPD.
5.4
Risk of Acute Cardiorespiratory Failure
Patients with acute underlying respiratory illness or compromised cardiac and/or respiratory
function may be at risk of serious exacerbation of their cardiac or respiratory compromise during
infusions. Appropriate medical support and monitoring measures should be readily available
during LUMIZYME infusion, and some patients may require prolonged observation times that
should be individualized based on the needs of the patient. Acute cardiorespiratory failure has
been observed in infantile-onset Pompe disease patients with underlying cardiac hypertrophy,
possibly associated with fluid overload with intravenous administration of LUMIZYME [see
Dosage and Administration (2.2)].
5.5
Risk of Cardiac Arrhythmia and Sudden Cardiac Death during General Anesthesia
for Central Venous Catheter Placement
Administration of general anesthesia can be complicated by the presence of severe cardiac and
skeletal (including respiratory) muscle weakness. Therefore, caution should be used when
administering general anesthesia. Ventricular arrhythmias and bradycardia, resulting in cardiac
arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in patients
with IOPD with cardiac hypertrophy during general anesthesia for central venous catheter
placement.
5.6
Risk of Developing Anti-alglucosidase Alfa Antibodies
As shown from clinical trials and published literature, individualized immune tolerance induction
regimen administered prior to and with initiation of LUMIZYME has been reported to aid
tolerability of LUMIZYME and reduce the development of high ADA titers in CRIM-negative
IOPD patients. Furthermore, CRIM status has been shown to be associated with immunogenicity
and patients’ responses to LUMIZYME. LUMIZYME-treated infants with IOPD who are
CRIM-negative (indicating no endogenous enzyme is detected) have shown poorer clinical
response (loss of motor function, ventilator dependence, or death) in the presence of high
sustained IgG ADA titers and positive inhibitory antibodies compared to CRIM-positive infants
[see Adverse Reactions (6.2)]. However, high and sustained ADA titers has also occurred in a
limited number of CRIM-positive patients, generally with very low endogenous enzyme [see
Reference ID: 5502619
7
Clinical Pharmacology (12.6)]. Therefore, these patients must be managed by a clinical
specialist knowledgeable in immune tolerance induction in Pompe disease.
Some alglucosidase alfa-treated patients who developed high sustained IgG ADA titers had
reduced efficacy. Some alglucosidase alfa-treated patients with high IgG ADA titers had a higher
incidence of IARs.
Patients with IOPD should have a cross-reactive immunologic material (CRIM) assessment early
in their disease course.
Anti-alglucosidase alfa antibody (referred to as ADA) titers should be obtained during
LUMIZYME treatment. Contact Genzyme Corporation at 1-800-745-4447 for information on
ADA testing.
Recommend the following ADA testing:
• Baseline serum ADA sample collection prior to the first LUMIZYME infusion is strongly
encouraged.
• For patients with:
o IOPD, suggest regular ADA monitoring during first year of treatment (example:
every 3 months).
o LOPD, suggest ADA be monitored within six months of LUMIZYME initiation
with subsequent monitoring as clinically warranted based on safety and efficacy
considerations.
• If patients [see Adverse Reactions (6.2) and Clinical Pharmacology (12.6)]:
o Develop hypersensitivity reactions, consider testing for IgG ADA, IgE ADA and
other mediators.
o Develop immune-mediated reactions that are not hypersensitivity reactions,
consider testing for IgG ADA.
o Lose or have a reduced clinical response, consider testing for IgG ADA and for
inhibitory antibody activity.
6
ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in the labeling:
• Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions
(5.1)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
In clinical trials, the most common adverse reactions (≥5%) following intravenous alglucosidase
alfa treatment were hypersensitivity reactions, and included anaphylaxis, rash, pyrexia,
flushing/feeling hot, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen
saturation, tachycardia, tachypnea, chest discomfort, dizziness, muscle twitching, agitation,
Reference ID: 5502619
8
cyanosis, erythema, hypertension/increased blood pressure, pallor, rigors, tremor, vomiting,
fatigue, and myalgia.
Adverse Reactions in Clinical Trials in Infantile-Onset and Juvenile-Onset Pompe Disease
Two multicenter, open-label clinical trials (Trials 1 and 2) [see Clinical Studies (14.1)] were
conducted in 39 patients with infantile-onset Pompe disease (IOPD), aged 1 month to 3.5 years
old. Approximately half of the patients (54%) were male. Patients were treated with intravenous
alglucosidase alfa 20 or 40 mg/kg every other week for periods ranging from 1 to 106 weeks
(mean: 61 weeks).
The most serious adverse reactions reported with alglucosidase alfa treatment included
anaphylaxis and acute cardiorespiratory failure.
The most common adverse reactions requiring intervention in these clinical trials were
hypersensitivity reactions, that occurred in 20 of 39 (51%) patients treated with alglucosidase
alfa, and included rash, pyrexia, urticaria, flushing, decreased oxygen saturation, cough,
tachypnea, tachycardia, hypertension/increased blood pressure, pallor, rigors, vomiting, cyanosis,
agitation, and tremor. These reactions were more likely to occur with higher infusion rates or
doses. Some patients who were pretreated with antihistamines, antipyretics and/or corticosteroids
still experienced hypersensitivity reactions.
Table 2 summarizes all adverse reactions that occurred in ≥5% of patients (2 or more patients)
treated with alglucosidase alfa in clinical trials described above.
Table 2: Adverse Reactions that Occurred in at Least 5% of Alglucosidase Alfa-Treated
Infantile-Onset Patients in Trials 1 and 2
Number of Patients
(N=39)
n (%)
Adverse Reaction
20 (51)
Rash (including rash erythematous, rash macular and maculopapular)
7 (18)
Pyrexia
6 (15)
Urticaria
5 (13)
Flushing
5 (13)
Hypertension/Increased Blood Pressure
4 (10)
Decreased Oxygen Saturation
3 (8)
Cough
3 (8)
Tachypnea
3 (8)
Tachycardia
3 (8)
Erythema
2 (5)
Vomiting
2 (5)
Rigors
2 (5)
Pallor
2 (5)
Cyanosis
2 (5)
Agitation
2 (5)
Tremor
2 (5)
Reference ID: 5502619
9
An open-label, single-center trial (Trial 3) was conducted in 18 treatment-naive patients with
IOPD who were treated with alglucosidase alfa [see Clinical Studies (14.1)]. Adverse reactions
observed in these patients were similar to patients with IOPD who received alglucosidase alfa in
other clinical trials.
Additional hypersensitivity reactions observed in patients with IOPD treated with alglucosidase
alfa in other clinical trials and expanded access programs included livedo reticularis, irritability,
retching, increased lacrimation, ventricular extrasystoles, nodal rhythm, rales, respiratory tract
irritation, and cold sweat.
Safety was also evaluated in 99 patients (51 male, 48 females) with Pompe disease in an
ongoing, open-label, prospective study in patients 12 months of age and older who were
previously treated with another alglucosidase alfa product and switched to LUMIZYME. Patients
were aged 1 to 18 years with a median duration of treatment of 437 days (range 13 to 466 days).
No new safety findings were observed following the switch to 4000 L scale of alglucosidase alfa.
Adverse Reactions in Clinical Trials in Late-Onset Pompe Disease
Assessment of adverse reactions in patients with late-onset Pompe disease (LOPD) is based on
the exposure of 90 patients (45 male, 45 female), aged 10 to 70 years, to intravenous infusions of
20 mg/kg alglucosidase alfa or placebo in a randomized, double-blind, placebo-controlled trial
(Trial 4). All patients were naive to enzyme replacement therapy. Patients were randomized in a
2:1 ratio and received intravenous alglucosidase alfa or placebo every other week for 78 weeks
(18 months). Two patients who received alglucosidase alfa discontinued the trial due to
anaphylactic reactions.
Serious adverse reactions reported with alglucosidase alfa included anaphylaxis, which presented
as angioedema, throat tightness and chest pain/discomfort. One patient with a history of Wolff-
Parkinson-White syndrome experienced a serious adverse reaction of supraventricular
tachycardia.
The most common adverse reactions (≥3%; 2 or more patients) observed in alglucosidase alfa
treated patients were hypersensitivity reactions and included anaphylaxis, headache, nausea,
urticaria, dizziness, chest discomfort, vomiting, hyperhidrosis, flushing/feeling hot, increased
blood pressure, paresthesia, pyrexia, local swelling, diarrhea, pruritus, rash, and throat tightness.
Delayed-onset reactions, defined as adverse reactions that occurred 2 to 48 hours after
completion of alglucosidase alfa infusion, that were observed in ≥3% more patients in the
alglucosidase alfa-treated group compared to patients in the placebo-treated group in the
controlled trial, included hyperhidrosis. Additional delayed-onset reactions that occurred in
alglucosidase alfa-treated patients included fatigue, myalgia, and nausea.
Table 3 summarizes the most common adverse reactions that occurred in at least 3% of
alglucosidase alfa-treated patients and with a higher incidence than the placebo-treated patients
in Trial 4 (patients with LOPD).
Reference ID: 5502619
10
Table 3: Adverse Reactions in Patients with LOPD (Trial 4)*
Adverse Reaction
Alglucosidase Alfa
n=60
N (%)
Placebo
n=30
N (%)
Hyperhidrosis
5 (8.3)
0 (0)
Urticaria
5 (8.3)
0 (0)
Anaphylaxis
4 (6.7)
0 (0)
Chest Discomfort
4 (6.7)
1 (3.3)
Muscle Twitching
4 (6.7)
1 (3.3)
Myalgia
3 (5.0)
1 (3.3)
Flushing/Feeling Hot
3 (5.0)
0 (0)
Increased Blood Pressure
3 (5.0)
0 (0)
Vomiting
3 (5.0)
0 (0)
Edema, Peripheral
2 (3.3)
0 (0)
Pruritus
2 (3.3)
0 (0)
Rash Papular
2 (3.3)
0 (0)
Throat Tightness
2 (3.3)
0 (0)
*
Adverse reactions that occurred in ≥3% of alglucosidase alfa-treated patients and with a higher incidence than placebo-
treated patients
6.2
Postmarketing Experience
The following adverse reactions have been identified during post approval use of alglucosidase
alfa. Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
In the postmarketing experience with LUMIZYME, serious adverse reactions have been
reported, including anaphylaxis [see Boxed Warning and Warnings and Precautions (5.1)].
Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in
infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [see
Boxed Warning and Warning and Precautions (5.3)].
Infusion associated reactions, including pyrexia, chills, fatigue, urticaria, rash, pruritus,
erythema, dyspnea, hypotension, bradycardia, tachycardia, flushing, nausea, headache, and
syncope have been reported with alglucosidase alfa.
In addition to the hypersensitivity reactions reported in clinical trials [see Adverse Reactions
(6.1)], the following hypersensitivity reactions have been reported in at least 2 patients and
included: anaphylactic shock, respiratory failure, respiratory arrest, cardiac arrest, hypoxia,
dyspnea, wheezing, convulsions, peripheral coldness, restlessness, nervousness, back pain,
stridor, pharyngeal edema, abdominal pain, apnea, muscle spasm, and conjunctivitis. In addition,
one case of hyperparathyroidism has been reported.
Systemic and cutaneous immune-mediated reactions, including proteinuria and nephrotic
syndrome secondary to membranous glomerulonephritis, and necrotizing skin lesions have been
reported in postmarketing safety experience with alglucosidase alfa [see Warnings and
Precautions (5.2)].
Reference ID: 5502619
11
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
LUMIZYME during pregnancy. Pregnant women and women of reproductive potential should
be encouraged to enroll in the Pompe patient registry. The registry will monitor the effect of
LUMIZYME on pregnant women and their offspring. For more information, visit
www.registrynxt.com or call 1-800-745-4447, extension 15500.
Risk Summary
Data from postmarketing reports and published case reports with alglucosidase alfa use in
pregnant women have not identified a LUMIZYME-associated risk of major birth defects,
miscarriage, or adverse maternal or fetal outcomes. The continuation of treatment for Pompe
disease during pregnancy should be individualized to the pregnant woman. Untreated Pompe
disease may result in worsening disease symptoms in pregnant women (see Clinical
Considerations).
Reproduction studies performed in mice and rabbits at doses resulting in exposures up to 0.4 or
0.5 times the human steady-state AUC (area under the plasma concentration-time curve),
respectively, during the period of organogenesis revealed no evidence of effects on embryo-fetal
development. In mice there was an increase in pup mortality during lactation at maternal
exposures 0.4 times the human steady-state AUC (see Data).
The background risk of major birth defects and miscarriage in the indicated population is
unknown. All pregnancies have a background risk of birth defect, loss or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo-fetal Risk
Untreated Pompe disease has been associated with worsening respiratory and musculoskeletal
symptoms in some pregnant women.
Data
Animal Data
All reproductive studies included pretreatment with diphenhydramine to prevent or minimize
hypersensitivity reactions. The effects of alglucosidase alfa were evaluated based on comparison
to a control group treated with diphenhydramine alone. Daily intravenous administration of
alglucosidase alfa up to 40 mg/kg in mice and rabbits (0.4 and 0.5 times the human steady-state
AUC, respectively, at the recommended biweekly dose) during the period of organogenesis had
no effects on embryo-fetal development. Administration of 40 mg/kg intravenously every other
day in mice (0.4 times the human steady-state AUC at the recommended biweekly dose) during
the period of organogenesis through lactation produced an increase in mortality of offspring
during the lactation period.
Reference ID: 5502619
12
8.2
Lactation
Risk Summary
Available published literature suggests the presence of alglucosidase alfa in human milk. There
are no reports of adverse effects of alglucosidase alfa on the breastfed infant. There is no
information on the effects of alglucosidase alfa on milk production. The developmental and
health benefits of breastfeeding should be considered along with the mother’s clinical need for
LUMIZYME and any potential adverse effects on the breastfed child from LUMIZYME or from
the underlying maternal condition.
Lactating women with Pompe disease treated with LUMIZYME should be encouraged to enroll
in the Pompe disease registry [see Use in Specific Populations (8.1)].
Clinical Considerations
A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk
during treatment and for 24 hours after LUMIZYME administration in order to minimize drug
exposure to a breastfed infant.
8.4
Pediatric Use
The safety and effectiveness of LUMIZYME has been established in pediatric patients with
Pompe disease [see Adverse Reactions (6.2)].The use of LUMIZYME for this pediatric
indication is supported by evidence from an adequate and well-controlled trial in 57 treatment-
naive pediatric patients with IOPD treated with alglucosidase alfa, aged 0.2 month to 3.5 years at
first infusion, (Trials 1, 2, and 3) [see Clinical Studies (14.1)] and 90 adult and pediatric patients
with LOPD in a randomized, double-blind, placebo-controlled trial including 2 patients 16 years
of age or less [see Clinical Studies (14.2)].
Anaphylaxis, hypersensitivity reactions, and acute cardiorespiratory failure have occurred in
pediatric patients [see Boxed Warning, Warnings and Precautions (5.1, 5.3)]. Additionally,
cardiac arrhythmia and sudden cardiac death have occurred in pediatric patients during general
anesthesia for central venous catheter placement [see Warnings and Precautions (5.4)].
8.5
Geriatric Use
The randomized, double-blind, placebo-controlled study of alglucosidase alfa did not include
sufficient numbers (n=4) of patients aged 65 years and over to determine whether they respond
differently from younger adult patients [see Clinical Studies (14.1)].
11
DESCRIPTION
Alglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme encoded by the
predominant of nine observed haplotypes of the human acid α-glucosidase (GAA) gene.
Alglucosidase alfa is produced by recombinant DNA technology in a Chinese hamster ovary cell
line. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α-1,4- and α-1,6
glycosidic linkages of lysosomal glycogen.
Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 Daltons for the polypeptide
chain, and a total mass of approximately 109,000 Daltons, including carbohydrates.
Alglucosidase alfa has a specific activity of 3.6 to 5.4 units/mg (one unit is defined as that
amount of activity that results in the hydrolysis of 1 micromole of synthetic substrate per minute
Reference ID: 5502619
13
under specified assay conditions). Alglucosidase alfa is intended for intravenous infusion. It is
supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for
reconstitution with 10.3 mL Sterile Water for Injection, USP. Each 50 mg vial contains 52.5 mg
alglucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic
heptahydrate, and 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution
as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of
10 mL at 5 mg/mL alglucosidase alfa. Alglucosidase alfa does not contain preservatives; each
vial is for single dose only.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Pompe disease (acid maltase deficiency, glycogen storage disease type II, GSD II, glycogenosis
type II) is an inherited disorder of glycogen metabolism caused by the absence or marked
deficiency of the lysosomal enzyme GAA.
Alglucosidase alfa provides an exogenous source of GAA. Binding to mannose-6-phosphate
receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA
molecule, after which it is internalized and transported into lysosomes, where it undergoes
proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity
in cleaving glycogen.
12.2
Pharmacodynamics
Clinical pharmacodynamic studies have not been conducted for alglucosidase alfa.
12.3
Pharmacokinetics
The pharmacokinetics of alglucosidase alfa was evaluated in 13 patients with infantile-onset
Pompe disease, aged 1 month to 7 months, who received 20 mg/kg (approximately as a 4-hour
infusion) or 40 mg/kg (approximately as a 6.5-hour infusion) of alglucosidase alfa every 2
weeks. The measurement of alglucosidase alfa plasma concentration was based on an activity
assay using an artificial substrate. Systemic exposure was approximately dose proportional
between the 20 and 40 mg/kg doses. Based on the pharmacokinetic blood samples collected for
12 hours after a 4-hour intravenous infusion of 20 mg/kg (n=5), the estimated mean AUC was
811 mcg∙hr/mL with 17% coefficient of variation [CV], Cmax was 162 mcg/mL with 19% CV,
clearance was 25 mL/hr/kg with 16% CV, and half-life was 2.3 hours with 17% CV.
The pharmacokinetics of alglucosidase alfa was also evaluated in a separate trial of 14 patients
with infantile-onset Pompe disease, aged 6 months to 3.5 years, who received 20 mg/kg of
alglucosidase alfa as a 4-hour infusion every 2 weeks. The pharmacokinetic parameters were
similar to those observed for the infantile-onset Pompe disease patients aged 1 month to 7
months who received the 20 mg/kg dose.
The pharmacokinetics of alglucosidase alfa was evaluated in another trial of 10 adult and 10
pediatric patients with Pompe disease who received a single dose of 20 mg/kg of alglucosidase
alfa as a 4-hour infusion. In pediatric patients, aged 7 months to 13.7 years, the estimated mean
AUC was 1,110 mcg∙hr/mL with 68% CV and Cmax was 204 mcg/mL with 46% CV. In adult
patients, aged 19 to 57 years, the estimated mean AUC was 1,890 mcg∙hr/mL with 51% CV and
Cmax was 307 mcg/mL with 47% CV.
Reference ID: 5502619
14
12.6
Immunogenicity
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
incidence of ADAs in the studies described below with the incidence of ADAs in other studies,
including those of LUMIZYME or of other alglucosidase alfa products.
Immunogenicity in Patients with Infantile-onset Pompe Disease
Thirty-nine patients with infantile-onset Pompe disease (IOPD), aged 1 month to 3.5 years, were
treated with 20 or 40 mg/kg of intravenous alglucosidase alfa every other week for periods that
ranged from 1 to 106 weeks (mean: 61 weeks) in two open-label clinical trials (Trials 1 and 2)
[see Clinical Studies (14.1, 14.2)]. In Trials 1 and 2, 34/38 (89%) of alglucosidase alfa-treated
patients tested positive for anti-alglucosidase alfa antibodies (referred to as ADA).
Immunogenicity in Patients with Late-onset Pompe Disease
Ninety patients with late-onset Pompe disease (LOPD), aged 10 to 70 years, were administered
20 mg/kg of intravenous alglucosidase alfa or intravenous placebo every other week (2:1 ratio)
for 78 weeks in a randomized, double-blinded, placebo-controlled trial (Trial 4) [see Clinical
Studies (14.2)]. In Trial 4, 59/59 (100%) of alglucosidase alfa-treated patients with available
samples developed ADA. These patients were all cross-reactive immunologic material (CRIM)
positive. Most patients who developed ADA did so within the first three months of exposure
(median time to seroconversion was four weeks).
Antibody titers for cellular uptake inhibition were present in 18 of 59 (31%) alglucosidase alfa
treated patients by Week 78. Patients who tested positive for cellular uptake inhibition tended to
have higher IgG titers than patients who tested negative for cellular uptake inhibition. None of
the 59 evaluable patients tested positive for inhibition of enzyme activity.
Immunogenicity in Patients with Infantile-onset Pompe Disease or Late-onset Pompe Disease
Some patients with IOPD or LOPD who were ADA positive in Trials 1, 2 and 4 tested positive
for inhibition of enzyme activity and/or uptake in in vitro assays. However, the clinical relevance
of this in vitro inhibition is unclear.
Negative CRIM status (indicating no endogenous enzyme is detected) is a risk factor for
LUMIZYME-treated patients to develop high and sustained ADA titers. However, high and
sustained ADA titers have also occurred in a limited number of CRIM-positive patients,
generally with very low endogenous enzyme.
Anti-Drug Antibody Effects on Pharmacokinetics
In Trials 1 and 2, 19 of 21 (90%) alglucosidase alfa-treated patients with IOPD - who had
pharmacokinetics (PK) and antibody titer data available at Week 12 - developed ADA. Of these
19 patients, 5 patients with antibody titers ≥12,800 at Week 12 had a 50% mean increase in
clearance (range 5% to 90%) from Week 1 to Week 12, while the 14 patients with antibody titers
<12,800 at Week 12 had no significant change in the mean clearance values at Week 1 and Week
12.
Reference ID: 5502619
15
In Trial 4, 5/32 (16%) of alglucosidase alfa-treated patients with LOPD that had evaluable PK
samples tested positive for cellular uptake inhibition. An approximately 1.2-fold to 1.8- fold
greater clearance was observed at Week 52 in 4 of 5 patients that tested positive for antibodies
that inhibit the cellular uptake of enzyme in an in vitro assay compared to Week 0. PK in 4 of
these 5 patients over time indicated an increase in clearance with increase in IgG titer.
Anti-Drug Antibody Effects on Safety and Efficacy
A small number of alglucosidase alfa-treated patients with LOPD who tested positive for
alglucosidase alfa-specific IgE antibodies experienced anaphylactic reactions [see Warnings and
Precautions (5.1)].
Some alglucosidase alfa-treated patients who developed high sustained ADA titers had reduced
efficacy. Furthermore, CRIM-negative infants have shown reduced clinical effect in the presence
of high sustained ADA titers with inhibitory activity [see Warnings and Precautions (5.6)].
There was no identified clinically significant effect of high ADA titers on the development of
IARs in LUMIZYME-treated patients.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic
potential have not been performed with alglucosidase alfa.
Intravenous administration of alglucosidase alfa every other day in mice at doses up to 40 mg/kg
(0.4 times the human AUC at the recommended biweekly dose) had no effect on fertility and
reproductive performance.
14
CLINICAL STUDIES
14.1
Clinical Trials in Infantile-Onset Pompe Disease
The safety and effectiveness of alglucosidase alfa in the treatment patients with infantile-onset
Pompe disease (IOPD) were assessed in 57 treatment-naive infantile-onset Pompe disease
patients, aged 0.2 month to 3.5 years at first alglucosidase alfa infusion, in three separate open-
label, single-arm clinical trials (Trials 1, 2, and 3).
Trial 1 (Patients with IOPD)
Trial 1 was an international, multicenter, open-label, clinical trial of 18 patients with IOPD. This
trial was conducted between 2003 and 2005. Patients were randomized 1:1 to receive either 20
mg/kg or 40 mg/kg of intravenous alglucosidase alfa every two weeks, with length of treatment
ranging from 52 to 106 weeks. Enrollment was restricted to patients 7 months of age or younger
at first infusion with clinical signs of Pompe disease and cardiac hypertrophy, and who did not
require ventilatory support at trial entry. Fourteen patients were cross reactive immunologic
material (CRIM) positive, and 4 patients were CRIM negative.
Efficacy was assessed by comparing the proportions of alglucosidase alfa-treated patients who
died or needed invasive ventilator support at 18 months of age with the mortality experience of a
historical cohort of untreated patients with IOPD with similar age and disease severity. In the
Reference ID: 5502619
16
historical cohort, 61 untreated patients with IOPD diagnosed by age 6 months, born between
1982 and 2002, were identified by a retrospective review of medical charts. By 18 months of
age, 15 of 18 (83%) alglucosidase alfa-treated patients were alive without invasive ventilatory
support and 3 (17%) required invasive ventilator support, whereas only one of the 61 (2%)
historical control patients was alive. No differences in outcome were observed between patients
who received 20 mg/kg versus 40 mg/kg.
Other outcome measures in this trial included unblinded assessments of motor function by the
Alberta Infant Motor Scale (AIMS), a measure of infant motor performance that assesses motor
maturation of the infant through age 18 months. Although gains in motor function were noted in
13 patients, the motor function was substantially delayed compared to normal infants of
comparable age in the majority of patients. Two of 9 patients who had initially demonstrated
gains in motor function after 12 months of alglucosidase alfa treatment regressed despite
continued treatment.
Changes from baseline to Month 12 in left ventricular mass index (LVMI), a measure of
pharmacodynamic effect, were evaluated by echocardiography. Fifteen patients who underwent
both baseline and Month 12 echocardiograms demonstrated decreases from baseline in LVMI
(mean decrease 118 g/m2, range 45 to 193 g/m2). However, the magnitude of the decrease in
LVMI did not correlate with the clinical outcome measure of ventilator-free survival.
Trial 2 (Patients with IOPD)
Trial 2 was an international, multicenter, non-randomized, open-label clinical trial that enrolled
21 patients with IOPD aged 3 months to 3.5 years at first infusion. Eighteen patients were CRIM
positive and 3 patients were CRIM negative. All patients received intravenous 20 mg/kg
alglucosidase alfa every other week for up to 104 weeks. Five of 21 patients were receiving
invasive ventilatory support at the time of first infusion.
The primary outcome measure was the proportion of patients alive at the conclusion of
treatment. At the 52-week interim analysis, 16 of 21 patients were alive. Sixteen patients were
free of invasive ventilatory support at the time of first infusion; of these, 4 died, 2 required
invasive ventilatory support, and 10 were free of invasive ventilatory support after 52 weeks of
treatment. For the 5 patients who were receiving invasive ventilatory support at baseline, 1 died,
and 4 remained on invasive ventilatory support at Week 52.
Trial 3 (Patients with IOPD)
Trial 3 was an open-label, single-center trial in 18 patients with IOPD who had a confirmed
diagnosis of Pompe disease as identified through a newborn screening program. All patients
were CRIM positive. Patients were treated with intravenous alglucosidase alfa prior to 6 months
of age (0.2 to 5.8 months at first infusion). Sixteen patients reached 18 months of age at the time
of analysis, and all (100%) were alive without invasive ventilator support.
14.2
Clinical Trials in Late-Onset Pompe Disease
The safety and efficacy of alglucosidase alfa were assessed in 90 patients with late-onset Pompe
disease (LOPD), aged 10 to 70 years, in a randomized, double-blind, placebo-controlled trial
(Trial 4). All patients were naive to enzyme replacement therapy. Patients were allocated in a 2:1
ratio and received 20 mg/kg of intravenous alglucosidase alfa (n=60) or intravenous placebo
(n=30) every other week for 78 weeks (18 months).
Reference ID: 5502619
17
60
C:
59
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<I.)
58
~
57
:;-
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56
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55
<I.) ...
54
a..
~
0 .__,
53
E
Oil
52
·i::
51
Q.
::;:i
50
u >
49
u..
48
47
46
I
-
Alglucosidase alfa
., • .,,. Placebo
~A-~
•• -•• -•• -.-•. -•. -•. -•. -•. •~-.----------·'-----------.♦-----·
• .......... . ..
·····•·················•···············■·······••••••••••••
0
12
26
38
52
64
78
Study Visit (Weeks)
Note: ANCOVA least squares means adjusting for baseline values
The youngest alglucosidase alfa-treated patient was 16 years of age, and the youngest placebo-
treated patient was 10 years of age. The trial population included 34 males and 26 females
(n=60) in the alglucosidase alfa group and 11 males and 19 females (n=30) in the placebo group.
At baseline, all patients were ambulatory (some required assistive walking devices), did not
require invasive ventilator support or non-invasive ventilation while awake and sitting upright,
and had a forced vital capacity (FVC) between 30 and 79% of predicted in the sitting position.
Patients who could not walk 40 meters in 6 minutes or were unable to perform appropriate
pulmonary and muscle function testing were excluded from the study.
A total of 81 of 90 patients completed the trial. Of the 9 patients who discontinued, 5 were in the
alglucosidase alfa group and 4 were in the placebo group. Three patients discontinued the study
due to an adverse event; two patients were in the alglucosidase alfa treatment group and one
patient was in placebo group.
At trial entry, the mean % predicted FVC in the sitting position among all patients was about
55%. After 78 weeks, the mean % predicted FVC increased to 56.2% for alglucosidase alfa
treated patients and decreased to 52.8% for placebo-treated patients indicating an alglucosidase
alfa treatment effect of 3.4% (95% confidence interval: [1.3% to 5.5%]; p=0.004). Stabilization
of % predicted FVC in the alglucosidase alfa-treated patients was observed (see Figure 1).
Figure 1: Mean FVC Upright (% Predicted) Over Time in Patients with LOPD (Trial 4)
At trial entry, the mean 6 minute walk test (6MWT) among all patients was about 330 meters.
After 78 weeks, the mean 6MWT increased by 25 meters for alglucosidase alfa-treated patients
and decreased by 3 meters for placebo-treated patients indicating an alglucosidase alfa treatment
effect of 28 meters (95% confidence interval: [-1 to 52 meters]; p=0.06) (see Figure 2).
Reference ID: 5502619
18
390
380
370
c::
ro
360
'°,-._
~t
t;~
350
~~
340
..><:.::
o:i <O
330
~g
'° ro
320
-;.~
.so
310
~°E
~ 0
300
·- f-,
c..n '--'
290
280
270
0
-
Alglucosidase alfa
•• .,,. Placebo
·············•············· .. ············•·················•··············•·················•
12
26
38
52
64
78
SU1dy Visit (Weeks)
Note: ANCOVA least squares means adjusting for baseline values
Figure 2: Mean Six Minute Walk Test Total Distance Walked Over Time in Patients with
LOPD (Trial 4)
16
HOW SUPPLIED/STORAGE AND HANDLING
LUMIZYME 50 mg vials are supplied as a sterile, nonpyrogenic, preservative-free, white to off-
white lyophilized cake or powder in single-dose vials.
NDC 58468-0160-1 (Carton of one single-dose vial)
NDC 58468-0160-2 (Carton of ten single-dose vials)
Store LUMIZYME under refrigeration between 2°C and 8°C (36°F and 46°F). Do not use
LUMIZYME after the expiration date on the vial.
17
PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions Including Anaphylaxis, Infusion-Associated Reactions (IARs) and
Immune-Mediated Reactions
Advise the patient and caregiver that life-threatening hypersensitivity reactions, including
anaphylaxis, IARs, and immune-mediated reactions may occur with LUMIZYME treatment.
Advise the patient and caregiver that anaphylaxis and immune-mediated reactions may occur
during the early course of enzyme replacement therapy and after extended duration of therapy.
Reference ID: 5502619
19
Inform the patient and caregiver of the symptoms of life-threatening hypersensitivity reactions
including anaphylaxis, IARs, and immune-mediated reactions and have them seek immediate
medical care should these symptoms occur [see Warning and Precautions (5.1, 5.2, 5.3)].
Risk of Acute Cardiorespiratory Failure
Advise the patient and caregiver that patients with underlying respiratory illness or compromised
cardiac or respiratory function may be at risk of acute cardiorespiratory failure. Patients with
compromised cardiac or respiratory function may require close observation during and after
alglucosidase alfa administration.
Pompe Registry
Inform the patient and their caregiver(s) that the Pompe Registry has been established to better
understand the variability and progression of Pompe disease, and to continue to monitor and
evaluate long-term effects of LUMIZYME on pregnant women and their offspring [see Use in
Specific Populations (8.1)]. Inform the patient and their caregiver(s) that their participation is
voluntary and may involve long-term follow-up and to visit www.registrynxt.com or call 1-800
745-4447, extension 15500.
LUMIZYME is manufactured and distributed by:
Genzyme Corporation
Cambridge, MA 02141
1-800-745-4447 (phone)
A SANOFI COMPANY
U.S. License Number: 1596
LUMIZYME and GENZYME are registered trademarks of Genzyme Corporation.
Reference ID: 5502619
20
| custom-source | 2025-02-12T15:48:23.339215 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125291s161lbl.pdf', 'application_number': 125291, 'submission_type': 'SUPPL ', 'submission_number': 161} |
80,778 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use OPDIVO
QVANTIG safely and effectively. See full prescribing information for
OPDIVO QVANTIG.
OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy) injection, for
subcutaneous use
Initial U.S. Approval: 2024
---------------------------INDICATIONS AND USAGE---------------------------
OPDIVO QVANTIG is a combination of nivolumab, a programmed death
receptor-1 (PD-1)-blocking antibody, and hyaluronidase, an endoglycosidase,
indicated for the treatment of:
Renal Cell Carcinoma (RCC)
adult patients with intermediate or poor risk advanced RCC, as a first-line
treatment following combination treatment with intravenous nivolumab and
ipilimumab. (1.1)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of renal cell carcinoma.
adult patients with advanced RCC, as a first-line treatment in combination
with cabozantinib. (1.1)
adult patients with advanced RCC who have received prior anti-angiogenic
therapy. (1.1)
Melanoma
adult patients with unresectable or metastatic melanoma. (1.2)
adult patients with unresectable or metastatic melanoma following
combination treatment with intravenous nivolumab and ipilimumab. (1.2)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of unresectable or metastatic
melanoma.
for the adjuvant treatment of adult patients with completely resected Stage
IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.3)
Non-Small Cell Lung Cancer (NSCLC)
adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in the
neoadjuvant setting, in combination with platinum-doublet chemotherapy.
(1.4)
adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and
no known EGFR mutations or ALK rearrangements, for neoadjuvant
treatment, in combination with platinum-doublet chemotherapy, followed by
OPDIVO QVANTIG monotherapy as adjuvant treatment after surgery. (1.5)
adult patients with metastatic NSCLC and progression on or after platinum-
based chemotherapy. Patients with EGFR or ALK genomic tumor
aberrations should have disease progression on FDA-approved therapy for
these aberrations prior to receiving OPDIVO QVANTIG. (1.6)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of metastatic NSCLC.
Squamous Cell Carcinoma of the Head and Neck (SCCHN)
adult patients with recurrent or metastatic SCCHN with disease progression
on or after a platinum-based therapy. (1.7)
Urothelial Carcinoma (UC)
adjuvant treatment of adult patients with UC who are at high risk of
recurrence after undergoing radical resection of UC. (1.8)
adult patients with unresectable or metastatic urothelial carcinoma, as first-
line treatment in combination with cisplatin and gemcitabine. (1.8)
adult patients with locally advanced or metastatic UC who:
have disease progression during or following platinum-containing
chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy. (1.8)
Colorectal Cancer
adult patients with MSI-H or dMMR metastatic CRC that has progressed
following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as
monotherapy or as monotherapy following combination treatment with
intravenous nivolumab and ipilimumab.a (1.9)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.
Hepatocellular Carcinoma (HCC)
adult patients with HCC previously treated with sorafenib and following
combination treatment with intravenous nivolumab and ipilimumab.a (1.10)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of HCC.
Esophageal Cancer
adult patients with completely resected esophageal or gastroesophageal
junction cancer with residual pathologic disease, who have received
neoadjuvant chemoradiotherapy (CRT). (1.11)
adult patients with unresectable advanced or metastatic esophageal
squamous cell carcinoma as first-line treatment in combination with
fluoropyrimidine- and platinum-containing chemotherapy. (1.11)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of patients with unresectable advanced
or metastatic ESCC.
adult patients with unresectable advanced, recurrent or metastatic
esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine
and platinum-based chemotherapy. (1.11)
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
adult patients with advanced or metastatic gastric cancer, gastroesophageal
junction cancer, and esophageal adenocarcinoma in combination with
fluoropyrimidine- and platinum-containing chemotherapy. (1.12)
a This indication is approved under accelerated approval based on overall
response rate and duration of response. Continued approval for this indication
may be contingent upon verification and description of clinical benefit in
confirmatory trials.
-------------------------DOSAGE AND ADMINISTRATION-------------------
OPDIVO QVANTIG has different dosage and administration
instructions than intravenous nivolumab products.
OPDIVO QVANTIG is for subcutaneous use only in the abdomen or
thigh.
OPDIVO QVANTIG is to be administered by a healthcare professional
only. (2.1)
OPDIVO QVANTIG is for subcutaneous use only.
Administer by subcutaneous injection over 3-5 minutes. (2.1)
Renal cell carcinoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks administered in combination with cabozantinib 40 mg once daily
without food. (2.2)
Melanoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Neoadjuvant and adjuvant treatment of resectable (tumors ≥4 cm or node
positive) non-small cell lung cancer
900 mg/15,000 units with platinum-doublet chemotherapy on the same
day every 3 weeks for 3 cycles, then single-agent OPDIVO QVANTIG
1,200 mg/20,000 units every 4 weeks after surgery for up to 13 cycles.
(2.2)
Metastatic non-small cell lung cancer
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Squamous cell carcinoma of the head and neck
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Urothelial carcinoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
First-line unresectable or metastatic urothelial carcinoma
900 mg/15,000 units every 3 weeks with cisplatin and gemcitabine on the
same day for up to 6 cycles, then 600 mg/10,000 units every 2 weeks or
1,200 mg/20,000 units every 4 weeks. (2.2)
Colorectal cancer
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Hepatocellular carcinoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Esophageal cancer
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks administered in combination with fluoropyrimidine- and platinum-
containing chemotherapy. (2.2)
Reference ID: 5503299
1
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
600
mg/10,000
units
every
2
weeks
in
combination
with
fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks.
(2.2)
900 mg/15,000 units every 3 weeks with fluoropyrimidine- and platinum-
containing chemotherapy every 3 weeks. (2.2)
See full Prescribing Information for preparation and administration
instructions and dosage modifications for adverse reactions.
---------------------DOSAGE FORMS AND STRENGTHS--------------------
Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120
mg/2,000 units per mL) in a single-dose vial. (3)
------------------------------CONTRAINDICATIONS-----------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS----------------------
Immune-Mediated Adverse Reactions: (5.1)
○ Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue, including the following: immune-
mediated pneumonitis, immune-mediated colitis, immune-mediated
hepatitis and hepatotoxicity, immune-mediated endocrinopathies,
immune-mediated
dermatologic
adverse
reactions, and
immune-
mediated nephritis and renal dysfunction.
○ Monitor for early identification and management. Evaluate liver enzymes,
creatinine, and thyroid function at baseline and periodically during
treatment.
○ Withhold or permanently discontinue based on severity and type of
reaction. (2.3)
Complications of allogeneic HSCT: Fatal and other serious complications
can occur in patients who receive allogeneic HSCT before or after being
treated with a PD-1/PD-L1 blocking antibody. (5.2)
Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive
potential of potential risk to a fetus and to use effective contraception. (5.3,
8.1, 8.3)
Treatment of patients with multiple myeloma with a PD-1 or PD-L1
blocking antibody in combination with a thalidomide analogue plus
dexamethasone is not recommended outside of controlled clinical trials.
(5.4)
-------------------------------ADVERSE REACTIONS----------------------------
Most common adverse reactions (10%) with OPDIVO QVANTIG as
monotherapy in patients with Renal Cell Carcinoma were:
musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea,
cough, and abdominal pain. (6.1)
Safety of OPDIVO QVANTIG for the following indications is based on
safety of intravenous nivolumab in these populations. The most common
adverse reactions with intravenous nivolumab for these indications are
presented below.
As monotherapy for the treatment of advanced renal cell carcinoma;
adjuvant treatment of completely resected Stage IIB, IIC, III, or IV
melanoma; unresectable or metastatic melanoma; adjuvant treatment of
NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck;
urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma;
esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea,
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back
pain, arthralgia, upper respiratory tract infection, pyrexia, headache,
abdominal pain, vomiting, and urinary tract infection. (6.1)
In combination with cabozantinib for the first-line treatment of advanced
renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar
erythrodysesthesia
syndrome,
stomatitis,
rash,
hypertension,
hypothyroidism, musculoskeletal pain, decreased appetite, nausea,
dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)
In combination with platinum-doublet chemotherapy for the neoadjuvant
treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and
rash. (6.1)
In combination with cisplatin and gemcitabine for the treatment of urothelial
cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased
appetite, rash, vomiting, and peripheral neuropathy. (6.1)
In combination with fluoropyrimidine-
and platinum-
containing
chemotherapy for the treatment of esophageal cancer and gastric cancer:
nausea, peripheral neuropathy, decreased appetite, fatigue, constipation,
stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb
at
1-800-721-5072
or
FDA
at
1-800-FDA-1088
or
www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS----------------------
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Advanced Renal Cell Carcinoma
1.2
Unresectable or Metastatic Melanoma
1.3
Adjuvant Treatment of Melanoma
1.4
Neoadjuvant Treatment of Resectable Non-Small
Cell Lung Cancer
1.5
Neoadjuvant and Adjuvant Treatment of Resectable
Non-Small Cell Lung Cancer
1.6
Metastatic Non-Small Cell Lung Cancer
1.7
Squamous Cell Carcinoma of the Head and Neck
1.8
Urothelial Carcinoma
1.9
Microsatellite Instability-High or Mismatch Repair
Deficient Metastatic Colorectal Cancer
1.10
Hepatocellular Carcinoma
1.11
Esophageal Cancer
1.12
Gastric Cancer, Gastroesophageal Junction Cancer,
and Esophageal Adenocarcinoma
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage and Administration Information
2.2
Recommended Dosage
2.3
Dose Modifications
2.4
Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Severe and Fatal Immune-Mediated Adverse
Reactions
2
5.2
Complications of Allogeneic Hematopoietic Stem
Cell Transplantation
5.3
Embryo-Fetal Toxicity
5.4
Increased Mortality in Patients with Multiple
Myeloma when Nivolumab Is Added to a
Thalidomide Analogue and Dexamethasone
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.6
Immunogenicity
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Advanced Renal Cell Carcinoma
Reference ID: 5503299
14.2
14.3
14.4
14.5
14.6
14.7
Unresectable or Metastatic Melanoma
Adjuvant Treatment of Melanoma
Neoadjuvant Treatment of Resectable Non-Small
Cell Lung Cancer
Neoadjuvant and Adjuvant Treatment of Resectable
Non-Small Cell Lung Cancer
Metastatic Non-Small Cell Lung Cancer
Recurrent or Metastatic Squamous Cell Carcinoma
of the Head and Neck
14.11
Esophageal Cancer
14.12
Gastric Cancer, Gastroesophageal Junction Cancer,
and Esophageal Adenocarcinoma
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
14.8
14.9
Urothelial Carcinoma
Microsatellite Instability-High or Mismatch Repair
Deficient Metastatic Colorectal Cancer
*Sections or subsections omitted from the full prescribing information
are not listed.
14.10
Hepatocellular Carcinoma
Reference ID: 5503299
3
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Advanced Renal Cell Carcinoma
OPDIVO QVANTIG™, as monotherapy, is indicated for the first-line treatment of adult patients
with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with
intravenous nivolumab and ipilimumab combination therapy.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of renal cell carcinoma.
OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of
adult patients with advanced RCC.
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
advanced RCC who have received prior anti-angiogenic therapy.
1.2
Unresectable or Metastatic Melanoma
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
unresectable or metastatic melanoma.
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
unresectable or metastatic melanoma following treatment with intravenous nivolumab and
ipilimumab combination therapy.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of unresectable or metastatic melanoma.
1.3
Adjuvant Treatment of Melanoma
OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients
with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.
1.4
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated as
neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small
cell lung cancer (NSCLC).
1.5
Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell
Lung Cancer
OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated for the
neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC
and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase
(ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting
after surgical resection.
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1.6
Metastatic Non-Small Cell Lung Cancer
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO
QVANTIG.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of metastatic NSCLC.
1.7
Squamous Cell Carcinoma of the Head and Neck
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease
progression on or after platinum-based therapy.
1.8
Urothelial Carcinoma
OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients
with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical
resection of UC.
OPDIVO QVANTIG, in combination with cisplatin and gemcitabine, is indicated for the first-line
treatment of adult patients with unresectable or metastatic UC.
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with locally
advanced or metastatic UC who:
have disease progression during or following platinum-containing chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
1.9
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic
Colorectal Cancer
OPDIVO QVANTIG, as monotherapy or as monotherapy following treatment with intravenous
nivolumab and ipilimumab combination therapy, is indicated for the treatment of adult patients
with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC
that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of MSI-H or dMMR metastatic CRC.
This indication is approved under accelerated approval based on overall response rate and duration
of response [see Clinical Studies (14.9)]. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in confirmatory trials.
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Reference ID: 5503299
1.10
Hepatocellular Carcinoma
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
hepatocellular carcinoma (HCC) who have been previously treated with sorafenib and following
treatment with intravenous nivolumab and ipilimumab.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of patients with HCC.
This indication is approved under accelerated approval based on overall response rate and duration
of response [see Clinical Studies (14.10)]. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in the confirmatory trials.
1.11
Esophageal Cancer
OPDIVO QVANTIG as monotherapy, is indicated for the adjuvant treatment of completely
resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult
patients who have received neoadjuvant chemoradiotherapy (CRT).
OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing
chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced
or metastatic esophageal squamous cell carcinoma (ESCC).
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of patients with unresectable advanced or metastatic ESCC.
OPDIVO QVANTIG as monotherapy, is indicated for the treatment of adult patients with
unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-
based chemotherapy.
1.12
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing
chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric
cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage and Administration Information
OPDIVO QVANTIG has different dosage and administration instructions than
intravenously administered nivolumab products [see Dosage and Administration (2.4)].
OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not
administer intravenously.
OPDIVO QVANTIG is to be administered by a healthcare professional only.
Adult patients currently receiving intravenous nivolumab as a single agent, or in combination with
chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next
scheduled dose.
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2.2
Recommended Dosage
The recommended dosages of OPDIVO QVANTIG as monotherapy agent are presented in
Table 1.
Table 1:
Recommended Dosages for OPDIVO QVANTIG as Monotherapy
Indication
Recommended OPDIVO QVANTIG
Dosage
Duration of Therapy
Advanced renal cell carcinoma†
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Until disease
progression or
unacceptable toxicity
Unresectable or metastatic melanoma†
Metastatic non-small cell lung cancer
Squamous cell carcinoma of the head and
neck
Locally advanced or metastatic urothelial
carcinoma
Microsatellite instability-high or mismatch
repair deficient metastatic colorectal cancer†
Hepatocellular carcinoma†
Esophageal squamous cell carcinoma
Adjuvant treatment of melanoma
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Until disease
recurrence or
unacceptable toxicity
for up to 1 year
Adjuvant treatment of urothelial carcinoma
Adjuvant treatment of resected esophageal or
gastroesophageal junction cancer
† Dosing recommendations for both monotherapy or following intravenous nivolumab and ipilimumab combination
therapy.
* Administer over 3-5 minutes.
The recommended dosages of OPDIVO QVANTIG in combination with other therapeutic agents
are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent
administered in combination with OPDIVO QVANTIG for the recommended dosage information,
as appropriate.
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Table 2:
Recommended Dosages for OPDIVO QVANTIG in Combination
with Other Therapeutic Agents
Indication
Recommended OPDIVO QVANTIG
Dosage
Duration of Therapy
Advanced renal cell
carcinoma
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Administer OPDIVO QVANTIG in
combination with cabozantinib 40 mg
orally once daily without food
OPDIVO QVANTIG: Until disease
progression, unacceptable toxicity, or up
to 2 years
Cabozantinib: Until disease progression
or unacceptable toxicity
Neoadjuvant treatment
of resectable non-small
cell lung cancer
900 mg nivolumab and 15,000 units
hyaluronidase* with platinum-doublet
chemotherapy on the same day every 3
weeks
In combination with platinum-doublet
chemotherapy for 3 cycles
Neoadjuvant and
adjuvant treatment of
resectable non-small
cell lung cancer
Neoadjuvant: 900 mg nivolumab and
15,000 units hyaluronidase* with
platinum-doublet chemotherapy on the
same day every 3 weeks
Neoadjuvant: in combination with
platinum-doublet chemotherapy until
disease progression or unacceptable
toxicity, for up to 4 cycles
Adjuvant: 1,200 mg nivolumab and 20,000
units hyaluronidase* every 4 weeks
Adjuvant: following neoadjuvant therapy
and surgery, administer as a single agent
until disease progression, recurrence, or
unacceptable toxicity, for up to 13 cycles
(up to 1 year)
First-line unresectable
or metastatic urothelial
carcinoma
900 mg nivolumab and 15,000 units
hyaluronidase* every 3 weeks
Administer OPDIVO QVANTIG in
combination with cisplatin and
gemcitabine on the same day every 3
weeks
In combination with cisplatin and
gemcitabine for up to 6 cycles
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
After completing up to 6 cycles of
combination therapy, administer as single
agent until disease progression,
unacceptable toxicity, or up to 2 years
from first dose
Esophageal squamous
cell carcinoma
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Administer OPDIVO QVANTIG in
combination with fluoropyrimidine- and
platinum-containing chemotherapy
Until disease progression, unacceptable
toxicity, or up to 2 years
Chemotherapy: Until disease progression
or unacceptable toxicity
Gastric cancer,
gastroesophageal
junction cancer, and
600 mg nivolumab and 10,000 units
hyaluronidase* with fluoropyrimidine- and
OPDIVO QVANTIG: Until disease
progression, unacceptable toxicity, or up
to 2 years
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Table 2:
Recommended Dosages for OPDIVO QVANTIG in Combination
with Other Therapeutic Agents
Indication
Recommended OPDIVO QVANTIG
Dosage
Duration of Therapy
esophageal
adenocarcinoma
platinum-containing chemotherapy every 2
weeks
or
900 mg nivolumab and 15,000 units
hyaluronidase* with fluoropyrimidine- and
platinum-containing chemotherapy every 3
weeks
Chemotherapy: Until disease progression
or unacceptable toxicity
* Administer over 3-5 minutes.
2.3
Dose Modifications
No dose reduction for OPDIVO QVANTIG is recommended. In general, withhold OPDIVO
QVANTIG for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue
OPDIVO QVANTIG for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent
severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment,
or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day
within 12 weeks of initiating steroids.
Dosage modifications for OPDIVO QVANTIG or OPDIVO QVANTIG in combination with other
anti-cancer agents for adverse reactions that require management different from these general
guidelines are summarized in Table 3 and Table 4.
Table 3:
Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction
Severity
Dosage
Modification
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Pneumonitis
Grade 2
Withholda
Grade 3 or 4
Permanently
discontinue
Colitis
For colitis in patients treated with combination
therapy with ipilimumab, see Table 4.
Grade 2 or 3
Withholda
Grade 4
Permanently
discontinue
Hepatitis with no tumor involvement of the liver
For liver enzyme elevations in patients treated
with combination therapy with cabozantinib, see
Table 4.
AST/ALT increases to >3 and ≤8
times ULN
or
Total bilirubin increases to >1.5 and
≤3 times ULN.
Withholda
AST or ALT increases to >8 times
ULN
or
Permanently
discontinue
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Total bilirubin increases to >3 times
ULN.
Hepatitis with tumor involvement of the liverb
Baseline AST/ALT is >1 and ≤3
times ULN and increases to >5 and
≤10 times ULN
or
Baseline AST/ALT is >3 and ≤5
times ULN and increases to >8 and
≤10 times ULN.
Withholda
AST/ALT increases to >10 times
ULN
or
Total bilirubin increases to >3 times
ULN.
Permanently
discontinue
Endocrinopathiesc
Grade 3 or 4
Withhold until
clinically stable or
permanently
discontinue
depending on
severity
Nephritis with Renal Dysfunction
Grade 2 or 3 increased blood
creatinine
Withholda
Grade 4 increased blood creatinine
Permanently
discontinue
Exfoliative Dermatologic Conditions
Suspected SJS, TEN, or DRESS
Withhold
Confirmed SJS, TEN, or DRESS
Permanently
discontinue
Myocarditis
Grades 2, 3, or 4
Permanently
discontinue
Neurological Toxicities
Grade 2
Withholda
Grade 3 or 4
Permanently
discontinue
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently
discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to
10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO
QVANTIG based on recommendations for hepatitis with no liver involvement.
c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with
hormone replacement. Resume once acute symptoms have resolved.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and
Systemic Symptoms, SJS = Stevens-Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of
normal
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Table 4:
Recommended Dosage Modifications for Adverse Reactions in
Patients Treated with Combination Therapy
Treatment
Adverse
Reaction
Severity
Dosage Modification
OPDIVO
QVANTIG in
combination with
cabozantinib
Liver enzyme
elevations
ALT or AST >3 times ULN but ≤10
times ULN with concurrent total
bilirubin <2 times ULN
Withholda both OPDIVO
QVANTIG and cabozantinib until
adverse reactions recoverb to
Grades 0-1
ALT or AST >10 times ULN or >3
times ULN with concurrent total
bilirubin ≥2 times ULN
Permanently discontinuea both
OPDIVO QVANTIG and
cabozantinib
a Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO QVANTIG is withheld or discontinued
when administered in combination with cabozantinib.
b After recovery, rechallenge with one or both of OPDIVO QVANTIG and cabozantinib may be considered. If
rechallenging with cabozantinib with or without OPDIVO QVANTIG, refer to cabozantinib Prescribing
Information.
2.4
Preparation and Administration
To prevent medication errors, check the vial labels to ensure that the drug being prepared and
administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do
NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be
administered by a healthcare professional.
Each OPDIVO QVANTIG vial is for one-time use only. It is a ready-to-use solution for injection.
It should not be diluted.
Visually inspect for particulate matter and discoloration prior to administration. OPDIVO
QVANTIG is a clear to opalescent, colorless to yellow solution. Discard if the solution is
discolored or contains extraneous particulate matter other than a few translucent-to-white particles.
Do not shake.
Preparation
No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and
polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane,
polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets.
A syringe and a transfer needle are needed to withdraw OPDIVO QVANTIG solution from the
vial. OPDIVO QVANTIG may be injected subcutaneously using a 23G-25G (3/8”-5/8”)
hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly).
600 mg nivolumab and 10,000 units hyaluronidase
o Allow 1 OPDIVO QVANTIG vial to reach room temperature, then withdraw 5 mL of
OPDIVO QVANTIG into the syringe.
900 mg nivolumab and 15,000 units hyaluronidase
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o Allow 2 OPDIVO QVANTIG vials to reach room temperature, then withdraw 5 mL
from one vial and 2.5 mL from the other vial, for a total volume of 7.5 mL of OPDIVO
QVANTIG into a single syringe.
1,200 mg nivolumab and 20,000 units hyaluronidase
o Allow 2 OPDIVO QVANTIG vials to reach room temperature, then withdraw 10 mL
of OPDIVO QVANTIG into a single syringe.
Select the appropriate syringe label provided in the carton that matches the prescribed dose and
apply to the prepared syringe.
Discard partially used or empty vials of OPDIVO QVANTIG.
If the dose is not to be used immediately, attach a tip cap to the syringe prior to storage. To avoid
clogging of the hypodermic injection needle, attach a 23G-25G (3/8”-5/8”) hypodermic injection
needle to the syringe immediately prior to administration.
Storage in Syringe
Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used
immediately, store the syringe:
In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 48 hours; do
not freeze, or
At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room
temperature for this duration does not require protection from light.
Discard if storage time exceeds these limits.
If stored in the refrigerator, allow the solution to come to room temperature before
administration.
Administration
Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4
quadrants of the abdomen, or thigh over a period of 3 to 5 minutes.
Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive
injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where
there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted,
continue administering at the same site, or at an alternate site.
During treatment with OPDIVO QVANTIG, do not administer other subcutaneous
medications at the same site used for OPDIVO QVANTIG.
3
DOSAGE FORMS AND STRENGTHS
Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per
mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial.
4
CONTRAINDICATIONS
None.
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5
WARNINGS AND PRECAUTIONS
5.1
Severe and Fatal Immune-Mediated Adverse Reactions
OPDIVO QVANTIG is a combination of a monoclonal antibody that belongs to a class of drugs
that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking
the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially
breaking peripheral tolerance, and inducing immune-mediated adverse reactions, and an
endoglycosidase used to increase the dispersion and absorption of co-administered drugs when
administered subcutaneously. Important immune-mediated adverse reactions listed under
Warnings and Precautions may not include all possible severe and fatal immune-mediated
reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system
or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a
PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest
during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can
also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure
safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that
may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases
of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude
alternative etiologies, including infection. Institute medical management promptly, including
specialty consultation as appropriate.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage
and Administration (2.3)]. In general, if OPDIVO QVANTIG requires interruption or
discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate
corticosteroid taper and continue to taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose immune-mediated adverse reactions are not
controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic
steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO QVANTIG can cause immune-mediated pneumonitis, which is defined as requiring use
of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking
antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic
radiation.
Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO
QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions. Pneumonitis led to
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permanent discontinuation of OPDIVO QVANTIG in 1.6% and withholding of OPDIVO
QVANTIG in 1.6% of patients.
Systemic corticosteroids were required in 100% (7/7) of patients with pneumonitis. Pneumonitis
resolved in 27% of the 7 patients. Of the 4 patients in whom OPDIVO QVANTIG was withheld
for pneumonitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%)
had recurrence of pneumonitis.
Immune-Mediated Colitis
OPDIVO QVANTIG can cause immune-mediated colitis, defined as requiring use of
corticosteroids and no clear alternate etiology. A common symptom included in the definition of
colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients
with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory
colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG,
including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions. Colitis led to withholding of
OPDIVO QVANTIG in 2.0% of patients.
Systemic corticosteroids were required in 100% (7/7) of patients with colitis. Colitis resolved in
71% of the 7 patients. Of the 5 patients in whom OPDIVO QVANTIG was withheld for colitis, 3
reinitiated OPDIVO QVANTIG after symptom improvement; of these, 2 (67%) had recurrence of
colitis.
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO QVANTIG can cause immune-mediated hepatitis, defined as requiring the use of
corticosteroids and no clear alternate etiology.
Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG,
including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions. Hepatitis led to permanent
discontinuation of OPDIVO QVANTIG in 0.8% and withholding of OPDIVO QVANTIG in 1.6%
of patients.
Systemic corticosteroids were required in 100% (6/6) of patients with hepatitis. Hepatitis resolved
in 67% of the 6 patients. Of the 2 patients in whom OPDIVO QVANTIG was withheld for
hepatitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%) had
recurrence of hepatitis.
Intravenous Nivolumab with Cabozantinib
Nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies
of Grade 3 and 4 ALT and AST elevations compared to nivolumab alone. Monitor liver enzymes
before initiation of and periodically throughout treatment. Consider more frequent monitoring of
liver enzymes as compared to when the drugs are administered as single agents. For elevated liver
enzymes, interrupt nivolumab and cabozantinib and consider administering corticosteroids [see
Dosage and Administration (2.3)].
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With the combination of intravenous nivolumab and cabozantinib, Grades 3 and 4 increased ALT
or AST were seen in 11% (35/320) of patients. ALT or AST >3 times ULN (Grade ≥2) was
reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST
resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST
who were rechallenged with either intravenous nivolumab (n=11) or cabozantinib (n=9)
administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST
was observed in 2 patients receiving intravenous nivolumab, 2 patients receiving cabozantinib,
and 7 patients receiving both intravenous nivolumab and cabozantinib.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically
indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration
(2.3)].
Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG,
including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions. Adrenal insufficiency led to
permanent discontinuation of OPDIVO QVANTIG in 0.4% of patients and withholding of
OPDIVO QVANTIG in 0.4% of patients.
Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency.
Adrenal insufficiency resolved in 20% of the 5 patients.
Intravenous Nivolumab with Cabozantinib
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous
nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions.
Adrenal insufficiency led to permanent discontinuation of intravenous nivolumab and
cabozantinib in 0.9% and withholding of intravenous nivolumab and cabozantinib in 2.8% of
patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement
therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15
patients. Of the 9 patients in whom intravenous nivolumab with cabozantinib was withheld for
adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6)
received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Hypophysitis
OPDIVO QVANTIG can cause immune-mediated hypophysitis. Hypophysitis can present with
acute symptoms associated with mass effect such as headache, photophobia, or visual field defects.
Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage
and Administration (2.3)].
Intravenous Nivolumab
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Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous
nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Hypophysitis led to permanent
discontinuation of intravenous nivolumab in 0.2% of patients. Approximately 67% (8/12) of
patients with hypophysitis received hormone replacement therapy, including systemic
corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom
intravenous nivolumab was withheld for hypophysitis, 2 reinitiated intravenous nivolumab after
symptom improvement; of these, none had recurrence of hypophysitis.
Thyroid Disorders
OPDIVO QVANTIG can cause immune-mediated thyroid disorders. Thyroiditis can present with
or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone
replacement or medical management as clinically indicated. Withhold or permanently discontinue
OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].
Thyroiditis
Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade
1 (0.4%) adverse reaction.
Systemic corticosteroids were not required in the patient with thyroiditis. Thyroiditis did not
resolve in this patient.
Hyperthyroidism
Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including
Grade 2 (0.4%) adverse reactions.
Systemic corticosteroids were not required in patients with hyperthyroidism. Hyperthyroidism
resolved in 50% of the 2 patients.
Hypothyroidism
Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including
Grade 2 (5.7%) adverse reactions. Hypothyroidism led to withholding of OPDIVO QVANTIG in
0.8% of patients.
Systemic corticosteroids were not required in patients with hypothyroidism. Hypothyroidism
resolved in 4.3% of the 23 patients. Of the 1 patient in whom OPDIVO QVANTIG was withheld
for hypothyroidism, OPDIVO QVANTIG was not reinitiated after symptom improvement.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment
with insulin as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see
Dosage and Administration (2.3)].
Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG.
No patients with diabetes required systemic corticosteroids. Diabetes did not resolve in this patient.
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Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO QVANTIG can cause immune-mediated nephritis, which is defined as requiring use of
steroids and no clear alternate etiology.
Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients
receiving OPDIVO QVANTIG. Immune-mediated nephritis and renal dysfunction led to
withholding of OPDIVO QVANTIG in 1.2% of patients.
Systemic corticosteroids were required in 100% (3/3) of patients with nephritis and renal
dysfunction. Nephritis and renal dysfunction resolved in 100% of the 3 patients. Of the 3 patients
in whom OPDIVO QVANTIG was withheld for nephritis or renal dysfunction, 1 reinitiated
OPDIVO QVANTIG after symptom improvement without recurrence of nephritis or renal
dysfunction.
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO QVANTIG can cause immune-mediated rash or dermatitis, defined as requiring the use
of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson
Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and
Systemic Symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients
and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage
and Administration (2.3)].
Immune-mediated rash occurred in 7% (17/247) of patients, including Grade 3 (0.8%) and Grade
2 (2.8%) adverse reactions. Immune-mediated rash led to withholding of OPDIVO QVANTIG in
1.2% of patients.
Systemic corticosteroids were required in 47% (8/17) of patients with immune-mediated rash.
Rash resolved in 77% of the 17 patients. Of the 3 patients in whom OPDIVO QVANTIG was
withheld for immune-mediated rash, all reinitiated OPDIVO QVANTIG after symptom
improvement; of these, all (100%) had recurrence of immune-mediated rash.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence
of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous
nivolumab as a single agent or in combination with chemotherapy or immunotherapy, or were
reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been
reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
Nervous
System:
Meningitis,
encephalitis,
myelitis
and
demyelination,
myasthenic
syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis,
autoimmune neuropathy
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be
associated with retinal detachment. Various grades of visual impairment, including blindness, can
17
Reference ID: 5503299
occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to
reduce the risk of permanent vision loss
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis,
duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated
sequelae including renal failure, arthritis, polymyalgia rheumatic
Endocrine: Hypoparathyroidism
Other
(Hematologic/Immune):
Hemolytic
anemia,
aplastic
anemia,
hemophagocytic
lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid
organ transplant rejection, other transplant (including corneal graft) rejection.
5.2
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic
stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking
antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD),
acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity
conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see
Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between
PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly.
Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or
after an allogeneic HSCT.
5.3
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause
fetal harm when administered to a pregnant woman. In animal reproduction studies, administration
of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted
in increased abortion and premature infant death. Advise pregnant women of the potential risk to
a fetus. Advise females of reproductive potential to use effective contraception during treatment
with OPDIVO QVANTIG and for 5 months after the last dose [see Use in Specific Populations
(8.1, 8.3)].
5.4
Increased Mortality in Patients with Multiple Myeloma when Nivolumab
Is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking
antibody, including intravenous nivolumab, to a thalidomide analogue plus dexamethasone, a use
for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality.
Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not recommended outside of
controlled clinical trials.
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6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling.
Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions
(5.1)]
Complications of Allogeneic HSCT [see Warnings and Precautions (5.2)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as a
single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous
nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with
cabozantinib (320 patients) for select adverse reactions.
Advanced Renal Cell Carcinoma
CHECKMATE-67T was a multicenter, randomized, open-label study in adult patients with
advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of
nivolumab and 20,000 units of hyaluronidase subcutaneously every 4 weeks (n=247) or 3 mg/kg
of nivolumab intravenously every 2 weeks (n=245). Among patients who received OPDIVO
QVANTIG, 52% were exposed for 6 months or longer and 20% were exposed for greater than 1
year.
Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious
adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%),
hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal
adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included
myocarditis, myositis, and colitis complications.
Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of
patients. The most common adverse reaction which resulted in permanent discontinuation was
pneumonitis (2%).
Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of
patients. Adverse reactions which required dosage interruption in >2% of patients included
COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each).
The most common adverse reactions (≥10%) were musculoskeletal pain, fatigue, pruritus, rash,
hypothyroidism, diarrhea, cough, and abdominal pain.
Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE 67T.
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Table 5:
Adverse Reactions* in ≥5% of Adult Patients with RCC Receiving
OPDIVO QVANTIG in CHECKMATE 67T
Adverse Reaction
OPDIVO QVANTIG
(n=247)
Intravenous Nivolumab
(n=245)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
Fatiguea
20
2.4
25
3.3
Injection site reactiona
8
0
0
0
Edema
5
0.4
11
0.8
Musculoskeletal and Connective Tissue
Musculoskeletal paina
31
1.6
39
3.3
Skin and Subcutaneous Tissue
Pruritus
16
0.4
21
0
Rasha
15
1.2
13
1.2
Gastrointestinal
Diarrheaa
11
0.4
14
0.4
Abdominal paina
10
0
10
0.4
Nausea
8
0
9
0
Constipation
8
0
6
0
Vomiting
6
0.4
4.9
0
Respiratory, Thoracic, and Mediastinal
Cough
11
0
11
0
Endocrine
Hypothyroidisma
12
0
17
0
Metabolism and Nutrition
Hyperglycemia
9
2.4
13
2.0
Decreased appetite
9
0
11
0.8
* Toxicity was graded per NCI CTCAE v5.
a Includes multiple related terms
Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG
include:
Cardiac: myocarditis
Respiratory, thoracic, and mediastinal: pneumonitis, dyspnea
Endocrine: adrenal insufficiency, hyperthyroidism, thyroiditis
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Gastrointestinal: colitis, pancreatitis
Hepatobiliary: hepatitis
Nervous system: peripheral neuropathy
Skin and subcutaneous tissue: psoriasis, erythema
Musculoskeletal and connective tissue: arthritis
Blood and lymphatic system: eosinophilia
Eye disorders: uveitis
Immune system: hypersensitivity
Table 6:
Laboratory Values Worsening from Baselinea (≥20%) in Patients
with RCC Receiving OPDIVO QVANTIG in CHECKMATE 67T
Laboratory Abnormality
OPDIVO QVANTIG
Intravenous Nivolumab
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Hematology
Hemoglobin decreased
46
7
48
9
Lymphocytes decreased
36
6
45
9
Chemistry
Creatinine increased
38
1.3
43
0.4
Sodium decreased
34
2.6
40
2.5
Potassium increased
34
3.0
45
2.9
Alkaline phosphatase increased
32
2.1
33
2.0
Calcium increased
29
2.1
31
4.1
Albumin decreased
25
1.7
35
0.4
ALT increased
21
1.3
26
4.1
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: OPDIVO QVANTIG group (range: 232 to 235 patients) and intravenous nivolumab group
(range: 240 to 244 patients).
Adverse Reactions in Patients Treated with Intravenous Nivolumab
The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1)]
has been established in adequate and well-controlled clinical studies of intravenous nivolumab.
Below is a description of adverse reactions in these adequate and well-controlled clinical studies.
First-line Renal Cell Carcinoma
CHECKMATE-214
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The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, a
randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients
received intravenous nivolumab 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously
every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3
mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first
4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.1)]. The median duration of treatment
was 7.9 months (range: 1 day to 21.4+ months) in intravenous nivolumab and ipilimumab-treated
patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial,
57% of patients in the intravenous nivolumab and ipilimumab arm were exposed to treatment for
>6 months and 38% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and
ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous
nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous
nivolumab and ipilimumab had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous
nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute
kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they
were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in
≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough,
pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which
have worsened compared to baseline in ≥30% of intravenous nivolumab and ipilimumab-treated
patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST,
hyponatremia, increased amylase, and lymphopenia.
Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, that
occurred in >15% of intravenous nivolumab and ipilimumab-treated patients in CHECKMATE
214.
Table 7:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Ipilimumab - CHECKMATE-214
Adverse Reaction
Intravenous Nivolumab and
Ipilimumab
(n=547)
Sunitinib
(n=535)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Adverse Reaction
99
65
99
76
General
Fatiguea
58
8
69
13
Pyrexia
25
0.7
17
0.6
Edemab
16
0.5
17
0.6
Skin and Subcutaneous Tissue
22
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Table 7:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Ipilimumab - CHECKMATE-214
Adverse Reaction
Intravenous Nivolumab and
Ipilimumab
(n=547)
Sunitinib
(n=535)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Rashc
39
3.7
25
1.1
Pruritus/generalized
pruritus
33
0.5
11
0
Gastrointestinal
Diarrhea
38
4.6
58
6
Nausea
30
2
43
1.5
Vomiting
20
0.9
28
2.1
Abdominal pain
19
1.6
24
1.9
Constipation
17
0.4
18
0
Musculoskeletal and Connective Tissue
Musculoskeletal paind
37
4
40
2.6
Arthralgia
23
1.3
16
0
Respiratory, Thoracic and Mediastinal
Cough/productive cough
28
0.2
25
0.4
Dyspnea/exertional
dyspnea
20
2.4
21
2.1
Metabolism and Nutrition
Decreased appetite
21
1.8
29
0.9
Nervous System
Headache
19
0.9
23
0.9
Endocrine
Hypothyroidism
18
0.4
27
0.2
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative,
erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, spinal pain.
23
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Table 8:
Laboratory Values Worsening from Baselinea Occurring in >15%
of Patients on Intravenous Nivolumab and Ipilimumab -
CHECKMATE-214
Laboratory Abnormality
Intravenous Nivolumab and
Ipilimumab
Sunitinib
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Chemistry
Increased lipase
48
20
51
20
Increased creatinine
42
2.1
46
1.7
Increased ALT
41
7
44
2.7
Increased AST
40
4.8
60
2.1
Increased amylase
39
12
33
7
Hyponatremia
39
10
36
7
Increased alkaline phosphatase
29
2
32
1
Hyperkalemia
29
2.4
28
2.9
Hypocalcemia
21
0.4
35
0.6
Hypomagnesemia
16
0.4
26
1.6
Hematology
Anemia
43
3
64
9
Lymphopenia
36
5
63
14
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and ipilimumab group (range: 490 to 538 patients) and sunitinib
group (range: 485 to 523 patients).
In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients
experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab and
ipilimumab group compared to the sunitinib group (31% and 61%, respectively).
CHECKMATE-9ER
The safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, a
randomized, open-label study in patients with previously untreated advanced RCC. Patients
received intravenous nivolumab 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg
orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment
followed by 2 weeks off (n=320) [see Clinical Studies (14.1)]. Cabozantinib could be interrupted
or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was
14 months (range: 0.2 to 27 months) in intravenous nivolumab and cabozantinib-treated patients.
In this trial, 82% of patients in the intravenous nivolumab and cabozantinib arm were exposed to
treatment for >6 months and 60% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and
cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia,
24
Reference ID: 5503299
pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal
perforations occurred in 3 (0.9%) patients.
Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib
occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both
drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption
or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3%
intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse
reaction at the same time, and 6% both drugs sequentially.
The most common adverse reactions reported in ≥20% of patients treated with intravenous
nivolumab
and
cabozantinib
were
diarrhea,
fatigue,
hepatotoxicity,
palmar-plantar
erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal
pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract
infection.
Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-9ER.
Table 9:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Cabozantinib - CHECKMATE-9ER
Adverse Reaction
Intravenous Nivolumab and
Cabozantinib
(n=320)
Sunitinib
(n=320)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Gastrointestinal
Diarrhea
64
7
47
4.4
Nausea
27
0.6
31
0.3
Abdominal paina
22
1.9
15
0.3
Vomiting
17
1.9
21
0.3
Dyspepsiab
15
0
22
0.3
General
Fatiguec
51
8
50
8
Hepatobiliary
Hepatotoxicityd
44
11
26
5
Skin and Subcutaneous Tissue
Palmar-plantar
erythrodysesthesia
syndrome
40
8
41
8
Stomatitise
37
3.4
46
4.4
Rashf
36
3.1
14
0
25
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Table 9:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Cabozantinib - CHECKMATE-9ER
Adverse Reaction
Intravenous Nivolumab and
Cabozantinib
(n=320)
Sunitinib
(n=320)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Pruritus
19
0.3
4.4
0
Vascular
Hypertensiong
36
13
39
14
Endocrine
Hypothyroidismh
34
0.3
30
0.3
Musculoskeletal and Connective Tissue
Musculoskeletal paini
33
3.8
29
3.1
Arthralgia
18
0.3
9
0.3
Metabolism and Nutrition
Decreased appetite
28
1.9
20
1.3
Nervous System
Dysgeusia
24
0
22
0
Headache
16
0
12
0.6
Respiratory, Thoracic and Mediastinal
Coughj
20
0.3
17
0
Dysphonia
17
0.3
3.4
0
Infections and Infestations
Upper respiratory tract
infectionk
20
0.3
8
0.3
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.
b Includes gastroesophageal reflux disease.
c Includes asthenia.
d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl
transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme
increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases
increased, hepatic failure.
e Includes mucosal inflammation, aphthous ulcer, mouth ulceration.
f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular,
rash macular, rash maculo-papular, rash papular, rash pruritic.
g Includes blood pressure increased, blood pressure systolic increased.
h Includes primary hypothyroidism.
i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, spinal pain.
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j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, rhinitis.
Table 10:
Laboratory Values Worsening from Baselinea Occurring in >20%
of Patients on Intravenous Nivolumab and Cabozantinib -
CHECKMATE-9ER
Laboratory Abnormality
Intravenous Nivolumab and
Cabozantinib
Sunitinib
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Chemistry
Increased ALT
79
9.8
39
3.5
Increased AST
77
7.9
57
2.6
Hypophosphatemia
69
28
48
10
Hypocalcemia
54
1.9
24
0.6
Hypomagnesemia
47
1.3
25
0.3
Hyperglycemia
44
3.5
44
1.7
Hyponatremia
43
11
36
12
Increased lipase
41
14
38
13
Increased amylase
41
10
28
6
Increased alkaline phosphatase
41
2.8
37
1.6
Increased creatinine
39
1.3
42
0.6
Hyperkalemia
35
4.7
27
1
Hypoglycemia
26
0.8
14
0.4
Hematology
Lymphopenia
42
6.6
45
10
Thrombocytopenia
41
0.3
70
9.7
Anemia
37
2.5
61
4.8
Leukopenia
37
0.3
66
5.1
Neutropenia
35
3.2
67
12
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and cabozantinib group (range: 170 to 317 patients) and sunitinib
group (range: 173 to 311 patients).
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
The safety of intravenous nivolumab was evaluated in CHECKMATE-025, a randomized open-
label trial in 803 patients with advanced RCC who had experienced disease progression during or
after at least one anti-angiogenic treatment regimen received intravenous nivolumab 3 mg/kg over
60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397)
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[see Clinical Studies (14.1)]. The median duration of treatment was 5.5 months (range: 1 day to
29.6+ months) in intravenous nivolumab-treated patients and 3.7 months (range: 6 days to 25.7+
months) in everolimus-treated patients.
Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous
nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous
nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab
patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had a dose
interruption for an adverse reaction.
The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury,
pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions
(≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite,
back pain, and arthralgia. The most common laboratory abnormalities which have worsened
compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia,
increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and
hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of
patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab
group compared to the everolimus group (26% and 14%, respectively).
Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-025.
Table 11:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab - CHECKMATE-025
Adverse Reaction
Intravenous Nivolumab
(n=406)
Everolimus
(n=397)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Adverse Reaction
98
56
96
62
General
Fatiguea
56
6
57
7
Pyrexia
17
0.7
20
0.8
Respiratory, Thoracic and Mediastinal
Cough/productive cough
34
0
38
0.5
Dyspnea/exertional dyspnea
27
3
31
2
Upper respiratory infectionb
18
0
11
0
Gastrointestinal
Nausea
28
0.5
29
1
Diarrheac
25
2.2
32
1.8
Constipation
23
0.5
18
0.5
28
Reference ID: 5503299
Table 11:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab - CHECKMATE-025
Adverse Reaction
Intravenous Nivolumab
(n=406)
Everolimus
(n=397)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Vomiting
16
0.5
16
0.5
Skin and Subcutaneous Tissue
Rashd
28
1.5
36
1
Pruritus/generalized pruritus
19
0
14
0
Metabolism and Nutrition
Decreased appetite
23
1.2
30
1.5
Musculoskeletal and Connective Tissue
Arthralgia
20
1
14
0.5
Back pain
21
3.4
16
2.8
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).
c Includes colitis, enterocolitis, and gastroenteritis.
d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash,
papular rash, pruritic rash, erythema multiforme, and erythema.
Other clinically important adverse reactions in CHECKMATE-025 were:
General Disorders and Administration Site Conditions: peripheral edema/edema
Gastrointestinal Disorders: abdominal pain/discomfort
Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain
Nervous System Disorders: headache/migraine, peripheral neuropathy
Investigations: weight decreased
Skin Disorders: palmar-plantar erythrodysesthesia
Table 12:
Laboratory Values Worsening from Baselinea Occurring in >15%
of Patients on Intravenous Nivolumab - CHECKMATE-025
Laboratory Abnormality
Intravenous Nivolumab
Everolimus
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Hematology
Lymphopenia
42
6
53
11
Anemia
39
8
69
16
29
Reference ID: 5503299
Table 12:
Laboratory Values Worsening from Baselinea Occurring in >15%
of Patients on Intravenous Nivolumab - CHECKMATE-025
Laboratory Abnormality
Intravenous Nivolumab
Everolimus
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Chemistry
Increased creatinine
42
2
45
1.6
Increased AST
33
2.8
39
1.6
Increased alkaline
phosphatase
32
2.3
32
0.8
Hyponatremia
32
7
26
6
Hyperkalemia
30
4
20
2.1
Hypocalcemia
23
0.9
26
1.3
Increased ALT
22
3.2
31
0.8
Hypercalcemia
19
3.2
6
0.3
Lipids
Increased triglycerides
32
1.5
67
11
Increased cholesterol
21
0.3
55
1.4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 259 to 401 patients) and everolimus group (range:
257 to 376 patients).
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
CHECKMATE-037
The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-
label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2)].
Patients had documented disease progression following treatment with ipilimumab and, if BRAF
V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease,
prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3
ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within
12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment
with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive
medications, a positive test for hepatitis B or C, and a history of HIV. Patients received intravenous
nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or
investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3
weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks.
The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in intravenous
nivolumab-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy
30
Reference ID: 5503299
treated patients. In this ongoing trial, 24% of patients received intravenous nivolumab for >6
months and 3% of patients received intravenous nivolumab for >1 year.
The population characteristics in the intravenous nivolumab group and the chemotherapy group
were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative
Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease,
73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior
therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more
patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at
baseline (51% vs. 38%).
Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab.
Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six
percent of patients receiving intravenous nivolumab had a dose interruption for an adverse
reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous
nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients
receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate
aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of
patients) was rash.
Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-037.
Table 13:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients and at a Higher Incidence than in the
Chemotherapy Arm (Between Arm Difference of ≥5% All Grades
or ≥2% Grades 3-4) - CHECKMATE-037
Adverse Reaction
Intravenous Nivolumab
(n=268)
Chemotherapy
(n=102)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Skin and Subcutaneous Tissue
Rasha
21
0.4
7
0
Pruritus
19
0
3.9
0
Respiratory, Thoracic and Mediastinal
Cough
17
0
6
0
Infections
Upper respiratory tract infectionb
11
0
2
0
General
Peripheral edema
10
0
5
0
Toxicity was graded per NCI CTCAE v4.
a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular
rash, vesicular rash, and acneiform dermatitis.
31
Reference ID: 5503299
b Includes rhinitis, pharyngitis, and nasopharyngitis.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab
were:
Cardiac Disorders: ventricular arrhythmia
Eye Disorders: iridocyclitis
General Disorders and Administration Site Conditions: infusion-related reactions
Investigations: increased amylase, increased lipase
Nervous System Disorders: dizziness, peripheral and sensory neuropathy
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo,
psoriasis
Table 14:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients and at a Higher
Incidence than in the Chemotherapy Arm (Between Arm Difference
of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037
Laboratory Abnormality
Intravenous Nivolumab
Chemotherapy
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Increased AST
28
2.4
12
1
Hyponatremia
25
5
18
1.1
Increased alkaline phosphatase
22
2.4
13
1.1
Increased ALT
16
1.6
5
0
Hyperkalemia
15
2
6
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 252 to 256 patients) and chemotherapy group (range:
94 to 96 patients).
Previously Untreated Metastatic Melanoma
CHECKMATE-066
The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, a randomized,
double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-
type unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial excluded patients
with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received
intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206)
or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of
exposure was 6.5 months (range: 1 day to 16.6 months) in intravenous nivolumab-treated patients.
In this trial, 47% of patients received intravenous nivolumab for >6 months and 12% of patients
received intravenous nivolumab for >1 year.
32
Reference ID: 5503299
The trial population characteristics in the intravenous nivolumab group and dacarbazine group:
59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous
melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH
at baseline. There were more patients in the intravenous nivolumab group with ECOG performance
status 0 (71% vs. 59%).
Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse
reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose
interruption in 26% of patients; no single type of adverse reaction accounted for the majority of
intravenous nivolumab discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of
patients receiving intravenous nivolumab.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving
intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%).
The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than
in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.
Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively,
in CHECKMATE-066.
Table 15:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients and at a Higher Incidence than in the Dacarbazine
Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades
3-4) - CHECKMATE-066
Adverse Reaction
Intravenous Nivolumab
(n=206)
Dacarbazine
(n=205)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
Fatigue
49
1.9
39
3.4
Edemaa
12
1.5
4.9
0
Musculoskeletal and Connective Tissue
Musculoskeletal painb
32
2.9
25
2.4
Skin and Subcutaneous Tissue
Rashc
28
1.5
12
0
Pruritus
23
0.5
12
0
Vitiligo
11
0
0.5
0
Erythema
10
0
2.9
0
Infections
Upper respiratory tract infectiond
17
0
6
0
Toxicity was graded per NCI CTCAE v4.
33
Reference ID: 5503299
a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral
edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular
rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and
skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab
were:
Nervous System Disorders: peripheral neuropathy
Table 16:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients and at a Higher
Incidence than in the Dacarbazine Arm (Between Arm Difference
of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066
Laboratory Abnormality
Intravenous Nivolumab
Dacarbazine
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Increased ALT
25
3
19
0.5
Increased AST
24
3.6
19
0.5
Increased alkaline phosphatase
21
2.6
14
1.6
Increased bilirubin
13
3.1
6
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 194 to 197 patients) and dacarbazine group (range:
186 to 193 patients).
CHECKMATE-067
The safety of intravenous nivolumab, administered with ipilimumab or as a single agent, was
evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with
previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial
excluded patients with autoimmune disease, a medical condition requiring systemic treatment with
corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive
medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C,
or a history of HIV.
Patients were randomized to receive:
Intravenous nivolumab 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous
infusion every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at
a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab and
ipilimumab arm; n=313), or
Intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks
(nivolumab arm; n=313), or
34
Reference ID: 5503299
Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab
arm; n=311).
The median duration of exposure to intravenous nivolumab was 2.8 months (range: 1 day to 36.4
months) for the intravenous nivolumab and ipilimumab arm and 6.6 months (range: 1 day to 36.0
months) for the intravenous nivolumab arm. In the intravenous nivolumab and ipilimumab arm,
39% were exposed to intravenous nivolumab for ≥6 months and 30% exposed for >1 year. In the
intravenous nivolumab arm, 53% were exposed for ≥6 months and 40% for >1 year.
The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG
performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC)
Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a
history of brain metastasis, and 22% had received adjuvant therapy.
Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and
51%) all occurred more frequently in the intravenous nivolumab and ipilimumab arm relative to
the intravenous nivolumab arm.
The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab and ipilimumab
arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10%
and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to
discontinuation of both drugs in the intravenous nivolumab and ipilimumab arm and of intravenous
nivolumab in the intravenous nivolumab arm, respectively, were colitis (10% and 0.6%), diarrhea
(8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis
(1.9% and 0.3%).
The most common (≥20%) adverse reactions in the intravenous nivolumab and ipilimumab arm
were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased
appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased
transaminases. The most common (≥20%) adverse reactions in the intravenous nivolumab arm
were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract
infection, decreased appetite, headache, constipation, arthralgia, and vomiting.
Tables 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities,
respectively, in CHECKMATE-067.
35
Reference ID: 5503299
Table 17:
Adverse Reactions Occurring in ≥10% of Patients on the
Intravenous Nivolumab and Ipilimumab Arm or the Intravenous
Nivolumab Arm and at a Higher Incidence than in the Ipilimumab
Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades
3-4) - CHECKMATE-067
Adverse Reaction
Intravenous Nivolumab
and
Ipilimumab
(n=313)
Intravenous Nivolumab
(n=313)
Ipilimumab
(n=311)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
General
Fatiguea
62
7
59
1.6
51
4.2
Pyrexia
40
1.6
16
0
18
0.6
Gastrointestinal
Diarrhea
54
11
36
5
47
7
Nausea
44
3.8
30
0.6
31
1.9
Vomiting
31
3.8
20
1
17
1.6
Skin and Subcutaneous Tissue
Rashb
53
6
40
1.9
42
3.5
Vitiligo
9
0
10
0.3
5
0
Musculoskeletal and Connective Tissue
Musculoskeletal
painc
32
2.6
42
3.8
36
1.9
Arthralgia
21
0.3
21
1
16
0.3
Metabolism and Nutrition
Decreased appetite
29
1.9
22
0
24
1.3
Respiratory, Thoracic and Mediastinal
Cough/productive
cough
27
0.3
28
0.6
22
0
Dyspnea/exertional
dyspnea
24
2.9
18
1.3
17
0.6
Infections
Upper respiratory
tract infectiond
23
0
22
0.3
17
0
Endocrine
Hypothyroidism
19
0.6
11
0
5
0
Hyperthyroidism
11
1.3
6
0
1
0
36
Reference ID: 5503299
Table 17:
Adverse Reactions Occurring in ≥10% of Patients on the
Intravenous Nivolumab and Ipilimumab Arm or the Intravenous
Nivolumab Arm and at a Higher Incidence than in the Ipilimumab
Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades
3-4) - CHECKMATE-067
Adverse Reaction
Intravenous Nivolumab
and
Ipilimumab
(n=313)
Intravenous Nivolumab
(n=313)
Ipilimumab
(n=311)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
Investigations
Decreased weight
12
0
7
0
7
0.3
Vascular
Hypertensione
7
2.2
11
5
9
2.3
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis,
exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash,
macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab
with ipilimumab or intravenous nivolumab as a single agent were:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders:
myopathy,
Sjogren’s
syndrome,
spondyloarthropathy, myositis (including polymyositis)
Nervous System Disorders: neuritis, peroneal nerve palsy
37
Reference ID: 5503299
Table 18:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥20% of Patients Treated with Intravenous Nivolumab with
Ipilimumab or Single-Agent Intravenous Nivolumab and at a
Higher Incidence than in the Ipilimumab Arm (Between Arm
Difference of ≥5% All Grades or ≥2% Grades 3-4) -
CHECKMATE-067
Laboratory Abnormality
Intravenous Nivolumab
and
Ipilimumab
Intravenous Nivolumab
Ipilimumab
All
Grades
(%)
Grade
3-4 (%)
All
Grades
(%)
Grade
3-4 (%)
All
Grades
(%)
Grade
3-4 (%)
Chemistry
Increased ALT
55
16
25
3
29
2.7
Hyperglycemia
53
5.3
46
7
26
0
Increased AST
52
13
29
3.7
29
1.7
Hyponatremia
45
10
22
3.3
26
7
Increased lipase
43
22
32
12
24
7
Increased alkaline
phosphatase
41
6
27
2
23
2
Hypocalcemia
31
1.1
15
0.7
20
0.7
Increased amylase
27
10
19
2.7
15
1.6
Increased creatinine
26
2.7
19
0.7
17
1.3
Hematology
Anemia
52
2.7
41
2.6
41
6
Lymphopenia
39
5
41
4.9
29
4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and ipilimumab (range: 75 to 297); intravenous nivolumab (range:
81 to 306); ipilimumab (range: 61 to 301).
Adjuvant Treatment of Melanoma
CHECKMATE-76K
The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-76K, a
randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C
melanoma who received intravenous nivolumab 480 mg by intravenous infusion over 30 minutes
every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264)
for up to 1 year [see Clinical Studies (14.3)]. The median duration of exposure was 11 months in
patients treated with intravenous nivolumab and 11 months in patients treated with placebo.
Serious adverse reactions occurred in 18% of patients treated with intravenous nivolumab. A fatal
adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent
38
Reference ID: 5503299
discontinuation of intravenous nivolumab due to an adverse reaction occurred in 17% of patients.
Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1%
of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%).
Dosage interruptions of intravenous nivolumab due to an adverse reaction occurred in 25% of
patients. Adverse reactions which required dosage interruption in >1% of patients included
COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT.
The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal
pain, rash, diarrhea, and pruritus.
Tables 19 and 20 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-76K.
Table 19:
Adverse Reactions Occurring in ≥10% of Patients Treated with
Intravenous Nivolumab - CHECKMATE-76K
Adverse Reaction
Intravenous Nivolumab
(n=524)
Placebo
(n=264)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
General
Fatiguea
36
0.4
34
0.4
Musculoskeletal and connective tissue
Musculoskeletal painb
30
0.4
26
0.4
Skin and Subcutaneous Tissue
Rashc
28
1.1
15
0.4
Pruritus
20
0.2
11
0
Gastrointestinal
Diarrhead
23
1.3
16
0
Nausea
14
0
11
0
Endocrine
Hypothyroidisme
14
0
2.3
0
Nervous system
Headachef
12
0.2
14
0.8
Toxicity was graded per NCI CTCAE v5.
a Includes asthenia.
b Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity.
c Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash,
pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash
pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption.
d Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitis
e Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased.
39
Reference ID: 5503299
f Includes cluster headache, migraine.
Table 20:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients -
CHECKMATE-76K
Laboratory Abnormality
Intravenous Nivolumab
(n=524)
Placebo
(n=264)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Hematology
Anemia
19
0
14
0
Lymphopenia
17
1.1
17
1.7
Neutropenia
10
0
10
0.4
Chemistry
AST increased
25
2.2
16
0.4
Lipase increased
22
2.9
21
2.3
ALT increased
20
2.1
15
0.4
Amylase increased
17
0.4
9
0
Creatinine increased
15
0.4
13
0
Sodium decreased
13
0.6
11
0.4
Potassium increased
13
1
15
1.1
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 262 to 513 patients) and placebo group (range: 138
to 261 patients).
CHECKMATE-238
The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-238, a
randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage
IV melanoma received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes
every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses
then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.3)].
The median duration of exposure was 11.5 months in intravenous nivolumab-treated patients and
was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received
intravenous nivolumab for >6 months.
Serious adverse reactions occurred in 18% of intravenous nivolumab-treated patients. Study
therapy was discontinued for adverse reactions in 9% of intravenous nivolumab-treated patients
and 42% of ipilimumab-treated patients. Twenty-eight percent of intravenous nivolumab-treated
patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions
occurred in 25% of intravenous nivolumab-treated patients.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab
treated patients were diarrhea and increased lipase and amylase. The most common adverse
40
Reference ID: 5503299
reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache,
nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated
adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-238.
Table 21:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients - CHECKMATE-238
Adverse Reaction
Intravenous Nivolumab
(n=452)
Ipilimumab 10 mg/kg
(n=453)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
General
Fatiguea
57
0.9
55
2.4
Gastrointestinal
Diarrhea
37
2.4
55
11
Nausea
23
0.2
28
0
Abdominal painb
21
0.2
23
0.9
Constipation
10
0
9
0
Skin and Subcutaneous Tissue
Rashc
35
1.1
47
5.3
Pruritus
28
0
37
1.1
Musculoskeletal and Connective Tissue
Musculoskeletal paind
32
0.4
27
0.4
Arthralgia
19
0.4
13
0.4
Nervous System
Headache
23
0.4
31
2.0
Dizzinesse
11
0
8
0
Infections
Upper respiratory tract
infectionf
22
0
15
0.2
Respiratory, Thoracic and Mediastinal
Cough/productive cough
19
0
19
0
Dyspnea/exertional dyspnea
10
0.4
10
0.2
Endocrine
Hypothyroidismg
12
0.2
7.5
0.4
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
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Reference ID: 5503299
b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized,
erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal
pain, and pain in extremity.
e Includes postural dizziness and vertigo.
f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection,
rhinitis, pharyngitis, and nasopharyngitis.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.
Table 22:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients -
CHECKMATE-238
Laboratory Abnormality
Intravenous Nivolumab
Ipilimumab 10 mg/kg
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Hematology
Lymphopenia
27
0.4
12
0.9
Anemia
26
0
34
0.5
Leukopenia
14
0
2.7
0.2
Neutropenia
13
0
6
0.5
Chemistry
Increased Lipase
25
7
23
9
Increased ALT
25
1.8
40
12
Increased AST
24
1.3
33
9
Increased Amylase
17
3.3
13
3.1
Hyponatremia
16
1.1
22
3.2
Hyperkalemia
12
0.2
9
0.5
Increased Creatinine
12
0
13
0
Hypocalcemia
10
0.7
16
0.5
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group
(range: 392 to 443 patients).
Non-Small Cell Lung Cancer
Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell
Lung Cancer
CHECKMATE-816
The safety of intravenous nivolumab in combination with platinum-doublet chemotherapy was
evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with
resectable NSCLC [see Clinical Studies (14.4)]. Patients received either intravenous nivolumab
42
Reference ID: 5503299
360 mg administered in combination with platinum-doublet chemotherapy administered every 3
weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles.
The median age of patients who received intravenous nivolumab in combination with platinum-
doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72%
male; 47% White, 50% Asian, and 2% Black/African American.
Serious adverse reactions occurred in 30% of patients who were treated with intravenous
nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2%
included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received
intravenous nivolumab in combination with platinum-doublet chemotherapy.
Study therapy with intravenous nivolumab in combination with platinum-doublet chemotherapy
was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one
treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting
in permanent discontinuation of intravenous nivolumab in combination with platinum-doublet
chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and
fatigue (1.1%).
The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased
appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were
neutropenia,
hyperglycemia,
leukopenia,
lymphopenia,
increased
amylase,
anemia,
thrombocytopenia, and hyponatremia.
Tables 23 and 24 summarize selected adverse reactions and laboratory abnormalities, respectively,
in CHECKMATE-816.
Table 23:
Adverse Reactions in >10% of Patients with Early-Stage NSCLC
Receiving Neoadjuvant Intravenous Nivolumab and Platinum-
Doublet Chemotherapy in CHECKMATE-816
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet Chemotherapy
(n=176)
Platinum-Doublet Chemotherapy
(n=176)
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Gastrointestinal
Nausea
38
0.6
45
1.1
Constipation
34
0
32
1.1
Vomiting
11
1.1
13
0.6
General
Fatiguea
26
2.3
23
1.1
Malaise
15
0.6
14
0.6
Metabolism and Nutrition
Decreased appetite
20
1.1
23
2.3
43
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Table 23:
Adverse Reactions in >10% of Patients with Early-Stage NSCLC
Receiving Neoadjuvant Intravenous Nivolumab and Platinum-
Doublet Chemotherapy in CHECKMATE-816
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet Chemotherapy
(n=176)
Platinum-Doublet Chemotherapy
(n=176)
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Skin and Subcutaneous Tissue
Rashb
20
2.3
7
0
Alopecia
11
0
15
0
Nervous System
Peripheral neuropathyc
13
0
6
0
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular
rash, and pruritic rash.
c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory
neuropathy.
Table 24:
Select Laboratory Values Worsening from Baselinea Occurring in
>20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant
Intravenous Nivolumab and Platinum-Doublet Chemotherapy in
CHECKMATE-816
Laboratory Abnormality
Intravenous Nivolumab and
Platinum-Doublet Chemotherapya
Platinum-Doublet Chemotherapya
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Hematology
Anemia
63
3.5
70
6
Neutropenia
58
22
58
27
Leukopenia
53
5
51
11
Lymphopenia
38
4.7
31
1.8
Thrombocytopenia
24
2.9
22
3
Chemistry
Hyperglycemia
37
6
35
2.9
Hypomagnesemia
25
1.2
29
1.2
Hyponatremia
25
2.4
28
1.8
Increased amylase
23
3.6
13
1.8
44
Reference ID: 5503299
Table 24:
Select Laboratory Values Worsening from Baselinea Occurring in
>20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant
Intravenous Nivolumab and Platinum-Doublet Chemotherapy in
CHECKMATE-816
Laboratory Abnormality
Intravenous Nivolumab and
Platinum-Doublet Chemotherapya
Platinum-Doublet Chemotherapya
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Increased ALT
23
0
20
1.2
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and platinum-doublet chemotherapy group (range: 73 to 171
patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients).
Neoadjuvant and Adjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive)
Non-Small Cell Lung Cancer
CHECKMATE-77T
The safety of intravenous nivolumab in combination with neoadjuvant platinum-doublet
chemotherapy followed by surgery and continued adjuvant treatment with intravenous nivolumab
as a single agent after surgery was evaluated in CHECKMATE-77T, a randomized, double-blind,
multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2
or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition) [see Clinical Studies (14.5)].
Patients with active autoimmune disease or a medical condition that required immunosuppression
were ineligible. The median duration of exposure to intravenous nivolumab was 10.3 months
(range: 1 day to 22.3 months).
The study population characteristics were: median age 66 years (range: 35 - 86); 71% male; 72%
White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or
Latino.
Adverse reactions occurring in patients with resectable NSCLC receiving intravenous nivolumab
in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed
as a single agent adjuvant treatment after surgery, were generally similar to those occurring in
patients in other clinical trials across tumor types receiving intravenous nivolumab in combination
with chemotherapy.
Neoadjuvant Phase of CHECKMATE-77T
A total of 228 patients received at least 1 dose of intravenous nivolumab in combination with
platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least 1 dose
of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment.
Serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in
combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent
(≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of
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Reference ID: 5503299
patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and
pneumonitis (0.4% each).
Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of
patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy
as neoadjuvant treatment; the most frequent (≥1%) adverse reaction that led to permanent
discontinuation of any study drug was peripheral sensory neuropathy (2.2%).
Of the 228 intravenous nivolumab-treated patients and 230 placebo-treated patients who received
neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to
adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous
nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2
patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19,
and myositis (1 patient each).
Of the 178 intravenous nivolumab-treated patients who received surgery, 4.5% (n=8) experienced
delay of surgery (surgery more than 6 weeks from last neoadjuvant treatment) due to adverse
reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay
of surgery due to adverse reactions.
Of the 178 intravenous nivolumab-treated patients who received surgery, 7% (n=13) did not
receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who
received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions.
Adjuvant Phase of CHECKMATE-77T
A total of 142 patients in the intravenous nivolumab arm and 152 patients in the placebo arm
received at least 1 dose of adjuvant treatment.
Of the patients who received single agent intravenous nivolumab as adjuvant treatment, 22%
experienced serious adverse reactions; the most frequent serious adverse reaction was
pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent
discontinuation of adjuvant intravenous nivolumab due to an adverse reaction occurred in 14% of
patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of
adjuvant intravenous nivolumab were pneumonitis (4.2%) and diarrhea (1.4%).
Second-line Treatment of Metastatic NSCLC
CHECKMATE-017 and CHECKMATE-057
The safety of intravenous nivolumab was evaluated in CHECKMATE-017, a randomized open-
label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after
one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a
randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and
progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical
Studies (14.6)]. These trials excluded patients with active autoimmune disease, medical conditions
requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients
received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks
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or docetaxel 75 mg/m2 intravenously every 3 weeks. The median duration of therapy in
intravenous nivolumab-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to
21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In
CHECKMATE-017, 36% of patients received intravenous nivolumab for at least 6 months and
18% of patients received intravenous nivolumab for at least 1 year and in CHECKMATE-057,
30% of patients received intravenous nivolumab for >6 months and 20% of patients received
intravenous nivolumab for >1 year.
Across both trials, the median age of intravenous nivolumab-treated patients was 61 years (range:
37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of
patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).
In CHECKMATE-057, in the intravenous nivolumab arm, seven deaths were due to infection
including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism,
and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients
receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 11% of patients and
was delayed in 28% of patients for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous
nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion,
pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions
(≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Tables 25 and 26 summarize selected adverse reactions and laboratory abnormalities, respectively,
in CHECKMATE-057.
Table 25:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients and at a Higher Incidence than Docetaxel
(Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -
CHECKMATE-017 and CHECKMATE-057
Adverse Reaction
Intravenous Nivolumab
(n=418)
Docetaxel
(n=397)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Respiratory, Thoracic and Mediastinal
Cough
31
0.7
24
0
Metabolism and Nutrition
Decreased appetite
28
1.4
23
1.5
Skin and Subcutaneous Tissue
Pruritus
10
0.2
2
0
Toxicity was graded per NCI CTCAE v4.
Other clinically important adverse reactions observed in intravenous nivolumab-treated patients
and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in
47
Reference ID: 5503299
section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all
Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).
Table 26:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients for all NCI
CTCAE Grades and at a Higher Incidence than Docetaxel (Between
Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -
CHECKMATE-017 and CHECKMATE-057
Laboratory Abnormality
Intravenous Nivolumab
Docetaxel
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Chemistry
Hyponatremia
35
7
34
4.9
Increased AST
27
1.9
13
0.8
Increased alkaline phosphatase
26
0.7
18
0.8
Increased ALT
22
1.7
17
0.5
Increased creatinine
18
0
12
0.5
Increased TSHb
14
N/A
6
N/A
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 405 to 417 patients) and docetaxel group (range: 372
to 390 patients), except for TSH: intravenous nivolumab group n=314 and docetaxel group n=297.
b Not graded per NCI CTCAE v4.
Squamous Cell Carcinoma of the Head and Neck
CHECKMATE-141
The safety of intravenous nivolumab was evaluated in CHECKMATE-141, a randomized, active-
controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with
progression during or within 6 months of receiving prior platinum-based therapy [see Clinical
Studies (14.7)]. The trial excluded patients with active autoimmune disease, medical conditions
requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx,
squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous
histologies (e.g., mucosal melanoma). Patients received intravenous nivolumab 3 mg/kg by
intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either
cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate
(40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The
median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in
intravenous nivolumab-treated patients. In this trial, 18% of patients received intravenous
nivolumab for >6 months and 2.5% of patients received intravenous nivolumab for >1 year.
The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the
intravenous nivolumab group were ≥65 years of age and 37% in the comparator group were ≥65
years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline
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ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line
of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and
90% had prior radiation therapy.
Serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab.
Intravenous nivolumab was discontinued in 14% of patients and was delayed in 24% of patients
for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with
SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.
The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous
nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.
The most common adverse reactions occurring in ≥10% of intravenous nivolumab-treated patients
and at a higher incidence than investigator’s choice were cough and dyspnea. The most common
laboratory abnormalities occurring in ≥10% of intravenous nivolumab-treated patients and at a
higher incidence than investigator’s choice were increased alkaline phosphatase, increased
amylase, hypercalcemia, hyperkalemia, and increased TSH.
Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC)
CHECKMATE-274
The safety of intravenous nivolumab was evaluated in CHECKMATE-274, a randomized,
double-blind, multicenter trial of adjuvant intravenous nivolumab versus placebo in adult patients
who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal
pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.8)]. Patients received
intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351)
or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median
duration of intravenous nivolumab treatment was 8.8 months (range: 0 to 12.5).
Serious adverse reactions occurred in 30% of intravenous nivolumab patients. The most frequent
serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse
reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Intravenous
nivolumab was discontinued for adverse reactions in 18% of patients. Intravenous nivolumab was
delayed for adverse reaction in 33% of patients.
The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea,
pruritus, musculoskeletal pain, and urinary tract infection.
Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-274.
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Table 27:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-274
Adverse Reaction
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Skin and Subcutaneous Tissue
Rasha
36
1.7
19
0.3
Pruritus
30
0
16
0
General
Fatigue/Asthenia
36
1.1
32
0.3
Pyrexia
10
0.3
10
0.3
Gastrointestinal
Diarrheab
30
2.8
27
1.7
Nausea
16
0.6
13
0
Abdominal painc
15
0.9
15
0.6
Constipation
13
0.3
15
0.3
Musculoskeletal and Connective Tissue
Musculoskeletal paind
28
0.6
24
0.9
Arthralgia
11
0.3
13
0
Infections
Urinary tract infectione
22
6
23
9
Upper respiratory tract infectionf
16
0.3
16
0.6
Endocrine
Hyperthyroidism
11
0
1.1
0
Hypothyroidism
11
0
2.3
0
Renal and Urinary Disorders
Renal dysfunctiong
17
1.7
16
0.9
Respiratory, Thoracic and Mediastinal
Coughh
14
0
11
0
Dyspneai
11
0.3
6
0.3
Metabolism and Nutrition
Decreased appetite
13
0.9
7
0.3
Nervous System Disorders
Dizzinessj
11
0.3
9
0
50
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Table 27:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-274
Adverse Reaction
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Hepatobiliary
Hepatitisk
11
4
8
0.6
Toxicity was graded per NCI CTCAE v4.
a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema
asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid,
photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo
papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and
urticaria.
b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis
c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain.
d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
myalgia, neck pain, pain in extremity and spinal pain.
e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic,
urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and
urosepsis.
f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased,
immune-mediated nephritis, nephritis, renal failure, and renal impairment.
h Includes cough, productive cough, and upper-airway cough syndrome.
i Includes dyspnea and exertional dyspnea.
j Includes dizziness, postural dizziness and vertigo.
k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased,
cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury,
hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased.
Table 28:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-274
Laboratory Abnormality
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased creatinine
36
1.7
36
2.6
Increased amylase
34
8
23
3.2
Increased lipase
33
12
31
10
Hyperkalemia
32
5
30
6
51
Reference ID: 5503299
Table 28:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-274
Laboratory Abnormality
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Increased alkaline phosphatase
24
2.3
15
0.6
Increased AST
24
3.5
16
0.9
Increased ALT
23
2.9
15
0.6
Hyponatremia
22
4.1
17
1.8
Hypocalcemia
17
1.2
11
0.9
Hypomagnesemia
16
0
9
0
Hypercalcemia
12
0.3
8
0.3
Hematology
Lymphopenia
33
2.9
27
1.5
Anemia
30
1.4
28
0.9
Neutropenia
11
0.6
10
0.3
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 322 to 348 patients) and placebo group (range: 312
to 341 patients).
First-line Treatment of Unresectable or Metastatic UC
CHECKMATE-901
The safety of intravenous nivolumab was evaluated in CHECKMATE-901, a randomized, open-
label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies
(14.8)]. Patients received either intravenous nivolumab 360 mg with cisplatin and gemcitabine
every 3 weeks for up to 6 cycles followed by single-agent intravenous nivolumab 480 mg every 4
weeks up to 2 years (n=304), or cisplatin and gemcitabine chemotherapy every 3 weeks for up to
6 cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin.
Among patients who received intravenous nivolumab with chemotherapy, the median duration of
intravenous nivolumab exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse
reactions occurred in 48% of patients receiving intravenous nivolumab in combination with
chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who
received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute
kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count
decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were
nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and
peripheral neuropathy.
52
Reference ID: 5503299
Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in
combination with chemotherapy; these included sepsis (1%).
Intravenous nivolumab and/or chemotherapy were discontinued in 30% of patients and were
delayed in 67% of patients for an adverse reaction.
Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-901.
Table 29:
Adverse Reactions Occurring in ≥10% of Treated Patients -
CHECKMATE-901
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet
Chemotherapy
(n=304)
Platinum-Doublet
Chemotherapy (n=288)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Gastrointestinal disorders
Nausea
52
0.3
53
1
Constipation
30
0
28
0.7
Vomiting
23
1.3
19
2.1
Diarrheaa
19
2
14
0
Abdominal painb
14
0.3
9
0.3
General
Fatiguec
48
3.9
43
4.2
Edemad
18
0
9
0.3
Pyrexiae
14
1
14
0
Musculoskeletal and Connective Tissue
Musculoskeletal painf
33
3
21
0.3
Metabolism and Nutrition
Decreased appetite
30
1.6
19
1
Skin and Subcutaneous Tissue
Rashg
25
2.3
7
0.3
Pruritus
17
0.7
3.5
0
Nervous System Disorders
Peripheral neuropathyh
20
0.7
14
0
Headachei
11
0
5
0
Infections
53
Reference ID: 5503299
Table 29:
Adverse Reactions Occurring in ≥10% of Treated Patients -
CHECKMATE-901
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet
Chemotherapy
(n=304)
Platinum-Doublet
Chemotherapy (n=288)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Urinary tract infectionj
19
8
18
8
Endocrine disorders
Hypothyroidismk
17
0
0.3
0
Renal and Urinary Disorders
Renal dysfunctionl
14
6
11
1.7
Hematuria
11
1
7
1.4
Investigations
Weight decreased
11
0.3
6
0
Toxicity was graded per NCI CTCAE v4.
a Includes colitis, immune-mediated enterocolitis.
b Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort,
gastrointestinal pain, and hepatic pain.
c Includes asthenia.
d Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema,
gravitational edema, and edema genital.
e Includes hyperthermia, body temperature increased and hyperpyrexia.
f Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia,
neck pain, pain in extremity, and spinal pain.
g Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis,
dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar
plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation.
h Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral
motor neuropathy, polyneuropathy.
i Includes occipital neuralgia.
j Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia
urinary tract infection.
k Includes blood stimulating hormone increased.
l Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia.
54
Reference ID: 5503299
Table 30:
Selected Laboratory Abnormalities Worsening from Baselinea
Occurring in ≥20% of Patients - CHECKMATE-901
Laboratory Abnormality
Intravenous Nivolumab and
Platinum-Doublet Chemotherapy
(n=304)
Platinum-Doublet Chemotherapy
(n=288)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Hematology
Anemia
88
21
80
21
Neutropenia
82
35
76
28
Lymphopenia
71
17
56
13
Thrombocytopenia
60
13
51
8
Chemistry
Increased creatinine
53
2.4
42
1.1
Hypomagnesemia
48
3.8
39
1.5
Hyponatremia
43
13
39
8
Hyperglycemia
41
3.9
37
3.2
Hypocalcemia
36
2.1
24
1.1
Hyperkalemia
33
3.0
32
1.1
Increased amylase
32
4.2
23
3.6
Increased AST
31
2.4
17
0.7
Increased ALT
29
2.4
19
0.7
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 289-301 patients) and chemotherapy group (range:
265-281 patients).
Previously Treated Advanced or Metastatic UC
CHECKMATE-275
The safety of intravenous nivolumab was evaluated in CHECKMATE-275, a single arm trial in
which 270 patients with locally advanced or metastatic UC had disease progression during or
following platinum-containing chemotherapy or had disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies
(14.8)]. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes
every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment
was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for
an adverse reaction.
Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients
(1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment
with intravenous nivolumab. Serious adverse reactions occurred in 54% of patients. Intravenous
nivolumab was discontinued for adverse reactions in 17% of patients.
55
Reference ID: 5503299
The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract
infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.
The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal
pain, nausea, and decreased appetite.
Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-275.
Table 31:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-275
Adverse Reaction
Intravenous Nivolumab
(n=270)
All Grades (%)
Grades 3-4 (%)
Adverse Reaction
99
51
General
Asthenia/fatigue/malaise
46
7
Pyrexia/tumor associated fever
17
0.4
Edema/peripheral edema/peripheral swelling
13
0.4
Musculoskeletal and Connective Tissue
Musculoskeletal paina
30
2.6
Arthralgia
10
0.7
Metabolism and Nutrition
Decreased appetite
22
2.2
Gastrointestinal
Nausea
22
0.7
Diarrhea
17
2.6
Constipation
16
0.4
Abdominal painb
13
1.5
Vomiting
12
1.9
Respiratory, Thoracic and Mediastinal
Cough/productive cough
18
0
Dyspnea/exertional dyspnea
14
3.3
Infections
Urinary tract infection/escherichia/fungal
urinary tract infection
17
7
Skin and Subcutaneous Tissue
Rashc
16
1.5
Pruritus
12
0
56
Reference ID: 5503299
I
I
Table 31:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-275
Adverse Reaction
Intravenous Nivolumab
(n=270)
All Grades (%)
Grades 3-4 (%)
Endocrine
Thyroid disordersd
15
0
Toxicity was graded per NCI CTCAE v4.
a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity and spinal pain.
b Includes abdominal discomfort, lower and upper abdominal pain.
c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular,
maculopapular, or pruritic.
d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism,
thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri
iodothyronine increased.
Table 32:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of Patients - CHECKMATE-275
Laboratory Abnormality
Intravenous Nivolumaba
All Grades (%)
Grades 3-4 (%)
Chemistry
Hyperglycemia
42
2.4
Hyponatremia
41
11
Increased creatinine
39
2
Increased alkaline phosphatase
33
5.5
Hypocalcemia
26
0.8
Increased AST
24
3.5
Increased lipase
20
7
Hyperkalemia
19
1.2
Increased ALT
18
1.2
Increased amylase
18
4.4
Hypomagnesemia
16
0
Hematology
Lymphopenia
42
9
Anemia
40
7
Thrombocytopenia
15
2.4
Leukopenia
11
0
57
Reference ID: 5503299
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: range: 84 to 256 patients.
MSI-H or dMMR Metastatic Colorectal Cancer
CHECKMATE-142
The safety of intravenous nivolumab administered as a single agent or in combination with
ipilimumab was evaluated in CHECKMATE-142, a multicenter, non-randomized, multiple
parallel-cohort, open-label trial [see Clinical Studies (14.9)]. In CHECKMATE-142, 74 patients
with mCRC received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes
every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC
received intravenous nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then
intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or until unacceptable
toxicity.
In the intravenous nivolumab with ipilimumab cohort, serious adverse reactions occurred in 47%
of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an
adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were
colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The
most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia,
musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.
Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used
to identify statistically significant differences between the two cohorts summarized below for any
adverse reaction.
Table 33:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-142
Adverse Reaction
Intravenous Nivolumab
(n=74)
Intravenous Nivolumab and
Ipilimumab
(n=119)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
General
Fatiguea
54
5
49
6
Pyrexia
24
0
36
0
Edemab
12
0
7
0
Gastrointestinal
Diarrhea
43
2.7
45
3.4
Abdominal painc
34
2.7
30
5
Nausea
34
1.4
26
0.8
Vomiting
28
4.1
20
1.7
58
Reference ID: 5503299
Table 33:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-142
Adverse Reaction
Intravenous Nivolumab
(n=74)
Intravenous Nivolumab and
Ipilimumab
(n=119)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Constipation
20
0
15
0
Musculoskeletal and Connective Tissue
Musculoskeletal paind
28
1.4
36
3.4
Arthralgia
19
0
14
0.8
Respiratory, Thoracic and Mediastinal
Cough
26
0
19
0.8
Dyspnea
8
1
13
1.7
Skin and Subcutaneous Tissue
Rashe
23
1.4
25
4.2
Pruritus
19
0
28
1.7
Dry Skin
7
0
11
0
Infections
Upper respiratory tract
infectionf
20
0
9
0
Endocrine
Hyperglycemia
19
2.7
6
1
Hypothyroidism
5
0
14
0.8
Hyperthyroidism
4
0
12
0
Nervous System
Headache
16
0
17
1.7
Dizziness
14
0
11
0
Metabolism and Nutrition
Decreased appetite
14
1.4
20
1.7
Psychiatric
Insomnia
9
0
13
0.8
Investigations
Weight decreased
8
0
10
0
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema and peripheral swelling.
c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
59
Reference ID: 5503299
d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.
e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.
f Includes nasopharyngitis and rhinitis.
Clinically important adverse reactions reported in <10% of patients receiving intravenous
nivolumab with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis
(0.8%).
Table 34:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-142
Laboratory Abnormality
Intravenous Nivolumab
(n=74)
Intravenous Nivolumab and
Ipilimumab
(n=119)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Hematology
Anemia
50
7
42
9
Lymphopenia
36
7
25
6
Neutropenia
20
4.3
18
0
Thrombocytopenia
16
1.4
26
0.9
Chemistry
Increased alkaline
phosphatase
37
2.8
28
5
Increased lipase
33
19
39
12
Increased ALT
32
2.8
33
12
Increased AST
31
1.4
40
12
Hyponatremia
27
4.3
26
5
Hypocalcemia
19
0
16
0
Hypomagnesemia
17
0
18
0
Increased amylase
16
4.8
36
3.4
Increased bilirubin
14
4.2
21
5
Hypokalemia
14
0
15
1.8
Increased creatinine
12
0
25
3.6
Hyperkalemia
11
0
23
0.9
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available. Number of evaluable patients ranges from 62 to 71 for the intravenous nivolumab cohort
and from 87 to 114 for the intravenous nivolumab and ipilimumab cohort.
Hepatocellular Carcinoma
CHECKMATE-040
60
Reference ID: 5503299
The safety of intravenous nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg was
evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis
enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see
Clinical Studies (14.10)] who progressed on or were intolerant to sorafenib. Intravenous
nivolumab and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent
intravenous nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.
During the intravenous nivolumab and ipilimumab combination period, 33 of 49 (67%) patients
received all 4 planned doses of intravenous nivolumab and ipilimumab. During the entire treatment
period, the median duration of exposure to intravenous nivolumab was 5.1 months (range: 0 to
35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of
patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment
for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in
29% of patients and delayed in 65% of patients for an adverse reaction.
The most frequent serious adverse reactions (reported in ≥4% of patients) were pyrexia, diarrhea,
anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage,
hyponatremia, increased blood bilirubin, and pneumonitis.
Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-040.
Table 35:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab in Combination with Ipilimumab in Cohort
4 of CHECKMATE-040
Adverse Reaction
Intravenous Nivolumab and Ipilimumab
(n=49)
All Grades (%)
Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rash
53
8
Pruritus
53
4
Musculoskeletal and Connective Tissue
Musculoskeletal pain
41
2
Arthralgia
10
0
Gastrointestinal
Diarrhea
39
4
Abdominal pain
22
6
Nausea
20
0
Ascites
14
6
Constipation
14
0
Dry mouth
12
0
Dyspepsia
12
2
61
Reference ID: 5503299
Table 35:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab in Combination with Ipilimumab in Cohort
4 of CHECKMATE-040
Adverse Reaction
Intravenous Nivolumab and Ipilimumab
(n=49)
All Grades (%)
Grades 3-4 (%)
Vomiting
12
2
Stomatitis
10
0
Respiratory, Thoracic and Mediastinal
Cough
37
0
Dyspnea
14
0
Pneumonitis
10
2
Metabolism and Nutrition
Decreased appetite
35
2
General
Fatigue
27
2
Pyrexia
27
0
Malaise
18
2
Edema
16
2
Influenza-like illness
14
0
Chills
10
0
Nervous System
Headache
22
0
Dizziness
20
0
Endocrine
Hypothyroidism
20
0
Adrenal insufficiency
18
4
Investigations
Weight decreased
20
0
Psychiatric
Insomnia
18
0
Blood and Lymphatic System
Anemia
10
4
Infections
Influenza
10
2
Vascular
62
Reference ID: 5503299
Table 35:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab in Combination with Ipilimumab in Cohort
4 of CHECKMATE-040
Adverse Reaction
Intravenous Nivolumab and Ipilimumab
(n=49)
All Grades (%)
Grades 3-4 (%)
Hypotension
10
0
Clinically important adverse reactions reported in <10% of patients who received intravenous
nivolumab with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine
phosphokinase (2%).
Table 36:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of Patients Receiving Intravenous Nivolumab in
Combination with Ipilimumab in Cohort 4 of CHECKMATE-040
Laboratory Abnormality
Intravenous Nivolumab and Ipilimumab
(n=47)
All Grades (%)
Grades 3-4 (%)
Hematology
Lymphopenia
53
13
Anemia
43
4.3
Neutropenia
43
9
Leukopenia
40
2.1
Thrombocytopenia
34
4.3
Chemistry
Increased AST
66
40
Increased ALT
66
21
Increased bilirubin
55
11
Increased lipase
51
26
Hyponatremia
49
32
Hypocalcemia
47
0
Increased alkaline phosphatase
40
4.3
Increased amylase
38
15
Hypokalemia
26
2.1
Hyperkalemia
23
4.3
Increased creatinine
21
0
Hypomagnesemia
11
0
63
Reference ID: 5503299
In patients who received intravenous nivolumab with ipilimumab, virologic breakthrough occurred
in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline,
respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA
for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined
as a 1 log increase in HCV RNA from baseline.
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
CHECKMATE-577
The safety of intravenous nivolumab was evaluated in CHECKMATE-577, a randomized,
placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely
resected (negative margins) esophageal or gastroesophageal junction cancer who had residual
pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.11)]. The trial
excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable
disease, autoimmune disease, or any condition requiring systemic treatment with either
corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications.
Patients received either intravenous nivolumab 240 mg or placebo by intravenous infusion over
30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion
over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease
recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of
exposure was 10.1 months (range: <0.1 to 14 months) in intravenous nivolumab-treated patients
and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received
intravenous nivolumab, 61% were exposed for >6 months and 54% were exposed for >9 months.
Serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab. A serious
adverse reaction reported in ≥2% of patients who received intravenous nivolumab was
pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who
received intravenous nivolumab.
Intravenous nivolumab was discontinued in 12% of patients and was delayed in 28% of patients
for an adverse reaction.
Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-577.
Table 37:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - CHECKMATE-577
Adverse Reaction
Intravenous Nivolumab
(n=532)
Placebo
(n=260)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Adverse Reaction
96
34
93
32
Gastrointestinal
Diarrhea
29
0.9
29
0.8
64
Reference ID: 5503299
Table 37:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - CHECKMATE-577
Adverse Reaction
Intravenous Nivolumab
(n=532)
Placebo
(n=260)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Adverse Reaction
96
34
93
32
Nausea
23
0.8
21
0
Abdominal Paina
17
0.8
20
1.5
Vomiting
15
0.6
16
1.2
Dysphagia
13
0.8
17
3.5
Dyspepsiab
12
0.2
16
0.4
Constipation
11
0
12
0
General
Fatiguec
34
1.3
29
1.5
Respiratory, Thoracic and Mediastinal
Coughd
20
0.2
21
0.4
Dyspneae
12
0.8
12
0.4
Skin and Subcutaneous Tissue
Rashf
21
0.9
10
0.4
Pruritus
13
0.4
6
0
Investigations
Weight decreased
13
0.4
9
0
Musculoskeletal and Connective Tissue
Musculoskeletal paing
21
0.6
20
0.8
Arthralgia
10
0.2
8
0
Metabolism and Nutrition
Decreased appetite
15
0.9
10
0.8
Endocrine
Hypothyroidism
11
0
1.5
0
a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
b Includes gastroesophageal reflux.
c Includes asthenia.
d Includes productive cough.
e Includes dyspnea exertional.
f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash
erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic.
65
Reference ID: 5503299
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia
intercostal, neck pain, pain in extremity, spinal pain.
Table 38:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-577
Laboratory Abnormality
Intravenous Nivolumab
(n=532)
Placebo
(n=260)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased AST
27
2.1
22
0.8
Increased alkaline phosphatase
25
0.8
18
0.8
Increased albumin
21
0.2
18
0
Increased ALT
20
1.9
16
1.2
Increased amylase
20
3.9
13
1.3
Hyponatremia
19
1.7
12
1.2
Hyperkalemia
17
0.8
15
1.6
Hypokalemia
12
1
11
1.2
Transaminases increasedb
11
1.5
6
1.2
Hematology
Lymphopenia
44
17
35
12
Anemia
27
0.8
21
0.4
Neutropenia
24
1.5
23
0.4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 163 to 526 patients) and Placebo group (range: 86 to
256 patients).
b Includes alanine aminotransferase increased, aspartate aminotransferase increased.
First-line Treatment of Unresectable Advanced or Metastatic ESCC
CHECKMATE-648
The safety of intravenous nivolumab in combination with chemotherapy or in combination with
ipilimumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter,
open-label trial in patients with previously untreated unresectable advanced, recurrent or
metastatic ESCC [see Clinical Studies (14.11)]. Patients received one of the following treatments:
intravenous nivolumab 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m2/day
intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on
day 1 (of a 4-week cycle).
intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg
every 6 weeks.
66
Reference ID: 5503299
5-FU (fluorouracil) 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and
cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Among patients who received intravenous nivolumab with chemotherapy, the median duration of
exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received intravenous
nivolumab and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to
24 months).
Serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in
combination with chemotherapy and in 69% of patients receiving intravenous nivolumab in
combination with ipilimumab. The most frequent serious adverse reactions reported in ≥2% of
patients who received intravenous nivolumab with chemotherapy were pneumonia (11%),
dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The
most frequent serious adverse reactions reported in ≥2% of patients who received intravenous
nivolumab with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration
pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite
(2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in
combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis,
pneumonia, and acute kidney injury and in 5 (1.6%) patients who received intravenous nivolumab
in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary
embolism, and acute respiratory distress syndrome.
Intravenous nivolumab and/or chemotherapy were discontinued in 39% of patients and were
delayed in 71% of patients for an adverse reaction. Intravenous nivolumab and/or ipilimumab were
discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction.
The most common adverse reactions reported in ≥20% of patients treated with intravenous
nivolumab in combination with chemotherapy were nausea, decreased appetite, fatigue,
constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in
≥20% of patients treated with intravenous nivolumab in combination with ipilimumab were rash,
fatigue, pyrexia, nausea, diarrhea, and constipation.
Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-648.
Table 39:
Adverse Reactions in ≥10% of Patients - CHECKMATE-648
Adverse Reaction
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Gastrointestinal
Nausea
65
4.2
22
0.6
56
2.6
67
Reference ID: 5503299
Table 39:
Adverse Reactions in ≥10% of Patients - CHECKMATE-648
Adverse Reaction
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Constipation
44
1.0
20
0.3
43
1
Stomatitisa
44
9
11
0.6
35
3
Diarrhea
29
2.9
22
1.9
20
2
Vomiting
23
2.3
15
1.6
19
3
Dysphagia
14
7
12
5
12
4.9
Abdominal painb
13
1.9
10
0.9
11
0.7
Metabolism and Nutrition
Decreased appetite
51
7
17
4
50
6
General
Fatiguec
47
3.5
28
2.5
41
4.9
Pyrexiad
19
0.3
23
0.9
12
0.3
Edemae
16
0
7
0
13
0
Nervous System
Peripheral
neuropathyf
18
1.3
2.8
0
13
1
Psychiatric
Insomnia
16
0
8
0
10
0.3
Skin and Subcutaneous Tissue
Rashg
16
0.6
31
3.1
7
0
Pruritus
11
0
17
0.9
3.6
0
Alopecia
10
0
11
0
Respiratory, Thoracic and Mediastinal
Coughh
16
0.3
13
0.3
13
0.3
Infections and Infestations
Pneumoniai
13
5
14
8
10
2.6
Endocrine
Hypothyroidism
7
0
14
0
0.3
0
Investigations
Weight decreased
12
0.6
12
1.9
11
1
68
Reference ID: 5503299
Table 39:
Adverse Reactions in ≥10% of Patients - CHECKMATE-648
Adverse Reaction
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Musculoskeletal and Connective Tissue
Musculoskeletal
painj
11
0.3
14
0.6
8
0.3
Toxicity was graded per NCI CTCAE v4.
a Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes asthenia and malaise.
d Includes tumor associated fever.
e Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
f Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and
peripheral sensory neuropathy.
g Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash,
rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic.
h Includes productive cough.
i Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal.
j Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
Table 40:
Laboratory Values Worsening from Baselinea Occurring in ≥10%
of Patients - CHECKMATE-648
Laboratory
Abnormality
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Hematology
Anemia
81
21
52
7
66
14
Lymphopenia
67
23
50
13
44
8
Neutropenia
61
18
13
1.3
48
13
Leukopenia
53
11
39
5
Thrombocytopenia
43
3.3
12
1
29
2.8
Chemistry
Hyponatremia
52
15
45
11
40
8
Hypocalcemia
43
3
32
0
23
0.7
Increased creatinine
41
2.3
15
0.7
31
0.7
Hypomagnesemia
35
1.7
15
0
25
1.8
69
Reference ID: 5503299
Table 40:
Laboratory Values Worsening from Baselinea Occurring in ≥10%
of Patients - CHECKMATE-648
Laboratory
Abnormality
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Hyperglycemia
34
0
43
4.3
36
0.8
Hyperkalemia
33
2.3
23
1.6
24
0.7
Hypokalemia
29
9
19
5
17
6
Increased alkaline
phosphatase
26
1.3
31
3.3
15
0
Increased AST
23
3.3
39
6
11
1.4
Increased ALT
23
2.3
33
6
8
0.7
Hypoglycemia
18
0.4
15
1.2
7
0
Hypercalcemia
11
2.6
15
2
8
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab with cisplatin and 5-FU group (range: 60 to 305 patients),
intravenous nivolumab and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to
283 patients).
Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal
Squamous Cell Carcinoma (ESCC)
ATTRACTION-3
The safety of intravenous nivolumab was evaluated in ATTRACTION-3, a randomized, active-
controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or
metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based
chemotherapy [see Clinical Studies (14.11)]. The trial excluded patients who were refractory or
intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment,
had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent
tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or
respiratory tract. Patients received intravenous nivolumab 240 mg by intravenous infusion over
30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously
every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed
by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity.
The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in intravenous
nivolumab-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel
treated patients. Among patients who received intravenous nivolumab, 26% were exposed for
>6 months and 10% were exposed for >1 year.
70
Reference ID: 5503299
Serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab. Serious
adverse reactions reported in ≥2% of patients who received intravenous nivolumab were
pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse
reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or
pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%),
gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).
Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients
for an adverse reaction.
Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in
ATTRACTION-3.
Table 41:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - ATTRACTION-3
Adverse Reaction
Intravenous Nivolumab
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rasha
22
1.9
28
1
Pruritus
12
0
7
0
Metabolism and Nutrition
Decreased appetiteb
21
1.9
35
5
Gastrointestinal
Diarrheac
18
1.9
17
1.4
Constipation
17
0
19
0
Nausea
11
0
20
0.5
Musculoskeletal and Connective Tissue
Musculoskeletal
paind
17
0
26
1.4
Infections
Upper respiratory
tract infectione
17
1
14
0
Pneumoniaf
13
5
19
9
Respiratory, Thoracic and Mediastinal
Coughg
16
0
14
0.5
General
Pyrexiah
16
0.5
19
0.5
Fatiguei
12
1.4
27
4.8
71
Reference ID: 5503299
I
I
I
I
I
I
Table 41:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - ATTRACTION-3
Adverse Reaction
Intravenous Nivolumab
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Blood and Lymphatic System
Anemiaj
13
8
30
13
Endocrine
Hypothyroidismk
11
0
1.4
0
Toxicity was graded per NCI CTCAE v4.
a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia
syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis,
dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or
pustular.
b Includes hypophagia, and food aversion.
c Includes colitis.
d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain
in extremity, arthritis, bone pain, and periarthritis calcarea.
e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper
respiratory infection with bronchitis.
f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia
in the intravenous nivolumab treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment
arm; these deaths occurred with paclitaxel only.
g Includes productive cough.
h Includes tumor-associated fever.
i Includes asthenia.
j Includes hemoglobin decreased, and iron deficiency anemia.
k Includes blood thyroid stimulating hormone increased.
72
Reference ID: 5503299
Table 42:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - ATTRACTION-3
Laboratory Abnormality
Intravenous Nivolumab
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased creatinine
78
0.5
68
0.5
Hyperglycemia
52
5
62
5
Hyponatremia
42
11
50
12
Increased AST
40
6
30
1
Increased alkaline phosphatase
33
4.8
24
1.0
Increased ALT
31
5
22
1.9
Hypercalcemia
22
6
14
2.9
Hyperkalemia
22
0.5
31
1
Hypoglycemia
14
1.4
14
0.5
Hypokalemia
11
2.9
13
3.4
Hematology
Lymphopenia
46
19
72
43
Anemia
42
9
71
17
Leukopenia
11
0.5
79
45
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (209 patients) and Docetaxel or Paclitaxel group (range: 207
to 208 patients).
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
CHECKMATE-649
The safety of intravenous nivolumab in combination with chemotherapy was evaluated in
CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously
untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal
adenocarcinoma [see Clinical Studies (14.12)]. The trial excluded patients who were known
human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous
system (CNS) metastases. Patients were randomized to receive intravenous nivolumab in
combination with chemotherapy or chemotherapy. Patients received one of the following
treatments:
intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin
and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and
oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
73
Reference ID: 5503299
Patients were treated with intravenous nivolumab in combination with chemotherapy or
chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median
duration of exposure was 6.8 months (range: 0 to 33.5 months) in intravenous nivolumab and
chemotherapy-treated patients. Among patients who received intravenous nivolumab and
chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.
Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous
nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile
neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic
shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and
disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients
treated with intravenous nivolumab in combination with chemotherapy. Intravenous nivolumab
and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in
76% of patients due to an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous
nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia
(3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The
most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab
in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea,
vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-649.
Table 43:
Adverse Reactions in ≥10% of Patients Receiving Intravenous
Nivolumab and Chemotherapy - CHECKMATE-649
Adverse Reaction
Intravenous Nivolumab and
mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Adverse Reaction
99
69
98
59
Nervous System
Peripheral neuropathya
53
7
46
4.8
Headache
11
0.8
6
0.3
Gastrointestinal
Nausea
48
3.2
44
3.7
Diarrhea
39
5
34
3.7
Vomiting
31
4.2
29
4.2
Abdominal painb
27
2.8
24
2.6
Constipation
25
0.6
21
0.4
74
Reference ID: 5503299
Table 43:
Adverse Reactions in ≥10% of Patients Receiving Intravenous
Nivolumab and Chemotherapy - CHECKMATE-649
Adverse Reaction
Intravenous Nivolumab and
mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Stomatitisc
17
1.8
13
0.8
General
Fatigued
44
7
40
5
Pyrexiae
19
1
11
0.4
Edemaf
12
0.5
8
0.1
Metabolism and Nutrition
Decreased appetite
29
3.6
26
2.5
Hypoalbuminemiag
14
0.3
9
0.3
Investigations
Weight decreased
17
1.3
15
0.7
Increased lipase
14
7
8
3.7
Increased amylase
12
3.1
5
0.4
Musculoskeletal and Connective Tissue
Musculoskeletal painh
20
1.3
14
2
Skin and Subcutaneous Tissue
Rashi
18
1.7
4.4
0.1
Palmar-plantar erythrodysesthesia
syndrome
13
1.5
12
0.8
Respiratory, Thoracic and Mediastinal
Coughj
13
0.1
9
0
Infections and Infestations
Upper respiratory tract infectionk
10
0.1
7
0.1
Toxicity was graded per NCI CTCAE v4.
a Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and
peripheral sensory neuropathy.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
d Includes asthenia.
e Includes tumor associated fever.
f Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
g Includes blood albumin decreased.
75
Reference ID: 5503299
h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, and spinal pain.
i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash,
nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, and rhinitis.
Table 44:
Laboratory Values Worsening from Baselinea Occurring in ≥10%
of Patients - CHECKMATE-649
Laboratory
Abnormality
Intravenous Nivolumab and
mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Hematology
Neutropenia
73
29
62
23
Leukopenia
69
12
59
9
Thrombocytopenia
68
7
63
4.4
Anemia
59
14
60
10
Lymphopenia
59
12
49
9
Chemistry
Increased AST
52
4.6
47
1.9
Hypocalcemia
42
1.6
37
1
Hyperglycemia
41
3.9
38
2.7
Increased ALT
37
3.4
30
1.9
Hyponatremia
34
6
24
5
Hypokalemia
27
7
24
4.8
Hyperbilirubinemia
24
2.8
21
2
Increased creatinine
15
1
9
0.5
Hyperkalemia
14
1.4
11
0.7
Hypoglycemia
12
0.7
9
0.2
Hypernatremia
11
0.5
7.1
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and mFOLFOX6 or CapeOX group (407 to 767 patients) or
mFOLFOX6 or CapeOX group (range: 405 to 735 patients).
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of intravenous
nivolumab. Because these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
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Eye: Vogt-Koyanagi-Harada (VKH) syndrome
Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Treatment refractory,
severe acute and chronic GVHD
Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including
fatal cases), autoimmune hemolytic anemia (including fatal cases)
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on data from animal studies and its mechanism of action [see Clinical Pharmacology
(12.1)], OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In
animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset
of organogenesis through delivery resulted in increased abortion and premature infant death (see
Data). Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin
G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the
developing fetus. The effects of OPDIVO QVANTIG are likely to be greater during the second
and third trimesters of pregnancy. There are no available data on OPDIVO QVANTIG use in
pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk
to a fetus.
The background risk in the U.S. general population of major birth defects is 2% to 4% and of
miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal Data
OPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see
Description (11)].
Nivolumab
A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal
immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of
pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on
prenatal and postnatal development were evaluated in monkeys that received nivolumab
intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels
of between 4 and 15 times higher than those observed at the clinical dose of 600 mg once every 2
weeks, 900 mg once every 3 weeks, or 1,200 mg once every 4 weeks (based on AUC). Nivolumab
administration resulted in a non-dose-related increase in spontaneous abortion and increased
neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the
risk of developing immune-mediated disorders or altering the normal immune response, and
immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18
of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with
nivolumab, there were no apparent malformations and no effects on neurobehavioral,
immunological, or clinical pathology parameters throughout the 6-month postnatal period.
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Hyaluronidase
In an embryo-fetal development study, mice were dosed daily by subcutaneous injection during
the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to
2,200,000 U/kg, which is at least 6,600 times higher than the human dose of 10,000 U once every
2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when
administered with nivolumab. The study found no evidence of teratogenicity. Reduced fetal weight
and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of
360,000 U/kg, which is at least 1,080 times higher than the human dose of 10,000 U once every 2
weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when
administered with nivolumab.
8.2
Lactation
Risk Summary
There are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the
breastfed child, or the effects on milk production. Because of the potential for serious adverse
reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months
after the last dose of OPDIVO QVANTIG.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO
QVANTIG [see Use in Specific Populations (8.1)].
Contraception
OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception
during treatment with OPDIVO QVANTIG and for 5 months following the last dose.
8.4
Pediatric Use
The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric
patients.
8.5
Geriatric Use
Monotherapy
Of the 248 patients who were randomized to monotherapy OPDIVO QVANTIG in clinical studies,
48% were 65 years and over and 14% were 75 years and over. No overall differences in safety or
effectiveness were observed between elderly patients and younger patients.
Single Agent Intravenous Nivolumab
Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and
esophageal or gastroesophageal junction cancer who were randomized to single agent intravenous
nivolumab in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No
overall differences in safety or effectiveness were observed between elderly patients and younger
patients [see Clinical Studies (14.1, 14.2, 14.3, 14.6, 14.8, 14.11, 14.12)].
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Clinical studies in patients with recurrent head and neck SCC, or dMMR or MSI-H metastatic
CRC (mCRC) who were treated with single agent intravenous nivolumab did not include sufficient
numbers of patients aged 65 years and over to determine whether they respond differently from
younger patients [see Clinical Studies (14.7, 14.9)].
Intravenous Nivolumab in Combination with Platinum-Containing Chemotherapy
Of the 179 patients with NSCLC who were randomized to intravenous nivolumab in combination
with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old
or older. No overall differences in safety or effectiveness were reported between patients older and
younger than 65 years [see Clinical Studies (14.4)].
Of the 229 patients with NSCLC who were randomized to intravenous nivolumab 360 mg in
combination with platinum-doublet chemotherapy every 3 weeks for up to 4 cycles, followed by
intravenous nivolumab 480 mg every 4 weeks, 56% were 65 years old or older and 7% were 75
years old or older. No overall differences in safety or effectiveness were reported between patients
older and younger than 65 years.
Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to intravenous
nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy, 42%
were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported
between elderly patients and younger patients [see Clinical Studies (14.11, 14.12)].
Of the 304 patients with UC who were treated with intravenous nivolumab in combination with
gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75
years or older. No overall differences in safety or effectiveness were observed between patients 65
years of age and over and younger patients. Clinical studies of intravenous nivolumab with
platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and
over to determine whether safety and effectiveness differs compared to younger patients. [see
Clinical Studies (14.8)].
In Combination with Cabozantinib
Of the 320 patients with renal cell carcinoma who were treated with intravenous nivolumab in
combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No
overall difference in safety was reported between elderly patients and younger patients [see
Clinical Studies (14.1)].
11
DESCRIPTION
OPDIVO QVANTIG is a fixed-combination drug product containing nivolumab and
hyaluronidase (human recombinant).
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4
kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a
recombinant Chinese Hamster Ovary (CHO) cell line.
Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and
absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human
recombinant) is a glycosylated single-chain protein produced by CHO cells containing a DNA
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plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human
recombinant) has a molecular weight of approximately 61 kDa.
OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-free,
clear to opalescent, colorless to yellow solution that may contain a few translucent-to-white
particles, supplied in a single-dose vial for subcutaneous use.
Each 5 mL single-dose vial of OPDIVO QVANTIG contains 600 mg of nivolumab and 10,000
units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (7.75 mg),
histidine hydrochloride monohydrate (10.5 mg), methionine (3.73 mg), pentetic acid (0.0985 mg),
polysorbate 80 (2.5 mg), sucrose (428 mg), and Water for Injection, USP. The pH is 5.5 to 6.5.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-
cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors
and signaling through this pathway can contribute to inhibition of active T-cell immune
surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody
that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1
pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is
depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural
components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days.
Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing
hyaluronan. In the doses administered, hyaluronidase in OPDIVO QVANTIG acts transiently and
locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is
restored within 24 to 48 hours.
12.2
Pharmacodynamics
Exposure-Response Relationship
The exposure-response relationship and time course of pharmacodynamics of OPDIVO
QVANTIG have not been fully characterized.
12.3
Pharmacokinetics
When comparing nivolumab exposures following OPDIVO QVANTIG to those of intravenous
nivolumab in CHECKMATE-67T [see Clinical Studies (14.1)], the geometric mean ratios
(GMRs) (90% CI) for time-averaged concentration (Cavg) over 28 days and at steady state were
2.10 (2.00, 2.20) and 1.98 (1.87, 2.11), respectively, and for minimum concentration (Cmin) at 28
days and at steady state were 1.60 (1.49, 1.72) and 1.77 (1.63, 1.93), respectively.
Steady state was achieved by 16 weeks. The systemic accumulation ratio was 2.3.
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Absorption
The geometric mean bioavailability (CV%) of nivolumab is 74% (14%). Peak concentrations
occurred by around 6 days.
Distribution
The geometric mean (CV%) volume of distribution at steady state is 6.8 L (27%).
Elimination
Nivolumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline
values of 24.5% (47.6%), resulting in a geometric mean steady-state clearance (CV%) of 8.2 mL/h
(53.9%) in patients with metastatic tumors; this decrease in clearance is not considered clinically
relevant. Nivolumab clearance does not decrease over time in patients with completely resected
melanoma, as the geometric mean population clearance is 24% lower in this patient population
compared with patients with metastatic melanoma at steady state.
The geometric mean (CV%) elimination half-life is 25 days (78%).
Specific Populations
Body weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1.73 m2), and performance status have
no clinically significant effects on the clearance of nivolumab.
12.6
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug
antibodies in other studies, including those of OPDIVO QVANTIG or of other nivolumab products
or hyaluronidase products.
During the 2-year treatment period in CHECKMATE-67T [see Clinical Studies (14.1)], 23%
(46/202) of patients who received OPDIVO QVANTIG developed anti-nivolumab antibodies
(ADA) and 4.3% (2/46) had neutralizing antibodies against nivolumab (NAb). The corresponding
incidence of ADA was 7% (15/215) and NAb was 0% (0/15) for intravenous nivolumab in the
same study. The incidence of anti-hyaluronidase antibodies in CHECKMATE-67T was 8.8%
(19/215); 5 (26%) of these 19 patients developed NAb.
Nivolumab clearance increased by approximately 26% in patients who received OPDIVO
QVANTIG and tested positive for ADA compared to patients who tested negative for ADA; this
change in clearance is not considered clinically significant. Local injection-site reactions were
reported in 15% (7/46) of patients who developed ADA to nivolumab and 7% (10/155) of patients
who did not develop ADA to nivolumab; however, all events were Grade 1 or 2 and resolved.
Because of low occurrence of anti-nivolumab or anti-hyaluronidase antibodies, the effect of ADA
on the effectiveness of OPDIVO QVANTIG is unknown.
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13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the potential of nivolumab for carcinogenicity or
genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month
repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female
reproductive organs; however, most animals in these studies were not sexually mature.
Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been
performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when
subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for
39 weeks at dose levels up to 220,000 U/kg, which is at least 600 times higher than the human
dose (U/kg basis), of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U
once every 4 weeks, no evidence of toxicity to the male or female reproductive system was found
through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual
cycles, and also from gross pathology, histopathology and organ weight data.
13.2
Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-1 signaling increased the severity of some infections and
enhanced inflammatory responses. Mycobacterium tuberculosis–infected PD-1 knockout mice
exhibit markedly decreased survival compared with wild-type controls, which correlated with
increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade
using a primate anti–PD-1 antibody was also shown to exacerbate M. tuberculosis infection in
rhesus macaques. PD-1 knockout mice have also shown decreased survival following infection
with lymphocytic choriomeningitis virus.
14
CLINICAL STUDIES
14.1
Advanced Renal Cell Carcinoma
Previously Treated Renal Cell Carcinoma – OPDIVO QVANTIG
The efficacy of OPDIVO QVANTIG was evaluated in CHECKMATE-67T (NCT04810078), a
multicenter, randomized, open-label study in patients with advanced or metastatic clear cell renal
cell carcinoma. Patients 18 years of age or older with histologically confirmed advanced or
metastatic renal cell carcinoma with a clear cell component, including those with sarcomatoid
features, and who received no more than 2 prior systemic treatment regimens were randomized to
receive OPDIVO QVANTIG (containing 1,200 mg of nivolumab and 20,000 units of
hyaluronidase) every 4 weeks subcutaneously, or nivolumab 3 mg/kg every 2 weeks intravenously.
Patients with untreated, symptomatic central nervous system (CNS) metastases; leptomeningeal
metastases; concurrent malignancies requiring treatment or history of prior malignancy within the
previous 2 years; active, known, or suspected autoimmune disease; or who received prior treatment
with a checkpoint inhibitor were excluded from the study. Patients with asymptomatic, stable CNS
metastases that did not require immediate treatment were eligible if there was no evidence of
progression within 28 days prior to the first dose of study drug administration. Stratification factors
for randomization were weight (<80 kg vs ≥80 kg) and International Metastatic Renal Cell
Carcinoma Database Consortium (IMDC) risk classification (favorable vs intermediate, vs poor
risk). The primary objective was to assess the nivolumab exposure of subcutaneous administration
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of OPDIVO QVANTIG as compared to the intravenous administration of nivolumab. The
secondary objective of the study was to evaluate overall response rate (ORR) by blinded
independent central review (BICR).
A total of 495 patients were randomized to receive either OPDIVO QVANTIG (n=248) or
intravenous nivolumab (n=247). The median age was 65 years (range: 20 to 93), with 51% ≥65
years of age and 14% ≥75 years of age; 68% male; 85% White, 12.5% not reported, 1% American
Indian or Alaska Native, 0.8% Asian, and 0.4% Black; 36% Hispanic or Latino, 33% not Hispanic
or Latino, and 31% not reported. Fifty-seven percent of patients weighed <80 kg and 43% weighed
≥80 kg. Baseline Karnofsky performance status was 70 (7%), 80 (20%), 90 (34%), or 100 (39%).
Patient distribution by IMDC risk categories was 21% favorable, 62% intermediate, and 17% poor.
When comparing subcutaneous administration of OPDIVO QVANTIG to the intravenous
administration of nivolumab, CHECKMATE-67T met the predefined acceptance margin for
pharmacokinetic endpoints, with the lower boundary of 90% confidence interval of geometric
mean ratios of not less than 0.8 for both serum nivolumab Cavg over 28 days and Cmin at steady
state. [see Clinical Pharmacology 12.3]. Efficacy results are shown in Table 45.
Table 45:
Efficacy Results - CHECKMATE-67T
OPDIVO QVANTIG
Intravenous Nivolumab
N=248
N=247
ORR per BICR, n (%)
60 (24)
45 (18)
95% CIa
(19, 30)
(14, 24)
a Confidence interval based on the Clopper and Pearson method.
RCC Trials - Intravenous Nivolumab
The effectiveness of OPDIVO QVANTIG has been established for the following:
as monotherapy, for advanced renal cell carcinoma (RCC) following treatment with
intravenous nivolumab and ipilimumab combination therapy (CHECKMATE-214 study).
in combination with cabozantinib, for the first-line treatment of adult patients with
advanced RCC (CHECKMATE-9ER study).
as monotherapy, for the treatment of adult patients with advanced RCC who have received
prior anti-angiogenic therapy (CHECKMATE-025 study).
Use of OPDIVO QVANTIG for these RCC indications is supported by evidence from adequate
and well-controlled studies conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab in the CHECKMATE-67T trial
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Below
is a description of the efficacy results of these adequate and well-controlled studies of intravenous
nivolumab in these RCC populations.
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First-line Renal Cell Carcinoma
CHECKMATE-214
CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label trial in patients with
previously untreated advanced RCC. Patients were included regardless of their PD-L1 status.
CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active
autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were
stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and
region.
Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic
risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma
diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower
limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of
normal, and absolute neutrophil count greater than the upper limit of normal).
Patients were randomized to nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every
3 weeks for 4 doses followed by nivolumab 3 mg/kg intravenously every two weeks (n=425), or
sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued
until disease progression or unacceptable toxicity.
The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% ≥65
years of age and 8% ≥75 years of age. The majority of patients were male (73%) and White (87%)
and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.
The major efficacy outcome measures were OS, PFS (independent radiographic review committee
[IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this
population, the trial demonstrated statistically significant improvement in OS and ORR for patients
randomized to intravenous nivolumab and ipilimumab as compared with sunitinib (Table 46 and
Figure 1). OS benefit was observed regardless of PD-L1 expression level. The trial did not
demonstrate a statistically significant improvement in PFS. Efficacy results are shown in Table 46
and Figure 1.
Table 46:
Efficacy Results - CHECKMATE-214
Intermediate/Poor-Risk
Intravenous Nivolumab
and Ipilimumab
(n=425)
Sunitinib
(n=422)
Overall Survival
Deaths (%)
140 (32.9)
188 (44.5)
Median survival (months)
NRa
25.9
Hazard ratio (99.8% CI)b
0.63 (0.44, 0.89)
p-valuec,d
<0.0001
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Table 46:
Efficacy Results - CHECKMATE-214
Intermediate/Poor-Risk
Intravenous Nivolumab
and Ipilimumab
(n=425)
Sunitinib
(n=422)
Confirmed Overall Response Rate (95% CI)
41.6% (36.9, 46.5)
26.5% (22.4, 31.0)
p-valuee,f
<0.0001
Complete response (CR)
40 (9.4)
5 (1.2)
Partial response (PR)
137 (32.2)
107 (25.4)
Median duration of response (months) (95% CI)
NRa (21.8, NRa)
18.2 (14.8, NRa)
Progression-free Survival
Disease progression or death (%)
228 (53.6)
228 (54.0)
Median (months)
11.6
8.4
Hazard ratio (99.1% CI)a
0.82 (0.64, 1.05)
p-valuec
NSg
a Not Reached
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared to alpha 0.002 in order to achieve statistical significance.
e Based on the stratified DerSimonian-Laird test.
f p-value is compared to alpha 0.001 in order to achieve statistical significance.
g Not Significant at alpha level of 0.009.
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1.0
0.9
ro 0.8
>
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CJ")
~ 0.6
Q)
>
0
0.5
-
0
l=' 0.4
:c
ro 0.3
..c
0 "-
a.. 0.2
A
Nivolumab + ipilimumab
0.1
- -e--- Sunitinib
0.0
0
3
6
Number of Subjects at Risk
Nivolumab + ipilimumab
425
399
372
Sunitinib
422
387
352
9
12
15
18
21
Overall Survival (Months)
348
332
318
300
241
315
288
253
225
179
24
119
89
27
44
34
30
2
3
-0-0
33
0
0
Figure 1:
Overall Survival (Intermediate/Poor Risk Population) -
CHECKMATE-214
CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to
intravenous nivolumab and ipilimumab (n=125) or to sunitinib (n=124). These patients were not
evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving
intravenous nivolumab and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI:
0.75, 2.81). The efficacy of intravenous nivolumab and ipilimumab in previously untreated renal
cell carcinoma with favorable-risk disease has not been established.
CHECKMATE-9ER
CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of intravenous
nivolumab combined with cabozantinib versus sunitinib in patients with previously untreated
advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical
conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic
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score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or
indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).
Patients were randomized to nivolumab 240 mg intravenously every 2 weeks and
cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a
6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until
disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond
RECIST-defined disease progression was permitted if the patient was clinically stable and
considered to be deriving clinical benefit by the investigator. Tumor assessments were performed
at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every
12 weeks thereafter.
The trial population characteristics were: median age 61 years (range: 28 to 90) with 38%
≥65 years of age and 10% ≥75 years of age. The majority of patients were male (74%) and
White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%,
respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate,
and 20% poor.
The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome
measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant
improvement in PFS, OS, and ORR for patients randomized to intravenous nivolumab and
cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre
specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated OS
analysis was conducted when 271 deaths were observed based on the pre-specified number of
deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 47 and Figures
2 and 3.
Table 47:
Efficacy Results - CHECKMATE-9ER
Intravenous Nivolumab
and Cabozantinib
(n=323)
Sunitinib
(n=328)
Progression-free Survival
Disease progression or death (%)
144 (45)
191 (58)
Median PFS (months)a (95% CI)
16.6 (12.5, 24.9)
8.3 (7.0, 9.7)
Hazard ratio (95% CI)b
0.51 (0.41, 0.64)
p-valuec,d
<0.0001
Overall Survival
Deaths (%)
67 (21)
99 (30)
Median OS (months)a (95% CI)
NRe
NR (22.6, NRe)
Hazard ratio (98.89% CI)b
0.60 (0.40, 0.89)
p-valuec,d,f
0.0010
87
Reference ID: 5503299
Table 47:
Efficacy Results - CHECKMATE-9ER
Intravenous Nivolumab
and Cabozantinib
(n=323)
Sunitinib
(n=328)
Updated Overall Survival
Deaths (%)
121 (37)
150 (46)
Median OS (months)a (95% CI)
37.7 (35.5, NR)
34.3 (29.0, NR)
Hazard ratio (95% CI)b
0.70 (0.55, 0.90)
Confirmed Objective Response Rate (95% CI)g
55.7% (50.1, 61.2)
27.1% (22.4, 32.3)
p-valueh
<0.0001
Complete Response
26 (8%)
15 (4.6%)
Partial Response
154 (48%)
74 (23%)
Median duration of response in months (95% CI)a
20.2 (17.3, NRe)
11.5 (8.3, 18.4)
a Based on Kaplan-Meier estimates.
b Stratified Cox proportional hazards model.
c Based on stratified log-rank test
d 2-sided p-values from stratified log-rank test.
e Not Reached
f p-value is compared with the allocated alpha of 0.0111 for this interim analysis
g CI based on the Clopper-Pearson method.
h 2-sided p-value from Cochran-Mantel-Haenszel test.
88
Reference ID: 5503299
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Nivolumab + Cabozantinib
~
I
---e-- Sunitinib
1----0
a.. 0.0
0
3
6
9
12
15
18
21
24
27
Progression Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + Cabozantinib
323
279
234
196
144
77
35
11
4
0
Sunitinib
328
228
159
122
79
31
10
4
1
0
Figure 2:
Progression-free Survival - CHECKMATE-9ER
89
Reference ID: 5503299
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0.9
~ 0.8
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0
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0 ,._
0... 0.2
A
Nivolumab + Cabozantinib
0.1
- -0- - Sunitinib
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
Number of Subjects at Risk
Nivolumab + Cabozantinib
Overall Survival (Months)
323 310 297 284 270 258 247 235 219 199 138
Sunitinib
328 299 275 257 239 226 215 198 187 166 109
80
42
11
59
23
6
1
2
0
0
Figure 3:
Updated Overall Survival - CHECKMATE-9ER
In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable,
intermediate, intermediate/poor, and poor risk demonstrated a HR (95% CI) of 1.03 (0.55, 1.92),
0.74 (0.54, 1.01), 0.65 (0.50, 0.85), and 0.49 (0.31, 0.79), respectively.
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
CHECKMATE-025 (NCT01668784) was a randomized (1:1), open-label trial in patients with
advanced RCC who had experienced disease progression during or after one or two prior anti
angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70%
and patients were included regardless of their PD-L1 status. The trial excluded patients with any
history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active
autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were
90
Reference ID: 5503299
stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the
number of prior anti-angiogenic therapies. Patients were randomized to nivolumab 3 mg/kg by
intravenous infusion every 2 weeks (n=410) or everolimus 10 mg orally daily (n=411). The first
tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks
thereafter for the first year and then every 12 weeks until progression or treatment discontinuation,
whichever occurred later. The major efficacy outcome measure was overall survival (OS).
The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% ≥65
years of age and 9% ≥75 years of age. The majority of patients were male (75%) and White (88%)
and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.
The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient
distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.
The trial demonstrated a statistically significant improvement in OS for patients randomized to
intravenous nivolumab as compared with everolimus at the prespecified interim analysis when 398
events were observed (70% of the planned number of events for final analysis). OS benefit was
observed regardless of PD-L1 expression level. Efficacy results are shown in Table 48 and Figure
4.
Table 48:
Efficacy Results - CHECKMATE-025
Intravenous Nivolumab
(n=410)
Everolimus
(n=411)
Overall Survival
Deaths (%)
183 (45)
215 (52)
Median survival (months) (95% CI)
25.0 (21.7, NRa)
19.6 (17.6, 23.1)
Hazard ratio (95% CI)b
0.73 (0.60, 0.89)
p-valuec,d
0.0018
Confirmed Overall Response Rate (95% CI)
21.5% (17.6, 25.8)
3.9% (2.2, 6.2)
Median duration of response (months)
(95% CI)
23.0 (12.0, NRa)
13.7 (8.3, 21.9)
Median time to onset of confirmed response
(months) (min, max)
3.0 (1.4, 13.0)
3.7 (1.5, 11.2)
a Not Reached
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0148 of the allocated alpha for this interim analysis.
91
Reference ID: 5503299
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0.9
0.8
~ 0.7
>
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0 ;:::, 0.5
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~
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0 .....
c... 0.3
0.2
A
Nivolumab
0.1
- -0- - Everolimus
0.0
0
3
6
9
Number at Risk
Nivolumab
12
15
18
21
Overall Survival (Months)
410
389
359
337
305
275
213
139
Everolimus
24
27
73
29
411
366
324
287
265
241
187
115
61
20
30
3
2
33
0
0
Figure 4:
Overall Survival - CHECKMATE-025
14.2
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously
treated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is
supported by evidence from an adequate and well-controlled study conducted with intravenous
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of this adequate and well-controlled study of intravenous nivolumab in this
melanoma population.
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-037
92
Reference ID: 5503299
CHECKMATE-037 (NCT01721746) was a multicenter, open-label trial that randomized (2:1)
patients with unresectable or metastatic melanoma to receive nivolumab 3 mg/kg intravenously
every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine
1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 intravenously every 3 weeks
and paclitaxel 175 mg/m2 intravenously every 3 weeks. Patients were required to have progression
of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF
inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring
systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4
ipilimumab-related adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related
adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the
initiating event. Tumor assessments were conducted 9 weeks after randomization then every 6
weeks for the first year, and every 12 weeks thereafter.
Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120
patients who received intravenous nivolumab in CHECKMATE-037 and in whom the minimum
duration of follow-up was 6 months. The major efficacy outcome measures in this population were
confirmed overall response rate (ORR) as measured by blinded independent central review using
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.
Among the 120 patients treated with intravenous nivolumab, the median age was 58 years (range:
25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was 0
(58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive
(22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic
therapies for metastatic disease (68%).
The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and
34 partial responses in intravenous nivolumab-treated patients. Of 38 patients with responses, 87%
had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13
patients with ongoing responses of 6 months or longer.
There were responses in patients with and without BRAF V600 mutation-positive melanoma. A
total of 405 patients were randomized and the median duration of OS was 15.7 months (95% CI:
12.9, 19.9) in nivolumab-treated patients compared to 14.4 months (95% CI: 11.7, 18.2) (HR 0.95;
95.54% CI: 0.73, 1.24) in patients assigned to investigator’s choice of treatment. Figure 5
summarizes the OS results.
93
Reference ID: 5503299
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0.8
~ 0.7
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0
0.5
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Nivolumab
0.1
- -e--- Investigator's Choice
0.0
0
3
6
9
Number of Subjects at Risk
Nivolumab
12
15
18
21
24
27
Overall Survival (Months)
272 230 208 178 158 138 123
112
103
71
Investigator's Choice
133
119
99
85
70
62
53
49
43
28
30
44
14
33
16
2
·---------
36
39
3
0
0
0
Figure 5:
Overall Survival - CHECKMATE-037*
*
The primary OS analysis was not adjusted to account for subsequent therapies, with 54
(40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may
be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors.
Previously Untreated Metastatic Melanoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously
untreated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is
supported by evidence from adequate and well-controlled studies conducted with intravenous
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of these adequate and well-controlled studies of intravenous nivolumab in this
melanoma population.
94
Reference ID: 5503299
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-066
CHECKMATE-066 (NCT01721772) was a multicenter, double-blind, randomized (1:1) trial in
418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were
randomized to receive either nivolumab 3 mg/kg by intravenous infusion every 2 weeks or
dacarbazine 1000 mg/m2 intravenously every 3 weeks until disease progression or unacceptable
toxicity. Randomization was stratified by PD-L1 status (≥5% of tumor cell membrane staining by
immunohistochemistry vs. <5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c).
Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous,
mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant
or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1;
absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The
trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after
randomization then every 6 weeks for the first year and then every 12 weeks thereafter. The major
efficacy outcome measure was overall survival (OS). Additional outcome measures included
investigator-assessed progression-free survival (PFS) and ORR per RECIST v1.1.
The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were
male, and 99.5% were White. Disease characteristics were M1c stage disease (61%), cutaneous
melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 ≥5% tumor cell
membrane expression (35%), and history of brain metastasis (4%). More patients in the
intravenous nivolumab arm had an ECOG performance status of 0 (71% vs. 58%).
CHECKMATE-066 demonstrated a statistically significant improvement in OS for the intravenous
nivolumab arm compared with the dacarbazine arm in an interim analysis based on 47% of the
total planned events for OS. At the time of analysis, 88% (63/72) of intravenous nivolumab-treated
patients had ongoing responses, which included 43 patients with ongoing response of 6 months or
longer. Efficacy results are shown in Table 49 and Figure 6.
Table 49:
Efficacy Results - CHECKMATE-066
Intravenous Nivolumab
(n=210)
Dacarbazine
(n=208)
Overall Survival
Deaths (%)
50 (24)
96 (46)
Median (months) (95% CI)
NRa
10.8 (9.3, 12.1)
Hazard ratio (95% CI)b
0.42 (0.30, 0.60)
p-valuec,d
<0.0001
Progression-free Survival
Disease progression or death (%)
108 (51)
163 (78)
Median (months) (95% CI)
5.1 (3.5, 10.8)
2.2 (2.1, 2.4)
95
Reference ID: 5503299
Table 49:
Efficacy Results - CHECKMATE-066
Intravenous Nivolumab
(n=210)
Dacarbazine
(n=208)
Hazard ratio (95% CI)b
0.43 (0.34, 0.56)
p-valuec,d
<0.0001
Overall Response Rate
34%
9%
(95% CI)
(28, 41)
(5, 13)
Complete response rate
4%
1%
Partial response rate
30%
8%
a Not Reached
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d p-value is compared with the allocated alpha of 0.0021 for this interim analysis.
96
Reference ID: 5503299
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0 ~ 0.5
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ro
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a.. 0.3
0.2
A
Nivolumab
0.1
- --0- - Dacarbazine
0.0
0
3
6
Q)..~, '·,
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9
12
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15
Number at Risk
Overall Survival (Months)
Nivolumab
210
185
150
105
45
8
Dacarbazine
208
177
123
82
22
3
18
0
0
Figure 6:
Overall Survival - CHECKMATE-066
CHECKMATE-067
CHECKMATE-067 (NCT01844505) was a multicenter, randomized (1:1:1), double-blind trial in
945 patients with previously untreated, unresectable or metastatic melanoma to one of the
following arms: intravenous nivolumab and ipilimumab, intravenous nivolumab, or ipilimumab.
Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior
to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of
active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring
systemic immunosuppression.
Patients were randomized to receive:
Nivolumab 1 mg/kg with ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses,
followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every
2 weeks (nivolumab and ipilimumab arm),
97
Reference ID: 5503299
Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm), or
Ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by placebo every
2 weeks (ipilimumab arm).
Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane
expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per
the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks
after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major
efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional
efficacy outcome measures were confirmed ORR and duration of response.
The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97%
White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage
IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%);
BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor cell membrane expression as
determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).
CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for
patients randomized to either intravenous nivolumab-containing arm as compared with the
ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to intravenous
nivolumab improves PFS or OS compared to intravenous nivolumab as a single agent. Efficacy
results are shown in Table 50 and Figure 7.
Table 50:
Efficacy Results - CHECKMATE-067
Intravenous
Nivolumab and
Ipilimumab
(n=314)
Intravenous
Nivolumab
(n=316)
Ipilimumab
(n=315)
Overall Survivala
Deaths (%)
128 (41)
142 (45)
197 (63)
Hazard ratiob (vs. ipilimumab)
(95% CI)
0.55
(0.44, 0.69)
0.63
(0.50, 0.78)
p-valuec, d
<0.0001
<0.0001
Progression-free Survivala
Disease progression or death
151 (48%)
174 (55%)
234 (74%)
Median (months)
(95% CI)
11.5
(8.9, 16.7)
6.9
(4.3, 9.5)
2.9
(2.8, 3.4)
Hazard ratiob (vs. ipilimumab)
(95% CI)
0.42
(0.34, 0.51)
0.57
(0.47, 0.69)
p-valuec, e
<0.0001
<0.0001
Confirmed Overall Response Ratea
50%
40%
14%
(95% CI)
(44, 55)
(34, 46)
(10, 18)
98
Reference ID: 5503299
Table 50:
Efficacy Results - CHECKMATE-067
Intravenous
Nivolumab and
Ipilimumab
(n=314)
Intravenous
Nivolumab
(n=316)
Ipilimumab
(n=315)
p-valuef
<0.0001
<0.0001
Complete response
8.9%
8.5%
1.9%
Partial response
41%
31%
12%
Duration of Response
Proportion ≥6 months in duration
76%
74%
63%
Range (months)
1.2+ to 15.8+
1.3+ to 14.6+
1.0+ to 13.8+
a OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and
ORR (secondary endpoint) results were based on primary analysis with 9 months of minimum follow-up.
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure),
then both p-values are considered significant.
e p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
f Based on the stratified Cochran-Mantel-Haenszel test.
+ Censored observation
99
Reference ID: 5503299
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0.9
0.8
ro
>
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....
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CfJ
ro 0.6
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> 0.5
0 -
0
;i?:' 0.4
:c
ro
..c 0.3
0 ....
c.. 0.2
0.1
0.0
0
3
6
9
Number of Subjects at Risk
Nivolumab
316
292 265 244
Nivolumab + lpilimumab
314 292 265 247
lpilimumab
315
285 254 228
A
Nivolumab
-* - Nivolumab + lpilimumab
- -0- - lpilimumab
-,
1
~1111111111.~
12
15
18
21
24
27
30
33
Overall Survival (Months)
230
213
201
191
181
175 157
55
226 221
209 200 198 192 170
49
205
182 164 149 136 129 104
34
36
3
7
4
39
0
0
0
Figure 7:
Overall Survival - CHECKMATE-067
Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR)
in the intravenous nivolumab and ipilimumab arm. The median OS was 36.9 months (95% CI:
28.3, NR) in the intravenous nivolumab arm and 19.9 months (95% CI: 16.9, 24.6) in the
ipilimumab arm.
Based on a minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9,
21.9) in the intravenous nivolumab and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the
intravenous nivolumab arm, and 2.9 months (95% CI: 2.8, 3.2) in the ipilimumab arm. Based on a
minimum follow-up of 28 months, the proportion of responses lasting ≥24 months was 55% in the
intravenous nivolumab and ipilimumab arm, 56% in the intravenous nivolumab arm, and 39% in
the ipilimumab arm.
100
Reference ID: 5503299
14.3
Adjuvant Treatment of Melanoma
The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of Stage
IIB, Stage IIC, Stage III, or Stage IV melanoma. Use of OPDIVO QVANTIG for this indication
is supported by evidence from adequate and well-controlled studies conducted with intravenous
nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a
description of the efficacy results of these adequate and well-controlled studies of intravenous
nivolumab in these melanoma populations.
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-76K
CHECKMATE-76K (NCT04099251) was a randomized, double-blind trial in 790 patients with
completely resected Stage IIB/C melanoma. Patients were randomized (2:1) to receive nivolumab
480 mg or placebo by intravenous infusion every 4 weeks for up to 1 year or until disease
recurrence or unacceptable toxicity. Enrollment required complete resection of the primary
melanoma with negative margins and a negative sentinel lymph node within 12 weeks prior to
randomization, and ECOG performance status of 0 or 1. The trial excluded patients with
ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic
treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other
immunosuppressive medications, as well as patients with prior therapy for melanoma except
surgery. Randomization was stratified by AJCC 8th staging system edition (T3b vs. T4a vs. T4b).
The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time
between the date of randomization and the date of first recurrence (local, regional, or distant
metastasis), new primary melanoma, or death, from any cause, whichever occurred first and as
assessed by the investigator. Tumor assessments were conducted every 26 weeks during years 1
3 and every 52 weeks thereafter until year 5.
The trial population characteristics were: median age 62 years (range: 19 to 92), 61% were male,
98% were White, 0.4% Black or African American, 0.1% Asian, and 1.1% race unknown, 2.2%
Hispanic or Latino, 58% Not Hispanic or Latino, 40% ethnicity unknown, and 94% had an ECOG
performance status of 0. Sixty one percent had stage IIB and 39% had stage IIC melanoma.
CHECKMATE-76K demonstrated a statistically significant improvement in RFS for patients
randomized to the intravenous nivolumab arm compared with the placebo arm. Efficacy results
are shown in Table 51 and Figure 8.
Table 51:
Efficacy Results - CHECKMATE-76K
Intravenous Nivolumab
n=526
Placebo
n=264
Recurrence-free Survival
Number of events, n (%)
66 (13%)
69 (26%)
Median (months)b
(95% CI)
NRa
(28.5, NR)
NRa
(21.6, NR)
101
Reference ID: 5503299
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0.9
0.8
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LL 0
~~ 0.6
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c.., C
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a;,
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0.1
c..
•
Nivolumab
- --0- - Placebo
0
3
6
9
12
15
18
21
24
27
30
33
Recurrence Free Survival per Investigator (Months)
Number of Subjects at Risk
Nivolumab 480 mg Q4W
526
492
444
364
261
185
116
54
19
6
2
0
Placebo Q4W
264
243
205
161
119
77
40
20
11
3
2
0
Table 51:
Efficacy Results - CHECKMATE-76K
Intravenous Nivolumab
Placebo
n=526
n=264
Hazard ratioc
0.42
(95% CI)
p-valued
(0.30, 0.59)
p<0.0001
a Not reached.
b Based on Kaplan-Meier estimates.
c Hazard Ratio is intravenous nivolumab over placebo based on a stratified Cox proportional hazard model.
d Based on a 2-sided stratified log-rank test. Boundary for statistical significance: p-value <0.033.
Figure 8:
Recurrence-free Survival - CHECKMATE-76K
CHECKMATE-238
CHECKMATE-238 (NCT02388906) was a randomized, double-blind trial in 906 patients with
completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive
nivolumab 3 mg/kg by intravenous infusion every 2 weeks or ipilimumab 10 mg/kg intravenously
every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment
102
Reference ID: 5503299
required complete resection of melanoma with margins negative for disease within 12 weeks prior
to randomization. The trial excluded patients with a history of ocular/uveal melanoma,
autoimmune disease, and any condition requiring systemic treatment with either corticosteroids
(≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as
patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical
resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6
months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on
5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs.
Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined
as the time between the date of randomization and the date of first recurrence (local, regional, or
distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and
as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks
for the first 2 years then every 6 months thereafter.
The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were
male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics
were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600
mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 ≥5% tumor cell
membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%),
and tumor ulceration (32%).
CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients
randomized to the intravenous nivolumab arm compared with the ipilimumab 10 mg/kg arm.
Efficacy results are shown in Table 52 and Figure 9.
Table 52:
Efficacy Results - CHECKMATE-238
Intravenous Nivolumab
N=453
Ipilimumab 10 mg/kg
N=453
Recurrence-free Survival
Number of events, n (%)
154 (34%)
206 (45%)
Median (months)
(95% CI)
NRa
NRa
(16.56, NRa)
Hazard ratiob
(95% CI)
p-valuec,d
0.65
(0.53, 0.80)
p<0.0001
Overall Survival
Number of events, n (%)e
100 (22%)
111 (25%)
Median (months)
(95% CI)
NRa
NRa
Hazard ratiob
(95% CI)
p-value
0.87
(0.67, 1.14)
0.3148
103
Reference ID: 5503299
1.0
0.9
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,._ 0.8
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0
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~ 0.2
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0 ,._
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---1:r- - Nivolumab
0.1
O
lpilimumab
0.0
0
3
6
Number of Subjects at Risk
Nivolumab
453
399
353
lpilimumab 1 O mg/kg
453
364
314
9
12
15
18
Recurrence-Free Survival (Months)
332
311
291
249
269
252
225
184
21
71
56
24
5
2
27
0
0
a Not reached.
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0244 of the allocated alpha for this analysis.
e At the time of the final OS analysis, fewer overall survival events were observed than originally anticipated
(approximately 302).
Figure 9:
Recurrence-free Survival - CHECKMATE-238
14.4
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
The effectiveness of OPDIVO QVANTIG has been established for the neoadjuvant treatment of
resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum doublet
chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from
adequate and well-controlled studies conducted with intravenous nivolumab (CHECKMATE-816,
NCT02998528), and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
104
Reference ID: 5503299
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of the adequate and well-controlled study of intravenous nivolumab in this lung
cancer population.
CHECKMATE-816
CHECKMATE-816 (NCT02998528) was a randomized, open label trial in patients with resectable
NSCLC. The trial included patients with resectable, histologically confirmed Stage IB (≥4 cm), II,
or IIIA NSCLC (per the 7th edition American Joint Committee on Cancer/Union for International
Cancer Control (AJCC/UICC) staging criteria), ECOG performance status 0 or 1, and measurable
disease (per RECIST version 1.1). Patients with unresectable or metastatic NSCLC, known EGFR
mutations or ALK translocations, Grade 2 or greater peripheral neuropathy, active autoimmune
disease, or medical conditions requiring systemic immunosuppression were excluded from the
study.
Patients were randomized to receive either:
nivolumab 360 mg administered intravenously over 30 minutes and platinum-doublet
chemotherapy administered intravenously every 3 weeks for up to 3 cycles, or
platinum-doublet chemotherapy administered every 3 weeks for up to 3 cycles.
Platinum-doublet chemotherapy consisted of paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin
AUC 5 or AUC 6 (any histology); pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (non-squamous
histology); or gemcitabine 1000 mg/m2 or 1250 mg/m2 and cisplatin 75 mg/m2 (squamous
histology). In the platinum-doublet chemotherapy arm, two additional treatment regimen options
included vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; or docetaxel 60 mg/m2 or
75 mg/m2 and cisplatin 75 mg/m2 (any histology).
Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or
non-quantifiable), disease stage (IB/II versus IIIA), and sex (male versus female). Tumor
assessments were performed at baseline, within 14 days of surgery, every 12 weeks after surgery
for 2 years, then every 6 months for 3 years, and every year for 5 years until disease recurrence or
progression. The major efficacy outcome measures were event-free survival (EFS) based on
blinded independent central review (BICR) assessment and pathologic complete response (pCR)
as evaluated by blinded independent pathology review (BIPR). Additional efficacy outcome
measures included OS.
A total of 358 patients were randomized to receive either intravenous nivolumab in combination
with platinum-doublet chemotherapy (n=179) or platinum-doublet chemotherapy (n=179). The
median age was 65 years (range: 34 to 84) with 51% of patients ≥65 years and 7% of patients ≥75
years, 50% were Asian, 47% were White, 2% were Black, and 71% were male. Baseline ECOG
performance status was 0 (67%) or 1 (33%); 50% had tumors with PD-L1 expression ≥1%; 35%
had stage IB/II and 64% had stage IIIA disease; 51% had tumors with squamous histology and
49% had tumors with non-squamous histology; and 89% were former/current smokers.
105
Reference ID: 5503299
Eighty-three percent of patients in the intravenous nivolumab in combination with platinum-
doublet chemotherapy arm had definitive surgery compared to 75% of patients in the platinum-
doublet chemotherapy arm.
The study demonstrated statistically significant improvements in EFS and pCR. Efficacy results
are presented in Table 53 and Figure 10.
Table 53:
Efficacy Results - CHECKMATE-816
Intravenous Nivolumab and
Platinum-Doublet
Chemotherapy
(n=179)
Platinum-Doublet
Chemotherapy
(n=179)
Event-free Survival (EFS) per BICR
Events (%)
64 (35.8)
87 (48.6)
Median (months)a
(95% CI)
31.6
(30.2, NR)
20.8
(14.0, 26.7)
Hazard Ratiob
(95% CI)
0.63
(0.45, 0.87)
Stratified log-rank p-valuec
0.0052
Pathologic Complete Response (pCR) per BIPR
Number of patients with pCR
43
4
pCR Rate (%), (95% CI)d
24.0 (18.0, 31.0)
2.2 (0.6, 5.6)
Estimated treatment difference
(95% CI)e
21.6 (15.1, 28.2)
p-valuef
<0.0001
Minimum follow-up for EFS was 21 months.
a Kaplan-Meier estimate.
b Based on a stratified Cox proportional hazard model.
c Based on a stratified log-rank test. Boundary for statistical significance: p-value <0.0262.
d Based on Clopper and Pearson method.
e Strata-adjusted difference based on Cochran-Mantel-Haenszel method of weighting.
f From stratified CMH test.
106
Reference ID: 5503299
a:
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0
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~
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0
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~
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
O
Nivolumab + platinum-doublet chemotherapy
- -A- - Platinum-doublet chemotherapy
0
3
6
9 12 15 18 21 2 4 27 30 33 36 39 42
Event Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + platinum-doublet chemotherapy
179 151 136 124 118 107 102 87 74 41
34 13
6
3
0
Platinum-doublet chemotherapy
179 144 126 109 94 83 75 61
52 26 24 13 11
4
0
Figure 10:
Event-Free Survival - CHECKMATE-816
At the time of the EFS analysis, 26% of the patients had died. A prespecified interim analysis for
OS resulted in a HR of 0.57 (95% CI: 0.38, 0.87), which did not cross the boundary for statistical
significance.
14.5
Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell
Lung Cancer
The effectiveness of OPDIVO QVANTIG has been established for neoadjuvant treatment of
resectable (tumors ≥4 cm or node positive) NSCLC and no EGFR mutations or ALK
rearrangements in combination with platinum doublet chemotherapy followed by adjuvant
treatment with intravenous nivolumab. Use of OPDIVO QVANTIG for this indication is supported
by evidence from adequate and well-controlled studies conducted with intravenous nivolumab
(CHECKMATE-77T, NCT04025879), and additional pharmacokinetic and safety data that
107
Reference ID: 5503299
demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and
intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below
is a description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this lung cancer population.
CHECKMATE-77T
The efficacy of intravenous nivolumab, in combination with platinum-doublet chemotherapy,
followed by surgery, and continued adjuvant treatment with intravenous nivolumab as a single
agent, was investigated in CHECKMATE-77T (NCT04025879), a randomized, double-blind trial
in 461 patients with resectable NSCLC. The trial included patients with resectable, suspected or
histologically confirmed Stage IIA (>4 cm) to IIIB (T3-T4 N2) NSCLC (per the 8th edition
American Joint Committee on Cancer (AJCC) Staging Manual), and ECOG performance status 0
or 1. Patients with unresectable or metastatic NSCLC, EGFR mutations or known ALK
translocations, brain metastasis, Grade 2 or greater peripheral neuropathy, interstitial lung disease
or active, non-infectious pneumonitis (symptomatic and/or requiring treatment), active
autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded
from the study. Randomization was stratified by tumor PD-L1 expression level (≥1% versus <1%
versus indeterminate/not evaluable), disease stage (Stage II versus Stage III), and tumor histology
(squamous versus nonsquamous).
Patients were randomized (1:1) to receive either:
Neoadjuvant nivolumab 360 mg administered intravenously over 30 minutes in
combination with one of the following platinum-doublet chemotherapy regimens every 3
weeks for four cycles:
o Paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or AUC 6 (any
histology)
o Pemetrexed 500 mg/m2, and cisplatin 75 mg/m2 or carboplatin AUC 5 or AUC 6
(nonsquamous histology)
o Cisplatin 75 mg/m2 and docetaxel 75 mg/m2 (squamous histology).
Within 90 days after the surgery, nivolumab 480 mg was administered intravenously over
30 minutes every 4 weeks.
or
Neoadjuvant placebo administered intravenously over 30 minutes in combination with
platinum-doublet chemotherapy (see above) every 3 weeks for four cycles. Within 90 days
after the surgery, placebo was administered intravenously over 30 minutes every 4 weeks.
All study medications were administered via intravenous infusion. Treatment continued until
disease progression, recurrence, or unacceptable toxicity for up to 13 cycles (1 year). Tumor
assessments were performed every 12 weeks for 2 years, then every 24 weeks for up to 5 years or
until disease recurrence or progression was confirmed by BICR.
The trial was not designed to isolate the effect of intravenous nivolumab in each phase
(neoadjuvant or adjuvant) of treatment.
108
Reference ID: 5503299
The major efficacy outcome measure was event-free survival (EFS) based on BICR assessment.
Additional efficacy outcome measures included overall survival (OS), pathologic complete
response (pCR), and major pathologic response (MPR).
The median age was 66 years (range: 35 to 86); 71% were male; 72% were White, 25% were
Asian, 1.7% were Black, and 1.5% were mixed race/ race unknown/ not reported; and 6% were
Hispanic or Latino. Baseline ECOG performance status was 0 (62%) or 1 (38%); 56% had tumors
with PD-L1 expression ≥1% and 40% had tumors with PD-L1 expression <1%; 35% had stage II
and 64% had stage III disease; 23% had N1 disease and 39% had N2 disease; 51% had tumors
with squamous histology and 49% had tumors with nonsquamous histology; and 90% were
former/current smokers.
Seventy-eight percent of patients in the neoadjuvant intravenous nivolumab in combination with
platinum-doublet chemotherapy followed by adjuvant intravenous nivolumab arm had definitive
surgery compared to 77% of patients in the neoadjuvant placebo and platinum-doublet
chemotherapy followed by placebo arm.
The study demonstrated a statistically significant improvement in EFS for patients treated with
neoadjuvant intravenous nivolumab in combination with platinum-doublet chemotherapy followed
by single agent intravenous nivolumab compared with patients randomized to placebo in
combination with platinum-doublet chemotherapy followed by placebo. Efficacy results are
presented in Table 54 and Figure 11.
Table 54:
Efficacy Results - CHECKMATE-77T
Neoadjuvant Intravenous
Nivolumab and Platinum-
Doublet
Chemotherapy/Adjuvant
Intravenous Nivolumab
(n=229)
Neoadjuvant Placebo and
Platinum-Doublet
Chemotherapy/Adjuvant
Placebo
(n=232)
Event-free Survival (EFS) per BICR
Events (%)
76 (33%)
113 (49%)
Median (months)a
(95% CI)
NR
(28.9, NR)
18.4
(13.6, 28.1)
Hazard Ratiob
(95% CI)
0.58
(0.43, 0.78)
Stratified log-rank p-valuec
0.00025
a Kaplan-Meier estimate.
b Based on a stratified Cox proportional hazard model.
c Based on a stratified log-rank test. Boundary for statistical significance: p-value <0.0264.
109
Reference ID: 5503299
a:
~ 0.9
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~ 0.8
~
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0.7
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;
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0 a:
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A
Nivolumab + platinum-doublet chemotherapy/Nivolumab
- -e-- Placebo + platinum-doublet chemotherapy/Placebo
0.0 .............. ..,.....,...... ............................ ..,.....,.........,......,.... .............. ..,.....,.........,......,.... .............. ..,.....,...... ........................... ..,.....,...... ...................................
0
3
6
9 12 15 18 21
24 27 30 33 36 39 42
Event Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + platinum-doublet chemotherapy/Nivolumab
229 208 173 157 141 134 115 89 69 46 20
7
4
2
0
Placebo + platinum-doublet chemotherapy/Placebo
232 204 165 138 118 106 78 59 44 29 19 10
6
1
0
Figure 11:
Event-Free Survival - CHECKMATE-77T
In a pre-specified descriptive analysis, the pCR rate was 25% (95% CI: 20, 31) in the intravenous
nivolumab arm and 4.7% (95% CI: 2.4, 8) in the placebo arm.
At the time of the EFS analysis, OS data were immature.
14.6
Metastatic Non-Small Cell Lung Cancer
Second-line Treatment of Metastatic NSCLC
The effectiveness of OPDIVO QVANTIG has been established for the treatment of NSCLC
previously treated with platinum-based chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved therapy for these aberrations
prior to receiving OPDIVO QVANTIG. Use of OPDIVO QVANTIG for this indication is
supported by evidence from adequate and well-controlled studies conducted with intravenous
110
Reference ID: 5503299
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of this adequate and well-controlled study of intravenous nivolumab in this lung
cancer population.
CHECKMATE-017
CHECKMATE-017 (NCT01642004) was a randomized (1:1), open-label trial in 272 patients with
metastatic squamous NSCLC who had experienced disease progression during or after one prior
platinum doublet-based chemotherapy regimen. Patients received nivolumab 3 mg/kg by
intravenous infusion every 2 weeks (n=135) or docetaxel 75 mg/m2 intravenously every 3 weeks
(n=137). Randomization was stratified by prior paclitaxel vs. other prior treatment and region
(US/Canada vs. Europe vs. Rest of World). This trial included patients regardless of their PD-L1
status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic
immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients
with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks
prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg
daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after
randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was
OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.
The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% ≥65
years of age and 11% ≥75 years of age. The majority of patients were White (93%) and male
(76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada
(32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%)
and 92% were former/current smokers. Baseline disease characteristics of the population as
reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All
patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors
of squamous-cell histology.
The trial demonstrated a statistically significant improvement in OS for patients randomized to
intravenous nivolumab as compared with docetaxel at the prespecified interim analysis when 199
events were observed (86% of the planned number of events for final analysis). Efficacy results
are shown in Table 55 and Figure 12.
Table 55:
Efficacy Results - CHECKMATE-017
Intravenous Nivolumab
(n=135)
Docetaxel
(n=137)
Overall Survival
Deaths (%)
86 (64%)
113 (82%)
Median (months)
(95% CI)
9.2
(7.3, 13.3)
6.0
(5.1, 7.3)
Hazard ratio (95% CI)a
0.59 (0.44, 0.79)
111
Reference ID: 5503299
Table 55:
Efficacy Results - CHECKMATE-017
Intravenous Nivolumab
(n=135)
Docetaxel
(n=137)
p-valueb,c
0.0002
Overall Response Rate
27 (20%)
12 (9%)
(95% CI)
(14, 28)
(5, 15)
p-valued
0.0083
Complete response
1 (0.7%)
0
Median duration of response (months)
(95% CI)
NRe
(9.8, NRe)
8.4
(3.6, 10.8)
Progression-free Survival
Disease progression or death (%)
105 (78%)
122 (89%)
Median (months)
3.5
2.8
Hazard ratio (95% CI)a
0.62 (0.47, 0.81)
p-valueb
0.0004
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with .0315 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached
112
Reference ID: 5503299
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0.8
ro
> 0.7
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0 ~ 0.5
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ro
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.. ,._,.lil,o.-q,
·---GJ-ED--------ee
- --0- - Docetaxel
3
6
9
12
15
18
21
24
Number at Risk
Overall Survival (Months)
Nivolumab
135
113
86
69
52
31
15
7
0
Docetaxel
137
103
68
45
30
14
7
2
0
Figure 12:
Overall Survival - CHECKMATE-017
Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial
population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with
quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells
expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC defined as ≥1% of tumor cells
expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival
were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in
the PD-L1 positive subgroup.
CHECKMATE-057
CHECKMATE-057 (NCT01673867) was a randomized (1:1), open-label trial in 582 patients with
metastatic non-squamous NSCLC who had experienced disease progression during or after one
prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in
patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients
113
Reference ID: 5503299
received nivolumab 3 mg/kg by intravenous infusion every 2 weeks (n=292) or docetaxel
75 mg/m2 intravenously every 3 weeks (n=290). Randomization was stratified by prior
maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded
patients with autoimmune disease, medical conditions requiring systemic immunosuppression,
symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain
metastases were eligible if neurologically stable. The first tumor assessments were conducted 9
weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome
measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.
In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.
The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients
≥65 years and 7% of patients ≥75 years. The majority of patients were White (92%) and male
(55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%)
and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79%
were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with
EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included
platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line
regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and
bronchoalveolar (0.9%).
CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients
randomized to intravenous nivolumab as compared with docetaxel at the prespecified interim
analysis when 413 events were observed (93% of the planned number of events for final analysis).
Efficacy results are shown in Table 56 and Figure 13.
Table 56:
Efficacy Results - CHECKMATE-057
Intravenous Nivolumab
(n=292)
Docetaxel
(n=290)
Overall Survival
Deaths (%)
190 (65%)
223 (77%)
Median (months)
(95% CI)
12.2
(9.7, 15.0)
9.4
(8.0, 10.7)
Hazard ratio (95% CI)a
0.73 (0.60, 0.89)
p-valueb,c
0.0015
Overall Response Rate
56 (19%)
36 (12%)
(95% CI)
(15, 24)
(9, 17)
p-valued
0.02
Complete response
4 (1.4%)
1 (0.3%)
Median duration of response (months)
(95% CI)
17
(8.4, NRe)
6
(4.4, 7.0)
Progression-free Survival
114
Reference ID: 5503299
1.0
0.9
0.8
~
> 0.7
'>
I.... 0.6
::::,
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0
0.5
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0
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a.. 0.3
0.2
0.1
0.0
0
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A
Nivolumab
- --0- - Docetaxel
3
6
9
"\ ... ......
12
..,, -.... "'®
15
18
Number at Risk
Overall Survival (Months)
Nivolumab
292
232
194
169
146
123
62
Docetaxel
290
244
194
150
111
88
34
21
24
27
32
9
0
10
5
0
Table 56:
Efficacy Results - CHECKMATE-057
Intravenous Nivolumab
(n=292)
Docetaxel
(n=290)
Disease progression or death (%)
234 (80%)
245 (84%)
Median (months)
2.3
4.2
Hazard ratio (95% CI)a
0.92 (0.77, 1.11)
p-valueb
0.39
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with .0408 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached.
Figure 13:
Overall Survival - CHECKMATE-057
115
Reference ID: 5503299
PD-L 1 expression level
:2:1 % (n = 246)
<1% (n = 209)
:2:5%
(n = 181)
<5% (n = 274)
:2:10% (n = 165)
<10% (n = 290)
0.25
•
•
•
0.5
1.0
Favors Nivolumab +-
PD-L 1 expression level
:2:1 % (n = 246)
•
<1% (n = 209)
:2:5%
(n = 181)
•
<5% (n=274)
:2: 10% (n = 165)
•
<10% (n = 290)
0.25
0.5
1.0
Favors Nivolumab +-
Median OS (months)
Unstratified HR Nivolumab Docetaxel
0.59
17.1
9.0
0.90
10.4
10.1
0.43
18.2
8.1
1.01
9.7
10.1
0.40
19.4
8.0
1.00
9.9
10.3
2.0
Median PFS (months)
Unstratified HR Nivolumab Docetaxel
2.0
0.70
4.2
4.5
1.19
2.1
3.6
0.54
5.0
3.8
1.31
0.52
1.24
2.1
5.0
2.1
4.2
3.6
4.2
Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial.
Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining
455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1
testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of
tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as ≥1% of tumor cells
expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had ≥1% but <5%
tumor cells with positive staining, 7% had ≥5% but <10% tumor cells with positive staining, and
67% had ≥10% tumor cells with positive staining. Figures 14 and 15 summarize the results of
prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells
expressing PD-L1.
Figure 14:
Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057
Figure 15:
Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057
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14.7
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and
Neck
The effectiveness of OPDIVO QVANTIG has been established for the treatment of recurrent or
metastatic squamous cell carcinoma of the head and neck with disease progression on or after
platinum-based therapy. Use of OPDIVO QVANTIG for this indication is supported by evidence
from an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this head and neck carcinoma population.
CHECKMATE-141
CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label trial
enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression
during or within 6 months of receiving platinum-based therapy administered in either the adjuvant,
neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded
patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or
metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology,
salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain
metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients
were randomized to receive nivolumab 3 mg/kg by intravenous infusion every 2 weeks or
investigator’s choice of cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2
weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2
intravenously weekly).
Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments
were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major
efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.
A total of 361 patients were randomized; 240 patients to the intravenous nivolumab arm and
121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab:
12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with
31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline
ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had
Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining
55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors,
24% had HPV p16-negative tumors, and 51% had unknown status.
The trial demonstrated a statistically significant improvement in OS for patients randomized to
intravenous nivolumab as compared with investigator’s choice at a pre-specified interim analysis
(78% of the planned number of events for final analysis). There were no statistically significant
differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95%
CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively).
Efficacy results are shown in Table 57 and Figure 16.
117
Reference ID: 5503299
Table 57:
Overall Survival - CHECKMATE-141
Intravenous Nivolumab
(n=240)
Cetuximab, Methotrexate or
Docetaxel
(n=121)
Overall Survival
Deaths (%)
133 (55%)
85 (70%)
Median (months)
(95% CI)
7.5
(5.5, 9.1)
5.1
(4.0, 6.0)
Hazard ratio (95% CI)a
0.70 (0.53, 0.92)
p-valueb,c
0.0101
a Based on stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with 0.0227 of the allocated alpha for this interim analysis.
118
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109
52
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17
5
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18
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0
Figure 16:
Overall Survival - CHECKMATE-141
Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1
IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-
quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1
negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD
L1 positive SCCHN, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory
subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median
survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the
PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median
survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the
PD-L1 positive SCCHN subgroup.
119
Reference ID: 5503299
14.8
Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC) at High Risk of Recurrence
The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of UC
at high risk of recurrence. Use of OPDIVO QVANTIG for this indication is supported by evidence
from an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this UC population.
CHECKMATE-274
CHECKMATE-274 (NCT02632409) was a randomized, double-blind, placebo-controlled study
of adjuvant intravenous nivolumab in patients who were within 120 days of radical resection (R0)
of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High
risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received
neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin
and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1
to receive nivolumab 240 mg or placebo by intravenous infusion every 2 weeks until recurrence
or until unacceptable toxicity for a maximum treatment duration of 1 year. Patients were stratified
by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ≥10 nodes removed),
tumor cells expressing PD-L1 (≥1% vs. <1%/indeterminate as determined by the central lab using
the PD-L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).
The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male;
76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335
(47%) of patients with node-positive UC, 44 (6%) had non–muscle-invasive (<pT2) primary
tumors. ECOG performance status was 0 (63%), 1 (35%), or 2 (2%). Prior neoadjuvant cisplatin
had been given to 43% of patients; of the 57% who did not receive prior neoadjuvant cisplatin,
reasons listed were ineligibility (22%), patient preference (33%), and other/not reported (2%).
Tumor PD-L1 expression was ≥1% in 40% of patients, and 21% of patients had upper tract UC.
The major efficacy outcome measures were investigator-assessed DFS in all randomized patients
and in patients with tumors expressing PD-L1 ≥1%. DFS was defined as time to first recurrence
(local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy
outcome measures included OS.
At the pre-specified interim analysis, CHECKMATE-274 demonstrated a statistically significant
improvement in DFS for patients randomized to intravenous nivolumab vs. placebo in the all
randomized patient population, as well as in the subpopulation of patients with PD-L1 ≥1%, as
shown in Table 58 and Figure 17.
In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS
was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard
ratio estimate was 1.15 (95% CI: 0.74, 1.80).
120
Reference ID: 5503299
In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the
unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64, 1.08).
OS data is immature with 33% of deaths in the overall randomized population. In the UTUC
subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).
Table 58:
Efficacy Results - CHECKMATE-274
All Randomized
PD-L1 ≥1%
Intravenous
Nivolumab
(n=353)
Placebo
(n=356)
Intravenous
Nivolumab
(n=140)
Placebo
(n=142)
Disease-free Survival
Eventsa, n (%)
Local recurrence
Distant recurrence
Death
170 (48)
47 (13)
108 (31)
14 (4)
204 (57)
64 (18)
127 (36)
10 (3)
55 (39)
10 (7)
40 (29)
5 (4)
81 (57)
24 (17)
52 (37)
5 (4)
Median DFS (months)b
(95% CI)
20.8
(16.5, 27.6)
10.8
(8.3, 13.9)
N.R.
(21.2, N.E.)
8.4
(5.6, 21.2)
Hazard ratioc
(95% CI)
0.70
(0.57, 0.86)
0.55
(0.39, 0.77)
p-value
0.0008d
0.0005e
N.R. Not reached, N.E. Not estimable
a Includes disease at baseline events (protocol deviations): n=1 in intravenous nivolumab arm and n=3 in placebo
arm.
b Based on Kaplan-Meier estimates.
c Stratified Cox proportional hazard model. Hazard ratio is intravenous nivolumab over placebo.
d Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status, PD-L1 status (≥1% vs
<1%/indeterminate). Boundary for statistical significance in all randomized patients: p-value <0.01784.
e Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status. Boundary for statistical
significance in all randomized patients with PD-L1 ≥1%: p-value <0.01282.
121
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24 27 30 33 36 39 42 45 48 51
Number of Subjects at Risk
Disease Free Survival (Months)
Nivolumab
353 296 244 212 178 154 126 106 85 68 57 51
36 23 20
3
1
0
Placebo
356 248 198 157 134 121 105 94 80 65 54 50 37 22 19 10
2 0
Figure 17: Disease-free Survival in All Randomized Patients - CHECKMATE-274
First-line Treatment of Unresectable or Metastatic UC
The effectiveness of OPDIVO QVANTIG has been established for the first-line treatment of
unresectable or metastatic UC in combination with cisplatin and gemcitabine. Use of OPDIVO
QVANTIG for this indication is supported by evidence from an adequate and well-controlled study
conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that
demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and
intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below
is a description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this UC population.
CHECKMATE-901
CHECKMATE-901 (NCT 03036098) was a randomized, open-label study in patients with
previously untreated unresectable or metastatic UC. Prior neoadjuvant or adjuvant chemotherapy
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Reference ID: 5503299
were permitted as long as the disease recurrence took place ≥12 months from completion of
therapy. Patients who were ineligible for cisplatin and those with active CNS metastases were
excluded. Stratification factors for randomization were PD-L1 status (≥1% vs. <1% or
indeterminate) and liver metastasis. Patients were randomized 1:1 to receive either:
Intravenous nivolumab 360 mg and cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000
mg/m2 on Days 1 and 8 of a 21-day cycle of a 21-day cycle for up to 6 cycles followed by
single-agent intravenous nivolumab 480 mg every 4 weeks until disease progression or
unacceptable toxicity. In the absence of disease progression or unacceptable toxicity,
intravenous nivolumab was continued for up to 2 years from first dose.
Cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day
cycle for up to 6 cycles, until disease progression or unacceptable toxicity.
The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST v1.1.
Additional efficacy outcome measures included ORR as assessed by BICR.
The median age was 65 years of age (range: 32 to 86) with 51% of patients ≥65 years of age and
12% of patients ≥75 years of age, 23% were Asian, 72% were White, 0.3% were Black, 0.3% were
American Indian or Alaska Native, 4.9% were Other, 12% were Hispanic or Latino, and 77% were
male. Baseline ECOG performance status was 0 (53%) or 1 (46%). At baseline, 87% of patients
had metastatic UC, including 20% with liver metastases, 11% had locally advanced UC, and 51%
had UC histologic variants. Forty-nine (16%) in the intravenous nivolumab in combination with
cisplatin-based chemotherapy arm and 43 (14%) in the cisplatin-based chemotherapy arm switched
from cisplatin to carboplatin after at least one cycle of cisplatin.
Efficacy results are presented in Table 59 and Figures 18 and 19.
Table 59:
Efficacy Results – CHECKMATE 901
Intravenous Nivolumab and
Cisplatin and Gemcitabine
(n=304)
Cisplatin and Gemcitabine
(n=304)
Overall Survival (OS)
Events, n (%)
172 (56.6)
193 (63.5)
Median (months)
(95% CI)a
21.7
(18.6, 26.4)
18.9
(14.7, 22.4)
Hazard ratio
(95% CI)b
0.78
(0.63, 0.96)
p-valuec
0.0171
Progression-free Survival (PFS)d
Events, n (%)
211 (69.4)
191 (62.8)
Median (months)
(95% CI)a
7.9
(7.6, 9.5)
7.6
(6.0, 7.8)
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Reference ID: 5503299
Table 59:
Efficacy Results – CHECKMATE 901
Intravenous Nivolumab and
Cisplatin and Gemcitabine
(n=304)
Cisplatin and Gemcitabine
(n=304)
Hazard ratio
(95% CI)b
0.72
(0.59, 0.88)
p-valuec
0.0012
Objective Response Rate (ORR)d
Response rate, n (%)
(95% CI)
175 (57.6%)
(51.8, 63.2)
131 (43.1%)
(37.5, 48.9)
Complete response rate, n (%)
66 (22%)
36 (12%)
Partial response rate, n (%)
109 (36%)
95 (31%)
Duration of Response (DoR)
Median (months)
(95% CI)a
9.5
(7.6, 15.1)
7.3
(5.7, 8.9)
a Based on Kaplan-Meier Estimates
b Stratified Cox proportional hazard model.
c 2 sided p values from stratified log-rank test.
d Assessed by BICR.
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Reference ID: 5503299
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Nivolumab with gemcitabine+cisplatin
- -0-- - Gemcitabine+cisplatin
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Overall Survival (Months)
Number of Subjects at Risk
Nivolumab with gemcitabine+cisplatin
304 286 264 228 196 167 142 119 97 84 69 58 48 36 25 20 15 12 7 4 2 0
Gemcitabine + cisplatin
304 277 242 208 166 140 122 102 82 65 49 39 33 24 17 16 13 9 4 4 1 0
Figure 18:
Overall Survival - CHECKMATE-901
125
Reference ID: 5503299
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54 57
Progression Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab with gemcitabine+cisplatin
304 253 179 116 82 65 57 49 41
36 31
26 19 14 11
10 6 5 1 0
Gemcitabine + cisplatin
304 223 119 63 35 25 17 12 10 9 8 6 5 2 1 1 0 0 0 0
Figure 19:
Progression-free Survival - CHECKMATE-901
Previously Treated Advanced or Metastatic Urothelial Carcinoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of patients with
locally advanced or metastatic UC and disease progression during or following platinum-
containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence
from an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this UC population.
CHECKMATE-275
CHECKMATE-275 (NCT02387996) was a single-arm trial in 270 patients with locally advanced
or metastatic UC who had disease progression during or following platinum-containing
126
Reference ID: 5503299
chemotherapy or who had disease progression within 12 months of treatment with a platinum-
containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain
or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic
immunosuppression, and ECOG performance status >1. Patients received nivolumab 3 mg/kg by
intravenous infusion every 2 weeks until unacceptable toxicity or either radiographic or clinical
progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks
and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as
assessed by IRRC using RECIST v1.1 and DOR.
The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven
percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four
percent of patients had disease progression following prior platinum-containing neoadjuvant or
adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the
metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior
carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting.
Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients
had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline.
Patients were included regardless of their PD-L1 status.
Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a
central laboratory and the results were used to define subgroups for pre-specified analyses. Of the
270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor
cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1
expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all
patients and the two PD-L1 subgroups are shown in Table 60. Median time to response was 1.9
months (range: 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant
or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).
Table 60:
Efficacy Results - CHECKMATE-275
All Patients
N=270
PD-L1 <1%
N=146
PD-L1 ≥1%
N=124
Confirmed Overall Response Rate, n (%)
(95% CI)
53 (19.6%)
(15.1, 24.9)
22 (15.1%)
(9.7, 21.9)
31 (25.0%)
(17.7, 33.6)
Complete response rate
7 (2.6%)
1 (0.7%)
6 (4.8%)
Partial response rate
46 (17.0%)
21 (14.4%)
25 (20.2%)
Median Duration of Responsea (months)
(range)
10.3 (1.9+, 12.0+)
7.6 (3.7, 12.0+)
NRb (1.9+, 12.0+)
a Estimated from the Kaplan-Meier Curve
b Not Reached
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14.9
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic
Colorectal Cancer
The effectiveness of OPDIVO QVANTIG has been established for the treatment of microsatellite
instability-high or mismatch repair deficient colorectal cancer (CRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO QVANTIG for
this indication is supported by evidence from an adequate and well-controlled study conducted
with
intravenous
nivolumab
(CHECKMATE-142,
NCT02060188),
and
additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this CRC population.
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-142
CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-
cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic
CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine- ,
oxaliplatin- , or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line
of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following:
active brain metastases, active autoimmune disease, or medical conditions requiring systemic
immunosuppression.
Patients enrolled in the single agent intravenous nivolumab MSI-H mCRC cohort received
nivolumab 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the
intravenous nivolumab and ipilimumab MSI-H mCRC cohort received nivolumab 3 mg/kg and
ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by nivolumab as a single
agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts
continued until unacceptable toxicity or radiographic progression.
Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks
thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using
RECIST v1.1.
A total of 74 patients were enrolled in the single-agent MSI-H mCRC intravenous nivolumab
cohort. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75
years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0
(43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74
patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%,
30%, 28%, 19%, and 16% received 0, 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease,
respectively, and 42% of patients had received an anti-EGFR antibody.
A total of 119 patients were enrolled in the intravenous nivolumab and ipilimumab MSI-H mCRC
cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75
years of age; 59% were male and 92% were White. Baseline ECOG performance status was 0
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Reference ID: 5503299
(45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients,
69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%,
24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively,
and 29% had received an anti-EGFR antibody.
Efficacy results for each of these single-arm cohorts are shown in Table 61.
Table 61:
Efficacy Results - CHECKMATE-142
Intravenous Nivolumaba
MSI-H/dMMR Cohort
Intravenous Nivolumab and
Ipilimumabb
MSI-H/dMMR Cohort
All Patients
(n=74)
Prior Treatment
(Fluoropyrimidine,
Oxaliplatin, and
Irinotecan)
(n=53)
All Patients
(n=119)
Prior Treatment
(Fluoropyrimidine,
Oxaliplatin, and
Irinotecan)
(n=82)
Overall Response Rate
per BICR; n (%)
28 (38%)
17 (32%)
71 (60%)
46 (56%)
(95% CI)c
(27, 50)
(20, 46)
(50, 69)
(45, 67)
Complete Response
(%)
8 (11%)
5 (9%)
17 (14%)
11 (13%)
Partial Response (%)
20 (27%)
12 (23%)
54 (45%)
35 (43%)
Duration of Response
Proportion of
responders with ≥6
months response
duration
86%
94%
89%
87%
Proportion of
responders with ≥12
months response
duration
82%
88%
77%
74%
a Minimum follow-up 33.7 months for all patients treated with intravenous nivolumab (n=74).
b Minimum follow-up 27.5 months for all patients treated with intravenous nivolumab and ipilimumab (n=119).
c Estimated using the Clopper-Pearson method.
14.10
Hepatocellular Carcinoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of hepatocellular
carcinoma in patients who have been previously treated with sorafenib and following treatment
with intravenous nivolumab and ipilimumab. Use of OPDIVO QVANTIG for this indication is
supported by evidence from an adequate and well-controlled study conducted with intravenous
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
129
Reference ID: 5503299
efficacy results of the adequate and well-controlled study of intravenous nivolumab in this
hepatocellular carcinoma population.
CHECKMATE-040
CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial that
evaluated the efficacy of intravenous nivolumab as a single agent and in combination with
ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant
to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and
Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain
metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV,
or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and
hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.
Tumor assessments were conducted every 6 weeks for 48 weeks and then every 12 weeks
thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed
by BICR using RECIST v1.1 and modified RECIST (mRECIST) for HCC. Duration of response
was also assessed.
The efficacy of intravenous nivolumab in combination with ipilimumab was evaluated in 49
patients (Cohort 4) who received intravenous nivolumab 1 mg/kg and ipilimumab 3 mg/kg
administered every 3 weeks for 4 doses, followed by single-agent intravenous nivolumab at
240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60
years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG
performance status was 0 (61%) or 1 (39%). Fifty-seven (57%) percent of patients had active HBV
infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The
etiology for HCC was alcoholic liver disease in 16% and non-alcoholic fatty liver disease in 6%
of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had
extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels ≥400 µg/L. Prior cancer
treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All
patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of
patients had received 2 or more prior systemic therapies.
Efficacy results are shown in Table 62. The results for intravenous nivolumab in combination with
ipilimumab in Cohort 4 are based on a minimum follow-up of 28 months.
Table 62:
Efficacy Results - Cohort 4 of CHECKMATE-040
Intravenous Nivolumab and
Ipilimumab
(Cohort 4)
(n=49)
Overall Response Rate per BICR,a n (%), RECIST v1.1
16 (33%)
(95% CI)b
(20, 48)
Complete response
4 (8%)
Partial response
12 (24%)
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Table 62:
Efficacy Results - Cohort 4 of CHECKMATE-040
Intravenous Nivolumab and
Ipilimumab
(Cohort 4)
(n=49)
Duration of Response per BICR,a RECIST v1.1
n=16
Range (months)
4.6, 30.5+
Percent with duration ≥6 months
88%
Percent with duration ≥12 months
56%
Percent with duration ≥24 months
31%
Overall Response Rate per BICR,a n (%), mRECIST
17 (35%)
(95% CI)b
(22, 50)
Complete response
6 (12%)
Partial response
11 (22%)
a Confirmed by BICR.
b Confidence interval is based on the Clopper and Pearson method.
14.11
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of
resected esophageal or gastroesophageal junction cancer with residual pathologic disease who
have received neoadjuvant chemoradiotherapy (CRT). Use of OPDIVO QVANTIG for this
indication is supported by evidence from an adequate and well-controlled study conducted with
intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated
comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous
nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a
description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this esophageal or gastroesophageal junction cancer population.
CHECKMATE-577
CHECKMATE-577 (NCT02743494) was a randomized, multicenter, double-blind trial in 794
patients with completely resected (negative margins) esophageal or gastroesophageal junction
cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT).
Patients were randomized (2:1) to receive either nivolumab 240 mg or placebo by intravenous
infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by
intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Treatment was until
disease recurrence, unacceptable toxicity, or for up to 1 year in total duration. Enrollment required
complete resection within 4 to 16 weeks prior to randomization. The trial excluded patients who
did not receive CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any
condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or
131
Reference ID: 5503299
equivalent) or other immunosuppressive medications. Randomization was stratified by tumor PD
L1 status (≥1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive
≥ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy
outcome measure was disease-free survival (DFS) defined as the time between the date of
randomization and the date of first recurrence (local, regional, or distant from the primary resected
site) or death, from any cause, whichever occurred first as assessed by the investigator prior to
subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence
every 12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5.
The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were
≥65 years of age, 85% were male, 15% were Asian, 82% were White, and 1.1% were Black.
Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis
carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node
status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%)
or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status ≥1% was positive for 16%
of patients and negative for 72% of patients. Baseline ECOG performance status was 0 (58%) or
1 (42%).
CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients
randomized to the intravenous nivolumab arm as compared with the placebo arm. DFS benefit was
observed regardless of tumor PD-L1 expression and histology.
Efficacy results are shown in Table 63 and Figure 20.
Table 63:
Efficacy Results - CHECKMATE-577
Intravenous Nivolumab
(n=532)
Placebo
(n=262)
Disease-free Survival
Number of events, n (%)
241 (45%)
155 (59%)
Median (months)
(95% CI)
22.4
(16.6, 34.0)
11.0
(8.3, 14.3)
Hazard ratioa
(95% CI)
0.69 (0.56, 0.85)
p-valueb
0.0003
a Based on a stratified proportional hazards model.
b Based on a stratified log-rank test.
132
Reference ID: 5503299
,._
1.0
.9
~
C) 0.9
~
en
Q)
>
C: 0.8
,._
Q)
Cl.. 0.7
~
>
·:;;:
0.6
,._
:::J
Cf)
Q) 0.5
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,._
LL
I
Q) 0.4
en
~
Q)
en
0.3
Cl -
0
~ 0.2
:.c
~ 0.1
.c
0
•
Nivolumab
- - 0- - • Placebo
,._
a.. 0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
Disease-Free Survival per Investigator (Months)
Number of Subjects at Risk
Nivolumab
532 430 364 306 249 212 181 147 92
68
41
22
8
4
3
0
Placebo
262 214 163 126 96
80
65
53
38
28
17
12
5
2
1
0
Figure 20:
Disease-free Survival - CHECKMATE-577
First-line Treatment of Unresectable Advanced or Metastatic Esophageal Squamous
Cell Carcinoma (ESCC)
The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-
containing chemotherapy has been established for the first-line treatment of unresectable advanced
or metastatic ESCC. Use of OPDIVO QVANTIG for this indication is supported by evidence from
an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this esophageal squamous cell carcinoma
population.
133
Reference ID: 5503299
CHECKMATE-648
CHECKMATE-648 (NCT03143153) was a randomized, active-controlled, open-label trial in
patients with previously untreated unresectable advanced, recurrent or metastatic ESCC
(squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable
for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which
was evaluated using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. A retrospective
scoring of a patient’s tumor PD-L1 status using Combined Positive Score (CPS), was also
conducted using the PD-L1-stained tumor specimens used for randomization. Patients were not
amenable to chemoradiation or surgery with curative intent. Prior treatment with curative intent
was allowed if completed more than six months prior to trial enrollment. The trial excluded patients
with brain metastasis that were symptomatic, had active autoimmune disease, used systemic
corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to
apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized
to receive one of the following treatments:
Intravenous nivolumab 240 mg on days 1 and 15, fluorouracil 800 mg/m2/day
intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on
day 1 (of a 4-week cycle).
Intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg
every 6 weeks.
Fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin
80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Patients received intravenous nivolumab until disease progression, unacceptable toxicity, or up to
2 years. In patients who received intravenous nivolumab in combination with chemotherapy and
in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment
regimen were allowed to be continued. Patients who discontinued combination therapy because of
an adverse reaction attributed to ipilimumab were permitted to continue intravenous nivolumab as
a single agent.
Randomization was stratified by TC PD-L1 expression (≥1% vs. <1% or indeterminate), region
(East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of
organs with metastases (≤1 vs. ≥2). The major efficacy outcome measures were OS and BICR-
assessed PFS in patients with TC PD-L1 expression ≥1%. Additional efficacy measures included
OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed
by BICR in TC PD-L1 expression ≥1% and in all randomized patients. The tumor assessments per
RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeks
thereafter.
A total of 970 patients were randomized in CHECKMATE-648 study among whom 965 and 906
patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively. The trial
population characteristics for all randomized patients were median age 64 years (range: 26 to 90),
47% were ≥65 years of age, 82% were male, 71% were Asian, 26% were White, and 1.1% were
Black or African American. Patients had histological confirmation of squamous cell carcinoma
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Reference ID: 5503299
(98%) or adenosquamous cell carcinoma (1.9%) in the esophagus. Baseline ECOG performance
status was 0 (47.0%) or 1 (53%).
Efficacy results are shown in Table 64 and Figures 21 and 22.
Table 64:
Efficacy Results - CHECKMATE-648
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=321)
Intravenous
Nivolumab
and
Ipilimumab
(n=325)
Cisplatin
and
Fluorouracil
(n=324)
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=158)
Intravenous
Nivolumab
and
Ipilimumab
(n=158)
Cisplatin
and
Fluorouracil
(n=157)
All Patients
TC PD-L1 expression ≥1%
Overall Survival
Deaths (%)
209 (65)
216 (66)
232 (72)
98 (62)
106 (67)
121 (77)
Median
(months)
(95% CI)
13.2
(11.1, 15.7)
12.8
(11.3, 15.5)
10.7
(9.4, 11.9)
15.4
(11.9, 19.5)
13.7
(11.2, 17.0)
9.1
(7.7, 10)
Hazard ratio
(95% CI)b
0.74
(0.61, 0.90)
0.78
(0.65, 0.95)
-
0.54
(0.41, 0.71)
0.64
(0.49, 0.84)
-
p-valuec
0.0021S1
0.0110S2
-
<0.0001S3
0.0010S4
-
Progression-free Survivala
Disease
progression
or death (%)
235 (73)
258 (79)
210 (65)
117 (74)
123 (78)
100 (64)
Median
(months)
(95% CI)
5.8
(5.6, 7.0)
2.9
(2.7, 4.2)
5.6
(4.3, 5.9)
6.9
(5.7, 8.3)
4.0
(2.4, 4.9)
4.4
(2.9, 5.8)
Hazard ratio
(95% CI)b
0.81
(0.67, 0.99)
1.26
(1.04, 1.52)
-
0.65
(0.49, 0.86)
1.02
(0.78, 1.34)
-
p-valuec
NS
NT
-
0.0023S5
NS
Overall
Response
Rate, n
(%)a, NT
152 (47.4)
90 (27.7)
87 (26.9)
84 (53.2)
56 (35.4)
31 (19.7)
(95% CI)
(41.8, 53.0)
(22.9, 32.9)
(22.1, 32.0)
(45.1, 61.1)
(28.0, 43.4)
(13.8, 26.8)
Complete
response (%)
43 (13.4)
36 (11.1)
20 (6.2)
26 (16.5)
28 (17.7)
8 (5.1)
Partial
response (%)
109 (34.0)
54 (16.6)
67 (20.7)
58 (36.7)
28 (17.7)
23 (14.6)
Duration of Response (months)a
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Reference ID: 5503299
1.0
0.9
~ 0.8
·~ 0.7
V,
-----B-- Nivolumab + ipilimumab
-A-- Nivolumab + chemolherapy
--+--- Chemotherapy
~ 0.6
~ 0.5
0
0 0.4
~
:s 0.3
"'
.0
0
0.2
.I:
0.1
0.0
0
6
9
~ ~ IB
~ M ll
~ ~ ~ S
G
Overall Survival (Months)
Number of Subjects at Risk
Nivolumab + ipilimumab
325 274 232 191 166 129 97
77
55
33
22
12
6
0
Nivolumab + chemotherapy
321 293 253 203 163 133 92
60
40
26
12
Chemotherapy
324 281 229 171
131
93
56
41
23
9
2
0
1.0
0.9
~ 0.8
·~ 0.7
V,
-----B-- Nivolumab + ipilimumab
- A-- Nivolumab + chemotherapy
--+--- Chemotherapy
~ 0.6
~ 0.5
0
9
12
15
18
21
24
27
30
33
36
39
Overall Survival (Months)
Number ot Subjects at Risk
Nivolumab + ipilimumab
158 136 116
98
89
63
50
40
31
20
11
9
0
Nivolumab + chemolherapy
158 143
129
105
88
70
53
36
22
16
0
Chemolherapy
157 135
105
72
52
36
21
12
4
0
Table 64:
Efficacy Results - CHECKMATE-648
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=321)
Intravenous
Nivolumab
and
Ipilimumab
(n=325)
Cisplatin
and
Fluorouracil
(n=324)
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=158)
Intravenous
Nivolumab
and
Ipilimumab
(n=158)
Cisplatin
and
Fluorouracil
(n=157)
All Patients
TC PD-L1 expression ≥1%
Median
(95% CI)
8.2
(6.9, 9.7)
11.1
(8.3, 14.0)
7.1
(5.7, 8.2)
8.4
(6.9, 12.4)
11.8
(7.1, 27.4)
5.7
(4.4, 8.7)
Range
1.4+, 35.9+
1.4+, 34.5+
1.4+, 31.8+
1.4+, 34.6+
1.4+, 34.5+
1.4+, 31.8+
a Assessed by BICR.
b Based on stratified Cox proportional hazard model. Hazard ratios are reported for each intravenous nivolumab
containing arm compared to chemotherapy within each analysis population.
c Based on a stratified 2-sided log-rank test.
S1, S2, S3, S4, S5
Significant p-value compared to stopping boundary of 0.009, 0.018, 0.005, 0.014, and 0.015
respectively.
NS: Not Statistically significant, NT: Not evaluated for statistical significance as per pre-specified hierarchical testing
procedure
Figure 21: Overall Survival – CHECKMATE-648
(A) OS in All Randomized Patients
(B) OS in TC PD-L1 ≥1%
136
Reference ID: 5503299
-----e----- Nivolumab + ipilimumab
-A-- Nivolumab + chemotherapy
--+-- Chemotherapy
6
9
~ m IB
~
~ ll
~
Progression Free Survival per BICA (Months)
Number of Subjects at Risk
Nivolumab + ipilimumab
325 149
86
65
52
31
22
18
13
10
5
Nivolumab + chemotherapy
m m ~ ~
~ ~ w G
w
Chemotherapy
324
170
90
43
19
8
5
33
36
39
-----e----- Nivolumab + ipilimumab
-A-- Nivolumab + chemotherapy
--+ -- Chemotherapy
9
12
15
18
21
24
27
Progression Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + ipilimumab
158
78
48
38
31
18
14
13
8
Nivolumab + chemotherapy
158
107
75
47
29
18
10
Chemotherapy
157
67
35
17
30
33
36
Figure 22: Progression-free Survival – CHECKMATE-648
(A) PFS in All Randomized Patients
(B) PFS in TC PD-L1 ≥1%
Exploratory subgroup analyses of patients with TC PD-L1 expression <1% (n=492) were
conducted. OS results for each intravenous nivolumab containing arm compared to chemotherapy
were:
Intravenous Nivolumab with Chemotherapy (n=163) vs. Chemotherapy (n=165):
unstratified OS HR was 0.99 (95% CI: 0.76, 1.29) with median OS of 12 months (95% CI:
9.9, 15.5) on the Intravenous Nivolumab with Chemotherapy arm and 12.2 months (95%
CI: 10.7, 14) on the Chemotherapy arm
Intravenous Nivolumab with Ipilimumab (n=164) vs. Chemotherapy (n=165): unstratified
OS HR was 0.97 (95% CI: 0.74, 1.26) with median OS of 12 months (95% CI: 10.1, 16.0)
on the Intravenous Nivolumab with Ipilimumab arm and 12.2 months (95% CI: 10.7, 14)
on the Chemotherapy arm
Exploratory subgroup analyses were also conducted by PD-L1 status per CPS (≥1 and <1) for each
intravenous nivolumab containing arm compared to chemotherapy. Among the 906 patients with
quantifiable PD-L1 CPS at baseline, 278 in the intravenous nivolumab with chemotherapy arm,
266 in the intravenous nivolumab with ipilimumab arm, and 280 in the chemotherapy arm had PD
L1 CPS ≥1. A total of 27 patients in the intravenous nivolumab with chemotherapy arm, 31 patients
in the intravenous nivolumab with ipilimumab arm, and 24 patients in the chemotherapy arm had
PD-L1 CPS <1.
OS results for each comparison by PD-L1 CPS status were:
Intravenous Nivolumab with Chemotherapy vs. Chemotherapy: unstratified OS HR was
0.69 (95% CI: 0.56, 0.84) for PD-L1 CPS ≥1 subgroup and 0.98 (95% CI: 0.50, 1.95) for
PD-L1 CPS <1 subgroup.
Intravenous Nivolumab with Ipilimumab vs. Chemotherapy: unstratified OS HR was 0.76
(95% CI: 0.62, 0.93) for PD-L1 CPS ≥1 subgroup and 1.0 (95% CI: 0.52, 1.94) for PD-L1
CPS <1 subgroup.
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Previously Treated Unresectable Advanced, Recurrent or Metastatic ESCC
The effectiveness of OPDIVO QVANTIG has been established for the treatment of unresectable
advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based
chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from an
adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this ESCC population.
ATTRACTION-3
ATTRACTION-3 (NCT02569242) was a multicenter, randomized (1:1), active-controlled,
open-label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were
refractory or intolerant to at least one fluoropyrimidine- and platinum-based regimen. The trial
enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively
using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who
were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or
required
treatment,
had
autoimmune
disease,
used
systemic
corticosteroids
or
immunosuppressants, or had apparent tumor invasion of organs adjacent to the esophageal tumor
or had stents in the esophagus or respiratory tract. Patients were randomized to receive
nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks or investigator’s choice
of taxane chemotherapy consisting of docetaxel (75 mg/m2 intravenously every 3 weeks) or
paclitaxel (100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off).
Randomization was stratified by region (Japan vs. Rest of World), number of organs with
metastases (≤1 vs. ≥2), and PD-L1 status (≥1% vs. <1% or indeterminate). Patients were treated
until disease progression, assessed by the investigator per RECIST v1.1, or unacceptable toxicity.
The tumor assessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter.
The major efficacy outcome measure was OS. Additional efficacy outcome measures were ORR
and PFS as assessed by the investigator using RECIST v1.1 and DOR.
A total of 419 patients were randomized; 210 to the intravenous nivolumab arm and 209 to the
investigator’s choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics
were: median age 65 years (range: 33 to 87), 53% were ≥65 years of age, 87% were male, 96%
were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic
therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in
ATTRACTION-3. Baseline ECOG performance status was 0 (50%) or 1 (50%).
ATTRACTION-3 demonstrated a statistically significant improvement in OS for patients
randomized to intravenous nivolumab as compared with investigator’s choice of taxane
chemotherapy. OS benefit was observed regardless of PD-L1 expression level. The minimum
follow-up was 17.6 months. Efficacy results are shown in Table 65 and Figure 23.
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Reference ID: 5503299
Table 65:
Efficacy Results - ATTRACTION-3
Intravenous Nivolumab
(n=210)
Docetaxel or Paclitaxel
(n=209)
Overall Survivala
Deaths (%)
160 (76%)
173 (83%)
Median (months)
(95% CI)
10.9
(9.2, 13.3)
8.4
(7.2, 9.9)
Hazard ratio (95% CI)b
0.77 (0.62, 0.96)
p-valuec
0.0189
Overall Response Rated
33 (19.3)
34 (21.5)
(95% CI)
(13.7, 26.0)
(15.4, 28.8)
Complete response (%)
1 (0.6)
2 (1.3)
Partial response (%)
32 (18.7)
32 (20.3)
Median duration of response (months)
(95% CI)
6.9
(5.4, 11.1)
3.9
(2.8, 4.2)
p-valuee
0.6323
Progression-free Survivala, f
Disease progression or death (%)
187 (89)
176 (84)
Median (months)
(95% CI)
1.7
(1.5, 2.7)
3.4
(3.0, 4.2)
Hazard ratio (95% CI)b
1.1 (0.9, 1.3)
a Based on ITT analysis
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d Based on Response Evaluable Set (RES) analysis, n=171 in intravenous nivolumab group and n=158 in
investigator’s choice group.
e Based on stratified Cochran-Mantel-Haenszel test; p-value not significant.
f PFS not tested due to pre-specified hierarchical testing strategy.
139
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100
-
Nivolumab
90
-------- INV choice
80
--
~ 70
0 -
~
>
60
">
....
::::,
Cf)
50
'+-
0
;e:,
40
:.a
~
..Cl
0
30
....
a..
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Number at Risk
Overall Survival (Months)
Nivolumab
210 182 167 147 126 111 95 82 70 60 43 25 17 13 7 4 3 0 0
INV choice
209 196 169 126 105 84 68 57 49 40 27 17 12 6 2 1 1 1 0
Figure 23:
Overall Survival - ATTRACTION-3
Of the 419 patients, 48% had PD-L1 positive ESCC, defined as ≥1% of tumor cells expressing
PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing
PD-L1.
In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69
(95% CI: 0.51, 0.94) with median survivals of 10.9 and 8.1 months for the intravenous nivolumab
and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1
negative subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9
and 9.3 months for the intravenous nivolumab and investigator’s choice arms, respectively.
14.12
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-
containing chemotherapy has been established for the treatment of gastric cancer,
140
Reference ID: 5503299
gastroesophageal junction cancer, and esophageal adenocarcinoma. Use of OPDIVO QVANTIG
for this indication is supported by evidence from an adequate and well-controlled study conducted
with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated
comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous
nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a
description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this population.
CHECKMATE-649
CHECKMATE-649 (NCT02872116) was a randomized, multicenter, open-label trial in patients
(n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal
junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1
status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx
assay at a central laboratory. The trial excluded patients who were known human epidermal growth
factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to
receive intravenous nivolumab in combination with chemotherapy (n=789) or chemotherapy
(n=792). Patients received one of the following treatments:
Intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin
and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
Intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and
oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients
who received intravenous nivolumab in combination with chemotherapy and in whom
chemotherapy was discontinued, intravenous nivolumab monotherapy was allowed to be given at
240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after
treatment initiation.
Randomization was stratified by tumor cell PD-L1 status (≥1% vs. <1% or indeterminate), region
(Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen
(mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD
L1 CPS ≥5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included
OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, and ORR and DOR as
assessed by BICR in patients with PD-L1 CPS ≥1 and ≥5, and in all randomized patients. Tumor
assessments were conducted per RECIST v1.1 every 6 weeks up to and including week 48, then
every 12 weeks thereafter.
The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were ≥65
years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline
ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had
adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the
esophagus.
CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for
patients with PD-L1 CPS ≥5. Statistically significant improvement in OS was also demonstrated
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for all randomized patients. The minimum follow-up was 12.1 months. Efficacy results are shown
in Table 66 and Figures 24, 25, and 26.
Table 66:
Efficacy Results - CHECKMATE-649
Intravenous
Nivolumab
and
mFOLFOX6
or CapeOX
(n=789)
mFOLFOX6
or CapeOX
(n=792)
Intravenous
Nivolumab
and
mFOLFOX6
or CapeOX
(n=641)
mFOLFOX6
or CapeOX
(n=655)
Intravenous
Nivolumab
and
mFOLFOX6
or CapeOX
(n=473)
mFOLFOX6
or CapeOX
(n=482)
All Patients
PD-L1 CPS ≥1
PD-L1 CPS ≥5
Overall Survival
Deaths (%)
544 (69)
591 (75)
434 (68)
492 (75)
309 (65)
362 (75)
Median
(months)
(95% CI)
13.8
(12.6, 14.6)
11.6
(10.9, 12.5)
14.0
(12.6, 15.0)
11.3
(10.6, 12.3)
14.4
(13.1, 16.2)
11.1
(10.0, 12.1)
Hazard ratio
(95% CI)a
0.80 (0.71, 0.90)
0.77 (0.68, 0.88)
0.71 (0.61, 0.83)
p-valueb
0.0002
<0.0001
<0.0001
Progression-free Survivalc
Disease
progression
or death (%)
559 (70.8)
557 (70.3)
454 (70.8)
472 (72.1)
328 (69.3)
350 (72.6)
Median
(months)
(95% CI)
7.7
(7.1, 8.5)
6.9
(6.6, 7.1)
7.5
(7.0, 8.4)
6.9
(6.1, 7.0)
7.7
(7.0, 9.2)
6.0
(5.6, 6.9)
Hazard ratio
(95% CI)a
0.77 (0.68, 0.87)
0.74 (0.65, 0.85)
0.68 (0.58, 0.79)
p-valueb
e
e
<0.0001
Overall
Response
Rate, n (%)c,d
370 (47)
293 (37)
314 (49)
249 (38)
237 (50)
184 (38)
(95% CI)
(43, 50)
(34, 40)
(45, 53)
(34, 42)
(46, 55)
(34, 43)
Complete
response (%)
78 (10)
52 (7)
65 (10)
42 (6)
55 (12)
34 (7)
Partial
response (%)
292 (37)
241 (30)
249 (39)
207 (32)
182 (38)
150 (31)
Duration of Response (months)c,d
Median
(95% CI)
Range
8.5
(7.2, 9.9)
1.0+, 29.6+
6.9
(5.8, 7.2)
1.2+, 30.8+
8.5
(7.7, 10.3)
1.1+, 29.6+
6.9
(5.8, 7.6)
1.2+, 30.8+
9.5
(8.1, 11.9)
1.1+, 29.6+
6.9
(5.6, 7.9)
1.2+, 30.8+
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Reference ID: 5503299
1.0
0.9
0.8
ro
>
·s;
..... 0.7
::::::i
Cf)
ro 0.6
.....
Q.)
> 0.5
0 -
0
;if:;' 0.4
:c
ro 0.3
.0
0 .....
CL 0.2
0.1
A
Nivolumab + chemotherapy
- -e--- Chemotherapy
6lXXX:lOOro -o ro
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
Number of Subjects at Risk
Overall Survival (Months)
Nivolumab + chemotherapy
789 731
621 506 420 308 226 147 100
49
34
14
2
0
Chemotherapy
792 697 586 469 359 239 160
94
59
35
15
7
2
0
a Based on stratified Cox proportional hazard model.
b Based on stratified log-rank test.
c Assessed by BICR.
d Based on confirmed response.
e Not evaluated for statistical significance.
In an exploratory analysis in patients with PD-L1 CPS <1 (n=265), the median OS was 13.1
months (95% CI: 9.8, 16.7) for the intravenous nivolumab and chemotherapy arm and 12.5 months
(95% CI: 10.1, 13.8) for the chemotherapy arm, with a stratified HR of 0.85 (95% CI: 0.63, 1.15).
In an exploratory analysis in patients with PD-L1 CPS <5 (n=606), the median OS was 12.4
months (95% CI: 10.6, 14.3) for the intravenous nivolumab and chemotherapy arm and 12.3
months (95% CI: 11.0, 13.2) for the chemotherapy arm, with a stratified HR of 0.94 (95% CI: 0.78,
1.14).
Figure 24:
Overall Survival (All Patients) - CHECKMATE-649
143
Reference ID: 5503299
1.0
0.9
0.8
ctS
>
·;;:: 0.7
.....
:::::s
Cf)
ctS 0.6
.....
Cl)
> 0.5
0 -
0
;i?:' 0.4
:B
ctS
..c 0.3
0 .....
c... 0.2
0.1
A
Nivolumab + chemotherapy
~
EID-E!OOB - -0
- -e--- Chemotherapy
0.0
0
3
6
9
12
Number of Subjects at Risk
Nivolumab + chemotherapy
641 595 502 412 344
Chemotherapy
655 575 483 383 292
15
18
21
24
27
30
Overall Survival (Months)
254 183
118
80
40
28
194
131
77
45
25
10
33
36
39
11
1
0
3
0
0
Figure 25:
Overall Survival (PD-L1 CPS ≥1) - CHECKMATE-649
144
Reference ID: 5503299
1.0
0.9
0.8
~
>
·s;: 0.7
i....
::::s
Cf)
~ 0.6
i....
Q)
> 0.5
0 -
0
>, 0.4
~
:c
~ 0.3
.c
I
0
·o,
~
'
0
i....
a.. 0.2
0.1
A
Nivolumab + chemotherapy
0&mx:fl}-«mml)(B3 - 0ll)
- -e--- Chemotherapy
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
Number of Subjects at Risk
Nivolumab + chemotherapy
Overall Survival (Months)
473 438 377
313
261
198
149
96
65
33
22
Chemotherapy
482 421
350
271
211
138
98
56
34
19
8
9
2
1
0
0
0
Figure 26:
Overall Survival (PD-L1 CPS ≥5) - CHECKMATE-649
16
HOW SUPPLIED/STORAGE AND HANDLING
OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-
free, clear to opalescent and colorless to yellow solution for subcutaneous use. It is supplied as an
individually packaged single-dose vial providing 600 mg nivolumab and 10,000 units
hyaluronidase per 5 mL (120 mg/ 2,000 units per mL) (NDC-00003-6120-01).
Store OPDIVO QVANTIG vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton
to protect from light.
Do not freeze or shake.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
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Reference ID: 5503299
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid
treatment and withholding or discontinuation of OPDIVO QVANTIG, including:
Pneumonitis: Advise patients to contact their healthcare provider immediately for any new
or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions
(5.1)].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or
severe abdominal pain [see Warnings and Precautions (5.1)].
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice,
severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or
bleeding [see Warnings and Precautions (5.1)].
Endocrinopathies: Advise patients to contact their healthcare provider immediately for
signs
or
symptoms
of
hypophysitis,
adrenal
insufficiency,
hypothyroidism,
hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].
Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider
immediately for signs or symptoms of nephritis including decreased urine output, blood in
urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction
[see Warnings and Precautions (5.1)].
Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately
for rash [see Warnings and Precautions (5.1)].
Other immune-mediated adverse reactions:
Advise patients that immune-mediated adverse reactions can occur and may involve any
organ system, and to contact their healthcare provider immediately for any new or
worsening signs or symptoms [see Warnings and Precautions (5.1)].
Advise patients of the risk of solid organ transplant rejection and other transplant (including
corneal graft) rejection. Advise patients to contact their healthcare provider immediately
for signs or symptoms of organ transplant rejection and other transplant (including corneal
graft) rejection [see Warnings and Precautions (5.1)].
Complications of Allogeneic HSCT
Advise patients of potential risk of post-transplant complications [see Warnings and
Precautions (5.2)].
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their
healthcare provider of a known or suspected pregnancy [see Warnings and Precautions
(5.3) and Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment
with OPDIVO QVANTIG and for 5 months following the last dose [see Use in Specific
Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with OPDIVO QVANTIG and for 5
months after the last dose [see Use in Specific Populations (8.2)].
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Reference ID: 5503299
Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713
Halozyme Therapeutics, Inc.
12390 El Camino Real
San Diego, CA 92130
U.S. License No. 2187
147
Reference ID: 5503299
MEDICATION GUIDE
OPDIVO QVANTIG™ (op-DEE-voh cue-VAN-tig)
(nivolumab and hyaluronidase-nvhy)
injection, for subcutaneous use
Read this Medication Guide before you start receiving OPDIVO QVANTIG and before each injection. There may be new
information. If your healthcare provider prescribes OPDIVO QVANTIG in combination with cabozantinib, also read the
Patient Information that comes with cabozantinib. This Medication Guide does not take the place of talking with your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about OPDIVO QVANTIG?
OPDIVO QVANTIG is a medicine that may treat certain cancers by working with your immune system. OPDIVO
QVANTIG can cause your immune system to attack normal organs and tissues in any area of your body and can affect
the way they work. These problems can sometimes become severe or can lead to death. These problems may happen
anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the
same time. Some of these problems may happen more often when OPDIVO QVANTIG is used in combination with
another therapy.
Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms,
including:
Lung problems.
cough
shortness of breath
chest pain
Intestinal problems.
diarrhea (loose stools) or more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucus
severe stomach-area (abdominal) pain or tenderness
Liver problems.
yellowing of your skin or the whites of your eyes
dark urine (tea colored)
severe nausea or vomiting
bleeding or bruising more easily than normal
pain on the right side of your stomach area (abdomen)
Hormone gland problems.
headaches that will not go away or unusual headaches
urinating more often than usual
eye sensitivity to light
hair loss
eye problems
feeling cold
rapid heartbeat
constipation
increased sweating
your voice gets deeper
extreme tiredness
dizziness or fainting
weight gain or weight loss
changes in mood or behavior, such as decreased sex
feeling more hungry or thirsty than usual
drive, irritability, or forgetfulness
Kidney problems.
decrease in your amount of urine
swelling of your ankles
blood in your urine
loss of appetite
Skin problems.
rash
painful sores or ulcers in mouth or nose, throat, or
itching
genital area
skin blistering or peeling
fever or flu-like symptoms
swollen lymph nodes
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune
system problems that can happen with OPDIVO QVANTIG. Call or see your healthcare provider right away for
any new or worsening signs or symptoms, which may include:
chest pain, irregular heartbeat, shortness of breath or swelling of ankles
confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or
numbness of the arms or legs
double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
persistent or severe muscle pain or weakness, muscle cramps
low red blood cells, bruising
Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you
should report and monitor you depending on the type of organ or tissue transplant that you have had.
148
Reference ID: 5503299
Getting medical treatment right away may help keep these problems from becoming more serious. Your
healthcare provider will check you for these problems during treatment with OPDIVO QVANTIG. Your healthcare provider
may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay
or completely stop treatment with OPDIVO QVANTIG, if you have severe side effects.
What is OPDIVO QVANTIG?
OPDIVO QVANTIG is a prescription medicine used to treat adults with:
a type of kidney cancer that has spread called advanced renal cell carcinoma (RCC).
○
OPDIVO QVANTIG may be used alone as a first treatment in certain people with advanced RCC, after completing
combination treatment with nivolumab given into the vein (intravenous nivolumab) and ipilimumab.
○
OPDIVO QVANTIG may be used in combination with cabozantinib as your first treatment for advanced RCC.
○
OPDIVO QVANTIG may be used alone when your cancer has spread after treatment with other cancer
medicines.
a type of skin cancer called melanoma.
○
OPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery
(advanced melanoma).
○
OPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery
(advanced melanoma), after completing combination treatment with intravenous nivolumab and ipilimumab.
○
OPDIVO QVANTIG may be used alone to help prevent Stage IIB, Stage IIC, Stage III, or Stage IV melanoma
from coming back after it has been completely removed by surgery.
a type of lung cancer called non-small cell lung cancer (NSCLC).
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another
chemotherapy medicine before you have surgery for early-stage NSCLC.
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another
chemotherapy medicine before you have surgery for early-stage NSCLC:
•
that does not have an abnormal EGFR or ALK gene, and
•
then OPDIVO QVANTIG may be continued alone after surgery to help prevent your lung cancer from coming
back.
○
OPDIVO QVANTIG may be used alone when your lung cancer:
has spread, and
•
you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
•
If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for
tumors with these abnormal genes, and it did not work or is no longer working.
head and neck cancer (squamous cell carcinoma).
○
OPDIVO QVANTIG may be used alone when your head and neck cancer:
•
has come back or spread, and
•
you have tried chemotherapy that contains platinum and it did not work or is no longer working.
cancer of the lining of the urinary tract (urothelial carcinoma).
○
OPDIVO QVANTIG may be used alone to help prevent cancer of the urinary tract from coming back after it was
removed by surgery.
○
OPDIVO QVANTIG may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your
first treatment when your urinary tract cancer has spread (metastatic) or cannot be removed by surgery.
○
OPDIVO QVANTIG may be used alone when your urinary tract cancer has spread (locally advanced or
metastatic), and:
•
you have tried chemotherapy that contains platinum, and it did not work or is no longer working, or
•
your cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before
or after surgery to remove your cancer.
a type of colon or rectal cancer (colorectal cancer or CRC).
○
OPDIVO QVANTIG may be used alone and after completing combination treatment with intravenous nivolumab
and ipilimumab, when your colon or rectal cancer:
•
has spread to other parts of the body (metastatic CRC), and
•
is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and
•
you have tried treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer
working.
a type of liver cancer called hepatocellular carcinoma (HCC).
○
OPDIVO QVANTIG may be used alone if you have previously received treatment with sorafenib and after
completing combination treatment with intravenous nivolumab and ipilimumab.
cancer of the tube that connects your throat to your stomach (esophageal cancer).
○
OPDIVO QVANTIG may be used alone to help prevent your esophageal or gastroesophageal junction cancer
from coming back when:
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Reference ID: 5503299
•
your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by
surgery to completely remove the cancer, but
•
some cancer cells were still present in the removed tumor or lymph nodes.
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum
as your first treatment when your esophageal cancer:
•
is a type called squamous cell carcinoma, and
•
cannot be removed with surgery (advanced), or
•
has spread to other parts of the body (metastatic).
○
OPDIVO QVANTIG may be used alone when your esophageal cancer:
•
is a type called squamous cell carcinoma, and
•
cannot be removed with surgery, has come back, or has spread to other parts of the body after you have
received chemotherapy that contains fluoropyrimidine and platinum.
cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal
junction cancer), and a type of cancer in the esophagus called esophageal adenocarcinoma.
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum
when your gastric, gastroesophageal junction, or esophageal cancer:
•
cannot be removed with surgery, or
•
has spread to other parts of the body.
It is not known if OPDIVO QVANTIG is safe and effective in children.
Before receiving OPDIVO QVANTIG, tell your healthcare provider about all of your medical conditions, including
if you:
have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant, including corneal transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have received radiation treatment to your chest area in the past
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
are pregnant or plan to become pregnant. OPDIVO QVANTIG can harm your unborn baby.
Females who are able to become pregnant:
○
Your healthcare provider should do a pregnancy test before you start receiving OPDIVO QVANTIG.
○
You should use an effective method of birth control during treatment and for 5 months after your last dose of
OPDIVO QVANTIG. Talk to your healthcare provider about birth control methods that you can use during this
time.
○
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment
with OPDIVO QVANTIG.
are breastfeeding or plan to breastfeed. It is not known if OPDIVO QVANTIG passes into your breast milk. Do not
breastfeed during treatment and for 5 months after your last dose of OPDIVO QVANTIG.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
How will I receive OPDIVO QVANTIG?
Your healthcare provider will give you OPDIVO QVANTIG as an injection under the skin, in the stomach area
(abdomen) or thigh, over about 3 to 5 minutes.
OPDIVO QVANTIG is usually given every 2, 3, or 4 weeks, depending on the dose you are receiving.
Your healthcare provider will decide how many treatments you will receive.
Your healthcare provider will do blood tests to check you for side effects.
For a type of kidney cancer called advanced renal cell carcinoma, your healthcare provider may also prescribe you
cabozantinib. Take cabozantinib exactly as your healthcare provider tells you.
If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of OPDIVO QVANTIG?
OPDIVO QVANTIG can cause serious side effects, including:
See “What is the most important information I should know about OPDIVO QVANTIG?”
Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow
(stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead
to death. These complications may happen if you underwent transplantation either before or after being treated with
OPDIVO QVANTIG. Your healthcare provider will monitor you for signs of complications if you have an allogeneic
stem cell transplant.
The most common side effects of OPDIVO QVANTIG when used alone in people with renal cell carcinoma
include:
pain in muscles, bones, and joints
low thyroid hormone levels
150
Reference ID: 5503299
feeling tired
diarrhea
itchy skin
cough
rash
stomach-area (abdominal) pain
The most common side effects observed with nivolumab given into the vein (intravenous nivolumab), which
may be experienced with OPDIVO QVANTIG, are shown below.
The most common side effects of intravenous nivolumab when used alone include:
feeling tired
weakness
upper respiratory tract infection
rash
cough
fever
pain in muscles, bones, and joints
shortness of breath
headache
itchy skin
constipation
stomach-area (abdominal) pain
diarrhea
decreased appetite
vomiting
nausea
back pain
urinary tract infection
The most common side effects of intravenous nivolumab when used in combination with cabozantinib as the
first treatment for advanced RCC include:
diarrhea
mouth sores
nausea
feeling tired
rash
change in the sense of taste
liver problems. See “What is the
high blood pressure
stomach-area (abdominal) pain
most important information I should
low thyroid hormone levels
cough
know about OPDIVO QVANTIG?”
pain in muscles, bones, and joints
upper respiratory tract infection
rash, redness, pain, swelling or
decreased appetite
blisters on the palms of your hands
or soles of your feet
The most common side effects of intravenous nivolumab when used in combination with platinum-containing
chemotherapy and another chemotherapy medicine before having surgery for NSCLC include:
nausea
feeling tired
rash
constipation
decreased appetite
The most common side effects of intravenous nivolumab when used in combination with cisplatin and
gemcitabine to treat urothelial cancer include:
nausea
constipation
vomiting
feeling tired
decreased appetite
numbness, pain, tingling or
pain in muscles, bones, and joints
rash
burning in your hands and feet
The most common side effects of intravenous nivolumab when used in combination with fluoropyrimidine and
platinum-containing chemotherapy to treat esophageal cancer and gastric cancer include:
nausea
feeling tired
vomiting
numbness, pain, tingling, or burning
constipation
stomach-area (abdominal) pain
in your hands or feet
mouth sores
pain in muscles, bones, and
decreased appetite
diarrhea
joints
These are not all the possible side effects of OPDIVO QVANTIG.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of OPDIVO QVANTIG.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your
pharmacist or healthcare provider for information about OPDIVO QVANTIG that is written for health professionals.
What are the ingredients in OPDIVO QVANTIG?
Active ingredients: nivolumab and hyaluronidase-nvhy
Inactive ingredients: histidine, histidine hydrochloride monohydrate, methionine, pentetic acid, polysorbate 80,
sucrose, and Water for Injection.
Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA U.S. License No. 1713
Halozyme Therapeutics, Inc., 12390 El Camino Real, San Diego, CA 92130, U.S. License No. 2187
OPDIVO QVANTIG™ is a trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.
For more information, call 1-855-673-4861 or go to www.Qvantig.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: December 2024
151
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| custom-source | 2025-02-12T15:48:23.446084 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761429s000lbl.pdf', 'application_number': 761429, 'submission_type': 'ORIG ', 'submission_number': 1} |
80,780 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use OPDIVO
QVANTIG safely and effectively. See full prescribing information for
OPDIVO QVANTIG.
OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy) injection, for
subcutaneous use
Initial U.S. Approval: 2024
---------------------------INDICATIONS AND USAGE---------------------------
OPDIVO QVANTIG is a combination of nivolumab, a programmed death
receptor-1 (PD-1)-blocking antibody, and hyaluronidase, an endoglycosidase,
indicated for the treatment of:
Renal Cell Carcinoma (RCC)
adult patients with intermediate or poor risk advanced RCC, as a first-line
treatment following combination treatment with intravenous nivolumab and
ipilimumab. (1.1)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of renal cell carcinoma.
adult patients with advanced RCC, as a first-line treatment in combination
with cabozantinib. (1.1)
adult patients with advanced RCC who have received prior anti-angiogenic
therapy. (1.1)
Melanoma
adult patients with unresectable or metastatic melanoma. (1.2)
adult patients with unresectable or metastatic melanoma following
combination treatment with intravenous nivolumab and ipilimumab. (1.2)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of unresectable or metastatic
melanoma.
for the adjuvant treatment of adult patients with completely resected Stage
IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.3)
Non-Small Cell Lung Cancer (NSCLC)
adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in the
neoadjuvant setting, in combination with platinum-doublet chemotherapy.
(1.4)
adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and
no known EGFR mutations or ALK rearrangements, for neoadjuvant
treatment, in combination with platinum-doublet chemotherapy, followed by
OPDIVO QVANTIG monotherapy as adjuvant treatment after surgery. (1.5)
adult patients with metastatic NSCLC and progression on or after platinum-
based chemotherapy. Patients with EGFR or ALK genomic tumor
aberrations should have disease progression on FDA-approved therapy for
these aberrations prior to receiving OPDIVO QVANTIG. (1.6)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of metastatic NSCLC.
Squamous Cell Carcinoma of the Head and Neck (SCCHN)
adult patients with recurrent or metastatic SCCHN with disease progression
on or after a platinum-based therapy. (1.7)
Urothelial Carcinoma (UC)
adjuvant treatment of adult patients with UC who are at high risk of
recurrence after undergoing radical resection of UC. (1.8)
adult patients with unresectable or metastatic urothelial carcinoma, as first-
line treatment in combination with cisplatin and gemcitabine. (1.8)
adult patients with locally advanced or metastatic UC who:
have disease progression during or following platinum-containing
chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy. (1.8)
Colorectal Cancer
adult patients with MSI-H or dMMR metastatic CRC that has progressed
following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as
monotherapy or as monotherapy following combination treatment with
intravenous nivolumab and ipilimumab.a (1.9)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.
Hepatocellular Carcinoma (HCC)
adult patients with HCC previously treated with sorafenib and following
combination treatment with intravenous nivolumab and ipilimumab.a (1.10)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of HCC.
Esophageal Cancer
adult patients with completely resected esophageal or gastroesophageal
junction cancer with residual pathologic disease, who have received
neoadjuvant chemoradiotherapy (CRT). (1.11)
adult patients with unresectable advanced or metastatic esophageal
squamous cell carcinoma as first-line treatment in combination with
fluoropyrimidine- and platinum-containing chemotherapy. (1.11)
Limitations of Use: OPDIVO QVANTIG is not indicated in combination
with ipilimumab for the treatment of patients with unresectable advanced
or metastatic ESCC.
adult patients with unresectable advanced, recurrent or metastatic
esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine
and platinum-based chemotherapy. (1.11)
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
adult patients with advanced or metastatic gastric cancer, gastroesophageal
junction cancer, and esophageal adenocarcinoma in combination with
fluoropyrimidine- and platinum-containing chemotherapy. (1.12)
a This indication is approved under accelerated approval based on overall
response rate and duration of response. Continued approval for this indication
may be contingent upon verification and description of clinical benefit in
confirmatory trials.
-------------------------DOSAGE AND ADMINISTRATION-------------------
OPDIVO QVANTIG has different dosage and administration
instructions than intravenous nivolumab products.
OPDIVO QVANTIG is for subcutaneous use only in the abdomen or
thigh.
OPDIVO QVANTIG is to be administered by a healthcare professional
only. (2.1)
OPDIVO QVANTIG is for subcutaneous use only.
Administer by subcutaneous injection over 3-5 minutes. (2.1)
Renal cell carcinoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks administered in combination with cabozantinib 40 mg once daily
without food. (2.2)
Melanoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Neoadjuvant and adjuvant treatment of resectable (tumors ≥4 cm or node
positive) non-small cell lung cancer
900 mg/15,000 units with platinum-doublet chemotherapy on the same
day every 3 weeks for 3 cycles, then single-agent OPDIVO QVANTIG
1,200 mg/20,000 units every 4 weeks after surgery for up to 13 cycles.
(2.2)
Metastatic non-small cell lung cancer
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Squamous cell carcinoma of the head and neck
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Urothelial carcinoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
First-line unresectable or metastatic urothelial carcinoma
900 mg/15,000 units every 3 weeks with cisplatin and gemcitabine on the
same day for up to 6 cycles, then 600 mg/10,000 units every 2 weeks or
1,200 mg/20,000 units every 4 weeks. (2.2)
Colorectal cancer
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Hepatocellular carcinoma
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
Esophageal cancer
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks. (2.2)
600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4
weeks administered in combination with fluoropyrimidine- and platinum-
containing chemotherapy. (2.2)
Reference ID: 5503239
1
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
600
mg/10,000
units
every
2
weeks
in
combination
with
fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks.
(2.2)
900 mg/15,000 units every 3 weeks with fluoropyrimidine- and platinum-
containing chemotherapy every 3 weeks. (2.2)
See full Prescribing Information for preparation and administration
instructions and dosage modifications for adverse reactions.
---------------------DOSAGE FORMS AND STRENGTHS--------------------
Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120
mg/2,000 units per mL) in a single-dose vial. (3)
------------------------------CONTRAINDICATIONS-----------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS----------------------
Immune-Mediated Adverse Reactions: (5.1)
○ Immune-mediated adverse reactions, which may be severe or fatal, can
occur in any organ system or tissue, including the following: immune-
mediated pneumonitis, immune-mediated colitis, immune-mediated
hepatitis and hepatotoxicity, immune-mediated endocrinopathies,
immune-mediated
dermatologic
adverse
reactions, and
immune-
mediated nephritis and renal dysfunction.
○ Monitor for early identification and management. Evaluate liver enzymes,
creatinine, and thyroid function at baseline and periodically during
treatment.
○ Withhold or permanently discontinue based on severity and type of
reaction. (2.3)
Complications of allogeneic HSCT: Fatal and other serious complications
can occur in patients who receive allogeneic HSCT before or after being
treated with a PD-1/PD-L1 blocking antibody. (5.2)
Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive
potential of potential risk to a fetus and to use effective contraception. (5.3,
8.1, 8.3)
Treatment of patients with multiple myeloma with a PD-1 or PD-L1
blocking antibody in combination with a thalidomide analogue plus
dexamethasone is not recommended outside of controlled clinical trials.
(5.4)
-------------------------------ADVERSE REACTIONS----------------------------
Most common adverse reactions (10%) with OPDIVO QVANTIG as
monotherapy in patients with Renal Cell Carcinoma were:
musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea,
cough, and abdominal pain. (6.1)
Safety of OPDIVO QVANTIG for the following indications is based on
safety of intravenous nivolumab in these populations. The most common
adverse reactions with intravenous nivolumab for these indications are
presented below.
As monotherapy for the treatment of advanced renal cell carcinoma;
adjuvant treatment of completely resected Stage IIB, IIC, III, or IV
melanoma; unresectable or metastatic melanoma; adjuvant treatment of
NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck;
urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma;
esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea,
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back
pain, arthralgia, upper respiratory tract infection, pyrexia, headache,
abdominal pain, vomiting, and urinary tract infection. (6.1)
In combination with cabozantinib for the first-line treatment of advanced
renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar
erythrodysesthesia
syndrome,
stomatitis,
rash,
hypertension,
hypothyroidism, musculoskeletal pain, decreased appetite, nausea,
dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)
In combination with platinum-doublet chemotherapy for the neoadjuvant
treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and
rash. (6.1)
In combination with cisplatin and gemcitabine for the treatment of urothelial
cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased
appetite, rash, vomiting, and peripheral neuropathy. (6.1)
In combination with fluoropyrimidine-
and platinum-
containing
chemotherapy for the treatment of esophageal cancer and gastric cancer:
nausea, peripheral neuropathy, decreased appetite, fatigue, constipation,
stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain.
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
Squibb
at
1-800-721-5072
or
FDA
at
1-800-FDA-1088
or
www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS----------------------
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 12/2024
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Advanced Renal Cell Carcinoma
1.2
Unresectable or Metastatic Melanoma
1.3
Adjuvant Treatment of Melanoma
1.4
Neoadjuvant Treatment of Resectable Non-Small
Cell Lung Cancer
1.5
Neoadjuvant and Adjuvant Treatment of Resectable
Non-Small Cell Lung Cancer
1.6
Metastatic Non-Small Cell Lung Cancer
1.7
Squamous Cell Carcinoma of the Head and Neck
1.8
Urothelial Carcinoma
1.9
Microsatellite Instability-High or Mismatch Repair
Deficient Metastatic Colorectal Cancer
1.10
Hepatocellular Carcinoma
1.11
Esophageal Cancer
1.12
Gastric Cancer, Gastroesophageal Junction Cancer,
and Esophageal Adenocarcinoma
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage and Administration Information
2.2
Recommended Dosage
2.3
Dose Modifications
2.4
Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Severe and Fatal Immune-Mediated Adverse
Reactions
2
5.2
Complications of Allogeneic Hematopoietic Stem
Cell Transplantation
5.3
Embryo-Fetal Toxicity
5.4
Increased Mortality in Patients with Multiple
Myeloma when Nivolumab Is Added to a
Thalidomide Analogue and Dexamethasone
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.6
Immunogenicity
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of
Fertility
13.2
Animal Toxicology and/or Pharmacology
14
CLINICAL STUDIES
14.1
Advanced Renal Cell Carcinoma
Reference ID: 5503239
14.2
14.3
14.4
14.5
14.6
14.7
Unresectable or Metastatic Melanoma
Adjuvant Treatment of Melanoma
Neoadjuvant Treatment of Resectable Non-Small
Cell Lung Cancer
Neoadjuvant and Adjuvant Treatment of Resectable
Non-Small Cell Lung Cancer
Metastatic Non-Small Cell Lung Cancer
Recurrent or Metastatic Squamous Cell Carcinoma
of the Head and Neck
14.11
Esophageal Cancer
14.12
Gastric Cancer, Gastroesophageal Junction Cancer,
and Esophageal Adenocarcinoma
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
14.8
14.9
Urothelial Carcinoma
Microsatellite Instability-High or Mismatch Repair
Deficient Metastatic Colorectal Cancer
*Sections or subsections omitted from the full prescribing information
are not listed.
14.10
Hepatocellular Carcinoma
Reference ID: 5503239
3
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Advanced Renal Cell Carcinoma
OPDIVO QVANTIG™, as monotherapy, is indicated for the first-line treatment of adult patients
with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with
intravenous nivolumab and ipilimumab combination therapy.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of renal cell carcinoma.
OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of
adult patients with advanced RCC.
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
advanced RCC who have received prior anti-angiogenic therapy.
1.2
Unresectable or Metastatic Melanoma
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
unresectable or metastatic melanoma.
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
unresectable or metastatic melanoma following treatment with intravenous nivolumab and
ipilimumab combination therapy.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of unresectable or metastatic melanoma.
1.3
Adjuvant Treatment of Melanoma
OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients
with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.
1.4
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated as
neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small
cell lung cancer (NSCLC).
1.5
Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell
Lung Cancer
OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated for the
neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC
and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase
(ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting
after surgical resection.
4
Reference ID: 5503239
1.6
Metastatic Non-Small Cell Lung Cancer
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based
chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO
QVANTIG.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of metastatic NSCLC.
1.7
Squamous Cell Carcinoma of the Head and Neck
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease
progression on or after platinum-based therapy.
1.8
Urothelial Carcinoma
OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients
with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical
resection of UC.
OPDIVO QVANTIG, in combination with cisplatin and gemcitabine, is indicated for the first-line
treatment of adult patients with unresectable or metastatic UC.
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with locally
advanced or metastatic UC who:
have disease progression during or following platinum-containing chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
1.9
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic
Colorectal Cancer
OPDIVO QVANTIG, as monotherapy or as monotherapy following treatment with intravenous
nivolumab and ipilimumab combination therapy, is indicated for the treatment of adult patients
with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC
that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of MSI-H or dMMR metastatic CRC.
This indication is approved under accelerated approval based on overall response rate and duration
of response [see Clinical Studies (14.9)]. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in confirmatory trials.
5
Reference ID: 5503239
1.10
Hepatocellular Carcinoma
OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with
hepatocellular carcinoma (HCC) who have been previously treated with sorafenib and following
treatment with intravenous nivolumab and ipilimumab.
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of patients with HCC.
This indication is approved under accelerated approval based on overall response rate and duration
of response [see Clinical Studies (14.10)]. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in the confirmatory trials.
1.11
Esophageal Cancer
OPDIVO QVANTIG as monotherapy, is indicated for the adjuvant treatment of completely
resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult
patients who have received neoadjuvant chemoradiotherapy (CRT).
OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing
chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced
or metastatic esophageal squamous cell carcinoma (ESCC).
Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the
treatment of patients with unresectable advanced or metastatic ESCC.
OPDIVO QVANTIG as monotherapy, is indicated for the treatment of adult patients with
unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-
based chemotherapy.
1.12
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing
chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric
cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage and Administration Information
OPDIVO QVANTIG has different dosage and administration instructions than
intravenously administered nivolumab products [see Dosage and Administration (2.4)].
OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not
administer intravenously.
OPDIVO QVANTIG is to be administered by a healthcare professional only.
Adult patients currently receiving intravenous nivolumab as a single agent, or in combination with
chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next
scheduled dose.
6
Reference ID: 5503239
2.2
Recommended Dosage
The recommended dosages of OPDIVO QVANTIG as monotherapy agent are presented in
Table 1.
Table 1:
Recommended Dosages for OPDIVO QVANTIG as Monotherapy
Indication
Recommended OPDIVO QVANTIG
Dosage
Duration of Therapy
Advanced renal cell carcinoma†
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Until disease
progression or
unacceptable toxicity
Unresectable or metastatic melanoma†
Metastatic non-small cell lung cancer
Squamous cell carcinoma of the head and
neck
Locally advanced or metastatic urothelial
carcinoma
Microsatellite instability-high or mismatch
repair deficient metastatic colorectal cancer†
Hepatocellular carcinoma†
Esophageal squamous cell carcinoma
Adjuvant treatment of melanoma
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Until disease
recurrence or
unacceptable toxicity
for up to 1 year
Adjuvant treatment of urothelial carcinoma
Adjuvant treatment of resected esophageal or
gastroesophageal junction cancer
† Dosing recommendations for both monotherapy or following intravenous nivolumab and ipilimumab combination
therapy.
* Administer over 3-5 minutes.
The recommended dosages of OPDIVO QVANTIG in combination with other therapeutic agents
are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent
administered in combination with OPDIVO QVANTIG for the recommended dosage information,
as appropriate.
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Table 2:
Recommended Dosages for OPDIVO QVANTIG in Combination
with Other Therapeutic Agents
Indication
Recommended OPDIVO QVANTIG
Dosage
Duration of Therapy
Advanced renal cell
carcinoma
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Administer OPDIVO QVANTIG in
combination with cabozantinib 40 mg
orally once daily without food
OPDIVO QVANTIG: Until disease
progression, unacceptable toxicity, or up
to 2 years
Cabozantinib: Until disease progression
or unacceptable toxicity
Neoadjuvant treatment
of resectable non-small
cell lung cancer
900 mg nivolumab and 15,000 units
hyaluronidase* with platinum-doublet
chemotherapy on the same day every 3
weeks
In combination with platinum-doublet
chemotherapy for 3 cycles
Neoadjuvant and
adjuvant treatment of
resectable non-small
cell lung cancer
Neoadjuvant: 900 mg nivolumab and
15,000 units hyaluronidase* with
platinum-doublet chemotherapy on the
same day every 3 weeks
Neoadjuvant: in combination with
platinum-doublet chemotherapy until
disease progression or unacceptable
toxicity, for up to 4 cycles
Adjuvant: 1,200 mg nivolumab and 20,000
units hyaluronidase* every 4 weeks
Adjuvant: following neoadjuvant therapy
and surgery, administer as a single agent
until disease progression, recurrence, or
unacceptable toxicity, for up to 13 cycles
(up to 1 year)
First-line unresectable
or metastatic urothelial
carcinoma
900 mg nivolumab and 15,000 units
hyaluronidase* every 3 weeks
Administer OPDIVO QVANTIG in
combination with cisplatin and
gemcitabine on the same day every 3
weeks
In combination with cisplatin and
gemcitabine for up to 6 cycles
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
After completing up to 6 cycles of
combination therapy, administer as single
agent until disease progression,
unacceptable toxicity, or up to 2 years
from first dose
Esophageal squamous
cell carcinoma
600 mg nivolumab and 10,000 units
hyaluronidase* every 2 weeks
or
1,200 mg nivolumab and 20,000 units
hyaluronidase* every 4 weeks
Administer OPDIVO QVANTIG in
combination with fluoropyrimidine- and
platinum-containing chemotherapy
Until disease progression, unacceptable
toxicity, or up to 2 years
Chemotherapy: Until disease progression
or unacceptable toxicity
Gastric cancer,
gastroesophageal
junction cancer, and
600 mg nivolumab and 10,000 units
hyaluronidase* with fluoropyrimidine- and
OPDIVO QVANTIG: Until disease
progression, unacceptable toxicity, or up
to 2 years
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Table 2:
Recommended Dosages for OPDIVO QVANTIG in Combination
with Other Therapeutic Agents
Indication
Recommended OPDIVO QVANTIG
Dosage
Duration of Therapy
esophageal
adenocarcinoma
platinum-containing chemotherapy every 2
weeks
or
900 mg nivolumab and 15,000 units
hyaluronidase* with fluoropyrimidine- and
platinum-containing chemotherapy every 3
weeks
Chemotherapy: Until disease progression
or unacceptable toxicity
* Administer over 3-5 minutes.
2.3
Dose Modifications
No dose reduction for OPDIVO QVANTIG is recommended. In general, withhold OPDIVO
QVANTIG for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue
OPDIVO QVANTIG for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent
severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment,
or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day
within 12 weeks of initiating steroids.
Dosage modifications for OPDIVO QVANTIG or OPDIVO QVANTIG in combination with other
anti-cancer agents for adverse reactions that require management different from these general
guidelines are summarized in Table 3 and Table 4.
Table 3:
Recommended Dosage Modifications for Adverse Reactions
Adverse Reaction
Severity
Dosage
Modification
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Pneumonitis
Grade 2
Withholda
Grade 3 or 4
Permanently
discontinue
Colitis
For colitis in patients treated with combination
therapy with ipilimumab, see Table 4.
Grade 2 or 3
Withholda
Grade 4
Permanently
discontinue
Hepatitis with no tumor involvement of the liver
For liver enzyme elevations in patients treated
with combination therapy with cabozantinib, see
Table 4.
AST/ALT increases to >3 and ≤8
times ULN
or
Total bilirubin increases to >1.5 and
≤3 times ULN.
Withholda
AST or ALT increases to >8 times
ULN
or
Permanently
discontinue
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Total bilirubin increases to >3 times
ULN.
Hepatitis with tumor involvement of the liverb
Baseline AST/ALT is >1 and ≤3
times ULN and increases to >5 and
≤10 times ULN
or
Baseline AST/ALT is >3 and ≤5
times ULN and increases to >8 and
≤10 times ULN.
Withholda
AST/ALT increases to >10 times
ULN
or
Total bilirubin increases to >3 times
ULN.
Permanently
discontinue
Endocrinopathiesc
Grade 3 or 4
Withhold until
clinically stable or
permanently
discontinue
depending on
severity
Nephritis with Renal Dysfunction
Grade 2 or 3 increased blood
creatinine
Withholda
Grade 4 increased blood creatinine
Permanently
discontinue
Exfoliative Dermatologic Conditions
Suspected SJS, TEN, or DRESS
Withhold
Confirmed SJS, TEN, or DRESS
Permanently
discontinue
Myocarditis
Grades 2, 3, or 4
Permanently
discontinue
Neurological Toxicities
Grade 2
Withholda
Grade 3 or 4
Permanently
discontinue
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently
discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to
10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO
QVANTIG based on recommendations for hepatitis with no liver involvement.
c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with
hormone replacement. Resume once acute symptoms have resolved.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and
Systemic Symptoms, SJS = Stevens-Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of
normal
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Table 4:
Recommended Dosage Modifications for Adverse Reactions in
Patients Treated with Combination Therapy
Treatment
Adverse
Reaction
Severity
Dosage Modification
OPDIVO
QVANTIG in
combination with
cabozantinib
Liver enzyme
elevations
ALT or AST >3 times ULN but ≤10
times ULN with concurrent total
bilirubin <2 times ULN
Withholda both OPDIVO
QVANTIG and cabozantinib until
adverse reactions recoverb to
Grades 0-1
ALT or AST >10 times ULN or >3
times ULN with concurrent total
bilirubin ≥2 times ULN
Permanently discontinuea both
OPDIVO QVANTIG and
cabozantinib
a Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO QVANTIG is withheld or discontinued
when administered in combination with cabozantinib.
b After recovery, rechallenge with one or both of OPDIVO QVANTIG and cabozantinib may be considered. If
rechallenging with cabozantinib with or without OPDIVO QVANTIG, refer to cabozantinib Prescribing
Information.
2.4
Preparation and Administration
To prevent medication errors, check the vial labels to ensure that the drug being prepared and
administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do
NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be
administered by a healthcare professional.
Each OPDIVO QVANTIG vial is for one-time use only. It is a ready-to-use solution for injection.
It should not be diluted.
Visually inspect for particulate matter and discoloration prior to administration. OPDIVO
QVANTIG is a clear to opalescent, colorless to yellow solution. Discard if the solution is
discolored or contains extraneous particulate matter other than a few translucent-to-white particles.
Do not shake.
Preparation
No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and
polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane,
polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets.
A syringe and a transfer needle are needed to withdraw OPDIVO QVANTIG solution from the
vial. OPDIVO QVANTIG may be injected subcutaneously using a 23G-25G (3/8”-5/8”)
hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly).
600 mg nivolumab and 10,000 units hyaluronidase
o Allow 1 OPDIVO QVANTIG vial to reach room temperature, then withdraw 5 mL of
OPDIVO QVANTIG into the syringe.
900 mg nivolumab and 15,000 units hyaluronidase
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o Allow 2 OPDIVO QVANTIG vials to reach room temperature, then withdraw 5 mL
from one vial and 2.5 mL from the other vial, for a total volume of 7.5 mL of OPDIVO
QVANTIG into a single syringe.
1,200 mg nivolumab and 20,000 units hyaluronidase
o Allow 2 OPDIVO QVANTIG vials to reach room temperature, then withdraw 10 mL
of OPDIVO QVANTIG into a single syringe.
Select the appropriate syringe label provided in the carton that matches the prescribed dose and
apply to the prepared syringe.
Discard partially used or empty vials of OPDIVO QVANTIG.
If the dose is not to be used immediately, attach a tip cap to the syringe prior to storage. To avoid
clogging of the hypodermic injection needle, attach a 23G-25G (3/8”-5/8”) hypodermic injection
needle to the syringe immediately prior to administration.
Storage in Syringe
Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used
immediately, store the syringe:
In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 48 hours; do
not freeze, or
At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room
temperature for this duration does not require protection from light.
Discard if storage time exceeds these limits.
If stored in the refrigerator, allow the solution to come to room temperature before
administration.
Administration
Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4
quadrants of the abdomen, or thigh over a period of 3 to 5 minutes.
Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive
injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where
there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted,
continue administering at the same site, or at an alternate site.
During treatment with OPDIVO QVANTIG, do not administer other subcutaneous
medications at the same site used for OPDIVO QVANTIG.
3
DOSAGE FORMS AND STRENGTHS
Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per
mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial.
4
CONTRAINDICATIONS
None.
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5
WARNINGS AND PRECAUTIONS
5.1
Severe and Fatal Immune-Mediated Adverse Reactions
OPDIVO QVANTIG is a combination of a monoclonal antibody that belongs to a class of drugs
that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking
the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially
breaking peripheral tolerance, and inducing immune-mediated adverse reactions, and an
endoglycosidase used to increase the dispersion and absorption of co-administered drugs when
administered subcutaneously. Important immune-mediated adverse reactions listed under
Warnings and Precautions may not include all possible severe and fatal immune-mediated
reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system
or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a
PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest
during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can
also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management of immune-mediated adverse reactions are essential to ensure
safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that
may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver
enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases
of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude
alternative etiologies, including infection. Institute medical management promptly, including
specialty consultation as appropriate.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage
and Administration (2.3)]. In general, if OPDIVO QVANTIG requires interruption or
discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or
equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate
corticosteroid taper and continue to taper over at least 1 month. Consider administration of other
systemic immunosuppressants in patients whose immune-mediated adverse reactions are not
controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic
steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
OPDIVO QVANTIG can cause immune-mediated pneumonitis, which is defined as requiring use
of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking
antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic
radiation.
Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO
QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions. Pneumonitis led to
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permanent discontinuation of OPDIVO QVANTIG in 1.6% and withholding of OPDIVO
QVANTIG in 1.6% of patients.
Systemic corticosteroids were required in 100% (7/7) of patients with pneumonitis. Pneumonitis
resolved in 27% of the 7 patients. Of the 4 patients in whom OPDIVO QVANTIG was withheld
for pneumonitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%)
had recurrence of pneumonitis.
Immune-Mediated Colitis
OPDIVO QVANTIG can cause immune-mediated colitis, defined as requiring use of
corticosteroids and no clear alternate etiology. A common symptom included in the definition of
colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients
with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory
colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG,
including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions. Colitis led to withholding of
OPDIVO QVANTIG in 2.0% of patients.
Systemic corticosteroids were required in 100% (7/7) of patients with colitis. Colitis resolved in
71% of the 7 patients. Of the 5 patients in whom OPDIVO QVANTIG was withheld for colitis, 3
reinitiated OPDIVO QVANTIG after symptom improvement; of these, 2 (67%) had recurrence of
colitis.
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO QVANTIG can cause immune-mediated hepatitis, defined as requiring the use of
corticosteroids and no clear alternate etiology.
Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG,
including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions. Hepatitis led to permanent
discontinuation of OPDIVO QVANTIG in 0.8% and withholding of OPDIVO QVANTIG in 1.6%
of patients.
Systemic corticosteroids were required in 100% (6/6) of patients with hepatitis. Hepatitis resolved
in 67% of the 6 patients. Of the 2 patients in whom OPDIVO QVANTIG was withheld for
hepatitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%) had
recurrence of hepatitis.
Intravenous Nivolumab with Cabozantinib
Nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies
of Grade 3 and 4 ALT and AST elevations compared to nivolumab alone. Monitor liver enzymes
before initiation of and periodically throughout treatment. Consider more frequent monitoring of
liver enzymes as compared to when the drugs are administered as single agents. For elevated liver
enzymes, interrupt nivolumab and cabozantinib and consider administering corticosteroids [see
Dosage and Administration (2.3)].
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With the combination of intravenous nivolumab and cabozantinib, Grades 3 and 4 increased ALT
or AST were seen in 11% (35/320) of patients. ALT or AST >3 times ULN (Grade ≥2) was
reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST
resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST
who were rechallenged with either intravenous nivolumab (n=11) or cabozantinib (n=9)
administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST
was observed in 2 patients receiving intravenous nivolumab, 2 patients receiving cabozantinib,
and 7 patients receiving both intravenous nivolumab and cabozantinib.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically
indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration
(2.3)].
Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG,
including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions. Adrenal insufficiency led to
permanent discontinuation of OPDIVO QVANTIG in 0.4% of patients and withholding of
OPDIVO QVANTIG in 0.4% of patients.
Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency.
Adrenal insufficiency resolved in 20% of the 5 patients.
Intravenous Nivolumab with Cabozantinib
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous
nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions.
Adrenal insufficiency led to permanent discontinuation of intravenous nivolumab and
cabozantinib in 0.9% and withholding of intravenous nivolumab and cabozantinib in 2.8% of
patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement
therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15
patients. Of the 9 patients in whom intravenous nivolumab with cabozantinib was withheld for
adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6)
received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Hypophysitis
OPDIVO QVANTIG can cause immune-mediated hypophysitis. Hypophysitis can present with
acute symptoms associated with mass effect such as headache, photophobia, or visual field defects.
Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage
and Administration (2.3)].
Intravenous Nivolumab
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Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous
nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Hypophysitis led to permanent
discontinuation of intravenous nivolumab in 0.2% of patients. Approximately 67% (8/12) of
patients with hypophysitis received hormone replacement therapy, including systemic
corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom
intravenous nivolumab was withheld for hypophysitis, 2 reinitiated intravenous nivolumab after
symptom improvement; of these, none had recurrence of hypophysitis.
Thyroid Disorders
OPDIVO QVANTIG can cause immune-mediated thyroid disorders. Thyroiditis can present with
or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone
replacement or medical management as clinically indicated. Withhold or permanently discontinue
OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.3)].
Thyroiditis
Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade
1 (0.4%) adverse reaction.
Systemic corticosteroids were not required in the patient with thyroiditis. Thyroiditis did not
resolve in this patient.
Hyperthyroidism
Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including
Grade 2 (0.4%) adverse reactions.
Systemic corticosteroids were not required in patients with hyperthyroidism. Hyperthyroidism
resolved in 50% of the 2 patients.
Hypothyroidism
Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including
Grade 2 (5.7%) adverse reactions. Hypothyroidism led to withholding of OPDIVO QVANTIG in
0.8% of patients.
Systemic corticosteroids were not required in patients with hypothyroidism. Hypothyroidism
resolved in 4.3% of the 23 patients. Of the 1 patient in whom OPDIVO QVANTIG was withheld
for hypothyroidism, OPDIVO QVANTIG was not reinitiated after symptom improvement.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment
with insulin as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see
Dosage and Administration (2.3)].
Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG.
No patients with diabetes required systemic corticosteroids. Diabetes did not resolve in this patient.
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Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO QVANTIG can cause immune-mediated nephritis, which is defined as requiring use of
steroids and no clear alternate etiology.
Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients
receiving OPDIVO QVANTIG. Immune-mediated nephritis and renal dysfunction led to
withholding of OPDIVO QVANTIG in 1.2% of patients.
Systemic corticosteroids were required in 100% (3/3) of patients with nephritis and renal
dysfunction. Nephritis and renal dysfunction resolved in 100% of the 3 patients. Of the 3 patients
in whom OPDIVO QVANTIG was withheld for nephritis or renal dysfunction, 1 reinitiated
OPDIVO QVANTIG after symptom improvement without recurrence of nephritis or renal
dysfunction.
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO QVANTIG can cause immune-mediated rash or dermatitis, defined as requiring the use
of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson
Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and
Systemic Symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients
and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.
Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage
and Administration (2.3)].
Immune-mediated rash occurred in 7% (17/247) of patients, including Grade 3 (0.8%) and Grade
2 (2.8%) adverse reactions. Immune-mediated rash led to withholding of OPDIVO QVANTIG in
1.2% of patients.
Systemic corticosteroids were required in 47% (8/17) of patients with immune-mediated rash.
Rash resolved in 77% of the 17 patients. Of the 3 patients in whom OPDIVO QVANTIG was
withheld for immune-mediated rash, all reinitiated OPDIVO QVANTIG after symptom
improvement; of these, all (100%) had recurrence of immune-mediated rash.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence
of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous
nivolumab as a single agent or in combination with chemotherapy or immunotherapy, or were
reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been
reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
Nervous
System:
Meningitis,
encephalitis,
myelitis
and
demyelination,
myasthenic
syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis,
autoimmune neuropathy
Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be
associated with retinal detachment. Various grades of visual impairment, including blindness, can
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occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to
reduce the risk of permanent vision loss
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis,
duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated
sequelae including renal failure, arthritis, polymyalgia rheumatic
Endocrine: Hypoparathyroidism
Other
(Hematologic/Immune):
Hemolytic
anemia,
aplastic
anemia,
hemophagocytic
lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing
lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid
organ transplant rejection, other transplant (including corneal graft) rejection.
5.2
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic
stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking
antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD),
acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity
conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see
Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between
PD-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly.
Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or
after an allogeneic HSCT.
5.3
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause
fetal harm when administered to a pregnant woman. In animal reproduction studies, administration
of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted
in increased abortion and premature infant death. Advise pregnant women of the potential risk to
a fetus. Advise females of reproductive potential to use effective contraception during treatment
with OPDIVO QVANTIG and for 5 months after the last dose [see Use in Specific Populations
(8.1, 8.3)].
5.4
Increased Mortality in Patients with Multiple Myeloma when Nivolumab
Is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking
antibody, including intravenous nivolumab, to a thalidomide analogue plus dexamethasone, a use
for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality.
Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in
combination with a thalidomide analogue plus dexamethasone is not recommended outside of
controlled clinical trials.
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6
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling.
Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions
(5.1)]
Complications of Allogeneic HSCT [see Warnings and Precautions (5.2)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as a
single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous
nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with
cabozantinib (320 patients) for select adverse reactions.
Advanced Renal Cell Carcinoma
CHECKMATE-67T was a multicenter, randomized, open-label study in adult patients with
advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of
nivolumab and 20,000 units of hyaluronidase subcutaneously every 4 weeks (n=247) or 3 mg/kg
of nivolumab intravenously every 2 weeks (n=245). Among patients who received OPDIVO
QVANTIG, 52% were exposed for 6 months or longer and 20% were exposed for greater than 1
year.
Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious
adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%),
hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal
adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included
myocarditis, myositis, and colitis complications.
Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of
patients. The most common adverse reaction which resulted in permanent discontinuation was
pneumonitis (2%).
Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of
patients. Adverse reactions which required dosage interruption in >2% of patients included
COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each).
The most common adverse reactions (≥10%) were musculoskeletal pain, fatigue, pruritus, rash,
hypothyroidism, diarrhea, cough, and abdominal pain.
Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE 67T.
19
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Table 5:
Adverse Reactions* in ≥5% of Adult Patients with RCC Receiving
OPDIVO QVANTIG in CHECKMATE 67T
Adverse Reaction
OPDIVO QVANTIG
(n=247)
Intravenous Nivolumab
(n=245)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
Fatiguea
20
2.4
25
3.3
Injection site reactiona
8
0
0
0
Edema
5
0.4
11
0.8
Musculoskeletal and Connective Tissue
Musculoskeletal paina
31
1.6
39
3.3
Skin and Subcutaneous Tissue
Pruritus
16
0.4
21
0
Rasha
15
1.2
13
1.2
Gastrointestinal
Diarrheaa
11
0.4
14
0.4
Abdominal paina
10
0
10
0.4
Nausea
8
0
9
0
Constipation
8
0
6
0
Vomiting
6
0.4
4.9
0
Respiratory, Thoracic, and Mediastinal
Cough
11
0
11
0
Endocrine
Hypothyroidisma
12
0
17
0
Metabolism and Nutrition
Hyperglycemia
9
2.4
13
2.0
Decreased appetite
9
0
11
0.8
* Toxicity was graded per NCI CTCAE v5.
a Includes multiple related terms
Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG
include:
Cardiac: myocarditis
Respiratory, thoracic, and mediastinal: pneumonitis, dyspnea
Endocrine: adrenal insufficiency, hyperthyroidism, thyroiditis
20
Reference ID: 5503239
Gastrointestinal: colitis, pancreatitis
Hepatobiliary: hepatitis
Nervous system: peripheral neuropathy
Skin and subcutaneous tissue: psoriasis, erythema
Musculoskeletal and connective tissue: arthritis
Blood and lymphatic system: eosinophilia
Eye disorders: uveitis
Immune system: hypersensitivity
Table 6:
Laboratory Values Worsening from Baselinea (≥20%) in Patients
with RCC Receiving OPDIVO QVANTIG in CHECKMATE 67T
Laboratory Abnormality
OPDIVO QVANTIG
Intravenous Nivolumab
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Hematology
Hemoglobin decreased
46
7
48
9
Lymphocytes decreased
36
6
45
9
Chemistry
Creatinine increased
38
1.3
43
0.4
Sodium decreased
34
2.6
40
2.5
Potassium increased
34
3.0
45
2.9
Alkaline phosphatase increased
32
2.1
33
2.0
Calcium increased
29
2.1
31
4.1
Albumin decreased
25
1.7
35
0.4
ALT increased
21
1.3
26
4.1
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: OPDIVO QVANTIG group (range: 232 to 235 patients) and intravenous nivolumab group
(range: 240 to 244 patients).
Adverse Reactions in Patients Treated with Intravenous Nivolumab
The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1)]
has been established in adequate and well-controlled clinical studies of intravenous nivolumab.
Below is a description of adverse reactions in these adequate and well-controlled clinical studies.
First-line Renal Cell Carcinoma
CHECKMATE-214
21
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The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, a
randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients
received intravenous nivolumab 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously
every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3
mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first
4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.1)]. The median duration of treatment
was 7.9 months (range: 1 day to 21.4+ months) in intravenous nivolumab and ipilimumab-treated
patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial,
57% of patients in the intravenous nivolumab and ipilimumab arm were exposed to treatment for
>6 months and 38% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and
ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous
nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous
nivolumab and ipilimumab had a dose interruption for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous
nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute
kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they
were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in
≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough,
pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which
have worsened compared to baseline in ≥30% of intravenous nivolumab and ipilimumab-treated
patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST,
hyponatremia, increased amylase, and lymphopenia.
Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, that
occurred in >15% of intravenous nivolumab and ipilimumab-treated patients in CHECKMATE
214.
Table 7:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Ipilimumab - CHECKMATE-214
Adverse Reaction
Intravenous Nivolumab and
Ipilimumab
(n=547)
Sunitinib
(n=535)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Adverse Reaction
99
65
99
76
General
Fatiguea
58
8
69
13
Pyrexia
25
0.7
17
0.6
Edemab
16
0.5
17
0.6
Skin and Subcutaneous Tissue
22
Reference ID: 5503239
Table 7:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Ipilimumab - CHECKMATE-214
Adverse Reaction
Intravenous Nivolumab and
Ipilimumab
(n=547)
Sunitinib
(n=535)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Rashc
39
3.7
25
1.1
Pruritus/generalized
pruritus
33
0.5
11
0
Gastrointestinal
Diarrhea
38
4.6
58
6
Nausea
30
2
43
1.5
Vomiting
20
0.9
28
2.1
Abdominal pain
19
1.6
24
1.9
Constipation
17
0.4
18
0
Musculoskeletal and Connective Tissue
Musculoskeletal paind
37
4
40
2.6
Arthralgia
23
1.3
16
0
Respiratory, Thoracic and Mediastinal
Cough/productive cough
28
0.2
25
0.4
Dyspnea/exertional
dyspnea
20
2.4
21
2.1
Metabolism and Nutrition
Decreased appetite
21
1.8
29
0.9
Nervous System
Headache
19
0.9
23
0.9
Endocrine
Hypothyroidism
18
0.4
27
0.2
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative,
erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, spinal pain.
23
Reference ID: 5503239
Table 8:
Laboratory Values Worsening from Baselinea Occurring in >15%
of Patients on Intravenous Nivolumab and Ipilimumab -
CHECKMATE-214
Laboratory Abnormality
Intravenous Nivolumab and
Ipilimumab
Sunitinib
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Chemistry
Increased lipase
48
20
51
20
Increased creatinine
42
2.1
46
1.7
Increased ALT
41
7
44
2.7
Increased AST
40
4.8
60
2.1
Increased amylase
39
12
33
7
Hyponatremia
39
10
36
7
Increased alkaline phosphatase
29
2
32
1
Hyperkalemia
29
2.4
28
2.9
Hypocalcemia
21
0.4
35
0.6
Hypomagnesemia
16
0.4
26
1.6
Hematology
Anemia
43
3
64
9
Lymphopenia
36
5
63
14
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and ipilimumab group (range: 490 to 538 patients) and sunitinib
group (range: 485 to 523 patients).
In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients
experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab and
ipilimumab group compared to the sunitinib group (31% and 61%, respectively).
CHECKMATE-9ER
The safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, a
randomized, open-label study in patients with previously untreated advanced RCC. Patients
received intravenous nivolumab 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg
orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment
followed by 2 weeks off (n=320) [see Clinical Studies (14.1)]. Cabozantinib could be interrupted
or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was
14 months (range: 0.2 to 27 months) in intravenous nivolumab and cabozantinib-treated patients.
In this trial, 82% of patients in the intravenous nivolumab and cabozantinib arm were exposed to
treatment for >6 months and 60% of patients were exposed to treatment for >1 year.
Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and
cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia,
24
Reference ID: 5503239
pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal
perforations occurred in 3 (0.9%) patients.
Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib
occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both
drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption
or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3%
intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse
reaction at the same time, and 6% both drugs sequentially.
The most common adverse reactions reported in ≥20% of patients treated with intravenous
nivolumab
and
cabozantinib
were
diarrhea,
fatigue,
hepatotoxicity,
palmar-plantar
erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal
pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract
infection.
Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-9ER.
Table 9:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Cabozantinib - CHECKMATE-9ER
Adverse Reaction
Intravenous Nivolumab and
Cabozantinib
(n=320)
Sunitinib
(n=320)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Gastrointestinal
Diarrhea
64
7
47
4.4
Nausea
27
0.6
31
0.3
Abdominal paina
22
1.9
15
0.3
Vomiting
17
1.9
21
0.3
Dyspepsiab
15
0
22
0.3
General
Fatiguec
51
8
50
8
Hepatobiliary
Hepatotoxicityd
44
11
26
5
Skin and Subcutaneous Tissue
Palmar-plantar
erythrodysesthesia
syndrome
40
8
41
8
Stomatitise
37
3.4
46
4.4
Rashf
36
3.1
14
0
25
Reference ID: 5503239
Table 9:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab and Cabozantinib - CHECKMATE-9ER
Adverse Reaction
Intravenous Nivolumab and
Cabozantinib
(n=320)
Sunitinib
(n=320)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Pruritus
19
0.3
4.4
0
Vascular
Hypertensiong
36
13
39
14
Endocrine
Hypothyroidismh
34
0.3
30
0.3
Musculoskeletal and Connective Tissue
Musculoskeletal paini
33
3.8
29
3.1
Arthralgia
18
0.3
9
0.3
Metabolism and Nutrition
Decreased appetite
28
1.9
20
1.3
Nervous System
Dysgeusia
24
0
22
0
Headache
16
0
12
0.6
Respiratory, Thoracic and Mediastinal
Coughj
20
0.3
17
0
Dysphonia
17
0.3
3.4
0
Infections and Infestations
Upper respiratory tract
infectionk
20
0.3
8
0.3
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.
b Includes gastroesophageal reflux disease.
c Includes asthenia.
d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl
transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme
increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases
increased, hepatic failure.
e Includes mucosal inflammation, aphthous ulcer, mouth ulceration.
f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular,
rash macular, rash maculo-papular, rash papular, rash pruritic.
g Includes blood pressure increased, blood pressure systolic increased.
h Includes primary hypothyroidism.
i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, spinal pain.
26
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j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, rhinitis.
Table 10:
Laboratory Values Worsening from Baselinea Occurring in >20%
of Patients on Intravenous Nivolumab and Cabozantinib -
CHECKMATE-9ER
Laboratory Abnormality
Intravenous Nivolumab and
Cabozantinib
Sunitinib
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Chemistry
Increased ALT
79
9.8
39
3.5
Increased AST
77
7.9
57
2.6
Hypophosphatemia
69
28
48
10
Hypocalcemia
54
1.9
24
0.6
Hypomagnesemia
47
1.3
25
0.3
Hyperglycemia
44
3.5
44
1.7
Hyponatremia
43
11
36
12
Increased lipase
41
14
38
13
Increased amylase
41
10
28
6
Increased alkaline phosphatase
41
2.8
37
1.6
Increased creatinine
39
1.3
42
0.6
Hyperkalemia
35
4.7
27
1
Hypoglycemia
26
0.8
14
0.4
Hematology
Lymphopenia
42
6.6
45
10
Thrombocytopenia
41
0.3
70
9.7
Anemia
37
2.5
61
4.8
Leukopenia
37
0.3
66
5.1
Neutropenia
35
3.2
67
12
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and cabozantinib group (range: 170 to 317 patients) and sunitinib
group (range: 173 to 311 patients).
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
The safety of intravenous nivolumab was evaluated in CHECKMATE-025, a randomized open-
label trial in 803 patients with advanced RCC who had experienced disease progression during or
after at least one anti-angiogenic treatment regimen received intravenous nivolumab 3 mg/kg over
60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397)
27
Reference ID: 5503239
[see Clinical Studies (14.1)]. The median duration of treatment was 5.5 months (range: 1 day to
29.6+ months) in intravenous nivolumab-treated patients and 3.7 months (range: 6 days to 25.7+
months) in everolimus-treated patients.
Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous
nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous
nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab
patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had a dose
interruption for an adverse reaction.
The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury,
pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions
(≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite,
back pain, and arthralgia. The most common laboratory abnormalities which have worsened
compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia,
increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and
hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of
patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab
group compared to the everolimus group (26% and 14%, respectively).
Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-025.
Table 11:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab - CHECKMATE-025
Adverse Reaction
Intravenous Nivolumab
(n=406)
Everolimus
(n=397)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Adverse Reaction
98
56
96
62
General
Fatiguea
56
6
57
7
Pyrexia
17
0.7
20
0.8
Respiratory, Thoracic and Mediastinal
Cough/productive cough
34
0
38
0.5
Dyspnea/exertional dyspnea
27
3
31
2
Upper respiratory infectionb
18
0
11
0
Gastrointestinal
Nausea
28
0.5
29
1
Diarrheac
25
2.2
32
1.8
Constipation
23
0.5
18
0.5
28
Reference ID: 5503239
Table 11:
Adverse Reactions in >15% of Patients Receiving Intravenous
Nivolumab - CHECKMATE-025
Adverse Reaction
Intravenous Nivolumab
(n=406)
Everolimus
(n=397)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Vomiting
16
0.5
16
0.5
Skin and Subcutaneous Tissue
Rashd
28
1.5
36
1
Pruritus/generalized pruritus
19
0
14
0
Metabolism and Nutrition
Decreased appetite
23
1.2
30
1.5
Musculoskeletal and Connective Tissue
Arthralgia
20
1
14
0.5
Back pain
21
3.4
16
2.8
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).
c Includes colitis, enterocolitis, and gastroenteritis.
d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash,
papular rash, pruritic rash, erythema multiforme, and erythema.
Other clinically important adverse reactions in CHECKMATE-025 were:
General Disorders and Administration Site Conditions: peripheral edema/edema
Gastrointestinal Disorders: abdominal pain/discomfort
Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain
Nervous System Disorders: headache/migraine, peripheral neuropathy
Investigations: weight decreased
Skin Disorders: palmar-plantar erythrodysesthesia
Table 12:
Laboratory Values Worsening from Baselinea Occurring in >15%
of Patients on Intravenous Nivolumab - CHECKMATE-025
Laboratory Abnormality
Intravenous Nivolumab
Everolimus
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Hematology
Lymphopenia
42
6
53
11
Anemia
39
8
69
16
29
Reference ID: 5503239
Table 12:
Laboratory Values Worsening from Baselinea Occurring in >15%
of Patients on Intravenous Nivolumab - CHECKMATE-025
Laboratory Abnormality
Intravenous Nivolumab
Everolimus
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Chemistry
Increased creatinine
42
2
45
1.6
Increased AST
33
2.8
39
1.6
Increased alkaline
phosphatase
32
2.3
32
0.8
Hyponatremia
32
7
26
6
Hyperkalemia
30
4
20
2.1
Hypocalcemia
23
0.9
26
1.3
Increased ALT
22
3.2
31
0.8
Hypercalcemia
19
3.2
6
0.3
Lipids
Increased triglycerides
32
1.5
67
11
Increased cholesterol
21
0.3
55
1.4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 259 to 401 patients) and everolimus group (range:
257 to 376 patients).
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
CHECKMATE-037
The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-
label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2)].
Patients had documented disease progression following treatment with ipilimumab and, if BRAF
V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease,
prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3
ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within
12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment
with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive
medications, a positive test for hepatitis B or C, and a history of HIV. Patients received intravenous
nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or
investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3
weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks.
The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in intravenous
nivolumab-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy
30
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treated patients. In this ongoing trial, 24% of patients received intravenous nivolumab for >6
months and 3% of patients received intravenous nivolumab for >1 year.
The population characteristics in the intravenous nivolumab group and the chemotherapy group
were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative
Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease,
73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior
therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more
patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at
baseline (51% vs. 38%).
Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab.
Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six
percent of patients receiving intravenous nivolumab had a dose interruption for an adverse
reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous
nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients
receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate
aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of
patients) was rash.
Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-037.
Table 13:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients and at a Higher Incidence than in the
Chemotherapy Arm (Between Arm Difference of ≥5% All Grades
or ≥2% Grades 3-4) - CHECKMATE-037
Adverse Reaction
Intravenous Nivolumab
(n=268)
Chemotherapy
(n=102)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Skin and Subcutaneous Tissue
Rasha
21
0.4
7
0
Pruritus
19
0
3.9
0
Respiratory, Thoracic and Mediastinal
Cough
17
0
6
0
Infections
Upper respiratory tract infectionb
11
0
2
0
General
Peripheral edema
10
0
5
0
Toxicity was graded per NCI CTCAE v4.
a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular
rash, vesicular rash, and acneiform dermatitis.
31
Reference ID: 5503239
b Includes rhinitis, pharyngitis, and nasopharyngitis.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab
were:
Cardiac Disorders: ventricular arrhythmia
Eye Disorders: iridocyclitis
General Disorders and Administration Site Conditions: infusion-related reactions
Investigations: increased amylase, increased lipase
Nervous System Disorders: dizziness, peripheral and sensory neuropathy
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo,
psoriasis
Table 14:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients and at a Higher
Incidence than in the Chemotherapy Arm (Between Arm Difference
of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037
Laboratory Abnormality
Intravenous Nivolumab
Chemotherapy
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Increased AST
28
2.4
12
1
Hyponatremia
25
5
18
1.1
Increased alkaline phosphatase
22
2.4
13
1.1
Increased ALT
16
1.6
5
0
Hyperkalemia
15
2
6
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 252 to 256 patients) and chemotherapy group (range:
94 to 96 patients).
Previously Untreated Metastatic Melanoma
CHECKMATE-066
The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, a randomized,
double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-
type unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial excluded patients
with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids
(>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received
intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206)
or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of
exposure was 6.5 months (range: 1 day to 16.6 months) in intravenous nivolumab-treated patients.
In this trial, 47% of patients received intravenous nivolumab for >6 months and 12% of patients
received intravenous nivolumab for >1 year.
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The trial population characteristics in the intravenous nivolumab group and dacarbazine group:
59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous
melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH
at baseline. There were more patients in the intravenous nivolumab group with ECOG performance
status 0 (71% vs. 59%).
Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse
reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose
interruption in 26% of patients; no single type of adverse reaction accounted for the majority of
intravenous nivolumab discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of
patients receiving intravenous nivolumab.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving
intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%).
The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than
in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.
Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively,
in CHECKMATE-066.
Table 15:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients and at a Higher Incidence than in the Dacarbazine
Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades
3-4) - CHECKMATE-066
Adverse Reaction
Intravenous Nivolumab
(n=206)
Dacarbazine
(n=205)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
General
Fatigue
49
1.9
39
3.4
Edemaa
12
1.5
4.9
0
Musculoskeletal and Connective Tissue
Musculoskeletal painb
32
2.9
25
2.4
Skin and Subcutaneous Tissue
Rashc
28
1.5
12
0
Pruritus
23
0.5
12
0
Vitiligo
11
0
0.5
0
Erythema
10
0
2.9
0
Infections
Upper respiratory tract infectiond
17
0
6
0
Toxicity was graded per NCI CTCAE v4.
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a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral
edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular
rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and
skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab
were:
Nervous System Disorders: peripheral neuropathy
Table 16:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients and at a Higher
Incidence than in the Dacarbazine Arm (Between Arm Difference
of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066
Laboratory Abnormality
Intravenous Nivolumab
Dacarbazine
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Increased ALT
25
3
19
0.5
Increased AST
24
3.6
19
0.5
Increased alkaline phosphatase
21
2.6
14
1.6
Increased bilirubin
13
3.1
6
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 194 to 197 patients) and dacarbazine group (range:
186 to 193 patients).
CHECKMATE-067
The safety of intravenous nivolumab, administered with ipilimumab or as a single agent, was
evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with
previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.2)]. The trial
excluded patients with autoimmune disease, a medical condition requiring systemic treatment with
corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive
medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C,
or a history of HIV.
Patients were randomized to receive:
Intravenous nivolumab 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous
infusion every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at
a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (nivolumab and
ipilimumab arm; n=313), or
Intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks
(nivolumab arm; n=313), or
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Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab
arm; n=311).
The median duration of exposure to intravenous nivolumab was 2.8 months (range: 1 day to 36.4
months) for the intravenous nivolumab and ipilimumab arm and 6.6 months (range: 1 day to 36.0
months) for the intravenous nivolumab arm. In the intravenous nivolumab and ipilimumab arm,
39% were exposed to intravenous nivolumab for ≥6 months and 30% exposed for >1 year. In the
intravenous nivolumab arm, 53% were exposed for ≥6 months and 40% for >1 year.
The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG
performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC)
Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a
history of brain metastasis, and 22% had received adjuvant therapy.
Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation
(47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and
51%) all occurred more frequently in the intravenous nivolumab and ipilimumab arm relative to
the intravenous nivolumab arm.
The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab and ipilimumab
arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10%
and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to
discontinuation of both drugs in the intravenous nivolumab and ipilimumab arm and of intravenous
nivolumab in the intravenous nivolumab arm, respectively, were colitis (10% and 0.6%), diarrhea
(8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis
(1.9% and 0.3%).
The most common (≥20%) adverse reactions in the intravenous nivolumab and ipilimumab arm
were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased
appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased
transaminases. The most common (≥20%) adverse reactions in the intravenous nivolumab arm
were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract
infection, decreased appetite, headache, constipation, arthralgia, and vomiting.
Tables 17 and 18 summarize the incidence of adverse reactions and laboratory abnormalities,
respectively, in CHECKMATE-067.
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Table 17:
Adverse Reactions Occurring in ≥10% of Patients on the
Intravenous Nivolumab and Ipilimumab Arm or the Intravenous
Nivolumab Arm and at a Higher Incidence than in the Ipilimumab
Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades
3-4) - CHECKMATE-067
Adverse Reaction
Intravenous Nivolumab
and
Ipilimumab
(n=313)
Intravenous Nivolumab
(n=313)
Ipilimumab
(n=311)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
General
Fatiguea
62
7
59
1.6
51
4.2
Pyrexia
40
1.6
16
0
18
0.6
Gastrointestinal
Diarrhea
54
11
36
5
47
7
Nausea
44
3.8
30
0.6
31
1.9
Vomiting
31
3.8
20
1
17
1.6
Skin and Subcutaneous Tissue
Rashb
53
6
40
1.9
42
3.5
Vitiligo
9
0
10
0.3
5
0
Musculoskeletal and Connective Tissue
Musculoskeletal
painc
32
2.6
42
3.8
36
1.9
Arthralgia
21
0.3
21
1
16
0.3
Metabolism and Nutrition
Decreased appetite
29
1.9
22
0
24
1.3
Respiratory, Thoracic and Mediastinal
Cough/productive
cough
27
0.3
28
0.6
22
0
Dyspnea/exertional
dyspnea
24
2.9
18
1.3
17
0.6
Infections
Upper respiratory
tract infectiond
23
0
22
0.3
17
0
Endocrine
Hypothyroidism
19
0.6
11
0
5
0
Hyperthyroidism
11
1.3
6
0
1
0
36
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Table 17:
Adverse Reactions Occurring in ≥10% of Patients on the
Intravenous Nivolumab and Ipilimumab Arm or the Intravenous
Nivolumab Arm and at a Higher Incidence than in the Ipilimumab
Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades
3-4) - CHECKMATE-067
Adverse Reaction
Intravenous Nivolumab
and
Ipilimumab
(n=313)
Intravenous Nivolumab
(n=313)
Ipilimumab
(n=311)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
All Grades
(%)
Grades
3-4 (%)
Investigations
Decreased weight
12
0
7
0
7
0.3
Vascular
Hypertensione
7
2.2
11
5
9
2.3
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis,
exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash,
macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.
Clinically important adverse reactions in <10% of patients who received intravenous nivolumab
with ipilimumab or intravenous nivolumab as a single agent were:
Gastrointestinal Disorders: stomatitis, intestinal perforation
Skin and Subcutaneous Tissue Disorders: vitiligo
Musculoskeletal and Connective Tissue Disorders:
myopathy,
Sjogren’s
syndrome,
spondyloarthropathy, myositis (including polymyositis)
Nervous System Disorders: neuritis, peroneal nerve palsy
37
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Table 18:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥20% of Patients Treated with Intravenous Nivolumab with
Ipilimumab or Single-Agent Intravenous Nivolumab and at a
Higher Incidence than in the Ipilimumab Arm (Between Arm
Difference of ≥5% All Grades or ≥2% Grades 3-4) -
CHECKMATE-067
Laboratory Abnormality
Intravenous Nivolumab
and
Ipilimumab
Intravenous Nivolumab
Ipilimumab
All
Grades
(%)
Grade
3-4 (%)
All
Grades
(%)
Grade
3-4 (%)
All
Grades
(%)
Grade
3-4 (%)
Chemistry
Increased ALT
55
16
25
3
29
2.7
Hyperglycemia
53
5.3
46
7
26
0
Increased AST
52
13
29
3.7
29
1.7
Hyponatremia
45
10
22
3.3
26
7
Increased lipase
43
22
32
12
24
7
Increased alkaline
phosphatase
41
6
27
2
23
2
Hypocalcemia
31
1.1
15
0.7
20
0.7
Increased amylase
27
10
19
2.7
15
1.6
Increased creatinine
26
2.7
19
0.7
17
1.3
Hematology
Anemia
52
2.7
41
2.6
41
6
Lymphopenia
39
5
41
4.9
29
4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and ipilimumab (range: 75 to 297); intravenous nivolumab (range:
81 to 306); ipilimumab (range: 61 to 301).
Adjuvant Treatment of Melanoma
CHECKMATE-76K
The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-76K, a
randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C
melanoma who received intravenous nivolumab 480 mg by intravenous infusion over 30 minutes
every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264)
for up to 1 year [see Clinical Studies (14.3)]. The median duration of exposure was 11 months in
patients treated with intravenous nivolumab and 11 months in patients treated with placebo.
Serious adverse reactions occurred in 18% of patients treated with intravenous nivolumab. A fatal
adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent
38
Reference ID: 5503239
discontinuation of intravenous nivolumab due to an adverse reaction occurred in 17% of patients.
Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1%
of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%).
Dosage interruptions of intravenous nivolumab due to an adverse reaction occurred in 25% of
patients. Adverse reactions which required dosage interruption in >1% of patients included
COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT.
The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal
pain, rash, diarrhea, and pruritus.
Tables 19 and 20 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-76K.
Table 19:
Adverse Reactions Occurring in ≥10% of Patients Treated with
Intravenous Nivolumab - CHECKMATE-76K
Adverse Reaction
Intravenous Nivolumab
(n=524)
Placebo
(n=264)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
General
Fatiguea
36
0.4
34
0.4
Musculoskeletal and connective tissue
Musculoskeletal painb
30
0.4
26
0.4
Skin and Subcutaneous Tissue
Rashc
28
1.1
15
0.4
Pruritus
20
0.2
11
0
Gastrointestinal
Diarrhead
23
1.3
16
0
Nausea
14
0
11
0
Endocrine
Hypothyroidisme
14
0
2.3
0
Nervous system
Headachef
12
0.2
14
0.8
Toxicity was graded per NCI CTCAE v5.
a Includes asthenia.
b Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity.
c Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash,
pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash
pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption.
d Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitis
e Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased.
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Reference ID: 5503239
f Includes cluster headache, migraine.
Table 20:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients -
CHECKMATE-76K
Laboratory Abnormality
Intravenous Nivolumab
(n=524)
Placebo
(n=264)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Hematology
Anemia
19
0
14
0
Lymphopenia
17
1.1
17
1.7
Neutropenia
10
0
10
0.4
Chemistry
AST increased
25
2.2
16
0.4
Lipase increased
22
2.9
21
2.3
ALT increased
20
2.1
15
0.4
Amylase increased
17
0.4
9
0
Creatinine increased
15
0.4
13
0
Sodium decreased
13
0.6
11
0.4
Potassium increased
13
1
15
1.1
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 262 to 513 patients) and placebo group (range: 138
to 261 patients).
CHECKMATE-238
The safety of intravenous nivolumab as a single agent was evaluated in CHECKMATE-238, a
randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage
IV melanoma received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes
every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses
then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.3)].
The median duration of exposure was 11.5 months in intravenous nivolumab-treated patients and
was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received
intravenous nivolumab for >6 months.
Serious adverse reactions occurred in 18% of intravenous nivolumab-treated patients. Study
therapy was discontinued for adverse reactions in 9% of intravenous nivolumab-treated patients
and 42% of ipilimumab-treated patients. Twenty-eight percent of intravenous nivolumab-treated
patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions
occurred in 25% of intravenous nivolumab-treated patients.
The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab
treated patients were diarrhea and increased lipase and amylase. The most common adverse
40
Reference ID: 5503239
reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache,
nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated
adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Tables 21 and 22 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-238.
Table 21:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients - CHECKMATE-238
Adverse Reaction
Intravenous Nivolumab
(n=452)
Ipilimumab 10 mg/kg
(n=453)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
General
Fatiguea
57
0.9
55
2.4
Gastrointestinal
Diarrhea
37
2.4
55
11
Nausea
23
0.2
28
0
Abdominal painb
21
0.2
23
0.9
Constipation
10
0
9
0
Skin and Subcutaneous Tissue
Rashc
35
1.1
47
5.3
Pruritus
28
0
37
1.1
Musculoskeletal and Connective Tissue
Musculoskeletal paind
32
0.4
27
0.4
Arthralgia
19
0.4
13
0.4
Nervous System
Headache
23
0.4
31
2.0
Dizzinesse
11
0
8
0
Infections
Upper respiratory tract
infectionf
22
0
15
0.2
Respiratory, Thoracic and Mediastinal
Cough/productive cough
19
0
19
0
Dyspnea/exertional dyspnea
10
0.4
10
0.2
Endocrine
Hypothyroidismg
12
0.2
7.5
0.4
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
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b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized,
erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal
pain, and pain in extremity.
e Includes postural dizziness and vertigo.
f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection,
rhinitis, pharyngitis, and nasopharyngitis.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.
Table 22:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients -
CHECKMATE-238
Laboratory Abnormality
Intravenous Nivolumab
Ipilimumab 10 mg/kg
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Hematology
Lymphopenia
27
0.4
12
0.9
Anemia
26
0
34
0.5
Leukopenia
14
0
2.7
0.2
Neutropenia
13
0
6
0.5
Chemistry
Increased Lipase
25
7
23
9
Increased ALT
25
1.8
40
12
Increased AST
24
1.3
33
9
Increased Amylase
17
3.3
13
3.1
Hyponatremia
16
1.1
22
3.2
Hyperkalemia
12
0.2
9
0.5
Increased Creatinine
12
0
13
0
Hypocalcemia
10
0.7
16
0.5
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group
(range: 392 to 443 patients).
Non-Small Cell Lung Cancer
Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell
Lung Cancer
CHECKMATE-816
The safety of intravenous nivolumab in combination with platinum-doublet chemotherapy was
evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with
resectable NSCLC [see Clinical Studies (14.4)]. Patients received either intravenous nivolumab
42
Reference ID: 5503239
360 mg administered in combination with platinum-doublet chemotherapy administered every 3
weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles.
The median age of patients who received intravenous nivolumab in combination with platinum-
doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72%
male; 47% White, 50% Asian, and 2% Black/African American.
Serious adverse reactions occurred in 30% of patients who were treated with intravenous
nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2%
included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received
intravenous nivolumab in combination with platinum-doublet chemotherapy.
Study therapy with intravenous nivolumab in combination with platinum-doublet chemotherapy
was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one
treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting
in permanent discontinuation of intravenous nivolumab in combination with platinum-doublet
chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and
fatigue (1.1%).
The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased
appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were
neutropenia,
hyperglycemia,
leukopenia,
lymphopenia,
increased
amylase,
anemia,
thrombocytopenia, and hyponatremia.
Tables 23 and 24 summarize selected adverse reactions and laboratory abnormalities, respectively,
in CHECKMATE-816.
Table 23:
Adverse Reactions in >10% of Patients with Early-Stage NSCLC
Receiving Neoadjuvant Intravenous Nivolumab and Platinum-
Doublet Chemotherapy in CHECKMATE-816
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet Chemotherapy
(n=176)
Platinum-Doublet Chemotherapy
(n=176)
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Gastrointestinal
Nausea
38
0.6
45
1.1
Constipation
34
0
32
1.1
Vomiting
11
1.1
13
0.6
General
Fatiguea
26
2.3
23
1.1
Malaise
15
0.6
14
0.6
Metabolism and Nutrition
Decreased appetite
20
1.1
23
2.3
43
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Table 23:
Adverse Reactions in >10% of Patients with Early-Stage NSCLC
Receiving Neoadjuvant Intravenous Nivolumab and Platinum-
Doublet Chemotherapy in CHECKMATE-816
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet Chemotherapy
(n=176)
Platinum-Doublet Chemotherapy
(n=176)
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Skin and Subcutaneous Tissue
Rashb
20
2.3
7
0
Alopecia
11
0
15
0
Nervous System
Peripheral neuropathyc
13
0
6
0
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular
rash, and pruritic rash.
c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory
neuropathy.
Table 24:
Select Laboratory Values Worsening from Baselinea Occurring in
>20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant
Intravenous Nivolumab and Platinum-Doublet Chemotherapy in
CHECKMATE-816
Laboratory Abnormality
Intravenous Nivolumab and
Platinum-Doublet Chemotherapya
Platinum-Doublet Chemotherapya
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Hematology
Anemia
63
3.5
70
6
Neutropenia
58
22
58
27
Leukopenia
53
5
51
11
Lymphopenia
38
4.7
31
1.8
Thrombocytopenia
24
2.9
22
3
Chemistry
Hyperglycemia
37
6
35
2.9
Hypomagnesemia
25
1.2
29
1.2
Hyponatremia
25
2.4
28
1.8
Increased amylase
23
3.6
13
1.8
44
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Table 24:
Select Laboratory Values Worsening from Baselinea Occurring in
>20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant
Intravenous Nivolumab and Platinum-Doublet Chemotherapy in
CHECKMATE-816
Laboratory Abnormality
Intravenous Nivolumab and
Platinum-Doublet Chemotherapya
Platinum-Doublet Chemotherapya
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Increased ALT
23
0
20
1.2
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and platinum-doublet chemotherapy group (range: 73 to 171
patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients).
Neoadjuvant and Adjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive)
Non-Small Cell Lung Cancer
CHECKMATE-77T
The safety of intravenous nivolumab in combination with neoadjuvant platinum-doublet
chemotherapy followed by surgery and continued adjuvant treatment with intravenous nivolumab
as a single agent after surgery was evaluated in CHECKMATE-77T, a randomized, double-blind,
multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2
or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition) [see Clinical Studies (14.5)].
Patients with active autoimmune disease or a medical condition that required immunosuppression
were ineligible. The median duration of exposure to intravenous nivolumab was 10.3 months
(range: 1 day to 22.3 months).
The study population characteristics were: median age 66 years (range: 35 - 86); 71% male; 72%
White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or
Latino.
Adverse reactions occurring in patients with resectable NSCLC receiving intravenous nivolumab
in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed
as a single agent adjuvant treatment after surgery, were generally similar to those occurring in
patients in other clinical trials across tumor types receiving intravenous nivolumab in combination
with chemotherapy.
Neoadjuvant Phase of CHECKMATE-77T
A total of 228 patients received at least 1 dose of intravenous nivolumab in combination with
platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least 1 dose
of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment.
Serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in
combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent
(≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of
45
Reference ID: 5503239
patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and
pneumonitis (0.4% each).
Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of
patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy
as neoadjuvant treatment; the most frequent (≥1%) adverse reaction that led to permanent
discontinuation of any study drug was peripheral sensory neuropathy (2.2%).
Of the 228 intravenous nivolumab-treated patients and 230 placebo-treated patients who received
neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to
adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous
nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2
patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19,
and myositis (1 patient each).
Of the 178 intravenous nivolumab-treated patients who received surgery, 4.5% (n=8) experienced
delay of surgery (surgery more than 6 weeks from last neoadjuvant treatment) due to adverse
reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay
of surgery due to adverse reactions.
Of the 178 intravenous nivolumab-treated patients who received surgery, 7% (n=13) did not
receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who
received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions.
Adjuvant Phase of CHECKMATE-77T
A total of 142 patients in the intravenous nivolumab arm and 152 patients in the placebo arm
received at least 1 dose of adjuvant treatment.
Of the patients who received single agent intravenous nivolumab as adjuvant treatment, 22%
experienced serious adverse reactions; the most frequent serious adverse reaction was
pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent
discontinuation of adjuvant intravenous nivolumab due to an adverse reaction occurred in 14% of
patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of
adjuvant intravenous nivolumab were pneumonitis (4.2%) and diarrhea (1.4%).
Second-line Treatment of Metastatic NSCLC
CHECKMATE-017 and CHECKMATE-057
The safety of intravenous nivolumab was evaluated in CHECKMATE-017, a randomized open-
label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after
one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a
randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and
progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical
Studies (14.6)]. These trials excluded patients with active autoimmune disease, medical conditions
requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients
received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks
46
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or docetaxel 75 mg/m2 intravenously every 3 weeks. The median duration of therapy in
intravenous nivolumab-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to
21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In
CHECKMATE-017, 36% of patients received intravenous nivolumab for at least 6 months and
18% of patients received intravenous nivolumab for at least 1 year and in CHECKMATE-057,
30% of patients received intravenous nivolumab for >6 months and 20% of patients received
intravenous nivolumab for >1 year.
Across both trials, the median age of intravenous nivolumab-treated patients was 61 years (range:
37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of
patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).
In CHECKMATE-057, in the intravenous nivolumab arm, seven deaths were due to infection
including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism,
and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients
receiving intravenous nivolumab. Intravenous nivolumab was discontinued in 11% of patients and
was delayed in 28% of patients for an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous
nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion,
pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions
(≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
Tables 25 and 26 summarize selected adverse reactions and laboratory abnormalities, respectively,
in CHECKMATE-057.
Table 25:
Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-
Treated Patients and at a Higher Incidence than Docetaxel
(Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -
CHECKMATE-017 and CHECKMATE-057
Adverse Reaction
Intravenous Nivolumab
(n=418)
Docetaxel
(n=397)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Respiratory, Thoracic and Mediastinal
Cough
31
0.7
24
0
Metabolism and Nutrition
Decreased appetite
28
1.4
23
1.5
Skin and Subcutaneous Tissue
Pruritus
10
0.2
2
0
Toxicity was graded per NCI CTCAE v4.
Other clinically important adverse reactions observed in intravenous nivolumab-treated patients
and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in
47
Reference ID: 5503239
section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all
Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).
Table 26:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Intravenous Nivolumab-Treated Patients for all NCI
CTCAE Grades and at a Higher Incidence than Docetaxel (Between
Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) -
CHECKMATE-017 and CHECKMATE-057
Laboratory Abnormality
Intravenous Nivolumab
Docetaxel
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Chemistry
Hyponatremia
35
7
34
4.9
Increased AST
27
1.9
13
0.8
Increased alkaline phosphatase
26
0.7
18
0.8
Increased ALT
22
1.7
17
0.5
Increased creatinine
18
0
12
0.5
Increased TSHb
14
N/A
6
N/A
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 405 to 417 patients) and docetaxel group (range: 372
to 390 patients), except for TSH: intravenous nivolumab group n=314 and docetaxel group n=297.
b Not graded per NCI CTCAE v4.
Squamous Cell Carcinoma of the Head and Neck
CHECKMATE-141
The safety of intravenous nivolumab was evaluated in CHECKMATE-141, a randomized, active-
controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with
progression during or within 6 months of receiving prior platinum-based therapy [see Clinical
Studies (14.7)]. The trial excluded patients with active autoimmune disease, medical conditions
requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx,
squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous
histologies (e.g., mucosal melanoma). Patients received intravenous nivolumab 3 mg/kg by
intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either
cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate
(40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The
median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in
intravenous nivolumab-treated patients. In this trial, 18% of patients received intravenous
nivolumab for >6 months and 2.5% of patients received intravenous nivolumab for >1 year.
The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the
intravenous nivolumab group were ≥65 years of age and 37% in the comparator group were ≥65
years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline
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ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line
of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and
90% had prior radiation therapy.
Serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab.
Intravenous nivolumab was discontinued in 14% of patients and was delayed in 24% of patients
for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with
SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.
The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous
nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.
The most common adverse reactions occurring in ≥10% of intravenous nivolumab-treated patients
and at a higher incidence than investigator’s choice were cough and dyspnea. The most common
laboratory abnormalities occurring in ≥10% of intravenous nivolumab-treated patients and at a
higher incidence than investigator’s choice were increased alkaline phosphatase, increased
amylase, hypercalcemia, hyperkalemia, and increased TSH.
Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC)
CHECKMATE-274
The safety of intravenous nivolumab was evaluated in CHECKMATE-274, a randomized,
double-blind, multicenter trial of adjuvant intravenous nivolumab versus placebo in adult patients
who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal
pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.8)]. Patients received
intravenous nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351)
or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median
duration of intravenous nivolumab treatment was 8.8 months (range: 0 to 12.5).
Serious adverse reactions occurred in 30% of intravenous nivolumab patients. The most frequent
serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse
reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Intravenous
nivolumab was discontinued for adverse reactions in 18% of patients. Intravenous nivolumab was
delayed for adverse reaction in 33% of patients.
The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea,
pruritus, musculoskeletal pain, and urinary tract infection.
Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-274.
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Table 27:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-274
Adverse Reaction
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Skin and Subcutaneous Tissue
Rasha
36
1.7
19
0.3
Pruritus
30
0
16
0
General
Fatigue/Asthenia
36
1.1
32
0.3
Pyrexia
10
0.3
10
0.3
Gastrointestinal
Diarrheab
30
2.8
27
1.7
Nausea
16
0.6
13
0
Abdominal painc
15
0.9
15
0.6
Constipation
13
0.3
15
0.3
Musculoskeletal and Connective Tissue
Musculoskeletal paind
28
0.6
24
0.9
Arthralgia
11
0.3
13
0
Infections
Urinary tract infectione
22
6
23
9
Upper respiratory tract infectionf
16
0.3
16
0.6
Endocrine
Hyperthyroidism
11
0
1.1
0
Hypothyroidism
11
0
2.3
0
Renal and Urinary Disorders
Renal dysfunctiong
17
1.7
16
0.9
Respiratory, Thoracic and Mediastinal
Coughh
14
0
11
0
Dyspneai
11
0.3
6
0.3
Metabolism and Nutrition
Decreased appetite
13
0.9
7
0.3
Nervous System Disorders
Dizzinessj
11
0.3
9
0
50
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Table 27:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-274
Adverse Reaction
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Hepatobiliary
Hepatitisk
11
4
8
0.6
Toxicity was graded per NCI CTCAE v4.
a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema
asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid,
photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo
papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and
urticaria.
b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis
c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain.
d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort,
myalgia, neck pain, pain in extremity and spinal pain.
e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic,
urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and
urosepsis.
f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased,
immune-mediated nephritis, nephritis, renal failure, and renal impairment.
h Includes cough, productive cough, and upper-airway cough syndrome.
i Includes dyspnea and exertional dyspnea.
j Includes dizziness, postural dizziness and vertigo.
k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased,
cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury,
hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased.
Table 28:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-274
Laboratory Abnormality
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased creatinine
36
1.7
36
2.6
Increased amylase
34
8
23
3.2
Increased lipase
33
12
31
10
Hyperkalemia
32
5
30
6
51
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Table 28:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-274
Laboratory Abnormality
Intravenous Nivolumab
(n=351)
Placebo
(n=348)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Increased alkaline phosphatase
24
2.3
15
0.6
Increased AST
24
3.5
16
0.9
Increased ALT
23
2.9
15
0.6
Hyponatremia
22
4.1
17
1.8
Hypocalcemia
17
1.2
11
0.9
Hypomagnesemia
16
0
9
0
Hypercalcemia
12
0.3
8
0.3
Hematology
Lymphopenia
33
2.9
27
1.5
Anemia
30
1.4
28
0.9
Neutropenia
11
0.6
10
0.3
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 322 to 348 patients) and placebo group (range: 312
to 341 patients).
First-line Treatment of Unresectable or Metastatic UC
CHECKMATE-901
The safety of intravenous nivolumab was evaluated in CHECKMATE-901, a randomized, open-
label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies
(14.8)]. Patients received either intravenous nivolumab 360 mg with cisplatin and gemcitabine
every 3 weeks for up to 6 cycles followed by single-agent intravenous nivolumab 480 mg every 4
weeks up to 2 years (n=304), or cisplatin and gemcitabine chemotherapy every 3 weeks for up to
6 cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin.
Among patients who received intravenous nivolumab with chemotherapy, the median duration of
intravenous nivolumab exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse
reactions occurred in 48% of patients receiving intravenous nivolumab in combination with
chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who
received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute
kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count
decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were
nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and
peripheral neuropathy.
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Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in
combination with chemotherapy; these included sepsis (1%).
Intravenous nivolumab and/or chemotherapy were discontinued in 30% of patients and were
delayed in 67% of patients for an adverse reaction.
Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-901.
Table 29:
Adverse Reactions Occurring in ≥10% of Treated Patients -
CHECKMATE-901
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet
Chemotherapy
(n=304)
Platinum-Doublet
Chemotherapy (n=288)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Gastrointestinal disorders
Nausea
52
0.3
53
1
Constipation
30
0
28
0.7
Vomiting
23
1.3
19
2.1
Diarrheaa
19
2
14
0
Abdominal painb
14
0.3
9
0.3
General
Fatiguec
48
3.9
43
4.2
Edemad
18
0
9
0.3
Pyrexiae
14
1
14
0
Musculoskeletal and Connective Tissue
Musculoskeletal painf
33
3
21
0.3
Metabolism and Nutrition
Decreased appetite
30
1.6
19
1
Skin and Subcutaneous Tissue
Rashg
25
2.3
7
0.3
Pruritus
17
0.7
3.5
0
Nervous System Disorders
Peripheral neuropathyh
20
0.7
14
0
Headachei
11
0
5
0
Infections
53
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Table 29:
Adverse Reactions Occurring in ≥10% of Treated Patients -
CHECKMATE-901
Adverse Reaction
Intravenous Nivolumab and
Platinum-Doublet
Chemotherapy
(n=304)
Platinum-Doublet
Chemotherapy (n=288)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Urinary tract infectionj
19
8
18
8
Endocrine disorders
Hypothyroidismk
17
0
0.3
0
Renal and Urinary Disorders
Renal dysfunctionl
14
6
11
1.7
Hematuria
11
1
7
1.4
Investigations
Weight decreased
11
0.3
6
0
Toxicity was graded per NCI CTCAE v4.
a Includes colitis, immune-mediated enterocolitis.
b Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort,
gastrointestinal pain, and hepatic pain.
c Includes asthenia.
d Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema,
gravitational edema, and edema genital.
e Includes hyperthermia, body temperature increased and hyperpyrexia.
f Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia,
neck pain, pain in extremity, and spinal pain.
g Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis,
dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar
plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation.
h Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral
motor neuropathy, polyneuropathy.
i Includes occipital neuralgia.
j Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia
urinary tract infection.
k Includes blood stimulating hormone increased.
l Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia.
54
Reference ID: 5503239
Table 30:
Selected Laboratory Abnormalities Worsening from Baselinea
Occurring in ≥20% of Patients - CHECKMATE-901
Laboratory Abnormality
Intravenous Nivolumab and
Platinum-Doublet Chemotherapy
(n=304)
Platinum-Doublet Chemotherapy
(n=288)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Hematology
Anemia
88
21
80
21
Neutropenia
82
35
76
28
Lymphopenia
71
17
56
13
Thrombocytopenia
60
13
51
8
Chemistry
Increased creatinine
53
2.4
42
1.1
Hypomagnesemia
48
3.8
39
1.5
Hyponatremia
43
13
39
8
Hyperglycemia
41
3.9
37
3.2
Hypocalcemia
36
2.1
24
1.1
Hyperkalemia
33
3.0
32
1.1
Increased amylase
32
4.2
23
3.6
Increased AST
31
2.4
17
0.7
Increased ALT
29
2.4
19
0.7
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 289-301 patients) and chemotherapy group (range:
265-281 patients).
Previously Treated Advanced or Metastatic UC
CHECKMATE-275
The safety of intravenous nivolumab was evaluated in CHECKMATE-275, a single arm trial in
which 270 patients with locally advanced or metastatic UC had disease progression during or
following platinum-containing chemotherapy or had disease progression within 12 months of
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies
(14.8)]. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes
every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment
was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for
an adverse reaction.
Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients
(1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment
with intravenous nivolumab. Serious adverse reactions occurred in 54% of patients. Intravenous
nivolumab was discontinued for adverse reactions in 17% of patients.
55
Reference ID: 5503239
The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract
infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.
The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal
pain, nausea, and decreased appetite.
Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-275.
Table 31:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-275
Adverse Reaction
Intravenous Nivolumab
(n=270)
All Grades (%)
Grades 3-4 (%)
Adverse Reaction
99
51
General
Asthenia/fatigue/malaise
46
7
Pyrexia/tumor associated fever
17
0.4
Edema/peripheral edema/peripheral swelling
13
0.4
Musculoskeletal and Connective Tissue
Musculoskeletal paina
30
2.6
Arthralgia
10
0.7
Metabolism and Nutrition
Decreased appetite
22
2.2
Gastrointestinal
Nausea
22
0.7
Diarrhea
17
2.6
Constipation
16
0.4
Abdominal painb
13
1.5
Vomiting
12
1.9
Respiratory, Thoracic and Mediastinal
Cough/productive cough
18
0
Dyspnea/exertional dyspnea
14
3.3
Infections
Urinary tract infection/escherichia/fungal
urinary tract infection
17
7
Skin and Subcutaneous Tissue
Rashc
16
1.5
Pruritus
12
0
56
Reference ID: 5503239
I
I
Table 31:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-275
Adverse Reaction
Intravenous Nivolumab
(n=270)
All Grades (%)
Grades 3-4 (%)
Endocrine
Thyroid disordersd
15
0
Toxicity was graded per NCI CTCAE v4.
a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity and spinal pain.
b Includes abdominal discomfort, lower and upper abdominal pain.
c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular,
maculopapular, or pruritic.
d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism,
thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri
iodothyronine increased.
Table 32:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of Patients - CHECKMATE-275
Laboratory Abnormality
Intravenous Nivolumaba
All Grades (%)
Grades 3-4 (%)
Chemistry
Hyperglycemia
42
2.4
Hyponatremia
41
11
Increased creatinine
39
2
Increased alkaline phosphatase
33
5.5
Hypocalcemia
26
0.8
Increased AST
24
3.5
Increased lipase
20
7
Hyperkalemia
19
1.2
Increased ALT
18
1.2
Increased amylase
18
4.4
Hypomagnesemia
16
0
Hematology
Lymphopenia
42
9
Anemia
40
7
Thrombocytopenia
15
2.4
Leukopenia
11
0
57
Reference ID: 5503239
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: range: 84 to 256 patients.
MSI-H or dMMR Metastatic Colorectal Cancer
CHECKMATE-142
The safety of intravenous nivolumab administered as a single agent or in combination with
ipilimumab was evaluated in CHECKMATE-142, a multicenter, non-randomized, multiple
parallel-cohort, open-label trial [see Clinical Studies (14.9)]. In CHECKMATE-142, 74 patients
with mCRC received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes
every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC
received intravenous nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then
intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or until unacceptable
toxicity.
In the intravenous nivolumab with ipilimumab cohort, serious adverse reactions occurred in 47%
of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an
adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were
colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The
most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia,
musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.
Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used
to identify statistically significant differences between the two cohorts summarized below for any
adverse reaction.
Table 33:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-142
Adverse Reaction
Intravenous Nivolumab
(n=74)
Intravenous Nivolumab and
Ipilimumab
(n=119)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
General
Fatiguea
54
5
49
6
Pyrexia
24
0
36
0
Edemab
12
0
7
0
Gastrointestinal
Diarrhea
43
2.7
45
3.4
Abdominal painc
34
2.7
30
5
Nausea
34
1.4
26
0.8
Vomiting
28
4.1
20
1.7
58
Reference ID: 5503239
Table 33:
Adverse Reactions Occurring in ≥10% of Patients -
CHECKMATE-142
Adverse Reaction
Intravenous Nivolumab
(n=74)
Intravenous Nivolumab and
Ipilimumab
(n=119)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Constipation
20
0
15
0
Musculoskeletal and Connective Tissue
Musculoskeletal paind
28
1.4
36
3.4
Arthralgia
19
0
14
0.8
Respiratory, Thoracic and Mediastinal
Cough
26
0
19
0.8
Dyspnea
8
1
13
1.7
Skin and Subcutaneous Tissue
Rashe
23
1.4
25
4.2
Pruritus
19
0
28
1.7
Dry Skin
7
0
11
0
Infections
Upper respiratory tract
infectionf
20
0
9
0
Endocrine
Hyperglycemia
19
2.7
6
1
Hypothyroidism
5
0
14
0.8
Hyperthyroidism
4
0
12
0
Nervous System
Headache
16
0
17
1.7
Dizziness
14
0
11
0
Metabolism and Nutrition
Decreased appetite
14
1.4
20
1.7
Psychiatric
Insomnia
9
0
13
0.8
Investigations
Weight decreased
8
0
10
0
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema and peripheral swelling.
c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
59
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d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.
e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.
f Includes nasopharyngitis and rhinitis.
Clinically important adverse reactions reported in <10% of patients receiving intravenous
nivolumab with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis
(0.8%).
Table 34:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-142
Laboratory Abnormality
Intravenous Nivolumab
(n=74)
Intravenous Nivolumab and
Ipilimumab
(n=119)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Hematology
Anemia
50
7
42
9
Lymphopenia
36
7
25
6
Neutropenia
20
4.3
18
0
Thrombocytopenia
16
1.4
26
0.9
Chemistry
Increased alkaline
phosphatase
37
2.8
28
5
Increased lipase
33
19
39
12
Increased ALT
32
2.8
33
12
Increased AST
31
1.4
40
12
Hyponatremia
27
4.3
26
5
Hypocalcemia
19
0
16
0
Hypomagnesemia
17
0
18
0
Increased amylase
16
4.8
36
3.4
Increased bilirubin
14
4.2
21
5
Hypokalemia
14
0
15
1.8
Increased creatinine
12
0
25
3.6
Hyperkalemia
11
0
23
0.9
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available. Number of evaluable patients ranges from 62 to 71 for the intravenous nivolumab cohort
and from 87 to 114 for the intravenous nivolumab and ipilimumab cohort.
Hepatocellular Carcinoma
CHECKMATE-040
60
Reference ID: 5503239
The safety of intravenous nivolumab 1 mg/kg in combination with ipilimumab 3 mg/kg was
evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis
enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see
Clinical Studies (14.10)] who progressed on or were intolerant to sorafenib. Intravenous
nivolumab and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent
intravenous nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.
During the intravenous nivolumab and ipilimumab combination period, 33 of 49 (67%) patients
received all 4 planned doses of intravenous nivolumab and ipilimumab. During the entire treatment
period, the median duration of exposure to intravenous nivolumab was 5.1 months (range: 0 to
35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of
patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment
for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in
29% of patients and delayed in 65% of patients for an adverse reaction.
The most frequent serious adverse reactions (reported in ≥4% of patients) were pyrexia, diarrhea,
anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage,
hyponatremia, increased blood bilirubin, and pneumonitis.
Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-040.
Table 35:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab in Combination with Ipilimumab in Cohort
4 of CHECKMATE-040
Adverse Reaction
Intravenous Nivolumab and Ipilimumab
(n=49)
All Grades (%)
Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rash
53
8
Pruritus
53
4
Musculoskeletal and Connective Tissue
Musculoskeletal pain
41
2
Arthralgia
10
0
Gastrointestinal
Diarrhea
39
4
Abdominal pain
22
6
Nausea
20
0
Ascites
14
6
Constipation
14
0
Dry mouth
12
0
Dyspepsia
12
2
61
Reference ID: 5503239
Table 35:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab in Combination with Ipilimumab in Cohort
4 of CHECKMATE-040
Adverse Reaction
Intravenous Nivolumab and Ipilimumab
(n=49)
All Grades (%)
Grades 3-4 (%)
Vomiting
12
2
Stomatitis
10
0
Respiratory, Thoracic and Mediastinal
Cough
37
0
Dyspnea
14
0
Pneumonitis
10
2
Metabolism and Nutrition
Decreased appetite
35
2
General
Fatigue
27
2
Pyrexia
27
0
Malaise
18
2
Edema
16
2
Influenza-like illness
14
0
Chills
10
0
Nervous System
Headache
22
0
Dizziness
20
0
Endocrine
Hypothyroidism
20
0
Adrenal insufficiency
18
4
Investigations
Weight decreased
20
0
Psychiatric
Insomnia
18
0
Blood and Lymphatic System
Anemia
10
4
Infections
Influenza
10
2
Vascular
62
Reference ID: 5503239
Table 35:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab in Combination with Ipilimumab in Cohort
4 of CHECKMATE-040
Adverse Reaction
Intravenous Nivolumab and Ipilimumab
(n=49)
All Grades (%)
Grades 3-4 (%)
Hypotension
10
0
Clinically important adverse reactions reported in <10% of patients who received intravenous
nivolumab with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine
phosphokinase (2%).
Table 36:
Laboratory Abnormalities Worsening from Baseline Occurring in
≥10% of Patients Receiving Intravenous Nivolumab in
Combination with Ipilimumab in Cohort 4 of CHECKMATE-040
Laboratory Abnormality
Intravenous Nivolumab and Ipilimumab
(n=47)
All Grades (%)
Grades 3-4 (%)
Hematology
Lymphopenia
53
13
Anemia
43
4.3
Neutropenia
43
9
Leukopenia
40
2.1
Thrombocytopenia
34
4.3
Chemistry
Increased AST
66
40
Increased ALT
66
21
Increased bilirubin
55
11
Increased lipase
51
26
Hyponatremia
49
32
Hypocalcemia
47
0
Increased alkaline phosphatase
40
4.3
Increased amylase
38
15
Hypokalemia
26
2.1
Hyperkalemia
23
4.3
Increased creatinine
21
0
Hypomagnesemia
11
0
63
Reference ID: 5503239
In patients who received intravenous nivolumab with ipilimumab, virologic breakthrough occurred
in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline,
respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA
for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined
as a 1 log increase in HCV RNA from baseline.
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
CHECKMATE-577
The safety of intravenous nivolumab was evaluated in CHECKMATE-577, a randomized,
placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely
resected (negative margins) esophageal or gastroesophageal junction cancer who had residual
pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.11)]. The trial
excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable
disease, autoimmune disease, or any condition requiring systemic treatment with either
corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications.
Patients received either intravenous nivolumab 240 mg or placebo by intravenous infusion over
30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion
over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease
recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of
exposure was 10.1 months (range: <0.1 to 14 months) in intravenous nivolumab-treated patients
and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received
intravenous nivolumab, 61% were exposed for >6 months and 54% were exposed for >9 months.
Serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab. A serious
adverse reaction reported in ≥2% of patients who received intravenous nivolumab was
pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who
received intravenous nivolumab.
Intravenous nivolumab was discontinued in 12% of patients and was delayed in 28% of patients
for an adverse reaction.
Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-577.
Table 37:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - CHECKMATE-577
Adverse Reaction
Intravenous Nivolumab
(n=532)
Placebo
(n=260)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Adverse Reaction
96
34
93
32
Gastrointestinal
Diarrhea
29
0.9
29
0.8
64
Reference ID: 5503239
Table 37:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - CHECKMATE-577
Adverse Reaction
Intravenous Nivolumab
(n=532)
Placebo
(n=260)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Adverse Reaction
96
34
93
32
Nausea
23
0.8
21
0
Abdominal Paina
17
0.8
20
1.5
Vomiting
15
0.6
16
1.2
Dysphagia
13
0.8
17
3.5
Dyspepsiab
12
0.2
16
0.4
Constipation
11
0
12
0
General
Fatiguec
34
1.3
29
1.5
Respiratory, Thoracic and Mediastinal
Coughd
20
0.2
21
0.4
Dyspneae
12
0.8
12
0.4
Skin and Subcutaneous Tissue
Rashf
21
0.9
10
0.4
Pruritus
13
0.4
6
0
Investigations
Weight decreased
13
0.4
9
0
Musculoskeletal and Connective Tissue
Musculoskeletal paing
21
0.6
20
0.8
Arthralgia
10
0.2
8
0
Metabolism and Nutrition
Decreased appetite
15
0.9
10
0.8
Endocrine
Hypothyroidism
11
0
1.5
0
a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
b Includes gastroesophageal reflux.
c Includes asthenia.
d Includes productive cough.
e Includes dyspnea exertional.
f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash
erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic.
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g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia
intercostal, neck pain, pain in extremity, spinal pain.
Table 38:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - CHECKMATE-577
Laboratory Abnormality
Intravenous Nivolumab
(n=532)
Placebo
(n=260)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased AST
27
2.1
22
0.8
Increased alkaline phosphatase
25
0.8
18
0.8
Increased albumin
21
0.2
18
0
Increased ALT
20
1.9
16
1.2
Increased amylase
20
3.9
13
1.3
Hyponatremia
19
1.7
12
1.2
Hyperkalemia
17
0.8
15
1.6
Hypokalemia
12
1
11
1.2
Transaminases increasedb
11
1.5
6
1.2
Hematology
Lymphopenia
44
17
35
12
Anemia
27
0.8
21
0.4
Neutropenia
24
1.5
23
0.4
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (range: 163 to 526 patients) and Placebo group (range: 86 to
256 patients).
b Includes alanine aminotransferase increased, aspartate aminotransferase increased.
First-line Treatment of Unresectable Advanced or Metastatic ESCC
CHECKMATE-648
The safety of intravenous nivolumab in combination with chemotherapy or in combination with
ipilimumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter,
open-label trial in patients with previously untreated unresectable advanced, recurrent or
metastatic ESCC [see Clinical Studies (14.11)]. Patients received one of the following treatments:
intravenous nivolumab 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m2/day
intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on
day 1 (of a 4-week cycle).
intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg
every 6 weeks.
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5-FU (fluorouracil) 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and
cisplatin 80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Among patients who received intravenous nivolumab with chemotherapy, the median duration of
exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received intravenous
nivolumab and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to
24 months).
Serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in
combination with chemotherapy and in 69% of patients receiving intravenous nivolumab in
combination with ipilimumab. The most frequent serious adverse reactions reported in ≥2% of
patients who received intravenous nivolumab with chemotherapy were pneumonia (11%),
dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The
most frequent serious adverse reactions reported in ≥2% of patients who received intravenous
nivolumab with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration
pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite
(2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%).
Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in
combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis,
pneumonia, and acute kidney injury and in 5 (1.6%) patients who received intravenous nivolumab
in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary
embolism, and acute respiratory distress syndrome.
Intravenous nivolumab and/or chemotherapy were discontinued in 39% of patients and were
delayed in 71% of patients for an adverse reaction. Intravenous nivolumab and/or ipilimumab were
discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction.
The most common adverse reactions reported in ≥20% of patients treated with intravenous
nivolumab in combination with chemotherapy were nausea, decreased appetite, fatigue,
constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in
≥20% of patients treated with intravenous nivolumab in combination with ipilimumab were rash,
fatigue, pyrexia, nausea, diarrhea, and constipation.
Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-648.
Table 39:
Adverse Reactions in ≥10% of Patients - CHECKMATE-648
Adverse Reaction
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Gastrointestinal
Nausea
65
4.2
22
0.6
56
2.6
67
Reference ID: 5503239
Table 39:
Adverse Reactions in ≥10% of Patients - CHECKMATE-648
Adverse Reaction
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Constipation
44
1.0
20
0.3
43
1
Stomatitisa
44
9
11
0.6
35
3
Diarrhea
29
2.9
22
1.9
20
2
Vomiting
23
2.3
15
1.6
19
3
Dysphagia
14
7
12
5
12
4.9
Abdominal painb
13
1.9
10
0.9
11
0.7
Metabolism and Nutrition
Decreased appetite
51
7
17
4
50
6
General
Fatiguec
47
3.5
28
2.5
41
4.9
Pyrexiad
19
0.3
23
0.9
12
0.3
Edemae
16
0
7
0
13
0
Nervous System
Peripheral
neuropathyf
18
1.3
2.8
0
13
1
Psychiatric
Insomnia
16
0
8
0
10
0.3
Skin and Subcutaneous Tissue
Rashg
16
0.6
31
3.1
7
0
Pruritus
11
0
17
0.9
3.6
0
Alopecia
10
0
11
0
Respiratory, Thoracic and Mediastinal
Coughh
16
0.3
13
0.3
13
0.3
Infections and Infestations
Pneumoniai
13
5
14
8
10
2.6
Endocrine
Hypothyroidism
7
0
14
0
0.3
0
Investigations
Weight decreased
12
0.6
12
1.9
11
1
68
Reference ID: 5503239
Table 39:
Adverse Reactions in ≥10% of Patients - CHECKMATE-648
Adverse Reaction
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Musculoskeletal and Connective Tissue
Musculoskeletal
painj
11
0.3
14
0.6
8
0.3
Toxicity was graded per NCI CTCAE v4.
a Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes asthenia and malaise.
d Includes tumor associated fever.
e Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
f Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and
peripheral sensory neuropathy.
g Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash,
rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic.
h Includes productive cough.
i Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal.
j Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain.
Table 40:
Laboratory Values Worsening from Baselinea Occurring in ≥10%
of Patients - CHECKMATE-648
Laboratory
Abnormality
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Hematology
Anemia
81
21
52
7
66
14
Lymphopenia
67
23
50
13
44
8
Neutropenia
61
18
13
1.3
48
13
Leukopenia
53
11
39
5
Thrombocytopenia
43
3.3
12
1
29
2.8
Chemistry
Hyponatremia
52
15
45
11
40
8
Hypocalcemia
43
3
32
0
23
0.7
Increased creatinine
41
2.3
15
0.7
31
0.7
Hypomagnesemia
35
1.7
15
0
25
1.8
69
Reference ID: 5503239
Table 40:
Laboratory Values Worsening from Baselinea Occurring in ≥10%
of Patients - CHECKMATE-648
Laboratory
Abnormality
Intravenous Nivolumab
with Cisplatin and 5-FU
(n=310)
Intravenous Nivolumab
and Ipilimumab
(n=322)
Cisplatin and 5-FU
(n=304)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Grades 1-4
(%)
Grades 3-4
(%)
Hyperglycemia
34
0
43
4.3
36
0.8
Hyperkalemia
33
2.3
23
1.6
24
0.7
Hypokalemia
29
9
19
5
17
6
Increased alkaline
phosphatase
26
1.3
31
3.3
15
0
Increased AST
23
3.3
39
6
11
1.4
Increased ALT
23
2.3
33
6
8
0.7
Hypoglycemia
18
0.4
15
1.2
7
0
Hypercalcemia
11
2.6
15
2
8
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab with cisplatin and 5-FU group (range: 60 to 305 patients),
intravenous nivolumab and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to
283 patients).
Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal
Squamous Cell Carcinoma (ESCC)
ATTRACTION-3
The safety of intravenous nivolumab was evaluated in ATTRACTION-3, a randomized, active-
controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or
metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based
chemotherapy [see Clinical Studies (14.11)]. The trial excluded patients who were refractory or
intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment,
had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent
tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or
respiratory tract. Patients received intravenous nivolumab 240 mg by intravenous infusion over
30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously
every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed
by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity.
The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in intravenous
nivolumab-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel
treated patients. Among patients who received intravenous nivolumab, 26% were exposed for
>6 months and 10% were exposed for >1 year.
70
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Serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab. Serious
adverse reactions reported in ≥2% of patients who received intravenous nivolumab were
pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse
reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or
pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%),
gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).
Intravenous nivolumab was discontinued in 13% of patients and was delayed in 27% of patients
for an adverse reaction.
Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in
ATTRACTION-3.
Table 41:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - ATTRACTION-3
Adverse Reaction
Intravenous Nivolumab
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Skin and Subcutaneous Tissue
Rasha
22
1.9
28
1
Pruritus
12
0
7
0
Metabolism and Nutrition
Decreased appetiteb
21
1.9
35
5
Gastrointestinal
Diarrheac
18
1.9
17
1.4
Constipation
17
0
19
0
Nausea
11
0
20
0.5
Musculoskeletal and Connective Tissue
Musculoskeletal
paind
17
0
26
1.4
Infections
Upper respiratory
tract infectione
17
1
14
0
Pneumoniaf
13
5
19
9
Respiratory, Thoracic and Mediastinal
Coughg
16
0
14
0.5
General
Pyrexiah
16
0.5
19
0.5
Fatiguei
12
1.4
27
4.8
71
Reference ID: 5503239
I
I
I
I
I
I
Table 41:
Adverse Reactions Occurring in ≥10% of Patients Receiving
Intravenous Nivolumab - ATTRACTION-3
Adverse Reaction
Intravenous Nivolumab
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades (%)
Grades 3-4 (%)
All Grades (%)
Grades 3-4 (%)
Blood and Lymphatic System
Anemiaj
13
8
30
13
Endocrine
Hypothyroidismk
11
0
1.4
0
Toxicity was graded per NCI CTCAE v4.
a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia
syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis,
dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or
pustular.
b Includes hypophagia, and food aversion.
c Includes colitis.
d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain
in extremity, arthritis, bone pain, and periarthritis calcarea.
e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper
respiratory infection with bronchitis.
f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia
in the intravenous nivolumab treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment
arm; these deaths occurred with paclitaxel only.
g Includes productive cough.
h Includes tumor-associated fever.
i Includes asthenia.
j Includes hemoglobin decreased, and iron deficiency anemia.
k Includes blood thyroid stimulating hormone increased.
72
Reference ID: 5503239
Table 42:
Laboratory Abnormalities Worsening from Baselinea Occurring in
≥10% of Patients - ATTRACTION-3
Laboratory Abnormality
Intravenous Nivolumab
(n=209)
Docetaxel or Paclitaxel
(n=208)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Chemistry
Increased creatinine
78
0.5
68
0.5
Hyperglycemia
52
5
62
5
Hyponatremia
42
11
50
12
Increased AST
40
6
30
1
Increased alkaline phosphatase
33
4.8
24
1.0
Increased ALT
31
5
22
1.9
Hypercalcemia
22
6
14
2.9
Hyperkalemia
22
0.5
31
1
Hypoglycemia
14
1.4
14
0.5
Hypokalemia
11
2.9
13
3.4
Hematology
Lymphopenia
46
19
72
43
Anemia
42
9
71
17
Leukopenia
11
0.5
79
45
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab group (209 patients) and Docetaxel or Paclitaxel group (range: 207
to 208 patients).
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
CHECKMATE-649
The safety of intravenous nivolumab in combination with chemotherapy was evaluated in
CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously
untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal
adenocarcinoma [see Clinical Studies (14.12)]. The trial excluded patients who were known
human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous
system (CNS) metastases. Patients were randomized to receive intravenous nivolumab in
combination with chemotherapy or chemotherapy. Patients received one of the following
treatments:
intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin
and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and
oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
73
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Patients were treated with intravenous nivolumab in combination with chemotherapy or
chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median
duration of exposure was 6.8 months (range: 0 to 33.5 months) in intravenous nivolumab and
chemotherapy-treated patients. Among patients who received intravenous nivolumab and
chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.
Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous
nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile
neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic
shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and
disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients
treated with intravenous nivolumab in combination with chemotherapy. Intravenous nivolumab
and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in
76% of patients due to an adverse reaction.
The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous
nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia
(3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The
most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab
in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea,
vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Tables 43 and 44 summarize the adverse reactions and laboratory abnormalities, respectively, in
CHECKMATE-649.
Table 43:
Adverse Reactions in ≥10% of Patients Receiving Intravenous
Nivolumab and Chemotherapy - CHECKMATE-649
Adverse Reaction
Intravenous Nivolumab and
mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Adverse Reaction
99
69
98
59
Nervous System
Peripheral neuropathya
53
7
46
4.8
Headache
11
0.8
6
0.3
Gastrointestinal
Nausea
48
3.2
44
3.7
Diarrhea
39
5
34
3.7
Vomiting
31
4.2
29
4.2
Abdominal painb
27
2.8
24
2.6
Constipation
25
0.6
21
0.4
74
Reference ID: 5503239
Table 43:
Adverse Reactions in ≥10% of Patients Receiving Intravenous
Nivolumab and Chemotherapy - CHECKMATE-649
Adverse Reaction
Intravenous Nivolumab and
mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Stomatitisc
17
1.8
13
0.8
General
Fatigued
44
7
40
5
Pyrexiae
19
1
11
0.4
Edemaf
12
0.5
8
0.1
Metabolism and Nutrition
Decreased appetite
29
3.6
26
2.5
Hypoalbuminemiag
14
0.3
9
0.3
Investigations
Weight decreased
17
1.3
15
0.7
Increased lipase
14
7
8
3.7
Increased amylase
12
3.1
5
0.4
Musculoskeletal and Connective Tissue
Musculoskeletal painh
20
1.3
14
2
Skin and Subcutaneous Tissue
Rashi
18
1.7
4.4
0.1
Palmar-plantar erythrodysesthesia
syndrome
13
1.5
12
0.8
Respiratory, Thoracic and Mediastinal
Coughj
13
0.1
9
0
Infections and Infestations
Upper respiratory tract infectionk
10
0.1
7
0.1
Toxicity was graded per NCI CTCAE v4.
a Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and
peripheral sensory neuropathy.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
d Includes asthenia.
e Includes tumor associated fever.
f Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
g Includes blood albumin decreased.
75
Reference ID: 5503239
h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in
extremity, and spinal pain.
i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash,
nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, and rhinitis.
Table 44:
Laboratory Values Worsening from Baselinea Occurring in ≥10%
of Patients - CHECKMATE-649
Laboratory
Abnormality
Intravenous Nivolumab and
mFOLFOX6 or CapeOX
(n=782)
mFOLFOX6 or CapeOX
(n=767)
Grades 1-4 (%)
Grades 3-4 (%)
Grades 1-4 (%)
Grades 3-4 (%)
Hematology
Neutropenia
73
29
62
23
Leukopenia
69
12
59
9
Thrombocytopenia
68
7
63
4.4
Anemia
59
14
60
10
Lymphopenia
59
12
49
9
Chemistry
Increased AST
52
4.6
47
1.9
Hypocalcemia
42
1.6
37
1
Hyperglycemia
41
3.9
38
2.7
Increased ALT
37
3.4
30
1.9
Hyponatremia
34
6
24
5
Hypokalemia
27
7
24
4.8
Hyperbilirubinemia
24
2.8
21
2
Increased creatinine
15
1
9
0.5
Hyperkalemia
14
1.4
11
0.7
Hypoglycemia
12
0.7
9
0.2
Hypernatremia
11
0.5
7.1
0
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
measurement available: intravenous nivolumab and mFOLFOX6 or CapeOX group (407 to 767 patients) or
mFOLFOX6 or CapeOX group (range: 405 to 735 patients).
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of intravenous
nivolumab. Because these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
76
Reference ID: 5503239
Eye: Vogt-Koyanagi-Harada (VKH) syndrome
Complications of Intravenous Nivolumab Treatment After Allogeneic HSCT: Treatment refractory,
severe acute and chronic GVHD
Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including
fatal cases), autoimmune hemolytic anemia (including fatal cases)
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on data from animal studies and its mechanism of action [see Clinical Pharmacology
(12.1)], OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In
animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset
of organogenesis through delivery resulted in increased abortion and premature infant death (see
Data). Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin
G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the
developing fetus. The effects of OPDIVO QVANTIG are likely to be greater during the second
and third trimesters of pregnancy. There are no available data on OPDIVO QVANTIG use in
pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk
to a fetus.
The background risk in the U.S. general population of major birth defects is 2% to 4% and of
miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal Data
OPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see
Description (11)].
Nivolumab
A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal
immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of
pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on
prenatal and postnatal development were evaluated in monkeys that received nivolumab
intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels
of between 4 and 15 times higher than those observed at the clinical dose of 600 mg once every 2
weeks, 900 mg once every 3 weeks, or 1,200 mg once every 4 weeks (based on AUC). Nivolumab
administration resulted in a non-dose-related increase in spontaneous abortion and increased
neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the
risk of developing immune-mediated disorders or altering the normal immune response, and
immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18
of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with
nivolumab, there were no apparent malformations and no effects on neurobehavioral,
immunological, or clinical pathology parameters throughout the 6-month postnatal period.
77
Reference ID: 5503239
Hyaluronidase
In an embryo-fetal development study, mice were dosed daily by subcutaneous injection during
the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to
2,200,000 U/kg, which is at least 6,600 times higher than the human dose of 10,000 U once every
2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when
administered with nivolumab. The study found no evidence of teratogenicity. Reduced fetal weight
and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of
360,000 U/kg, which is at least 1,080 times higher than the human dose of 10,000 U once every 2
weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when
administered with nivolumab.
8.2
Lactation
Risk Summary
There are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the
breastfed child, or the effects on milk production. Because of the potential for serious adverse
reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months
after the last dose of OPDIVO QVANTIG.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO
QVANTIG [see Use in Specific Populations (8.1)].
Contraception
OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception
during treatment with OPDIVO QVANTIG and for 5 months following the last dose.
8.4
Pediatric Use
The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric
patients.
8.5
Geriatric Use
Monotherapy
Of the 248 patients who were randomized to monotherapy OPDIVO QVANTIG in clinical studies,
48% were 65 years and over and 14% were 75 years and over. No overall differences in safety or
effectiveness were observed between elderly patients and younger patients.
Single Agent Intravenous Nivolumab
Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and
esophageal or gastroesophageal junction cancer who were randomized to single agent intravenous
nivolumab in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No
overall differences in safety or effectiveness were observed between elderly patients and younger
patients [see Clinical Studies (14.1, 14.2, 14.3, 14.6, 14.8, 14.11, 14.12)].
78
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Clinical studies in patients with recurrent head and neck SCC, or dMMR or MSI-H metastatic
CRC (mCRC) who were treated with single agent intravenous nivolumab did not include sufficient
numbers of patients aged 65 years and over to determine whether they respond differently from
younger patients [see Clinical Studies (14.7, 14.9)].
Intravenous Nivolumab in Combination with Platinum-Containing Chemotherapy
Of the 179 patients with NSCLC who were randomized to intravenous nivolumab in combination
with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old
or older. No overall differences in safety or effectiveness were reported between patients older and
younger than 65 years [see Clinical Studies (14.4)].
Of the 229 patients with NSCLC who were randomized to intravenous nivolumab 360 mg in
combination with platinum-doublet chemotherapy every 3 weeks for up to 4 cycles, followed by
intravenous nivolumab 480 mg every 4 weeks, 56% were 65 years old or older and 7% were 75
years old or older. No overall differences in safety or effectiveness were reported between patients
older and younger than 65 years.
Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to intravenous
nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy, 42%
were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported
between elderly patients and younger patients [see Clinical Studies (14.11, 14.12)].
Of the 304 patients with UC who were treated with intravenous nivolumab in combination with
gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75
years or older. No overall differences in safety or effectiveness were observed between patients 65
years of age and over and younger patients. Clinical studies of intravenous nivolumab with
platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and
over to determine whether safety and effectiveness differs compared to younger patients. [see
Clinical Studies (14.8)].
In Combination with Cabozantinib
Of the 320 patients with renal cell carcinoma who were treated with intravenous nivolumab in
combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No
overall difference in safety was reported between elderly patients and younger patients [see
Clinical Studies (14.1)].
11
DESCRIPTION
OPDIVO QVANTIG is a fixed-combination drug product containing nivolumab and
hyaluronidase (human recombinant).
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4
kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a
recombinant Chinese Hamster Ovary (CHO) cell line.
Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and
absorption of co-administered drugs when administered subcutaneously. Hyaluronidase (human
recombinant) is a glycosylated single-chain protein produced by CHO cells containing a DNA
79
Reference ID: 5503239
plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human
recombinant) has a molecular weight of approximately 61 kDa.
OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-free,
clear to opalescent, colorless to yellow solution that may contain a few translucent-to-white
particles, supplied in a single-dose vial for subcutaneous use.
Each 5 mL single-dose vial of OPDIVO QVANTIG contains 600 mg of nivolumab and 10,000
units of hyaluronidase (human recombinant), and the inactive ingredients: histidine (7.75 mg),
histidine hydrochloride monohydrate (10.5 mg), methionine (3.73 mg), pentetic acid (0.0985 mg),
polysorbate 80 (2.5 mg), sucrose (428 mg), and Water for Injection, USP. The pH is 5.5 to 6.5.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-
cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors
and signaling through this pathway can contribute to inhibition of active T-cell immune
surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody
that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1
pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is
depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural
components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days.
Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing
hyaluronan. In the doses administered, hyaluronidase in OPDIVO QVANTIG acts transiently and
locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is
restored within 24 to 48 hours.
12.2
Pharmacodynamics
Exposure-Response Relationship
The exposure-response relationship and time course of pharmacodynamics of OPDIVO
QVANTIG have not been fully characterized.
12.3
Pharmacokinetics
When comparing nivolumab exposures following OPDIVO QVANTIG to those of intravenous
nivolumab in CHECKMATE-67T [see Clinical Studies (14.1)], the geometric mean ratios
(GMRs) (90% CI) for time-averaged concentration (Cavg) over 28 days and at steady state were
2.10 (2.00, 2.20) and 1.98 (1.87, 2.11), respectively, and for minimum concentration (Cmin) at 28
days and at steady state were 1.60 (1.49, 1.72) and 1.77 (1.63, 1.93), respectively.
Steady state was achieved by 16 weeks. The systemic accumulation ratio was 2.3.
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Absorption
The geometric mean bioavailability (CV%) of nivolumab is 74% (14%). Peak concentrations
occurred by around 6 days.
Distribution
The geometric mean (CV%) volume of distribution at steady state is 6.8 L (27%).
Elimination
Nivolumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline
values of 24.5% (47.6%), resulting in a geometric mean steady-state clearance (CV%) of 8.2 mL/h
(53.9%) in patients with metastatic tumors; this decrease in clearance is not considered clinically
relevant. Nivolumab clearance does not decrease over time in patients with completely resected
melanoma, as the geometric mean population clearance is 24% lower in this patient population
compared with patients with metastatic melanoma at steady state.
The geometric mean (CV%) elimination half-life is 25 days (78%).
Specific Populations
Body weight (35 to 153 kg), sex, eGFR (24 to 124 mL/min/1.73 m2), and performance status have
no clinically significant effects on the clearance of nivolumab.
12.6
Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and
specificity of the assay. Differences in assay methods preclude meaningful comparisons of the
incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug
antibodies in other studies, including those of OPDIVO QVANTIG or of other nivolumab products
or hyaluronidase products.
During the 2-year treatment period in CHECKMATE-67T [see Clinical Studies (14.1)], 23%
(46/202) of patients who received OPDIVO QVANTIG developed anti-nivolumab antibodies
(ADA) and 4.3% (2/46) had neutralizing antibodies against nivolumab (NAb). The corresponding
incidence of ADA was 7% (15/215) and NAb was 0% (0/15) for intravenous nivolumab in the
same study. The incidence of anti-hyaluronidase antibodies in CHECKMATE-67T was 8.8%
(19/215); 5 (26%) of these 19 patients developed NAb.
Nivolumab clearance increased by approximately 26% in patients who received OPDIVO
QVANTIG and tested positive for ADA compared to patients who tested negative for ADA; this
change in clearance is not considered clinically significant. Local injection-site reactions were
reported in 15% (7/46) of patients who developed ADA to nivolumab and 7% (10/155) of patients
who did not develop ADA to nivolumab; however, all events were Grade 1 or 2 and resolved.
Because of low occurrence of anti-nivolumab or anti-hyaluronidase antibodies, the effect of ADA
on the effectiveness of OPDIVO QVANTIG is unknown.
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13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the potential of nivolumab for carcinogenicity or
genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month
repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female
reproductive organs; however, most animals in these studies were not sexually mature.
Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been
performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when
subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for
39 weeks at dose levels up to 220,000 U/kg, which is at least 600 times higher than the human
dose (U/kg basis), of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U
once every 4 weeks, no evidence of toxicity to the male or female reproductive system was found
through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual
cycles, and also from gross pathology, histopathology and organ weight data.
13.2
Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-1 signaling increased the severity of some infections and
enhanced inflammatory responses. Mycobacterium tuberculosis–infected PD-1 knockout mice
exhibit markedly decreased survival compared with wild-type controls, which correlated with
increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade
using a primate anti–PD-1 antibody was also shown to exacerbate M. tuberculosis infection in
rhesus macaques. PD-1 knockout mice have also shown decreased survival following infection
with lymphocytic choriomeningitis virus.
14
CLINICAL STUDIES
14.1
Advanced Renal Cell Carcinoma
Previously Treated Renal Cell Carcinoma – OPDIVO QVANTIG
The efficacy of OPDIVO QVANTIG was evaluated in CHECKMATE-67T (NCT04810078), a
multicenter, randomized, open-label study in patients with advanced or metastatic clear cell renal
cell carcinoma. Patients 18 years of age or older with histologically confirmed advanced or
metastatic renal cell carcinoma with a clear cell component, including those with sarcomatoid
features, and who received no more than 2 prior systemic treatment regimens were randomized to
receive OPDIVO QVANTIG (containing 1,200 mg of nivolumab and 20,000 units of
hyaluronidase) every 4 weeks subcutaneously, or nivolumab 3 mg/kg every 2 weeks intravenously.
Patients with untreated, symptomatic central nervous system (CNS) metastases; leptomeningeal
metastases; concurrent malignancies requiring treatment or history of prior malignancy within the
previous 2 years; active, known, or suspected autoimmune disease; or who received prior treatment
with a checkpoint inhibitor were excluded from the study. Patients with asymptomatic, stable CNS
metastases that did not require immediate treatment were eligible if there was no evidence of
progression within 28 days prior to the first dose of study drug administration. Stratification factors
for randomization were weight (<80 kg vs ≥80 kg) and International Metastatic Renal Cell
Carcinoma Database Consortium (IMDC) risk classification (favorable vs intermediate, vs poor
risk). The primary objective was to assess the nivolumab exposure of subcutaneous administration
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of OPDIVO QVANTIG as compared to the intravenous administration of nivolumab. The
secondary objective of the study was to evaluate overall response rate (ORR) by blinded
independent central review (BICR).
A total of 495 patients were randomized to receive either OPDIVO QVANTIG (n=248) or
intravenous nivolumab (n=247). The median age was 65 years (range: 20 to 93), with 51% ≥65
years of age and 14% ≥75 years of age; 68% male; 85% White, 12.5% not reported, 1% American
Indian or Alaska Native, 0.8% Asian, and 0.4% Black; 36% Hispanic or Latino, 33% not Hispanic
or Latino, and 31% not reported. Fifty-seven percent of patients weighed <80 kg and 43% weighed
≥80 kg. Baseline Karnofsky performance status was 70 (7%), 80 (20%), 90 (34%), or 100 (39%).
Patient distribution by IMDC risk categories was 21% favorable, 62% intermediate, and 17% poor.
When comparing subcutaneous administration of OPDIVO QVANTIG to the intravenous
administration of nivolumab, CHECKMATE-67T met the predefined acceptance margin for
pharmacokinetic endpoints, with the lower boundary of 90% confidence interval of geometric
mean ratios of not less than 0.8 for both serum nivolumab Cavg over 28 days and Cmin at steady
state. [see Clinical Pharmacology 12.3]. Efficacy results are shown in Table 45.
Table 45:
Efficacy Results - CHECKMATE-67T
OPDIVO QVANTIG
Intravenous Nivolumab
N=248
N=247
ORR per BICR, n (%)
60 (24)
45 (18)
95% CIa
(19, 30)
(14, 24)
a Confidence interval based on the Clopper and Pearson method.
RCC Trials - Intravenous Nivolumab
The effectiveness of OPDIVO QVANTIG has been established for the following:
as monotherapy, for advanced renal cell carcinoma (RCC) following treatment with
intravenous nivolumab and ipilimumab combination therapy (CHECKMATE-214 study).
in combination with cabozantinib, for the first-line treatment of adult patients with
advanced RCC (CHECKMATE-9ER study).
as monotherapy, for the treatment of adult patients with advanced RCC who have received
prior anti-angiogenic therapy (CHECKMATE-025 study).
Use of OPDIVO QVANTIG for these RCC indications is supported by evidence from adequate
and well-controlled studies conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab in the CHECKMATE-67T trial
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Below
is a description of the efficacy results of these adequate and well-controlled studies of intravenous
nivolumab in these RCC populations.
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Reference ID: 5503239
First-line Renal Cell Carcinoma
CHECKMATE-214
CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label trial in patients with
previously untreated advanced RCC. Patients were included regardless of their PD-L1 status.
CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active
autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were
stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and
region.
Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic
risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma
diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower
limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of
normal, and absolute neutrophil count greater than the upper limit of normal).
Patients were randomized to nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every
3 weeks for 4 doses followed by nivolumab 3 mg/kg intravenously every two weeks (n=425), or
sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued
until disease progression or unacceptable toxicity.
The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% ≥65
years of age and 8% ≥75 years of age. The majority of patients were male (73%) and White (87%)
and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.
The major efficacy outcome measures were OS, PFS (independent radiographic review committee
[IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this
population, the trial demonstrated statistically significant improvement in OS and ORR for patients
randomized to intravenous nivolumab and ipilimumab as compared with sunitinib (Table 46 and
Figure 1). OS benefit was observed regardless of PD-L1 expression level. The trial did not
demonstrate a statistically significant improvement in PFS. Efficacy results are shown in Table 46
and Figure 1.
Table 46:
Efficacy Results - CHECKMATE-214
Intermediate/Poor-Risk
Intravenous Nivolumab
and Ipilimumab
(n=425)
Sunitinib
(n=422)
Overall Survival
Deaths (%)
140 (32.9)
188 (44.5)
Median survival (months)
NRa
25.9
Hazard ratio (99.8% CI)b
0.63 (0.44, 0.89)
p-valuec,d
<0.0001
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Table 46:
Efficacy Results - CHECKMATE-214
Intermediate/Poor-Risk
Intravenous Nivolumab
and Ipilimumab
(n=425)
Sunitinib
(n=422)
Confirmed Overall Response Rate (95% CI)
41.6% (36.9, 46.5)
26.5% (22.4, 31.0)
p-valuee,f
<0.0001
Complete response (CR)
40 (9.4)
5 (1.2)
Partial response (PR)
137 (32.2)
107 (25.4)
Median duration of response (months) (95% CI)
NRa (21.8, NRa)
18.2 (14.8, NRa)
Progression-free Survival
Disease progression or death (%)
228 (53.6)
228 (54.0)
Median (months)
11.6
8.4
Hazard ratio (99.1% CI)a
0.82 (0.64, 1.05)
p-valuec
NSg
a Not Reached
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared to alpha 0.002 in order to achieve statistical significance.
e Based on the stratified DerSimonian-Laird test.
f p-value is compared to alpha 0.001 in order to achieve statistical significance.
g Not Significant at alpha level of 0.009.
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3
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Number of Subjects at Risk
Nivolumab + ipilimumab
425
399
372
Sunitinib
422
387
352
9
12
15
18
21
Overall Survival (Months)
348
332
318
300
241
315
288
253
225
179
24
119
89
27
44
34
30
2
3
-0-0
33
0
0
Figure 1:
Overall Survival (Intermediate/Poor Risk Population) -
CHECKMATE-214
CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to
intravenous nivolumab and ipilimumab (n=125) or to sunitinib (n=124). These patients were not
evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving
intravenous nivolumab and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI:
0.75, 2.81). The efficacy of intravenous nivolumab and ipilimumab in previously untreated renal
cell carcinoma with favorable-risk disease has not been established.
CHECKMATE-9ER
CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of intravenous
nivolumab combined with cabozantinib versus sunitinib in patients with previously untreated
advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical
conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic
86
Reference ID: 5503239
score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or
indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).
Patients were randomized to nivolumab 240 mg intravenously every 2 weeks and
cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a
6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until
disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond
RECIST-defined disease progression was permitted if the patient was clinically stable and
considered to be deriving clinical benefit by the investigator. Tumor assessments were performed
at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every
12 weeks thereafter.
The trial population characteristics were: median age 61 years (range: 28 to 90) with 38%
≥65 years of age and 10% ≥75 years of age. The majority of patients were male (74%) and
White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%,
respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate,
and 20% poor.
The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome
measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant
improvement in PFS, OS, and ORR for patients randomized to intravenous nivolumab and
cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre
specified subgroups of IMDC risk categories and PD-L1 tumor expression status. An updated OS
analysis was conducted when 271 deaths were observed based on the pre-specified number of
deaths for the pre-planned final analysis of OS. Efficacy results are shown in Table 47 and Figures
2 and 3.
Table 47:
Efficacy Results - CHECKMATE-9ER
Intravenous Nivolumab
and Cabozantinib
(n=323)
Sunitinib
(n=328)
Progression-free Survival
Disease progression or death (%)
144 (45)
191 (58)
Median PFS (months)a (95% CI)
16.6 (12.5, 24.9)
8.3 (7.0, 9.7)
Hazard ratio (95% CI)b
0.51 (0.41, 0.64)
p-valuec,d
<0.0001
Overall Survival
Deaths (%)
67 (21)
99 (30)
Median OS (months)a (95% CI)
NRe
NR (22.6, NRe)
Hazard ratio (98.89% CI)b
0.60 (0.40, 0.89)
p-valuec,d,f
0.0010
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Reference ID: 5503239
Table 47:
Efficacy Results - CHECKMATE-9ER
Intravenous Nivolumab
and Cabozantinib
(n=323)
Sunitinib
(n=328)
Updated Overall Survival
Deaths (%)
121 (37)
150 (46)
Median OS (months)a (95% CI)
37.7 (35.5, NR)
34.3 (29.0, NR)
Hazard ratio (95% CI)b
0.70 (0.55, 0.90)
Confirmed Objective Response Rate (95% CI)g
55.7% (50.1, 61.2)
27.1% (22.4, 32.3)
p-valueh
<0.0001
Complete Response
26 (8%)
15 (4.6%)
Partial Response
154 (48%)
74 (23%)
Median duration of response in months (95% CI)a
20.2 (17.3, NRe)
11.5 (8.3, 18.4)
a Based on Kaplan-Meier estimates.
b Stratified Cox proportional hazards model.
c Based on stratified log-rank test
d 2-sided p-values from stratified log-rank test.
e Not Reached
f p-value is compared with the allocated alpha of 0.0111 for this interim analysis
g CI based on the Clopper-Pearson method.
h 2-sided p-value from Cochran-Mantel-Haenszel test.
88
Reference ID: 5503239
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---e-- Sunitinib
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6
9
12
15
18
21
24
27
Progression Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + Cabozantinib
323
279
234
196
144
77
35
11
4
0
Sunitinib
328
228
159
122
79
31
10
4
1
0
Figure 2:
Progression-free Survival - CHECKMATE-9ER
89
Reference ID: 5503239
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6
9
12
15
18
21
24
27
30
33
36
39
42
45
Number of Subjects at Risk
Nivolumab + Cabozantinib
Overall Survival (Months)
323 310 297 284 270 258 247 235 219 199 138
Sunitinib
328 299 275 257 239 226 215 198 187 166 109
80
42
11
59
23
6
1
2
0
0
Figure 3:
Updated Overall Survival - CHECKMATE-9ER
In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable,
intermediate, intermediate/poor, and poor risk demonstrated a HR (95% CI) of 1.03 (0.55, 1.92),
0.74 (0.54, 1.01), 0.65 (0.50, 0.85), and 0.49 (0.31, 0.79), respectively.
Previously Treated Renal Cell Carcinoma
CHECKMATE-025
CHECKMATE-025 (NCT01668784) was a randomized (1:1), open-label trial in patients with
advanced RCC who had experienced disease progression during or after one or two prior anti
angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70%
and patients were included regardless of their PD-L1 status. The trial excluded patients with any
history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active
autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were
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Reference ID: 5503239
stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the
number of prior anti-angiogenic therapies. Patients were randomized to nivolumab 3 mg/kg by
intravenous infusion every 2 weeks (n=410) or everolimus 10 mg orally daily (n=411). The first
tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks
thereafter for the first year and then every 12 weeks until progression or treatment discontinuation,
whichever occurred later. The major efficacy outcome measure was overall survival (OS).
The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% ≥65
years of age and 9% ≥75 years of age. The majority of patients were male (75%) and White (88%)
and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.
The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient
distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.
The trial demonstrated a statistically significant improvement in OS for patients randomized to
intravenous nivolumab as compared with everolimus at the prespecified interim analysis when 398
events were observed (70% of the planned number of events for final analysis). OS benefit was
observed regardless of PD-L1 expression level. Efficacy results are shown in Table 48 and Figure
4.
Table 48:
Efficacy Results - CHECKMATE-025
Intravenous Nivolumab
(n=410)
Everolimus
(n=411)
Overall Survival
Deaths (%)
183 (45)
215 (52)
Median survival (months) (95% CI)
25.0 (21.7, NRa)
19.6 (17.6, 23.1)
Hazard ratio (95% CI)b
0.73 (0.60, 0.89)
p-valuec,d
0.0018
Confirmed Overall Response Rate (95% CI)
21.5% (17.6, 25.8)
3.9% (2.2, 6.2)
Median duration of response (months)
(95% CI)
23.0 (12.0, NRa)
13.7 (8.3, 21.9)
Median time to onset of confirmed response
(months) (min, max)
3.0 (1.4, 13.0)
3.7 (1.5, 11.2)
a Not Reached
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0148 of the allocated alpha for this interim analysis.
91
Reference ID: 5503239
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0.1
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0.0
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6
9
Number at Risk
Nivolumab
12
15
18
21
Overall Survival (Months)
410
389
359
337
305
275
213
139
Everolimus
24
27
73
29
411
366
324
287
265
241
187
115
61
20
30
3
2
33
0
0
Figure 4:
Overall Survival - CHECKMATE-025
14.2
Unresectable or Metastatic Melanoma
Previously Treated Metastatic Melanoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously
treated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is
supported by evidence from an adequate and well-controlled study conducted with intravenous
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of this adequate and well-controlled study of intravenous nivolumab in this
melanoma population.
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-037
92
Reference ID: 5503239
CHECKMATE-037 (NCT01721746) was a multicenter, open-label trial that randomized (2:1)
patients with unresectable or metastatic melanoma to receive nivolumab 3 mg/kg intravenously
every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine
1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 intravenously every 3 weeks
and paclitaxel 175 mg/m2 intravenously every 3 weeks. Patients were required to have progression
of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF
inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring
systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4
ipilimumab-related adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related
adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the
initiating event. Tumor assessments were conducted 9 weeks after randomization then every 6
weeks for the first year, and every 12 weeks thereafter.
Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120
patients who received intravenous nivolumab in CHECKMATE-037 and in whom the minimum
duration of follow-up was 6 months. The major efficacy outcome measures in this population were
confirmed overall response rate (ORR) as measured by blinded independent central review using
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.
Among the 120 patients treated with intravenous nivolumab, the median age was 58 years (range:
25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was 0
(58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive
(22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic
therapies for metastatic disease (68%).
The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and
34 partial responses in intravenous nivolumab-treated patients. Of 38 patients with responses, 87%
had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13
patients with ongoing responses of 6 months or longer.
There were responses in patients with and without BRAF V600 mutation-positive melanoma. A
total of 405 patients were randomized and the median duration of OS was 15.7 months (95% CI:
12.9, 19.9) in nivolumab-treated patients compared to 14.4 months (95% CI: 11.7, 18.2) (HR 0.95;
95.54% CI: 0.73, 1.24) in patients assigned to investigator’s choice of treatment. Figure 5
summarizes the OS results.
93
Reference ID: 5503239
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Nivolumab
0.1
- -e--- Investigator's Choice
0.0
0
3
6
9
Number of Subjects at Risk
Nivolumab
12
15
18
21
24
27
Overall Survival (Months)
272 230 208 178 158 138 123
112
103
71
Investigator's Choice
133
119
99
85
70
62
53
49
43
28
30
44
14
33
16
2
·---------
36
39
3
0
0
0
Figure 5:
Overall Survival - CHECKMATE-037*
*
The primary OS analysis was not adjusted to account for subsequent therapies, with 54
(40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may
be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors.
Previously Untreated Metastatic Melanoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of previously
untreated unresectable or metastatic melanoma. Use of OPDIVO QVANTIG for this indication is
supported by evidence from adequate and well-controlled studies conducted with intravenous
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of these adequate and well-controlled studies of intravenous nivolumab in this
melanoma population.
94
Reference ID: 5503239
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-066
CHECKMATE-066 (NCT01721772) was a multicenter, double-blind, randomized (1:1) trial in
418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were
randomized to receive either nivolumab 3 mg/kg by intravenous infusion every 2 weeks or
dacarbazine 1000 mg/m2 intravenously every 3 weeks until disease progression or unacceptable
toxicity. Randomization was stratified by PD-L1 status (≥5% of tumor cell membrane staining by
immunohistochemistry vs. <5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c).
Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous,
mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant
or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1;
absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The
trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after
randomization then every 6 weeks for the first year and then every 12 weeks thereafter. The major
efficacy outcome measure was overall survival (OS). Additional outcome measures included
investigator-assessed progression-free survival (PFS) and ORR per RECIST v1.1.
The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were
male, and 99.5% were White. Disease characteristics were M1c stage disease (61%), cutaneous
melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 ≥5% tumor cell
membrane expression (35%), and history of brain metastasis (4%). More patients in the
intravenous nivolumab arm had an ECOG performance status of 0 (71% vs. 58%).
CHECKMATE-066 demonstrated a statistically significant improvement in OS for the intravenous
nivolumab arm compared with the dacarbazine arm in an interim analysis based on 47% of the
total planned events for OS. At the time of analysis, 88% (63/72) of intravenous nivolumab-treated
patients had ongoing responses, which included 43 patients with ongoing response of 6 months or
longer. Efficacy results are shown in Table 49 and Figure 6.
Table 49:
Efficacy Results - CHECKMATE-066
Intravenous Nivolumab
(n=210)
Dacarbazine
(n=208)
Overall Survival
Deaths (%)
50 (24)
96 (46)
Median (months) (95% CI)
NRa
10.8 (9.3, 12.1)
Hazard ratio (95% CI)b
0.42 (0.30, 0.60)
p-valuec,d
<0.0001
Progression-free Survival
Disease progression or death (%)
108 (51)
163 (78)
Median (months) (95% CI)
5.1 (3.5, 10.8)
2.2 (2.1, 2.4)
95
Reference ID: 5503239
Table 49:
Efficacy Results - CHECKMATE-066
Intravenous Nivolumab
(n=210)
Dacarbazine
(n=208)
Hazard ratio (95% CI)b
0.43 (0.34, 0.56)
p-valuec,d
<0.0001
Overall Response Rate
34%
9%
(95% CI)
(28, 41)
(5, 13)
Complete response rate
4%
1%
Partial response rate
30%
8%
a Not Reached
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d p-value is compared with the allocated alpha of 0.0021 for this interim analysis.
96
Reference ID: 5503239
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3
6
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15
Number at Risk
Overall Survival (Months)
Nivolumab
210
185
150
105
45
8
Dacarbazine
208
177
123
82
22
3
18
0
0
Figure 6:
Overall Survival - CHECKMATE-066
CHECKMATE-067
CHECKMATE-067 (NCT01844505) was a multicenter, randomized (1:1:1), double-blind trial in
945 patients with previously untreated, unresectable or metastatic melanoma to one of the
following arms: intravenous nivolumab and ipilimumab, intravenous nivolumab, or ipilimumab.
Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior
to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of
active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring
systemic immunosuppression.
Patients were randomized to receive:
Nivolumab 1 mg/kg with ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses,
followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every
2 weeks (nivolumab and ipilimumab arm),
97
Reference ID: 5503239
Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm), or
Ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by placebo every
2 weeks (ipilimumab arm).
Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane
expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per
the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks
after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major
efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional
efficacy outcome measures were confirmed ORR and duration of response.
The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97%
White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage
IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%);
BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor cell membrane expression as
determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).
CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for
patients randomized to either intravenous nivolumab-containing arm as compared with the
ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to intravenous
nivolumab improves PFS or OS compared to intravenous nivolumab as a single agent. Efficacy
results are shown in Table 50 and Figure 7.
Table 50:
Efficacy Results - CHECKMATE-067
Intravenous
Nivolumab and
Ipilimumab
(n=314)
Intravenous
Nivolumab
(n=316)
Ipilimumab
(n=315)
Overall Survivala
Deaths (%)
128 (41)
142 (45)
197 (63)
Hazard ratiob (vs. ipilimumab)
(95% CI)
0.55
(0.44, 0.69)
0.63
(0.50, 0.78)
p-valuec, d
<0.0001
<0.0001
Progression-free Survivala
Disease progression or death
151 (48%)
174 (55%)
234 (74%)
Median (months)
(95% CI)
11.5
(8.9, 16.7)
6.9
(4.3, 9.5)
2.9
(2.8, 3.4)
Hazard ratiob (vs. ipilimumab)
(95% CI)
0.42
(0.34, 0.51)
0.57
(0.47, 0.69)
p-valuec, e
<0.0001
<0.0001
Confirmed Overall Response Ratea
50%
40%
14%
(95% CI)
(44, 55)
(34, 46)
(10, 18)
98
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Table 50:
Efficacy Results - CHECKMATE-067
Intravenous
Nivolumab and
Ipilimumab
(n=314)
Intravenous
Nivolumab
(n=316)
Ipilimumab
(n=315)
p-valuef
<0.0001
<0.0001
Complete response
8.9%
8.5%
1.9%
Partial response
41%
31%
12%
Duration of Response
Proportion ≥6 months in duration
76%
74%
63%
Range (months)
1.2+ to 15.8+
1.3+ to 14.6+
1.0+ to 13.8+
a OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and
ORR (secondary endpoint) results were based on primary analysis with 9 months of minimum follow-up.
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure),
then both p-values are considered significant.
e p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
f Based on the stratified Cochran-Mantel-Haenszel test.
+ Censored observation
99
Reference ID: 5503239
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9
Number of Subjects at Risk
Nivolumab
316
292 265 244
Nivolumab + lpilimumab
314 292 265 247
lpilimumab
315
285 254 228
A
Nivolumab
-* - Nivolumab + lpilimumab
- -0- - lpilimumab
-,
1
~1111111111.~
12
15
18
21
24
27
30
33
Overall Survival (Months)
230
213
201
191
181
175 157
55
226 221
209 200 198 192 170
49
205
182 164 149 136 129 104
34
36
3
7
4
39
0
0
0
Figure 7:
Overall Survival - CHECKMATE-067
Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR)
in the intravenous nivolumab and ipilimumab arm. The median OS was 36.9 months (95% CI:
28.3, NR) in the intravenous nivolumab arm and 19.9 months (95% CI: 16.9, 24.6) in the
ipilimumab arm.
Based on a minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9,
21.9) in the intravenous nivolumab and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the
intravenous nivolumab arm, and 2.9 months (95% CI: 2.8, 3.2) in the ipilimumab arm. Based on a
minimum follow-up of 28 months, the proportion of responses lasting ≥24 months was 55% in the
intravenous nivolumab and ipilimumab arm, 56% in the intravenous nivolumab arm, and 39% in
the ipilimumab arm.
100
Reference ID: 5503239
14.3
Adjuvant Treatment of Melanoma
The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of Stage
IIB, Stage IIC, Stage III, or Stage IV melanoma. Use of OPDIVO QVANTIG for this indication
is supported by evidence from adequate and well-controlled studies conducted with intravenous
nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a
description of the efficacy results of these adequate and well-controlled studies of intravenous
nivolumab in these melanoma populations.
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-76K
CHECKMATE-76K (NCT04099251) was a randomized, double-blind trial in 790 patients with
completely resected Stage IIB/C melanoma. Patients were randomized (2:1) to receive nivolumab
480 mg or placebo by intravenous infusion every 4 weeks for up to 1 year or until disease
recurrence or unacceptable toxicity. Enrollment required complete resection of the primary
melanoma with negative margins and a negative sentinel lymph node within 12 weeks prior to
randomization, and ECOG performance status of 0 or 1. The trial excluded patients with
ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic
treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other
immunosuppressive medications, as well as patients with prior therapy for melanoma except
surgery. Randomization was stratified by AJCC 8th staging system edition (T3b vs. T4a vs. T4b).
The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time
between the date of randomization and the date of first recurrence (local, regional, or distant
metastasis), new primary melanoma, or death, from any cause, whichever occurred first and as
assessed by the investigator. Tumor assessments were conducted every 26 weeks during years 1
3 and every 52 weeks thereafter until year 5.
The trial population characteristics were: median age 62 years (range: 19 to 92), 61% were male,
98% were White, 0.4% Black or African American, 0.1% Asian, and 1.1% race unknown, 2.2%
Hispanic or Latino, 58% Not Hispanic or Latino, 40% ethnicity unknown, and 94% had an ECOG
performance status of 0. Sixty one percent had stage IIB and 39% had stage IIC melanoma.
CHECKMATE-76K demonstrated a statistically significant improvement in RFS for patients
randomized to the intravenous nivolumab arm compared with the placebo arm. Efficacy results
are shown in Table 51 and Figure 8.
Table 51:
Efficacy Results - CHECKMATE-76K
Intravenous Nivolumab
n=526
Placebo
n=264
Recurrence-free Survival
Number of events, n (%)
66 (13%)
69 (26%)
Median (months)b
(95% CI)
NRa
(28.5, NR)
NRa
(21.6, NR)
101
Reference ID: 5503239
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Nivolumab
- --0- - Placebo
0
3
6
9
12
15
18
21
24
27
30
33
Recurrence Free Survival per Investigator (Months)
Number of Subjects at Risk
Nivolumab 480 mg Q4W
526
492
444
364
261
185
116
54
19
6
2
0
Placebo Q4W
264
243
205
161
119
77
40
20
11
3
2
0
Table 51:
Efficacy Results - CHECKMATE-76K
Intravenous Nivolumab
Placebo
n=526
n=264
Hazard ratioc
0.42
(95% CI)
p-valued
(0.30, 0.59)
p<0.0001
a Not reached.
b Based on Kaplan-Meier estimates.
c Hazard Ratio is intravenous nivolumab over placebo based on a stratified Cox proportional hazard model.
d Based on a 2-sided stratified log-rank test. Boundary for statistical significance: p-value <0.033.
Figure 8:
Recurrence-free Survival - CHECKMATE-76K
CHECKMATE-238
CHECKMATE-238 (NCT02388906) was a randomized, double-blind trial in 906 patients with
completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive
nivolumab 3 mg/kg by intravenous infusion every 2 weeks or ipilimumab 10 mg/kg intravenously
every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment
102
Reference ID: 5503239
required complete resection of melanoma with margins negative for disease within 12 weeks prior
to randomization. The trial excluded patients with a history of ocular/uveal melanoma,
autoimmune disease, and any condition requiring systemic treatment with either corticosteroids
(≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as
patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical
resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6
months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on
5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs.
Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined
as the time between the date of randomization and the date of first recurrence (local, regional, or
distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and
as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks
for the first 2 years then every 6 months thereafter.
The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were
male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics
were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600
mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 ≥5% tumor cell
membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%),
and tumor ulceration (32%).
CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients
randomized to the intravenous nivolumab arm compared with the ipilimumab 10 mg/kg arm.
Efficacy results are shown in Table 52 and Figure 9.
Table 52:
Efficacy Results - CHECKMATE-238
Intravenous Nivolumab
N=453
Ipilimumab 10 mg/kg
N=453
Recurrence-free Survival
Number of events, n (%)
154 (34%)
206 (45%)
Median (months)
(95% CI)
NRa
NRa
(16.56, NRa)
Hazard ratiob
(95% CI)
p-valuec,d
0.65
(0.53, 0.80)
p<0.0001
Overall Survival
Number of events, n (%)e
100 (22%)
111 (25%)
Median (months)
(95% CI)
NRa
NRa
Hazard ratiob
(95% CI)
p-value
0.87
(0.67, 1.14)
0.3148
103
Reference ID: 5503239
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0.1
O
lpilimumab
0.0
0
3
6
Number of Subjects at Risk
Nivolumab
453
399
353
lpilimumab 1 O mg/kg
453
364
314
9
12
15
18
Recurrence-Free Survival (Months)
332
311
291
249
269
252
225
184
21
71
56
24
5
2
27
0
0
a Not reached.
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0244 of the allocated alpha for this analysis.
e At the time of the final OS analysis, fewer overall survival events were observed than originally anticipated
(approximately 302).
Figure 9:
Recurrence-free Survival - CHECKMATE-238
14.4
Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer
The effectiveness of OPDIVO QVANTIG has been established for the neoadjuvant treatment of
resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum doublet
chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from
adequate and well-controlled studies conducted with intravenous nivolumab (CHECKMATE-816,
NCT02998528), and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
104
Reference ID: 5503239
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of the adequate and well-controlled study of intravenous nivolumab in this lung
cancer population.
CHECKMATE-816
CHECKMATE-816 (NCT02998528) was a randomized, open label trial in patients with resectable
NSCLC. The trial included patients with resectable, histologically confirmed Stage IB (≥4 cm), II,
or IIIA NSCLC (per the 7th edition American Joint Committee on Cancer/Union for International
Cancer Control (AJCC/UICC) staging criteria), ECOG performance status 0 or 1, and measurable
disease (per RECIST version 1.1). Patients with unresectable or metastatic NSCLC, known EGFR
mutations or ALK translocations, Grade 2 or greater peripheral neuropathy, active autoimmune
disease, or medical conditions requiring systemic immunosuppression were excluded from the
study.
Patients were randomized to receive either:
nivolumab 360 mg administered intravenously over 30 minutes and platinum-doublet
chemotherapy administered intravenously every 3 weeks for up to 3 cycles, or
platinum-doublet chemotherapy administered every 3 weeks for up to 3 cycles.
Platinum-doublet chemotherapy consisted of paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin
AUC 5 or AUC 6 (any histology); pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (non-squamous
histology); or gemcitabine 1000 mg/m2 or 1250 mg/m2 and cisplatin 75 mg/m2 (squamous
histology). In the platinum-doublet chemotherapy arm, two additional treatment regimen options
included vinorelbine 25 mg/m2 or 30 mg/m2 and cisplatin 75 mg/m2; or docetaxel 60 mg/m2 or
75 mg/m2 and cisplatin 75 mg/m2 (any histology).
Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or
non-quantifiable), disease stage (IB/II versus IIIA), and sex (male versus female). Tumor
assessments were performed at baseline, within 14 days of surgery, every 12 weeks after surgery
for 2 years, then every 6 months for 3 years, and every year for 5 years until disease recurrence or
progression. The major efficacy outcome measures were event-free survival (EFS) based on
blinded independent central review (BICR) assessment and pathologic complete response (pCR)
as evaluated by blinded independent pathology review (BIPR). Additional efficacy outcome
measures included OS.
A total of 358 patients were randomized to receive either intravenous nivolumab in combination
with platinum-doublet chemotherapy (n=179) or platinum-doublet chemotherapy (n=179). The
median age was 65 years (range: 34 to 84) with 51% of patients ≥65 years and 7% of patients ≥75
years, 50% were Asian, 47% were White, 2% were Black, and 71% were male. Baseline ECOG
performance status was 0 (67%) or 1 (33%); 50% had tumors with PD-L1 expression ≥1%; 35%
had stage IB/II and 64% had stage IIIA disease; 51% had tumors with squamous histology and
49% had tumors with non-squamous histology; and 89% were former/current smokers.
105
Reference ID: 5503239
Eighty-three percent of patients in the intravenous nivolumab in combination with platinum-
doublet chemotherapy arm had definitive surgery compared to 75% of patients in the platinum-
doublet chemotherapy arm.
The study demonstrated statistically significant improvements in EFS and pCR. Efficacy results
are presented in Table 53 and Figure 10.
Table 53:
Efficacy Results - CHECKMATE-816
Intravenous Nivolumab and
Platinum-Doublet
Chemotherapy
(n=179)
Platinum-Doublet
Chemotherapy
(n=179)
Event-free Survival (EFS) per BICR
Events (%)
64 (35.8)
87 (48.6)
Median (months)a
(95% CI)
31.6
(30.2, NR)
20.8
(14.0, 26.7)
Hazard Ratiob
(95% CI)
0.63
(0.45, 0.87)
Stratified log-rank p-valuec
0.0052
Pathologic Complete Response (pCR) per BIPR
Number of patients with pCR
43
4
pCR Rate (%), (95% CI)d
24.0 (18.0, 31.0)
2.2 (0.6, 5.6)
Estimated treatment difference
(95% CI)e
21.6 (15.1, 28.2)
p-valuef
<0.0001
Minimum follow-up for EFS was 21 months.
a Kaplan-Meier estimate.
b Based on a stratified Cox proportional hazard model.
c Based on a stratified log-rank test. Boundary for statistical significance: p-value <0.0262.
d Based on Clopper and Pearson method.
e Strata-adjusted difference based on Cochran-Mantel-Haenszel method of weighting.
f From stratified CMH test.
106
Reference ID: 5503239
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0
~
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~
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0
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1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
O
Nivolumab + platinum-doublet chemotherapy
- -A- - Platinum-doublet chemotherapy
0
3
6
9 12 15 18 21 2 4 27 30 33 36 39 42
Event Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + platinum-doublet chemotherapy
179 151 136 124 118 107 102 87 74 41
34 13
6
3
0
Platinum-doublet chemotherapy
179 144 126 109 94 83 75 61
52 26 24 13 11
4
0
Figure 10:
Event-Free Survival - CHECKMATE-816
At the time of the EFS analysis, 26% of the patients had died. A prespecified interim analysis for
OS resulted in a HR of 0.57 (95% CI: 0.38, 0.87), which did not cross the boundary for statistical
significance.
14.5
Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell
Lung Cancer
The effectiveness of OPDIVO QVANTIG has been established for neoadjuvant treatment of
resectable (tumors ≥4 cm or node positive) NSCLC and no EGFR mutations or ALK
rearrangements in combination with platinum doublet chemotherapy followed by adjuvant
treatment with intravenous nivolumab. Use of OPDIVO QVANTIG for this indication is supported
by evidence from adequate and well-controlled studies conducted with intravenous nivolumab
(CHECKMATE-77T, NCT04025879), and additional pharmacokinetic and safety data that
107
Reference ID: 5503239
demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and
intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below
is a description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this lung cancer population.
CHECKMATE-77T
The efficacy of intravenous nivolumab, in combination with platinum-doublet chemotherapy,
followed by surgery, and continued adjuvant treatment with intravenous nivolumab as a single
agent, was investigated in CHECKMATE-77T (NCT04025879), a randomized, double-blind trial
in 461 patients with resectable NSCLC. The trial included patients with resectable, suspected or
histologically confirmed Stage IIA (>4 cm) to IIIB (T3-T4 N2) NSCLC (per the 8th edition
American Joint Committee on Cancer (AJCC) Staging Manual), and ECOG performance status 0
or 1. Patients with unresectable or metastatic NSCLC, EGFR mutations or known ALK
translocations, brain metastasis, Grade 2 or greater peripheral neuropathy, interstitial lung disease
or active, non-infectious pneumonitis (symptomatic and/or requiring treatment), active
autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded
from the study. Randomization was stratified by tumor PD-L1 expression level (≥1% versus <1%
versus indeterminate/not evaluable), disease stage (Stage II versus Stage III), and tumor histology
(squamous versus nonsquamous).
Patients were randomized (1:1) to receive either:
Neoadjuvant nivolumab 360 mg administered intravenously over 30 minutes in
combination with one of the following platinum-doublet chemotherapy regimens every 3
weeks for four cycles:
o Paclitaxel 175 mg/m2 or 200 mg/m2 and carboplatin AUC 5 or AUC 6 (any
histology)
o Pemetrexed 500 mg/m2, and cisplatin 75 mg/m2 or carboplatin AUC 5 or AUC 6
(nonsquamous histology)
o Cisplatin 75 mg/m2 and docetaxel 75 mg/m2 (squamous histology).
Within 90 days after the surgery, nivolumab 480 mg was administered intravenously over
30 minutes every 4 weeks.
or
Neoadjuvant placebo administered intravenously over 30 minutes in combination with
platinum-doublet chemotherapy (see above) every 3 weeks for four cycles. Within 90 days
after the surgery, placebo was administered intravenously over 30 minutes every 4 weeks.
All study medications were administered via intravenous infusion. Treatment continued until
disease progression, recurrence, or unacceptable toxicity for up to 13 cycles (1 year). Tumor
assessments were performed every 12 weeks for 2 years, then every 24 weeks for up to 5 years or
until disease recurrence or progression was confirmed by BICR.
The trial was not designed to isolate the effect of intravenous nivolumab in each phase
(neoadjuvant or adjuvant) of treatment.
108
Reference ID: 5503239
The major efficacy outcome measure was event-free survival (EFS) based on BICR assessment.
Additional efficacy outcome measures included overall survival (OS), pathologic complete
response (pCR), and major pathologic response (MPR).
The median age was 66 years (range: 35 to 86); 71% were male; 72% were White, 25% were
Asian, 1.7% were Black, and 1.5% were mixed race/ race unknown/ not reported; and 6% were
Hispanic or Latino. Baseline ECOG performance status was 0 (62%) or 1 (38%); 56% had tumors
with PD-L1 expression ≥1% and 40% had tumors with PD-L1 expression <1%; 35% had stage II
and 64% had stage III disease; 23% had N1 disease and 39% had N2 disease; 51% had tumors
with squamous histology and 49% had tumors with nonsquamous histology; and 90% were
former/current smokers.
Seventy-eight percent of patients in the neoadjuvant intravenous nivolumab in combination with
platinum-doublet chemotherapy followed by adjuvant intravenous nivolumab arm had definitive
surgery compared to 77% of patients in the neoadjuvant placebo and platinum-doublet
chemotherapy followed by placebo arm.
The study demonstrated a statistically significant improvement in EFS for patients treated with
neoadjuvant intravenous nivolumab in combination with platinum-doublet chemotherapy followed
by single agent intravenous nivolumab compared with patients randomized to placebo in
combination with platinum-doublet chemotherapy followed by placebo. Efficacy results are
presented in Table 54 and Figure 11.
Table 54:
Efficacy Results - CHECKMATE-77T
Neoadjuvant Intravenous
Nivolumab and Platinum-
Doublet
Chemotherapy/Adjuvant
Intravenous Nivolumab
(n=229)
Neoadjuvant Placebo and
Platinum-Doublet
Chemotherapy/Adjuvant
Placebo
(n=232)
Event-free Survival (EFS) per BICR
Events (%)
76 (33%)
113 (49%)
Median (months)a
(95% CI)
NR
(28.9, NR)
18.4
(13.6, 28.1)
Hazard Ratiob
(95% CI)
0.58
(0.43, 0.78)
Stratified log-rank p-valuec
0.00025
a Kaplan-Meier estimate.
b Based on a stratified Cox proportional hazard model.
c Based on a stratified log-rank test. Boundary for statistical significance: p-value <0.0264.
109
Reference ID: 5503239
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~ 0.9
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~
·c:
0.7
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;
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0 a:
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A
Nivolumab + platinum-doublet chemotherapy/Nivolumab
- -e-- Placebo + platinum-doublet chemotherapy/Placebo
0.0 .............. ..,.....,...... ............................ ..,.....,.........,......,.... .............. ..,.....,.........,......,.... .............. ..,.....,...... ........................... ..,.....,...... ...................................
0
3
6
9 12 15 18 21
24 27 30 33 36 39 42
Event Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + platinum-doublet chemotherapy/Nivolumab
229 208 173 157 141 134 115 89 69 46 20
7
4
2
0
Placebo + platinum-doublet chemotherapy/Placebo
232 204 165 138 118 106 78 59 44 29 19 10
6
1
0
Figure 11:
Event-Free Survival - CHECKMATE-77T
In a pre-specified descriptive analysis, the pCR rate was 25% (95% CI: 20, 31) in the intravenous
nivolumab arm and 4.7% (95% CI: 2.4, 8) in the placebo arm.
At the time of the EFS analysis, OS data were immature.
14.6
Metastatic Non-Small Cell Lung Cancer
Second-line Treatment of Metastatic NSCLC
The effectiveness of OPDIVO QVANTIG has been established for the treatment of NSCLC
previously treated with platinum-based chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved therapy for these aberrations
prior to receiving OPDIVO QVANTIG. Use of OPDIVO QVANTIG for this indication is
supported by evidence from adequate and well-controlled studies conducted with intravenous
110
Reference ID: 5503239
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
efficacy results of this adequate and well-controlled study of intravenous nivolumab in this lung
cancer population.
CHECKMATE-017
CHECKMATE-017 (NCT01642004) was a randomized (1:1), open-label trial in 272 patients with
metastatic squamous NSCLC who had experienced disease progression during or after one prior
platinum doublet-based chemotherapy regimen. Patients received nivolumab 3 mg/kg by
intravenous infusion every 2 weeks (n=135) or docetaxel 75 mg/m2 intravenously every 3 weeks
(n=137). Randomization was stratified by prior paclitaxel vs. other prior treatment and region
(US/Canada vs. Europe vs. Rest of World). This trial included patients regardless of their PD-L1
status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic
immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients
with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks
prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg
daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after
randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was
OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.
The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% ≥65
years of age and 11% ≥75 years of age. The majority of patients were White (93%) and male
(76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada
(32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%)
and 92% were former/current smokers. Baseline disease characteristics of the population as
reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All
patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors
of squamous-cell histology.
The trial demonstrated a statistically significant improvement in OS for patients randomized to
intravenous nivolumab as compared with docetaxel at the prespecified interim analysis when 199
events were observed (86% of the planned number of events for final analysis). Efficacy results
are shown in Table 55 and Figure 12.
Table 55:
Efficacy Results - CHECKMATE-017
Intravenous Nivolumab
(n=135)
Docetaxel
(n=137)
Overall Survival
Deaths (%)
86 (64%)
113 (82%)
Median (months)
(95% CI)
9.2
(7.3, 13.3)
6.0
(5.1, 7.3)
Hazard ratio (95% CI)a
0.59 (0.44, 0.79)
111
Reference ID: 5503239
Table 55:
Efficacy Results - CHECKMATE-017
Intravenous Nivolumab
(n=135)
Docetaxel
(n=137)
p-valueb,c
0.0002
Overall Response Rate
27 (20%)
12 (9%)
(95% CI)
(14, 28)
(5, 15)
p-valued
0.0083
Complete response
1 (0.7%)
0
Median duration of response (months)
(95% CI)
NRe
(9.8, NRe)
8.4
(3.6, 10.8)
Progression-free Survival
Disease progression or death (%)
105 (78%)
122 (89%)
Median (months)
3.5
2.8
Hazard ratio (95% CI)a
0.62 (0.47, 0.81)
p-valueb
0.0004
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with .0315 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached
112
Reference ID: 5503239
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.. ,._,.lil,o.-q,
·---GJ-ED--------ee
- --0- - Docetaxel
3
6
9
12
15
18
21
24
Number at Risk
Overall Survival (Months)
Nivolumab
135
113
86
69
52
31
15
7
0
Docetaxel
137
103
68
45
30
14
7
2
0
Figure 12:
Overall Survival - CHECKMATE-017
Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial
population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with
quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells
expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC defined as ≥1% of tumor cells
expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival
were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in
the PD-L1 positive subgroup.
CHECKMATE-057
CHECKMATE-057 (NCT01673867) was a randomized (1:1), open-label trial in 582 patients with
metastatic non-squamous NSCLC who had experienced disease progression during or after one
prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in
patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients
113
Reference ID: 5503239
received nivolumab 3 mg/kg by intravenous infusion every 2 weeks (n=292) or docetaxel
75 mg/m2 intravenously every 3 weeks (n=290). Randomization was stratified by prior
maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded
patients with autoimmune disease, medical conditions requiring systemic immunosuppression,
symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain
metastases were eligible if neurologically stable. The first tumor assessments were conducted 9
weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome
measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.
In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.
The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients
≥65 years and 7% of patients ≥75 years. The majority of patients were White (92%) and male
(55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%)
and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79%
were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with
EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included
platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line
regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and
bronchoalveolar (0.9%).
CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients
randomized to intravenous nivolumab as compared with docetaxel at the prespecified interim
analysis when 413 events were observed (93% of the planned number of events for final analysis).
Efficacy results are shown in Table 56 and Figure 13.
Table 56:
Efficacy Results - CHECKMATE-057
Intravenous Nivolumab
(n=292)
Docetaxel
(n=290)
Overall Survival
Deaths (%)
190 (65%)
223 (77%)
Median (months)
(95% CI)
12.2
(9.7, 15.0)
9.4
(8.0, 10.7)
Hazard ratio (95% CI)a
0.73 (0.60, 0.89)
p-valueb,c
0.0015
Overall Response Rate
56 (19%)
36 (12%)
(95% CI)
(15, 24)
(9, 17)
p-valued
0.02
Complete response
4 (1.4%)
1 (0.3%)
Median duration of response (months)
(95% CI)
17
(8.4, NRe)
6
(4.4, 7.0)
Progression-free Survival
114
Reference ID: 5503239
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0.9
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A
Nivolumab
- --0- - Docetaxel
3
6
9
"\ ... ......
12
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15
18
Number at Risk
Overall Survival (Months)
Nivolumab
292
232
194
169
146
123
62
Docetaxel
290
244
194
150
111
88
34
21
24
27
32
9
0
10
5
0
Table 56:
Efficacy Results - CHECKMATE-057
Intravenous Nivolumab
(n=292)
Docetaxel
(n=290)
Disease progression or death (%)
234 (80%)
245 (84%)
Median (months)
2.3
4.2
Hazard ratio (95% CI)a
0.92 (0.77, 1.11)
p-valueb
0.39
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with .0408 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached.
Figure 13:
Overall Survival - CHECKMATE-057
115
Reference ID: 5503239
PD-L 1 expression level
:2:1 % (n = 246)
<1% (n = 209)
:2:5%
(n = 181)
<5% (n = 274)
:2:10% (n = 165)
<10% (n = 290)
0.25
•
•
•
0.5
1.0
Favors Nivolumab +-
PD-L 1 expression level
:2:1 % (n = 246)
•
<1% (n = 209)
:2:5%
(n = 181)
•
<5% (n=274)
:2: 10% (n = 165)
•
<10% (n = 290)
0.25
0.5
1.0
Favors Nivolumab +-
Median OS (months)
Unstratified HR Nivolumab Docetaxel
0.59
17.1
9.0
0.90
10.4
10.1
0.43
18.2
8.1
1.01
9.7
10.1
0.40
19.4
8.0
1.00
9.9
10.3
2.0
Median PFS (months)
Unstratified HR Nivolumab Docetaxel
2.0
0.70
4.2
4.5
1.19
2.1
3.6
0.54
5.0
3.8
1.31
0.52
1.24
2.1
5.0
2.1
4.2
3.6
4.2
Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial.
Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining
455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1
testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of
tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as ≥1% of tumor cells
expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had ≥1% but <5%
tumor cells with positive staining, 7% had ≥5% but <10% tumor cells with positive staining, and
67% had ≥10% tumor cells with positive staining. Figures 14 and 15 summarize the results of
prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells
expressing PD-L1.
Figure 14:
Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057
Figure 15:
Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057
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Reference ID: 5503239
14.7
Recurrent or Metastatic Squamous Cell Carcinoma of the Head and
Neck
The effectiveness of OPDIVO QVANTIG has been established for the treatment of recurrent or
metastatic squamous cell carcinoma of the head and neck with disease progression on or after
platinum-based therapy. Use of OPDIVO QVANTIG for this indication is supported by evidence
from an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this head and neck carcinoma population.
CHECKMATE-141
CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label trial
enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression
during or within 6 months of receiving platinum-based therapy administered in either the adjuvant,
neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded
patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or
metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology,
salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain
metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients
were randomized to receive nivolumab 3 mg/kg by intravenous infusion every 2 weeks or
investigator’s choice of cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2
weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2
intravenously weekly).
Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments
were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major
efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.
A total of 361 patients were randomized; 240 patients to the intravenous nivolumab arm and
121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab:
12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with
31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline
ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had
Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining
55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors,
24% had HPV p16-negative tumors, and 51% had unknown status.
The trial demonstrated a statistically significant improvement in OS for patients randomized to
intravenous nivolumab as compared with investigator’s choice at a pre-specified interim analysis
(78% of the planned number of events for final analysis). There were no statistically significant
differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95%
CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively).
Efficacy results are shown in Table 57 and Figure 16.
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Reference ID: 5503239
Table 57:
Overall Survival - CHECKMATE-141
Intravenous Nivolumab
(n=240)
Cetuximab, Methotrexate or
Docetaxel
(n=121)
Overall Survival
Deaths (%)
133 (55%)
85 (70%)
Median (months)
(95% CI)
7.5
(5.5, 9.1)
5.1
(4.0, 6.0)
Hazard ratio (95% CI)a
0.70 (0.53, 0.92)
p-valueb,c
0.0101
a Based on stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with 0.0227 of the allocated alpha for this interim analysis.
118
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1.0
1.,
0.9
0.8
1.'
0.7
ro
>
-~ 0.6
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:.c
15 0.4
0 '-
a.. 0.3
0.2
0.1
---- Nivolumab
--• -- Inv Choice
0.0
0
3
Number at Risk
Nivolumab
240
167
INV Choice
121
87
6
9
L
-
-
,
I
.t.- ' . - ....... - '
'
L -
-
-
-,
'
... -
-
- .t.- -
.t.
12
15
Overall Survival (Months)
109
52
24
7
42
17
5
1
18
0
0
Figure 16:
Overall Survival - CHECKMATE-141
Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1
IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-
quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1
negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD
L1 positive SCCHN, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory
subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median
survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the
PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median
survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the
PD-L1 positive SCCHN subgroup.
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14.8
Urothelial Carcinoma
Adjuvant Treatment of Urothelial Carcinoma (UC) at High Risk of Recurrence
The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of UC
at high risk of recurrence. Use of OPDIVO QVANTIG for this indication is supported by evidence
from an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this UC population.
CHECKMATE-274
CHECKMATE-274 (NCT02632409) was a randomized, double-blind, placebo-controlled study
of adjuvant intravenous nivolumab in patients who were within 120 days of radical resection (R0)
of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High
risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received
neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin
and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1
to receive nivolumab 240 mg or placebo by intravenous infusion every 2 weeks until recurrence
or until unacceptable toxicity for a maximum treatment duration of 1 year. Patients were stratified
by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ≥10 nodes removed),
tumor cells expressing PD-L1 (≥1% vs. <1%/indeterminate as determined by the central lab using
the PD-L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).
The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male;
76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335
(47%) of patients with node-positive UC, 44 (6%) had non–muscle-invasive (<pT2) primary
tumors. ECOG performance status was 0 (63%), 1 (35%), or 2 (2%). Prior neoadjuvant cisplatin
had been given to 43% of patients; of the 57% who did not receive prior neoadjuvant cisplatin,
reasons listed were ineligibility (22%), patient preference (33%), and other/not reported (2%).
Tumor PD-L1 expression was ≥1% in 40% of patients, and 21% of patients had upper tract UC.
The major efficacy outcome measures were investigator-assessed DFS in all randomized patients
and in patients with tumors expressing PD-L1 ≥1%. DFS was defined as time to first recurrence
(local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy
outcome measures included OS.
At the pre-specified interim analysis, CHECKMATE-274 demonstrated a statistically significant
improvement in DFS for patients randomized to intravenous nivolumab vs. placebo in the all
randomized patient population, as well as in the subpopulation of patients with PD-L1 ≥1%, as
shown in Table 58 and Figure 17.
In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS
was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard
ratio estimate was 1.15 (95% CI: 0.74, 1.80).
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In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the
unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64, 1.08).
OS data is immature with 33% of deaths in the overall randomized population. In the UTUC
subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).
Table 58:
Efficacy Results - CHECKMATE-274
All Randomized
PD-L1 ≥1%
Intravenous
Nivolumab
(n=353)
Placebo
(n=356)
Intravenous
Nivolumab
(n=140)
Placebo
(n=142)
Disease-free Survival
Eventsa, n (%)
Local recurrence
Distant recurrence
Death
170 (48)
47 (13)
108 (31)
14 (4)
204 (57)
64 (18)
127 (36)
10 (3)
55 (39)
10 (7)
40 (29)
5 (4)
81 (57)
24 (17)
52 (37)
5 (4)
Median DFS (months)b
(95% CI)
20.8
(16.5, 27.6)
10.8
(8.3, 13.9)
N.R.
(21.2, N.E.)
8.4
(5.6, 21.2)
Hazard ratioc
(95% CI)
0.70
(0.57, 0.86)
0.55
(0.39, 0.77)
p-value
0.0008d
0.0005e
N.R. Not reached, N.E. Not estimable
a Includes disease at baseline events (protocol deviations): n=1 in intravenous nivolumab arm and n=3 in placebo
arm.
b Based on Kaplan-Meier estimates.
c Stratified Cox proportional hazard model. Hazard ratio is intravenous nivolumab over placebo.
d Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status, PD-L1 status (≥1% vs
<1%/indeterminate). Boundary for statistical significance in all randomized patients: p-value <0.01784.
e Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status. Boundary for statistical
significance in all randomized patients with PD-L1 ≥1%: p-value <0.01282.
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353 296 244 212 178 154 126 106 85 68 57 51
36 23 20
3
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0
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356 248 198 157 134 121 105 94 80 65 54 50 37 22 19 10
2 0
Figure 17: Disease-free Survival in All Randomized Patients - CHECKMATE-274
First-line Treatment of Unresectable or Metastatic UC
The effectiveness of OPDIVO QVANTIG has been established for the first-line treatment of
unresectable or metastatic UC in combination with cisplatin and gemcitabine. Use of OPDIVO
QVANTIG for this indication is supported by evidence from an adequate and well-controlled study
conducted with intravenous nivolumab, and additional pharmacokinetic and safety data that
demonstrated comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and
intravenous nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below
is a description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this UC population.
CHECKMATE-901
CHECKMATE-901 (NCT 03036098) was a randomized, open-label study in patients with
previously untreated unresectable or metastatic UC. Prior neoadjuvant or adjuvant chemotherapy
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Reference ID: 5503239
were permitted as long as the disease recurrence took place ≥12 months from completion of
therapy. Patients who were ineligible for cisplatin and those with active CNS metastases were
excluded. Stratification factors for randomization were PD-L1 status (≥1% vs. <1% or
indeterminate) and liver metastasis. Patients were randomized 1:1 to receive either:
Intravenous nivolumab 360 mg and cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000
mg/m2 on Days 1 and 8 of a 21-day cycle of a 21-day cycle for up to 6 cycles followed by
single-agent intravenous nivolumab 480 mg every 4 weeks until disease progression or
unacceptable toxicity. In the absence of disease progression or unacceptable toxicity,
intravenous nivolumab was continued for up to 2 years from first dose.
Cisplatin 70 mg/m2 on Day 1 and gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day
cycle for up to 6 cycles, until disease progression or unacceptable toxicity.
The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST v1.1.
Additional efficacy outcome measures included ORR as assessed by BICR.
The median age was 65 years of age (range: 32 to 86) with 51% of patients ≥65 years of age and
12% of patients ≥75 years of age, 23% were Asian, 72% were White, 0.3% were Black, 0.3% were
American Indian or Alaska Native, 4.9% were Other, 12% were Hispanic or Latino, and 77% were
male. Baseline ECOG performance status was 0 (53%) or 1 (46%). At baseline, 87% of patients
had metastatic UC, including 20% with liver metastases, 11% had locally advanced UC, and 51%
had UC histologic variants. Forty-nine (16%) in the intravenous nivolumab in combination with
cisplatin-based chemotherapy arm and 43 (14%) in the cisplatin-based chemotherapy arm switched
from cisplatin to carboplatin after at least one cycle of cisplatin.
Efficacy results are presented in Table 59 and Figures 18 and 19.
Table 59:
Efficacy Results – CHECKMATE 901
Intravenous Nivolumab and
Cisplatin and Gemcitabine
(n=304)
Cisplatin and Gemcitabine
(n=304)
Overall Survival (OS)
Events, n (%)
172 (56.6)
193 (63.5)
Median (months)
(95% CI)a
21.7
(18.6, 26.4)
18.9
(14.7, 22.4)
Hazard ratio
(95% CI)b
0.78
(0.63, 0.96)
p-valuec
0.0171
Progression-free Survival (PFS)d
Events, n (%)
211 (69.4)
191 (62.8)
Median (months)
(95% CI)a
7.9
(7.6, 9.5)
7.6
(6.0, 7.8)
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Table 59:
Efficacy Results – CHECKMATE 901
Intravenous Nivolumab and
Cisplatin and Gemcitabine
(n=304)
Cisplatin and Gemcitabine
(n=304)
Hazard ratio
(95% CI)b
0.72
(0.59, 0.88)
p-valuec
0.0012
Objective Response Rate (ORR)d
Response rate, n (%)
(95% CI)
175 (57.6%)
(51.8, 63.2)
131 (43.1%)
(37.5, 48.9)
Complete response rate, n (%)
66 (22%)
36 (12%)
Partial response rate, n (%)
109 (36%)
95 (31%)
Duration of Response (DoR)
Median (months)
(95% CI)a
9.5
(7.6, 15.1)
7.3
(5.7, 8.9)
a Based on Kaplan-Meier Estimates
b Stratified Cox proportional hazard model.
c 2 sided p values from stratified log-rank test.
d Assessed by BICR.
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Nivolumab with gemcitabine+cisplatin
- -0-- - Gemcitabine+cisplatin
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Overall Survival (Months)
Number of Subjects at Risk
Nivolumab with gemcitabine+cisplatin
304 286 264 228 196 167 142 119 97 84 69 58 48 36 25 20 15 12 7 4 2 0
Gemcitabine + cisplatin
304 277 242 208 166 140 122 102 82 65 49 39 33 24 17 16 13 9 4 4 1 0
Figure 18:
Overall Survival - CHECKMATE-901
125
Reference ID: 5503239
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Progression Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab with gemcitabine+cisplatin
304 253 179 116 82 65 57 49 41
36 31
26 19 14 11
10 6 5 1 0
Gemcitabine + cisplatin
304 223 119 63 35 25 17 12 10 9 8 6 5 2 1 1 0 0 0 0
Figure 19:
Progression-free Survival - CHECKMATE-901
Previously Treated Advanced or Metastatic Urothelial Carcinoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of patients with
locally advanced or metastatic UC and disease progression during or following platinum-
containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence
from an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this UC population.
CHECKMATE-275
CHECKMATE-275 (NCT02387996) was a single-arm trial in 270 patients with locally advanced
or metastatic UC who had disease progression during or following platinum-containing
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Reference ID: 5503239
chemotherapy or who had disease progression within 12 months of treatment with a platinum-
containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain
or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic
immunosuppression, and ECOG performance status >1. Patients received nivolumab 3 mg/kg by
intravenous infusion every 2 weeks until unacceptable toxicity or either radiographic or clinical
progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks
and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as
assessed by IRRC using RECIST v1.1 and DOR.
The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven
percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four
percent of patients had disease progression following prior platinum-containing neoadjuvant or
adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the
metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior
carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting.
Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients
had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline.
Patients were included regardless of their PD-L1 status.
Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a
central laboratory and the results were used to define subgroups for pre-specified analyses. Of the
270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor
cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1
expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all
patients and the two PD-L1 subgroups are shown in Table 60. Median time to response was 1.9
months (range: 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant
or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).
Table 60:
Efficacy Results - CHECKMATE-275
All Patients
N=270
PD-L1 <1%
N=146
PD-L1 ≥1%
N=124
Confirmed Overall Response Rate, n (%)
(95% CI)
53 (19.6%)
(15.1, 24.9)
22 (15.1%)
(9.7, 21.9)
31 (25.0%)
(17.7, 33.6)
Complete response rate
7 (2.6%)
1 (0.7%)
6 (4.8%)
Partial response rate
46 (17.0%)
21 (14.4%)
25 (20.2%)
Median Duration of Responsea (months)
(range)
10.3 (1.9+, 12.0+)
7.6 (3.7, 12.0+)
NRb (1.9+, 12.0+)
a Estimated from the Kaplan-Meier Curve
b Not Reached
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14.9
Microsatellite Instability-High or Mismatch Repair Deficient Metastatic
Colorectal Cancer
The effectiveness of OPDIVO QVANTIG has been established for the treatment of microsatellite
instability-high or mismatch repair deficient colorectal cancer (CRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO QVANTIG for
this indication is supported by evidence from an adequate and well-controlled study conducted
with
intravenous
nivolumab
(CHECKMATE-142,
NCT02060188),
and
additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this CRC population.
OPDIVO QVANTIG is not indicated for the treatment of pediatric patients.
CHECKMATE-142
CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-
cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic
CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine- ,
oxaliplatin- , or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line
of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following:
active brain metastases, active autoimmune disease, or medical conditions requiring systemic
immunosuppression.
Patients enrolled in the single agent intravenous nivolumab MSI-H mCRC cohort received
nivolumab 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the
intravenous nivolumab and ipilimumab MSI-H mCRC cohort received nivolumab 3 mg/kg and
ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by nivolumab as a single
agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts
continued until unacceptable toxicity or radiographic progression.
Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks
thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using
RECIST v1.1.
A total of 74 patients were enrolled in the single-agent MSI-H mCRC intravenous nivolumab
cohort. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75
years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0
(43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74
patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%,
30%, 28%, 19%, and 16% received 0, 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease,
respectively, and 42% of patients had received an anti-EGFR antibody.
A total of 119 patients were enrolled in the intravenous nivolumab and ipilimumab MSI-H mCRC
cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75
years of age; 59% were male and 92% were White. Baseline ECOG performance status was 0
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Reference ID: 5503239
(45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients,
69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%,
24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively,
and 29% had received an anti-EGFR antibody.
Efficacy results for each of these single-arm cohorts are shown in Table 61.
Table 61:
Efficacy Results - CHECKMATE-142
Intravenous Nivolumaba
MSI-H/dMMR Cohort
Intravenous Nivolumab and
Ipilimumabb
MSI-H/dMMR Cohort
All Patients
(n=74)
Prior Treatment
(Fluoropyrimidine,
Oxaliplatin, and
Irinotecan)
(n=53)
All Patients
(n=119)
Prior Treatment
(Fluoropyrimidine,
Oxaliplatin, and
Irinotecan)
(n=82)
Overall Response Rate
per BICR; n (%)
28 (38%)
17 (32%)
71 (60%)
46 (56%)
(95% CI)c
(27, 50)
(20, 46)
(50, 69)
(45, 67)
Complete Response
(%)
8 (11%)
5 (9%)
17 (14%)
11 (13%)
Partial Response (%)
20 (27%)
12 (23%)
54 (45%)
35 (43%)
Duration of Response
Proportion of
responders with ≥6
months response
duration
86%
94%
89%
87%
Proportion of
responders with ≥12
months response
duration
82%
88%
77%
74%
a Minimum follow-up 33.7 months for all patients treated with intravenous nivolumab (n=74).
b Minimum follow-up 27.5 months for all patients treated with intravenous nivolumab and ipilimumab (n=119).
c Estimated using the Clopper-Pearson method.
14.10
Hepatocellular Carcinoma
The effectiveness of OPDIVO QVANTIG has been established for the treatment of hepatocellular
carcinoma in patients who have been previously treated with sorafenib and following treatment
with intravenous nivolumab and ipilimumab. Use of OPDIVO QVANTIG for this indication is
supported by evidence from an adequate and well-controlled study conducted with intravenous
nivolumab, and additional pharmacokinetic and safety data that demonstrated comparable
pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous nivolumab
[see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a description of the
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efficacy results of the adequate and well-controlled study of intravenous nivolumab in this
hepatocellular carcinoma population.
CHECKMATE-040
CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial that
evaluated the efficacy of intravenous nivolumab as a single agent and in combination with
ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant
to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and
Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain
metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV,
or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and
hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.
Tumor assessments were conducted every 6 weeks for 48 weeks and then every 12 weeks
thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed
by BICR using RECIST v1.1 and modified RECIST (mRECIST) for HCC. Duration of response
was also assessed.
The efficacy of intravenous nivolumab in combination with ipilimumab was evaluated in 49
patients (Cohort 4) who received intravenous nivolumab 1 mg/kg and ipilimumab 3 mg/kg
administered every 3 weeks for 4 doses, followed by single-agent intravenous nivolumab at
240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60
years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG
performance status was 0 (61%) or 1 (39%). Fifty-seven (57%) percent of patients had active HBV
infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The
etiology for HCC was alcoholic liver disease in 16% and non-alcoholic fatty liver disease in 6%
of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had
extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels ≥400 µg/L. Prior cancer
treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All
patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of
patients had received 2 or more prior systemic therapies.
Efficacy results are shown in Table 62. The results for intravenous nivolumab in combination with
ipilimumab in Cohort 4 are based on a minimum follow-up of 28 months.
Table 62:
Efficacy Results - Cohort 4 of CHECKMATE-040
Intravenous Nivolumab and
Ipilimumab
(Cohort 4)
(n=49)
Overall Response Rate per BICR,a n (%), RECIST v1.1
16 (33%)
(95% CI)b
(20, 48)
Complete response
4 (8%)
Partial response
12 (24%)
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Table 62:
Efficacy Results - Cohort 4 of CHECKMATE-040
Intravenous Nivolumab and
Ipilimumab
(Cohort 4)
(n=49)
Duration of Response per BICR,a RECIST v1.1
n=16
Range (months)
4.6, 30.5+
Percent with duration ≥6 months
88%
Percent with duration ≥12 months
56%
Percent with duration ≥24 months
31%
Overall Response Rate per BICR,a n (%), mRECIST
17 (35%)
(95% CI)b
(22, 50)
Complete response
6 (12%)
Partial response
11 (22%)
a Confirmed by BICR.
b Confidence interval is based on the Clopper and Pearson method.
14.11
Esophageal Cancer
Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer
The effectiveness of OPDIVO QVANTIG has been established for the adjuvant treatment of
resected esophageal or gastroesophageal junction cancer with residual pathologic disease who
have received neoadjuvant chemoradiotherapy (CRT). Use of OPDIVO QVANTIG for this
indication is supported by evidence from an adequate and well-controlled study conducted with
intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated
comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous
nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a
description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this esophageal or gastroesophageal junction cancer population.
CHECKMATE-577
CHECKMATE-577 (NCT02743494) was a randomized, multicenter, double-blind trial in 794
patients with completely resected (negative margins) esophageal or gastroesophageal junction
cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT).
Patients were randomized (2:1) to receive either nivolumab 240 mg or placebo by intravenous
infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by
intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Treatment was until
disease recurrence, unacceptable toxicity, or for up to 1 year in total duration. Enrollment required
complete resection within 4 to 16 weeks prior to randomization. The trial excluded patients who
did not receive CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any
condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or
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Reference ID: 5503239
equivalent) or other immunosuppressive medications. Randomization was stratified by tumor PD
L1 status (≥1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive
≥ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy
outcome measure was disease-free survival (DFS) defined as the time between the date of
randomization and the date of first recurrence (local, regional, or distant from the primary resected
site) or death, from any cause, whichever occurred first as assessed by the investigator prior to
subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence
every 12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5.
The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were
≥65 years of age, 85% were male, 15% were Asian, 82% were White, and 1.1% were Black.
Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis
carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node
status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%)
or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status ≥1% was positive for 16%
of patients and negative for 72% of patients. Baseline ECOG performance status was 0 (58%) or
1 (42%).
CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients
randomized to the intravenous nivolumab arm as compared with the placebo arm. DFS benefit was
observed regardless of tumor PD-L1 expression and histology.
Efficacy results are shown in Table 63 and Figure 20.
Table 63:
Efficacy Results - CHECKMATE-577
Intravenous Nivolumab
(n=532)
Placebo
(n=262)
Disease-free Survival
Number of events, n (%)
241 (45%)
155 (59%)
Median (months)
(95% CI)
22.4
(16.6, 34.0)
11.0
(8.3, 14.3)
Hazard ratioa
(95% CI)
0.69 (0.56, 0.85)
p-valueb
0.0003
a Based on a stratified proportional hazards model.
b Based on a stratified log-rank test.
132
Reference ID: 5503239
,._
1.0
.9
~
C) 0.9
~
en
Q)
>
C: 0.8
,._
Q)
Cl.. 0.7
~
>
·:;;:
0.6
,._
:::J
Cf)
Q) 0.5
Q)
,._
LL
I
Q) 0.4
en
~
Q)
en
0.3
Cl -
0
~ 0.2
:.c
~ 0.1
.c
0
•
Nivolumab
- - 0- - • Placebo
,._
a.. 0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
Disease-Free Survival per Investigator (Months)
Number of Subjects at Risk
Nivolumab
532 430 364 306 249 212 181 147 92
68
41
22
8
4
3
0
Placebo
262 214 163 126 96
80
65
53
38
28
17
12
5
2
1
0
Figure 20:
Disease-free Survival - CHECKMATE-577
First-line Treatment of Unresectable Advanced or Metastatic Esophageal Squamous
Cell Carcinoma (ESCC)
The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-
containing chemotherapy has been established for the first-line treatment of unresectable advanced
or metastatic ESCC. Use of OPDIVO QVANTIG for this indication is supported by evidence from
an adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this esophageal squamous cell carcinoma
population.
133
Reference ID: 5503239
CHECKMATE-648
CHECKMATE-648 (NCT03143153) was a randomized, active-controlled, open-label trial in
patients with previously untreated unresectable advanced, recurrent or metastatic ESCC
(squamous or adenosquamous histology). The trial enrolled patients whose tumor was evaluable
for tumor cell (TC) PD-L1 expression [also called PD-L1 tumor proportion score (TPS)], which
was evaluated using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. A retrospective
scoring of a patient’s tumor PD-L1 status using Combined Positive Score (CPS), was also
conducted using the PD-L1-stained tumor specimens used for randomization. Patients were not
amenable to chemoradiation or surgery with curative intent. Prior treatment with curative intent
was allowed if completed more than six months prior to trial enrollment. The trial excluded patients
with brain metastasis that were symptomatic, had active autoimmune disease, used systemic
corticosteroids or immunosuppressants, or patients at high risk of bleeding or fistula due to
apparent invasion of tumor to organs adjacent to the esophageal tumor. Patients were randomized
to receive one of the following treatments:
Intravenous nivolumab 240 mg on days 1 and 15, fluorouracil 800 mg/m2/day
intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m2 intravenously on
day 1 (of a 4-week cycle).
Intravenous nivolumab 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg
every 6 weeks.
Fluorouracil 800 mg/m2/day intravenously on days 1 through 5 (for 5 days), and cisplatin
80 mg/m2 intravenously on day 1 (of a 4-week cycle).
Patients received intravenous nivolumab until disease progression, unacceptable toxicity, or up to
2 years. In patients who received intravenous nivolumab in combination with chemotherapy and
in whom either fluorouracil and/or cisplatin were discontinued, other components of the treatment
regimen were allowed to be continued. Patients who discontinued combination therapy because of
an adverse reaction attributed to ipilimumab were permitted to continue intravenous nivolumab as
a single agent.
Randomization was stratified by TC PD-L1 expression (≥1% vs. <1% or indeterminate), region
(East Asia vs. Rest of Asia vs. Rest of World), ECOG performance status (0 vs. 1), and number of
organs with metastases (≤1 vs. ≥2). The major efficacy outcome measures were OS and BICR-
assessed PFS in patients with TC PD-L1 expression ≥1%. Additional efficacy measures included
OS in all randomized patients, BICR-assessed PFS in all randomized patients, and ORR assessed
by BICR in TC PD-L1 expression ≥1% and in all randomized patients. The tumor assessments per
RECIST v1.1 were conducted every 6 weeks up to and including week 48, then every 12 weeks
thereafter.
A total of 970 patients were randomized in CHECKMATE-648 study among whom 965 and 906
patients had quantifiable TC PD-L1 expression and CPS at baseline, respectively. The trial
population characteristics for all randomized patients were median age 64 years (range: 26 to 90),
47% were ≥65 years of age, 82% were male, 71% were Asian, 26% were White, and 1.1% were
Black or African American. Patients had histological confirmation of squamous cell carcinoma
134
Reference ID: 5503239
(98%) or adenosquamous cell carcinoma (1.9%) in the esophagus. Baseline ECOG performance
status was 0 (47.0%) or 1 (53%).
Efficacy results are shown in Table 64 and Figures 21 and 22.
Table 64:
Efficacy Results - CHECKMATE-648
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=321)
Intravenous
Nivolumab
and
Ipilimumab
(n=325)
Cisplatin
and
Fluorouracil
(n=324)
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=158)
Intravenous
Nivolumab
and
Ipilimumab
(n=158)
Cisplatin
and
Fluorouracil
(n=157)
All Patients
TC PD-L1 expression ≥1%
Overall Survival
Deaths (%)
209 (65)
216 (66)
232 (72)
98 (62)
106 (67)
121 (77)
Median
(months)
(95% CI)
13.2
(11.1, 15.7)
12.8
(11.3, 15.5)
10.7
(9.4, 11.9)
15.4
(11.9, 19.5)
13.7
(11.2, 17.0)
9.1
(7.7, 10)
Hazard ratio
(95% CI)b
0.74
(0.61, 0.90)
0.78
(0.65, 0.95)
-
0.54
(0.41, 0.71)
0.64
(0.49, 0.84)
-
p-valuec
0.0021S1
0.0110S2
-
<0.0001S3
0.0010S4
-
Progression-free Survivala
Disease
progression
or death (%)
235 (73)
258 (79)
210 (65)
117 (74)
123 (78)
100 (64)
Median
(months)
(95% CI)
5.8
(5.6, 7.0)
2.9
(2.7, 4.2)
5.6
(4.3, 5.9)
6.9
(5.7, 8.3)
4.0
(2.4, 4.9)
4.4
(2.9, 5.8)
Hazard ratio
(95% CI)b
0.81
(0.67, 0.99)
1.26
(1.04, 1.52)
-
0.65
(0.49, 0.86)
1.02
(0.78, 1.34)
-
p-valuec
NS
NT
-
0.0023S5
NS
Overall
Response
Rate, n
(%)a, NT
152 (47.4)
90 (27.7)
87 (26.9)
84 (53.2)
56 (35.4)
31 (19.7)
(95% CI)
(41.8, 53.0)
(22.9, 32.9)
(22.1, 32.0)
(45.1, 61.1)
(28.0, 43.4)
(13.8, 26.8)
Complete
response (%)
43 (13.4)
36 (11.1)
20 (6.2)
26 (16.5)
28 (17.7)
8 (5.1)
Partial
response (%)
109 (34.0)
54 (16.6)
67 (20.7)
58 (36.7)
28 (17.7)
23 (14.6)
Duration of Response (months)a
135
Reference ID: 5503239
1.0
0.9
~ 0.8
·~ 0.7
V,
-----B-- Nivolumab + ipilimumab
-A-- Nivolumab + chemolherapy
--+--- Chemotherapy
~ 0.6
~ 0.5
0
0 0.4
~
:s 0.3
"'
.0
0
0.2
.I:
0.1
0.0
0
6
9
~ ~ IB
~ M ll
~ ~ ~ S
G
Overall Survival (Months)
Number of Subjects at Risk
Nivolumab + ipilimumab
325 274 232 191 166 129 97
77
55
33
22
12
6
0
Nivolumab + chemotherapy
321 293 253 203 163 133 92
60
40
26
12
Chemotherapy
324 281 229 171
131
93
56
41
23
9
2
0
1.0
0.9
~ 0.8
·~ 0.7
V,
-----B-- Nivolumab + ipilimumab
- A-- Nivolumab + chemotherapy
--+--- Chemotherapy
~ 0.6
~ 0.5
0
9
12
15
18
21
24
27
30
33
36
39
Overall Survival (Months)
Number ot Subjects at Risk
Nivolumab + ipilimumab
158 136 116
98
89
63
50
40
31
20
11
9
0
Nivolumab + chemolherapy
158 143
129
105
88
70
53
36
22
16
0
Chemolherapy
157 135
105
72
52
36
21
12
4
0
Table 64:
Efficacy Results - CHECKMATE-648
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=321)
Intravenous
Nivolumab
and
Ipilimumab
(n=325)
Cisplatin
and
Fluorouracil
(n=324)
Intravenous
Nivolumab
with
Cisplatin
and
Fluorouracil
(n=158)
Intravenous
Nivolumab
and
Ipilimumab
(n=158)
Cisplatin
and
Fluorouracil
(n=157)
All Patients
TC PD-L1 expression ≥1%
Median
(95% CI)
8.2
(6.9, 9.7)
11.1
(8.3, 14.0)
7.1
(5.7, 8.2)
8.4
(6.9, 12.4)
11.8
(7.1, 27.4)
5.7
(4.4, 8.7)
Range
1.4+, 35.9+
1.4+, 34.5+
1.4+, 31.8+
1.4+, 34.6+
1.4+, 34.5+
1.4+, 31.8+
a Assessed by BICR.
b Based on stratified Cox proportional hazard model. Hazard ratios are reported for each intravenous nivolumab
containing arm compared to chemotherapy within each analysis population.
c Based on a stratified 2-sided log-rank test.
S1, S2, S3, S4, S5
Significant p-value compared to stopping boundary of 0.009, 0.018, 0.005, 0.014, and 0.015
respectively.
NS: Not Statistically significant, NT: Not evaluated for statistical significance as per pre-specified hierarchical testing
procedure
Figure 21: Overall Survival – CHECKMATE-648
(A) OS in All Randomized Patients
(B) OS in TC PD-L1 ≥1%
136
Reference ID: 5503239
-----e----- Nivolumab + ipilimumab
-A-- Nivolumab + chemotherapy
--+-- Chemotherapy
6
9
~ m IB
~
~ ll
~
Progression Free Survival per BICA (Months)
Number of Subjects at Risk
Nivolumab + ipilimumab
325 149
86
65
52
31
22
18
13
10
5
Nivolumab + chemotherapy
m m ~ ~
~ ~ w G
w
Chemotherapy
324
170
90
43
19
8
5
33
36
39
-----e----- Nivolumab + ipilimumab
-A-- Nivolumab + chemotherapy
--+ -- Chemotherapy
9
12
15
18
21
24
27
Progression Free Survival per BICR (Months)
Number of Subjects at Risk
Nivolumab + ipilimumab
158
78
48
38
31
18
14
13
8
Nivolumab + chemotherapy
158
107
75
47
29
18
10
Chemotherapy
157
67
35
17
30
33
36
Figure 22: Progression-free Survival – CHECKMATE-648
(A) PFS in All Randomized Patients
(B) PFS in TC PD-L1 ≥1%
Exploratory subgroup analyses of patients with TC PD-L1 expression <1% (n=492) were
conducted. OS results for each intravenous nivolumab containing arm compared to chemotherapy
were:
Intravenous Nivolumab with Chemotherapy (n=163) vs. Chemotherapy (n=165):
unstratified OS HR was 0.99 (95% CI: 0.76, 1.29) with median OS of 12 months (95% CI:
9.9, 15.5) on the Intravenous Nivolumab with Chemotherapy arm and 12.2 months (95%
CI: 10.7, 14) on the Chemotherapy arm
Intravenous Nivolumab with Ipilimumab (n=164) vs. Chemotherapy (n=165): unstratified
OS HR was 0.97 (95% CI: 0.74, 1.26) with median OS of 12 months (95% CI: 10.1, 16.0)
on the Intravenous Nivolumab with Ipilimumab arm and 12.2 months (95% CI: 10.7, 14)
on the Chemotherapy arm
Exploratory subgroup analyses were also conducted by PD-L1 status per CPS (≥1 and <1) for each
intravenous nivolumab containing arm compared to chemotherapy. Among the 906 patients with
quantifiable PD-L1 CPS at baseline, 278 in the intravenous nivolumab with chemotherapy arm,
266 in the intravenous nivolumab with ipilimumab arm, and 280 in the chemotherapy arm had PD
L1 CPS ≥1. A total of 27 patients in the intravenous nivolumab with chemotherapy arm, 31 patients
in the intravenous nivolumab with ipilimumab arm, and 24 patients in the chemotherapy arm had
PD-L1 CPS <1.
OS results for each comparison by PD-L1 CPS status were:
Intravenous Nivolumab with Chemotherapy vs. Chemotherapy: unstratified OS HR was
0.69 (95% CI: 0.56, 0.84) for PD-L1 CPS ≥1 subgroup and 0.98 (95% CI: 0.50, 1.95) for
PD-L1 CPS <1 subgroup.
Intravenous Nivolumab with Ipilimumab vs. Chemotherapy: unstratified OS HR was 0.76
(95% CI: 0.62, 0.93) for PD-L1 CPS ≥1 subgroup and 1.0 (95% CI: 0.52, 1.94) for PD-L1
CPS <1 subgroup.
137
Reference ID: 5503239
Previously Treated Unresectable Advanced, Recurrent or Metastatic ESCC
The effectiveness of OPDIVO QVANTIG has been established for the treatment of unresectable
advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based
chemotherapy. Use of OPDIVO QVANTIG for this indication is supported by evidence from an
adequate and well-controlled study conducted with intravenous nivolumab, and additional
pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety
profiles between OPDIVO QVANTIG and intravenous nivolumab [see Adverse Reactions (6.1)
and Clinical Pharmacology (12.3)]. Below is a description of the efficacy results of the adequate
and well-controlled study of intravenous nivolumab in this ESCC population.
ATTRACTION-3
ATTRACTION-3 (NCT02569242) was a multicenter, randomized (1:1), active-controlled,
open-label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were
refractory or intolerant to at least one fluoropyrimidine- and platinum-based regimen. The trial
enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively
using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who
were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or
required
treatment,
had
autoimmune
disease,
used
systemic
corticosteroids
or
immunosuppressants, or had apparent tumor invasion of organs adjacent to the esophageal tumor
or had stents in the esophagus or respiratory tract. Patients were randomized to receive
nivolumab 240 mg by intravenous infusion over 30 minutes every 2 weeks or investigator’s choice
of taxane chemotherapy consisting of docetaxel (75 mg/m2 intravenously every 3 weeks) or
paclitaxel (100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off).
Randomization was stratified by region (Japan vs. Rest of World), number of organs with
metastases (≤1 vs. ≥2), and PD-L1 status (≥1% vs. <1% or indeterminate). Patients were treated
until disease progression, assessed by the investigator per RECIST v1.1, or unacceptable toxicity.
The tumor assessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter.
The major efficacy outcome measure was OS. Additional efficacy outcome measures were ORR
and PFS as assessed by the investigator using RECIST v1.1 and DOR.
A total of 419 patients were randomized; 210 to the intravenous nivolumab arm and 209 to the
investigator’s choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics
were: median age 65 years (range: 33 to 87), 53% were ≥65 years of age, 87% were male, 96%
were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic
therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in
ATTRACTION-3. Baseline ECOG performance status was 0 (50%) or 1 (50%).
ATTRACTION-3 demonstrated a statistically significant improvement in OS for patients
randomized to intravenous nivolumab as compared with investigator’s choice of taxane
chemotherapy. OS benefit was observed regardless of PD-L1 expression level. The minimum
follow-up was 17.6 months. Efficacy results are shown in Table 65 and Figure 23.
138
Reference ID: 5503239
Table 65:
Efficacy Results - ATTRACTION-3
Intravenous Nivolumab
(n=210)
Docetaxel or Paclitaxel
(n=209)
Overall Survivala
Deaths (%)
160 (76%)
173 (83%)
Median (months)
(95% CI)
10.9
(9.2, 13.3)
8.4
(7.2, 9.9)
Hazard ratio (95% CI)b
0.77 (0.62, 0.96)
p-valuec
0.0189
Overall Response Rated
33 (19.3)
34 (21.5)
(95% CI)
(13.7, 26.0)
(15.4, 28.8)
Complete response (%)
1 (0.6)
2 (1.3)
Partial response (%)
32 (18.7)
32 (20.3)
Median duration of response (months)
(95% CI)
6.9
(5.4, 11.1)
3.9
(2.8, 4.2)
p-valuee
0.6323
Progression-free Survivala, f
Disease progression or death (%)
187 (89)
176 (84)
Median (months)
(95% CI)
1.7
(1.5, 2.7)
3.4
(3.0, 4.2)
Hazard ratio (95% CI)b
1.1 (0.9, 1.3)
a Based on ITT analysis
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d Based on Response Evaluable Set (RES) analysis, n=171 in intravenous nivolumab group and n=158 in
investigator’s choice group.
e Based on stratified Cochran-Mantel-Haenszel test; p-value not significant.
f PFS not tested due to pre-specified hierarchical testing strategy.
139
Reference ID: 5503239
100
-
Nivolumab
90
-------- INV choice
80
--
~ 70
0 -
~
>
60
">
....
::::,
Cf)
50
'+-
0
;e:,
40
:.a
~
..Cl
0
30
....
a..
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Number at Risk
Overall Survival (Months)
Nivolumab
210 182 167 147 126 111 95 82 70 60 43 25 17 13 7 4 3 0 0
INV choice
209 196 169 126 105 84 68 57 49 40 27 17 12 6 2 1 1 1 0
Figure 23:
Overall Survival - ATTRACTION-3
Of the 419 patients, 48% had PD-L1 positive ESCC, defined as ≥1% of tumor cells expressing
PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing
PD-L1.
In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69
(95% CI: 0.51, 0.94) with median survivals of 10.9 and 8.1 months for the intravenous nivolumab
and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1
negative subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9
and 9.3 months for the intravenous nivolumab and investigator’s choice arms, respectively.
14.12
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal
Adenocarcinoma
The effectiveness of OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-
containing chemotherapy has been established for the treatment of gastric cancer,
140
Reference ID: 5503239
gastroesophageal junction cancer, and esophageal adenocarcinoma. Use of OPDIVO QVANTIG
for this indication is supported by evidence from an adequate and well-controlled study conducted
with intravenous nivolumab, and additional pharmacokinetic and safety data that demonstrated
comparable pharmacokinetics and safety profiles between OPDIVO QVANTIG and intravenous
nivolumab [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Below is a
description of the efficacy results of the adequate and well-controlled study of intravenous
nivolumab in this population.
CHECKMATE-649
CHECKMATE-649 (NCT02872116) was a randomized, multicenter, open-label trial in patients
(n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal
junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1
status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx
assay at a central laboratory. The trial excluded patients who were known human epidermal growth
factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to
receive intravenous nivolumab in combination with chemotherapy (n=789) or chemotherapy
(n=792). Patients received one of the following treatments:
Intravenous nivolumab 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin
and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
Intravenous nivolumab 360 mg in combination with CapeOX (capecitabine and
oxaliplatin) every 3 weeks or CapeOX every 3 weeks.
Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients
who received intravenous nivolumab in combination with chemotherapy and in whom
chemotherapy was discontinued, intravenous nivolumab monotherapy was allowed to be given at
240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after
treatment initiation.
Randomization was stratified by tumor cell PD-L1 status (≥1% vs. <1% or indeterminate), region
(Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen
(mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD
L1 CPS ≥5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included
OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, and ORR and DOR as
assessed by BICR in patients with PD-L1 CPS ≥1 and ≥5, and in all randomized patients. Tumor
assessments were conducted per RECIST v1.1 every 6 weeks up to and including week 48, then
every 12 weeks thereafter.
The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were ≥65
years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline
ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had
adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the
esophagus.
CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for
patients with PD-L1 CPS ≥5. Statistically significant improvement in OS was also demonstrated
141
Reference ID: 5503239
for all randomized patients. The minimum follow-up was 12.1 months. Efficacy results are shown
in Table 66 and Figures 24, 25, and 26.
Table 66:
Efficacy Results - CHECKMATE-649
Intravenous
Nivolumab
and
mFOLFOX6
or CapeOX
(n=789)
mFOLFOX6
or CapeOX
(n=792)
Intravenous
Nivolumab
and
mFOLFOX6
or CapeOX
(n=641)
mFOLFOX6
or CapeOX
(n=655)
Intravenous
Nivolumab
and
mFOLFOX6
or CapeOX
(n=473)
mFOLFOX6
or CapeOX
(n=482)
All Patients
PD-L1 CPS ≥1
PD-L1 CPS ≥5
Overall Survival
Deaths (%)
544 (69)
591 (75)
434 (68)
492 (75)
309 (65)
362 (75)
Median
(months)
(95% CI)
13.8
(12.6, 14.6)
11.6
(10.9, 12.5)
14.0
(12.6, 15.0)
11.3
(10.6, 12.3)
14.4
(13.1, 16.2)
11.1
(10.0, 12.1)
Hazard ratio
(95% CI)a
0.80 (0.71, 0.90)
0.77 (0.68, 0.88)
0.71 (0.61, 0.83)
p-valueb
0.0002
<0.0001
<0.0001
Progression-free Survivalc
Disease
progression
or death (%)
559 (70.8)
557 (70.3)
454 (70.8)
472 (72.1)
328 (69.3)
350 (72.6)
Median
(months)
(95% CI)
7.7
(7.1, 8.5)
6.9
(6.6, 7.1)
7.5
(7.0, 8.4)
6.9
(6.1, 7.0)
7.7
(7.0, 9.2)
6.0
(5.6, 6.9)
Hazard ratio
(95% CI)a
0.77 (0.68, 0.87)
0.74 (0.65, 0.85)
0.68 (0.58, 0.79)
p-valueb
e
e
<0.0001
Overall
Response
Rate, n (%)c,d
370 (47)
293 (37)
314 (49)
249 (38)
237 (50)
184 (38)
(95% CI)
(43, 50)
(34, 40)
(45, 53)
(34, 42)
(46, 55)
(34, 43)
Complete
response (%)
78 (10)
52 (7)
65 (10)
42 (6)
55 (12)
34 (7)
Partial
response (%)
292 (37)
241 (30)
249 (39)
207 (32)
182 (38)
150 (31)
Duration of Response (months)c,d
Median
(95% CI)
Range
8.5
(7.2, 9.9)
1.0+, 29.6+
6.9
(5.8, 7.2)
1.2+, 30.8+
8.5
(7.7, 10.3)
1.1+, 29.6+
6.9
(5.8, 7.6)
1.2+, 30.8+
9.5
(8.1, 11.9)
1.1+, 29.6+
6.9
(5.6, 7.9)
1.2+, 30.8+
142
Reference ID: 5503239
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0.9
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ro
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A
Nivolumab + chemotherapy
- -e--- Chemotherapy
6lXXX:lOOro -o ro
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
Number of Subjects at Risk
Overall Survival (Months)
Nivolumab + chemotherapy
789 731
621 506 420 308 226 147 100
49
34
14
2
0
Chemotherapy
792 697 586 469 359 239 160
94
59
35
15
7
2
0
a Based on stratified Cox proportional hazard model.
b Based on stratified log-rank test.
c Assessed by BICR.
d Based on confirmed response.
e Not evaluated for statistical significance.
In an exploratory analysis in patients with PD-L1 CPS <1 (n=265), the median OS was 13.1
months (95% CI: 9.8, 16.7) for the intravenous nivolumab and chemotherapy arm and 12.5 months
(95% CI: 10.1, 13.8) for the chemotherapy arm, with a stratified HR of 0.85 (95% CI: 0.63, 1.15).
In an exploratory analysis in patients with PD-L1 CPS <5 (n=606), the median OS was 12.4
months (95% CI: 10.6, 14.3) for the intravenous nivolumab and chemotherapy arm and 12.3
months (95% CI: 11.0, 13.2) for the chemotherapy arm, with a stratified HR of 0.94 (95% CI: 0.78,
1.14).
Figure 24:
Overall Survival (All Patients) - CHECKMATE-649
143
Reference ID: 5503239
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0.9
0.8
ctS
>
·;;:: 0.7
.....
:::::s
Cf)
ctS 0.6
.....
Cl)
> 0.5
0 -
0
;i?:' 0.4
:B
ctS
..c 0.3
0 .....
c... 0.2
0.1
A
Nivolumab + chemotherapy
~
EID-E!OOB - -0
- -e--- Chemotherapy
0.0
0
3
6
9
12
Number of Subjects at Risk
Nivolumab + chemotherapy
641 595 502 412 344
Chemotherapy
655 575 483 383 292
15
18
21
24
27
30
Overall Survival (Months)
254 183
118
80
40
28
194
131
77
45
25
10
33
36
39
11
1
0
3
0
0
Figure 25:
Overall Survival (PD-L1 CPS ≥1) - CHECKMATE-649
144
Reference ID: 5503239
1.0
0.9
0.8
~
>
·s;: 0.7
i....
::::s
Cf)
~ 0.6
i....
Q)
> 0.5
0 -
0
>, 0.4
~
:c
~ 0.3
.c
I
0
·o,
~
'
0
i....
a.. 0.2
0.1
A
Nivolumab + chemotherapy
0&mx:fl}-«mml)(B3 - 0ll)
- -e--- Chemotherapy
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
Number of Subjects at Risk
Nivolumab + chemotherapy
Overall Survival (Months)
473 438 377
313
261
198
149
96
65
33
22
Chemotherapy
482 421
350
271
211
138
98
56
34
19
8
9
2
1
0
0
0
Figure 26:
Overall Survival (PD-L1 CPS ≥5) - CHECKMATE-649
16
HOW SUPPLIED/STORAGE AND HANDLING
OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy) injection is a sterile, preservative-
free, clear to opalescent and colorless to yellow solution for subcutaneous use. It is supplied as an
individually packaged single-dose vial providing 600 mg nivolumab and 10,000 units
hyaluronidase per 5 mL (120 mg/ 2,000 units per mL) (NDC-00003-6120-01).
Store OPDIVO QVANTIG vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton
to protect from light.
Do not freeze or shake.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
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Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid
treatment and withholding or discontinuation of OPDIVO QVANTIG, including:
Pneumonitis: Advise patients to contact their healthcare provider immediately for any new
or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions
(5.1)].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or
severe abdominal pain [see Warnings and Precautions (5.1)].
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice,
severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or
bleeding [see Warnings and Precautions (5.1)].
Endocrinopathies: Advise patients to contact their healthcare provider immediately for
signs
or
symptoms
of
hypophysitis,
adrenal
insufficiency,
hypothyroidism,
hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].
Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider
immediately for signs or symptoms of nephritis including decreased urine output, blood in
urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction
[see Warnings and Precautions (5.1)].
Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately
for rash [see Warnings and Precautions (5.1)].
Other immune-mediated adverse reactions:
Advise patients that immune-mediated adverse reactions can occur and may involve any
organ system, and to contact their healthcare provider immediately for any new or
worsening signs or symptoms [see Warnings and Precautions (5.1)].
Advise patients of the risk of solid organ transplant rejection and other transplant (including
corneal graft) rejection. Advise patients to contact their healthcare provider immediately
for signs or symptoms of organ transplant rejection and other transplant (including corneal
graft) rejection [see Warnings and Precautions (5.1)].
Complications of Allogeneic HSCT
Advise patients of potential risk of post-transplant complications [see Warnings and
Precautions (5.2)].
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their
healthcare provider of a known or suspected pregnancy [see Warnings and Precautions
(5.3) and Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment
with OPDIVO QVANTIG and for 5 months following the last dose [see Use in Specific
Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with OPDIVO QVANTIG and for 5
months after the last dose [see Use in Specific Populations (8.2)].
146
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Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713
Halozyme Therapeutics, Inc.
12390 El Camino Real
San Diego, CA 92130
U.S. License No. 2187
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Reference ID: 5503239
MEDICATION GUIDE
OPDIVO QVANTIG™ (op-DEE-voh cue-VAN-tig)
(nivolumab and hyaluronidase-nvhy)
injection, for subcutaneous use
Read this Medication Guide before you start receiving OPDIVO QVANTIG and before each injection. There may be new
information. If your healthcare provider prescribes OPDIVO QVANTIG in combination with cabozantinib, also read the
Patient Information that comes with cabozantinib. This Medication Guide does not take the place of talking with your
healthcare provider about your medical condition or your treatment.
What is the most important information I should know about OPDIVO QVANTIG?
OPDIVO QVANTIG is a medicine that may treat certain cancers by working with your immune system. OPDIVO
QVANTIG can cause your immune system to attack normal organs and tissues in any area of your body and can affect
the way they work. These problems can sometimes become severe or can lead to death. These problems may happen
anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the
same time. Some of these problems may happen more often when OPDIVO QVANTIG is used in combination with
another therapy.
Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms,
including:
Lung problems.
cough
shortness of breath
chest pain
Intestinal problems.
diarrhea (loose stools) or more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucus
severe stomach-area (abdominal) pain or tenderness
Liver problems.
yellowing of your skin or the whites of your eyes
dark urine (tea colored)
severe nausea or vomiting
bleeding or bruising more easily than normal
pain on the right side of your stomach area (abdomen)
Hormone gland problems.
headaches that will not go away or unusual headaches
urinating more often than usual
eye sensitivity to light
hair loss
eye problems
feeling cold
rapid heartbeat
constipation
increased sweating
your voice gets deeper
extreme tiredness
dizziness or fainting
weight gain or weight loss
changes in mood or behavior, such as decreased sex
feeling more hungry or thirsty than usual
drive, irritability, or forgetfulness
Kidney problems.
decrease in your amount of urine
swelling of your ankles
blood in your urine
loss of appetite
Skin problems.
rash
painful sores or ulcers in mouth or nose, throat, or
itching
genital area
skin blistering or peeling
fever or flu-like symptoms
swollen lymph nodes
Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune
system problems that can happen with OPDIVO QVANTIG. Call or see your healthcare provider right away for
any new or worsening signs or symptoms, which may include:
chest pain, irregular heartbeat, shortness of breath or swelling of ankles
confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or
numbness of the arms or legs
double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
persistent or severe muscle pain or weakness, muscle cramps
low red blood cells, bruising
Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you
should report and monitor you depending on the type of organ or tissue transplant that you have had.
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Getting medical treatment right away may help keep these problems from becoming more serious. Your
healthcare provider will check you for these problems during treatment with OPDIVO QVANTIG. Your healthcare provider
may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay
or completely stop treatment with OPDIVO QVANTIG, if you have severe side effects.
What is OPDIVO QVANTIG?
OPDIVO QVANTIG is a prescription medicine used to treat adults with:
a type of kidney cancer that has spread called advanced renal cell carcinoma (RCC).
○
OPDIVO QVANTIG may be used alone as a first treatment in certain people with advanced RCC, after completing
combination treatment with nivolumab given into the vein (intravenous nivolumab) and ipilimumab.
○
OPDIVO QVANTIG may be used in combination with cabozantinib as your first treatment for advanced RCC.
○
OPDIVO QVANTIG may be used alone when your cancer has spread after treatment with other cancer
medicines.
a type of skin cancer called melanoma.
○
OPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery
(advanced melanoma).
○
OPDIVO QVANTIG may be used alone to treat melanoma that has spread or cannot be removed by surgery
(advanced melanoma), after completing combination treatment with intravenous nivolumab and ipilimumab.
○
OPDIVO QVANTIG may be used alone to help prevent Stage IIB, Stage IIC, Stage III, or Stage IV melanoma
from coming back after it has been completely removed by surgery.
a type of lung cancer called non-small cell lung cancer (NSCLC).
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another
chemotherapy medicine before you have surgery for early-stage NSCLC.
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains platinum and another
chemotherapy medicine before you have surgery for early-stage NSCLC:
•
that does not have an abnormal EGFR or ALK gene, and
•
then OPDIVO QVANTIG may be continued alone after surgery to help prevent your lung cancer from coming
back.
○
OPDIVO QVANTIG may be used alone when your lung cancer:
has spread, and
•
you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
•
If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for
tumors with these abnormal genes, and it did not work or is no longer working.
head and neck cancer (squamous cell carcinoma).
○
OPDIVO QVANTIG may be used alone when your head and neck cancer:
•
has come back or spread, and
•
you have tried chemotherapy that contains platinum and it did not work or is no longer working.
cancer of the lining of the urinary tract (urothelial carcinoma).
○
OPDIVO QVANTIG may be used alone to help prevent cancer of the urinary tract from coming back after it was
removed by surgery.
○
OPDIVO QVANTIG may be used in combination with chemotherapy medicines cisplatin and gemcitabine as your
first treatment when your urinary tract cancer has spread (metastatic) or cannot be removed by surgery.
○
OPDIVO QVANTIG may be used alone when your urinary tract cancer has spread (locally advanced or
metastatic), and:
•
you have tried chemotherapy that contains platinum, and it did not work or is no longer working, or
•
your cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before
or after surgery to remove your cancer.
a type of colon or rectal cancer (colorectal cancer or CRC).
○
OPDIVO QVANTIG may be used alone and after completing combination treatment with intravenous nivolumab
and ipilimumab, when your colon or rectal cancer:
•
has spread to other parts of the body (metastatic CRC), and
•
is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and
•
you have tried treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer
working.
a type of liver cancer called hepatocellular carcinoma (HCC).
○
OPDIVO QVANTIG may be used alone if you have previously received treatment with sorafenib and after
completing combination treatment with intravenous nivolumab and ipilimumab.
cancer of the tube that connects your throat to your stomach (esophageal cancer).
○
OPDIVO QVANTIG may be used alone to help prevent your esophageal or gastroesophageal junction cancer
from coming back when:
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Reference ID: 5503239
•
your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by
surgery to completely remove the cancer, but
•
some cancer cells were still present in the removed tumor or lymph nodes.
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum
as your first treatment when your esophageal cancer:
•
is a type called squamous cell carcinoma, and
•
cannot be removed with surgery (advanced), or
•
has spread to other parts of the body (metastatic).
○
OPDIVO QVANTIG may be used alone when your esophageal cancer:
•
is a type called squamous cell carcinoma, and
•
cannot be removed with surgery, has come back, or has spread to other parts of the body after you have
received chemotherapy that contains fluoropyrimidine and platinum.
cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal
junction cancer), and a type of cancer in the esophagus called esophageal adenocarcinoma.
○
OPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum
when your gastric, gastroesophageal junction, or esophageal cancer:
•
cannot be removed with surgery, or
•
has spread to other parts of the body.
It is not known if OPDIVO QVANTIG is safe and effective in children.
Before receiving OPDIVO QVANTIG, tell your healthcare provider about all of your medical conditions, including
if you:
have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant, including corneal transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have received radiation treatment to your chest area in the past
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
are pregnant or plan to become pregnant. OPDIVO QVANTIG can harm your unborn baby.
Females who are able to become pregnant:
○
Your healthcare provider should do a pregnancy test before you start receiving OPDIVO QVANTIG.
○
You should use an effective method of birth control during treatment and for 5 months after your last dose of
OPDIVO QVANTIG. Talk to your healthcare provider about birth control methods that you can use during this
time.
○
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment
with OPDIVO QVANTIG.
are breastfeeding or plan to breastfeed. It is not known if OPDIVO QVANTIG passes into your breast milk. Do not
breastfeed during treatment and for 5 months after your last dose of OPDIVO QVANTIG.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
How will I receive OPDIVO QVANTIG?
Your healthcare provider will give you OPDIVO QVANTIG as an injection under the skin, in the stomach area
(abdomen) or thigh, over about 3 to 5 minutes.
OPDIVO QVANTIG is usually given every 2, 3, or 4 weeks, depending on the dose you are receiving.
Your healthcare provider will decide how many treatments you will receive.
Your healthcare provider will do blood tests to check you for side effects.
For a type of kidney cancer called advanced renal cell carcinoma, your healthcare provider may also prescribe you
cabozantinib. Take cabozantinib exactly as your healthcare provider tells you.
If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of OPDIVO QVANTIG?
OPDIVO QVANTIG can cause serious side effects, including:
See “What is the most important information I should know about OPDIVO QVANTIG?”
Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow
(stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead
to death. These complications may happen if you underwent transplantation either before or after being treated with
OPDIVO QVANTIG. Your healthcare provider will monitor you for signs of complications if you have an allogeneic
stem cell transplant.
The most common side effects of OPDIVO QVANTIG when used alone in people with renal cell carcinoma
include:
pain in muscles, bones, and joints
low thyroid hormone levels
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Reference ID: 5503239
feeling tired
diarrhea
itchy skin
cough
rash
stomach-area (abdominal) pain
The most common side effects observed with nivolumab given into the vein (intravenous nivolumab), which
may be experienced with OPDIVO QVANTIG, are shown below.
The most common side effects of intravenous nivolumab when used alone include:
feeling tired
weakness
upper respiratory tract infection
rash
cough
fever
pain in muscles, bones, and joints
shortness of breath
headache
itchy skin
constipation
stomach-area (abdominal) pain
diarrhea
decreased appetite
vomiting
nausea
back pain
urinary tract infection
The most common side effects of intravenous nivolumab when used in combination with cabozantinib as the
first treatment for advanced RCC include:
diarrhea
mouth sores
nausea
feeling tired
rash
change in the sense of taste
liver problems. See “What is the
high blood pressure
stomach-area (abdominal) pain
most important information I should
low thyroid hormone levels
cough
know about OPDIVO QVANTIG?”
pain in muscles, bones, and joints
upper respiratory tract infection
rash, redness, pain, swelling or
decreased appetite
blisters on the palms of your hands
or soles of your feet
The most common side effects of intravenous nivolumab when used in combination with platinum-containing
chemotherapy and another chemotherapy medicine before having surgery for NSCLC include:
nausea
feeling tired
rash
constipation
decreased appetite
The most common side effects of intravenous nivolumab when used in combination with cisplatin and
gemcitabine to treat urothelial cancer include:
nausea
constipation
vomiting
feeling tired
decreased appetite
numbness, pain, tingling or
pain in muscles, bones, and joints
rash
burning in your hands and feet
The most common side effects of intravenous nivolumab when used in combination with fluoropyrimidine and
platinum-containing chemotherapy to treat esophageal cancer and gastric cancer include:
nausea
feeling tired
vomiting
numbness, pain, tingling, or burning
constipation
stomach-area (abdominal) pain
in your hands or feet
mouth sores
pain in muscles, bones, and
decreased appetite
diarrhea
joints
These are not all the possible side effects of OPDIVO QVANTIG.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of OPDIVO QVANTIG.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your
pharmacist or healthcare provider for information about OPDIVO QVANTIG that is written for health professionals.
What are the ingredients in OPDIVO QVANTIG?
Active ingredients: nivolumab and hyaluronidase-nvhy
Inactive ingredients: histidine, histidine hydrochloride monohydrate, methionine, pentetic acid, polysorbate 80,
sucrose, and Water for Injection.
Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA U.S. License No. 1713
Halozyme Therapeutics, Inc., 12390 El Camino Real, San Diego, CA 92130, U.S. License No. 2187
OPDIVO QVANTIG™ is a trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.
For more information, call 1-855-673-4861 or go to www.Qvantig.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: December 2024
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| custom-source | 2025-02-12T15:48:23.527979 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761381s000lbl.pdf', 'application_number': 761381, 'submission_type': 'ORIG ', 'submission_number': 1} |
80,794 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
STIOLTO RESPIMAT safely and effectively. See full prescribing
information for STIOLTO RESPIMAT.
STIOLTO® RESPIMAT® (tiotropium bromide and olodaterol inhalation
spray), for oral inhalation use
Initial U.S. Approval: 2015
----------------------------INDICATIONS AND USAGE---------------------------
STIOLTO RESPIMAT is a combination of tiotropium bromide, an
anticholinergic and olodaterol, a long-acting beta2-adrenergic agonist (LABA)
indicated for the long-term, once-daily maintenance treatment of patients with
chronic obstructive pulmonary disease (COPD). (1.1)
Important limitations:
•
STIOLTO RESPIMAT is NOT indicated to treat acute deterioration of
COPD. (1.1)
•
STIOLTO RESPIMAT is NOT indicated to treat asthma. (1.1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
•
For oral inhalation only.
•
Two inhalations of STIOLTO RESPIMAT once-daily at the same time
of day. (2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Inhalation spray: Each actuation from the mouthpiece delivers 2.5 mcg
tiotropium (equivalent to 3.124 mcg tiotropium bromide monohydrate), and
2.5 mcg olodaterol (equivalent to 2.736 mcg olodaterol hydrochloride).
Two actuations equal one dose. (3)
-------------------------------CONTRAINDICATIONS------------------------------
•
Use of a LABA, including STIOLTO RESPIMAT, without an inhaled
corticosteroid is contraindicated in patients with asthma. (4)
•
Hypersensitivity to tiotropium, ipratropium, olodaterol, or any
component of this product. (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
•
LABA as monotherapy (without an inhaled corticosteroid) for asthma
increases the risk of serious asthma-related events. (5.1)
•
Do not initiate STIOLTO RESPIMAT in acutely deteriorating COPD
patients. (5.2)
•
Do not use for relief of acute symptoms. Concomitant short-acting beta2-
agonists can be used as needed for acute relief. (5.2)
•
Do not exceed the recommended dosage. Excessive use of STIOLTO
RESPIMAT, or use in conjunction with other medications containing
LABA can result in clinically significant cardiovascular effects and may
be fatal. (5.3)
•
Immediate hypersensitivity reactions: Discontinue STIOLTO
RESPIMAT at once and consider alternatives if immediate
hypersensitivity reactions, including angioedema, urticaria, rash,
bronchospasm, or anaphylaxis, occur. (5.4)
•
Life-threatening paradoxical bronchospasm can occur. Discontinue
STIOLTO RESPIMAT immediately. (5.5)
•
Use with caution in patients with cardiovascular or convulsive disorders,
thyrotoxicosis, or sensitivity to sympathomimetic drugs. (5.6, 5.7)
•
Worsening of narrow-angle glaucoma may occur. Use with caution in
patients with narrow-angle glaucoma and instruct patients to consult a
physician immediately if this occurs. (5.8)
•
Worsening of urinary retention may occur. Use with caution in patients
with prostatic hyperplasia or bladder-neck obstruction and instruct
patients to consult a physician immediately if this occurs. (5.9)
•
Be alert to hypokalemia and hyperglycemia. (5.11)
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions (>3% incidence and more than an active
control) were nasopharyngitis, cough, and back pain.
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
•
Other adrenergic drugs may potentiate effect. Use with caution. (5.3,
7.1)
•
Xanthine derivatives, steroids, diuretics, or non-potassium sparing
diuretics may potentiate hypokalemia or ECG changes. Use with
caution. (7.2, 7.3)
•
MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc
interval may potentiate effect on cardiovascular system. Use with
extreme caution. (7.4)
•
Beta-blockers may decrease effectiveness. Use with caution and only
when medically necessary. (7.5)
•
Anticholinergics: May interact additively with concomitantly used
anticholinergic medications. Avoid administration of STIOLTO
RESPIMAT with other anticholinergic-containing drugs. (7.6)
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Patients with moderate to severe renal impairment should be monitored
closely for potential anticholinergic side effects. (2, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: x/202x
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Maintenance Treatment of COPD
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Administration Information
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Serious Asthma-Related Events – Hospitalizations, Intubations,
Death
5.2 Deterioration of Disease and Acute Episodes
5.3 Excessive Use of STIOLTO RESPIMAT and Use With Other
Long-Acting Beta2-Agonists
5.4 Immediate Hypersensitivity Reactions
5.5 Paradoxical Bronchospasm
5.6 Cardiovascular Effects
5.7 Coexisting Conditions
5.8 Worsening of Narrow-Angle Glaucoma
5.9 Worsening of Urinary Retention
5.10 Renal Impairment
5.11 Hypokalemia and Hyperglycemia
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary
Disease
7
DRUG INTERACTIONS
7.1 Adrenergic Drugs
7.2 Sympathomimetics, Xanthine Derivatives, Steroids, or Diuretics
7.3 Non-Potassium Sparing Diuretics
7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc
Prolonging Drugs
7.5 Beta-Blockers
7.6 Anticholinergics
7.7 Inhibitors of Cytochrome P450 and P-gp Efflux Transporter
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
2
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
____________________________________________________________________________________________________________
3
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1 Maintenance Treatment of COPD
STIOLTO RESPIMAT is a combination of tiotropium bromide and olodaterol indicated for long-term, once-daily maintenance treatment of patients with chronic
obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Important Limitations of Use
•
STIOLTO RESPIMAT is not indicated to treat acute deteriorations of COPD [see Warnings and Precautions (5.2)].
•
STIOLTO RESPIMAT is not indicated to treat asthma. The safety and effectiveness of STIOLTO RESPIMAT in asthma have not been established.
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of STIOLTO RESPIMAT is two inhalations once-daily at the same time of the day. Do not use STIOLTO RESPIMAT more than two
inhalations every 24 hours.
2.2 Administration Information
For oral inhalation only.
Prior to first use, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and the unit is primed. When using the unit for the first time,
patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed
and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are
to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use [see Patient Counseling Information
(17)].
No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given
STIOLTO RESPIMAT should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.10), Use in Specific Populations (8.5, 8.6, 8.7), and
Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Inhalation Spray: STIOLTO RESPIMAT consists of a STIOLTO RESPIMAT inhaler and an aluminum cylinder (STIOLTO RESPIMAT cartridge) containing a
combination of tiotropium bromide (as the monohydrate) and olodaterol (as the hydrochloride). The STIOLTO RESPIMAT cartridge is intended only for use with the
STIOLTO RESPIMAT inhaler.
Each actuation from the STIOLTO RESPIMAT inhaler delivers 2.5 mcg tiotropium (equivalent to 3.124 mcg tiotropium bromide monohydrate) and 2.5 mcg olodaterol
(equivalent to 2.736 mcg olodaterol hydrochloride) from the mouthpiece.
Two actuations equal one dose.
4
CONTRAINDICATIONS
Use of a LABA, including STIOLTO RESPIMAT, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5.1)].
STIOLTO RESPIMAT is not indicated for the treatment of asthma.
STIOLTO RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product [see Warnings and
Precautions (5.4)].
In clinical trials and postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or
throat), itching, or rash have been reported. Hypersensitivity reactions were also reported in clinical trials with STIOLTO RESPIMAT.
5
WARNINGS AND PRECAUTIONS
5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death
•
The safety and efficacy of STIOLTO RESPIMAT in patients with asthma have not been established. STIOLTO RESPIMAT is not indicated for the
treatment of asthma [see Contraindications (4)].
•
Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk
of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related
hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose
combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations,
intubations, death) compared with ICS alone.
•
A 28-week, placebo-controlled US study comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an
increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo;
RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of LABA, including olodaterol, one of the active
ingredients in STIOLTO RESPIMAT.
•
No study adequate to determine whether the rate of asthma-related death is increased in patients treated with STIOLTO RESPIMAT has been conducted.
•
Available data do not suggest an increased risk of death with use of LABA in patients with COPD.
5.2 Deterioration of Disease and Acute Episodes
STIOLTO RESPIMAT should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. STIOLTO RESPIMAT has not
been studied in patients with acutely deteriorating COPD. The use of STIOLTO RESPIMAT in this setting is inappropriate.
STIOLTO RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STIOLTO
RESPIMAT has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled
short-acting beta2-agonist.
4
When beginning STIOLTO RESPIMAT, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be
instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing STIOLTO
RESPIMAT, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled
beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.
COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If STIOLTO RESPIMAT no longer controls symptoms of
bronchoconstriction, or the patient’s inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than
usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once.
Increasing the daily dosage of STIOLTO RESPIMAT beyond the recommended dosage is not appropriate in this situation.
5.3 Excessive Use of STIOLTO RESPIMAT and Use With Other Long-Acting Beta2-Agonists
As with other inhaled drugs containing beta2-adrenergic agents, STIOLTO RESPIMAT should not be used more often than recommended, at higher doses than
recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects
and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
5.4 Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue or throat), rash, bronchospasm, anaphylaxis, or itching may
occur after administration of STIOLTO RESPIMAT. If such a reaction occurs, therapy with STIOLTO RESPIMAT should be stopped at once and alternative
treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine or its
derivatives should be closely monitored for similar hypersensitivity reactions to STIOLTO RESPIMAT.
5.5 Paradoxical Bronchospasm
As with other inhaled medicines, STIOLTO RESPIMAT may cause paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs,
STIOLTO RESPIMAT should be stopped immediately and alternative therapy instituted.
5.6 Cardiovascular Effects
Olodaterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or
diastolic blood pressure, and/or symptoms. If such effects occur, STIOLTO RESPIMAT may need to be discontinued. In addition, beta-agonists have been reported to
produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is
unknown. Long acting beta2-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency,
cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension.
5.7 Coexisting Conditions
Olodaterol, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or
suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when
administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
5.8 Worsening of Narrow-Angle Glaucoma
STIOLTO RESPIMAT should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute
narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and
corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
5.9 Worsening of Urinary Retention
STIOLTO RESPIMAT should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic
hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder neck obstruction.
Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
5.10 Renal Impairment
Because tiotropium is a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with
STIOLTO RESPIMAT should be monitored closely for anticholinergic side effects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
5.11 Hypokalemia and Hyperglycemia
Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects [see Clinical
Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may
produce increases in plasma glucose.
In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment [see Drug Interactions (7.2)], which may increase the
susceptibility for cardiac arrhythmias.
Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of olodaterol with the
rates similar to those for placebo controls. Olodaterol has not been investigated in patients whose diabetes mellitus is not well controlled.
6
ADVERSE REACTIONS
LABA, such as olodaterol, one of the active components in STIOLTO RESPIMAT, as monotherapy (without an inhaled corticosteroid) for asthma, increase the risk of
asthma-related events. STIOLTO RESPIMAT is not indicated for the treatment of asthma [see Warning and Precautions (5.1)].
The following adverse reactions are described, or described in greater detail, in other sections:
•
Immediate hypersensitivity reactions [see Warnings and Precautions (5.4)]
•
Paradoxical bronchospasm [see Warnings and Precautions (5.5)]
•
Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.8)]
•
Worsening of urinary retention [see Warnings and Precautions (5.9)]
5
6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly
compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice.
The clinical program for STIOLTO RESPIMAT included 7,151 subjects with COPD in two 52-week active-controlled trials, one 12-week placebo-controlled trial,
three 6-week placebo-controlled cross-over trials, and four additional trials of shorter duration. A total of 1,988 subjects received at least 1 dose of STIOLTO
RESPIMAT. Adverse reactions observed in the ≤12-week trials were consistent with those observed in the 52-week trials, which formed the primary safety database.
The primary safety database consisted of pooled data from the two 52-week double-blind, active-controlled, parallel group confirmatory clinical trials (Trials 1 and 2).
These trials included 5,162 adult COPD patients (72.9% males and 27.1% females) 40 years of age and older. Of these patients, 1,029 were treated with STIOLTO
RESPIMAT once daily. The STIOLTO RESPIMAT group was composed of mostly Caucasians (71.1%) with a mean age of 63.8 years and a mean percent predicted
FEV1 at baseline of 43.2%. In these two trials, tiotropium 5 mcg and olodaterol 5 mcg were included as active control arms and no placebo was used.
In these two clinical trials, 74% of patients exposed to STIOLTO RESPIMAT reported an adverse reaction compared to 76.6% and 73.3% in the olodaterol 5 mcg and
tiotropium 5 mcg groups, respectively. The proportion of patients who discontinued due to an adverse reaction was 7.4% for STIOLTO RESPIMAT treated patients
compared to 9.9% and 9.0% for olodaterol 5 mcg and tiotropium 5 mcg treated patients. The adverse reaction most commonly leading to discontinuation was worsening
COPD.
The most common serious adverse reactions were COPD exacerbation and pneumonia.
Table 1 shows all adverse drug reactions that occurred with an incidence of >3% in the STIOLTO RESPIMAT treatment group and a higher incidence rate than the
active comparator groups listed.
Table 1
Number and frequency of adverse drug reactions greater than 3% (and higher than any of the comparators tiotropium and/or olodaterol) in
COPD patients exposed to STIOLTO RESPIMAT: Pooled data from the two 52-week, double-blind, active-controlled clinical trials in COPD
patients 40 years of age and older
Treatment
STIOLTO RESPIMAT
(once daily)
Tiotropium
(5 mcg once daily)
Olodaterol
(5 mcg once daily)
Body system (adverse drug reaction)
n=1,029
n (%)
n=1,033
n (%)
n=1,038
n (%)
Infections and infestations
Nasopharyngitis
128 (12.4)
121 (11.7)
131 (12.6)
Respiratory, thoracic, and mediastinal disorders
Cough
40 (3.9)
45 (4.4)
31 (3.0)
Musculoskeletal and connective tissue disorders
Back Pain
37 (3.6)
19 (1.8)
35 (3.4)
Other adverse drug reactions in patients receiving STIOLTO RESPIMAT that occurred in ≤3% of patients in clinical studies are listed below:
Metabolism and nutrition disorders: dehydration
Nervous system disorders: dizziness, insomnia
Eye disorders: glaucoma, intraocular pressure increased, vision blurred
Cardiac/vascular disorders: atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension
Respiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis
Gastrointestinal disorders: dry mouth, constipation, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal
obstruction including ileus paralytic
Skin and subcutaneous disorders: rash, pruritus, angioneurotic edema, urticaria, skin infection, and skin ulcer, dry skin, hypersensitivity (including immediate reactions)
Musculoskeletal and connective tissue disorders: arthralgia, joint swelling
Renal and urinary disorders: urinary retention, dysuria, and urinary tract infection
COPD Exacerbation Reduction Trial
In a one year trial (Trial 5) of 7,880 patients to compare rates of COPD exacerbations, 3,939 patients were treated with STIOLTO RESPIMAT and 3,941 patients were
treated with tiotropium 5 mcg inhalation spray. The safety profile of STIOLTO RESPIMAT was similar to that of tiotropium 5 mcg inhalation spray and consistent with
that documented in the STIOLTO RESPIMAT primary safety database.
7
DRUG INTERACTIONS
7.1 Adrenergic Drugs
If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of olodaterol, one component of
STIOLTO RESPIMAT, may be potentiated [see Warnings and Precautions (5.3, 5.6, 5.10, 5.11)].
7.2 Sympathomimetics, Xanthine Derivatives, Steroids, or Diuretics
Tiotropium has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled
steroids, without increases in adverse reactions. Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of
olodaterol [see Warnings and Precautions (5.11)].
7.3 Non-Potassium Sparing Diuretics
The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely
worsened by beta-agonists, especially when the recommended dosage of the beta-agonist is exceeded. Although the clinical significance of these effects is not known,
caution is advised in the co-administration of STIOLTO RESPIMAT with non-potassium sparing diuretics.
6
7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs
STIOLTO RESPIMAT, as with other drugs containing beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase
inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be
potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
7.5 Beta-Blockers
Beta-adrenergic receptor antagonists (beta-blockers) and the olodaterol component of STIOLTO RESPIMAT may interfere with the effect of each other when
administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore,
patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there
may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they
should be administered with caution.
7.6 Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid co-administration of STIOLTO RESPIMAT with
other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.8, 5.9) and Adverse Reactions
(6)].
7.7 Inhibitors of Cytochrome P450 and P-gp Efflux Transporter
In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol maximum plasma concentrations and AUC was
observed [see Pharmacokinetics (12.3)]. Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dosage. No
dosage adjustment of STIOLTO RESPIMAT is necessary.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no adequate and well-controlled clinical studies with STIOLTO RESPIMAT or its individual components, tiotropium bromide and olodaterol, in pregnant
women to inform of drug-associated risk of adverse pregnancy-related outcomes. Animal reproduction studies were conducted with the individual components of
STIOLTO RESPIMAT, tiotropium bromide and olodaterol. There are clinical considerations with the use of STIOLTO RESPIMAT in pregnant women (see Clinical
Considerations). STIOLTO RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal
reproduction studies, no structural abnormalities were observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the period of
organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID). Increased post-implantation loss was
observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively (see Data). Based on animal studies,
olodaterol was not teratogenic when administered to pregnant rats or rabbits during organogenesis at inhalation doses of approximately 2,731 or 1,353 times the
MRHDID (on an AUC basis), in rats or rabbits, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect,
loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Labor and Delivery
There are no adequate and well-controlled human studies that have investigated the effects of STIOLTO RESPIMAT on preterm labor or labor at term. Because of the
potential for beta-agonist interference with uterine contractility, use of STIOLTO RESPIMAT during labor should be restricted to those patients in whom the benefits
clearly outweigh the risks.
Data
Animal Data
Animal reproduction studies with the combination of tiotropium and olodaterol are not available; however, studies are available with the individual components.
Tiotropium
In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and
8 times the MRHDID, respectively (on a mcg/m2 basis at inhalation doses of 1,471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural
abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean
pup weights, and a delay in pup sexual maturation at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of
78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m2 basis at
a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m2 basis at
inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).
Olodaterol
Olodaterol was not teratogenic in rats at inhalation doses approximately 2,731 times the MRHDID (on an AUC basis at a maternal inhalation dose of
1,054 mcg/kg/day). No significant effects occurred in rabbits at inhalation doses approximately 1,353 times the MRHDID in adults (on an AUC basis at a maternal
inhalation dose of 974 mcg/kg/day). Placental transfer of olodaterol was observed in pregnant rats.
Olodaterol has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHDID in adults (on an AUC basis at a
maternal inhalation dose of 2,489 mcg/kg/day). Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split
or distorted sternum.
8.2 Lactation
Risk Summary
There are no data on the presence of tiotropium or olodaterol in human milk, the effects on the breastfed infant, or the effects on milk production. Tiotropium,
olodaterol, and/or their metabolites are present in the milk of lactating rats, however, due to species-specific differences in lactation physiology, the clinical relevance of
these data are not clear (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for STIOLTO
RESPIMAT and any potential adverse effects on the breastfed child from STIOLTO RESPIMAT or from the underlying maternal condition.
Data
7
The distributions of tiotropium bromide or olodaterol into milk were investigated in separate studies after a single intravenous administration of 10 mg/kg or
0.4 μmol/kg, respectively, to lactating rats. Tiotropium, olodaterol, and/or their metabolites are present in the milk of lactating rats at concentrations above those in
plasma.
8.4 Pediatric Use
COPD does not normally occur in children. The safety and effectiveness of STIOLTO RESPIMAT in the pediatric population has not been established.
8.5 Geriatric Use
Based on available data, no adjustment of STIOLTO RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].
Of the 1,029 patients who received STIOLTO RESPIMAT at the recommended dose once daily in the clinical studies from the pooled 1-year database, 525 (51.0%)
were <65 years of age, 407 (39.6%) were 65 to <75, 96 (9.3%) were 75 to <85, and 1 (0.1%) was ≥85.
No overall differences in effectiveness were observed, and in the 1-year pooled data, the adverse drug reaction profiles were similar in the older population compared to
the patient population overall.
8.6 Hepatic Impairment
No dose adjustment is needed in patients with mild and moderate hepatic impairment. A study in subjects with severe hepatic impairment was not performed [see
Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dose adjustment is required for patients with renal impairment. However, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min)
treated with STIOLTO RESPIMAT should be monitored closely for anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.10),
and Clinical Pharmacology (12.3)].
10
OVERDOSAGE
STIOLTO RESPIMAT contains both tiotropium bromide and olodaterol; therefore, the risks associated with overdosage for the individual components described below
apply to STIOLTO RESPIMAT.
Tiotropium
High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled
dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-
daily inhalation of 141 mcg of tiotropium. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, were observed following
14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.
Olodaterol
The expected signs and symptoms with overdosage of olodaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs
and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia,
anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled
sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of olodaterol.
Treatment of overdosage consists of discontinuation of STIOLTO RESPIMAT together with institution of appropriate symptomatic and supportive therapy. The
judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient
evidence to determine if dialysis is beneficial for overdosage of STIOLTO RESPIMAT. Cardiac monitoring is recommended in cases of overdosage.
11
DESCRIPTION
STIOLTO RESPIMAT is a combination of tiotropium, an anticholinergic, and olodaterol, a long-acting beta2-adrenergic agonist (LABA).
The drug substance tiotropium bromide monohydrate is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-
azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish
white powder. It is sparingly soluble in water and soluble in methanol.
The structural formula is:
Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O.
The drug substance olodaterol hydrochloride is chemically described as 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-
dimethylethyl]-amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly
soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C21H26N2O5 x HCl as a hydrochloride. The conversion
factor from salt to free base is 1.094.
The structural formula is:
9
The effect of 5 mcg and 10 mcg olodaterol on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772
patients in the 48-week, placebo-controlled phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart
rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between olodaterol 5 mcg, 10 mcg, and
placebo.
12.3 Pharmacokinetics
STIOLTO RESPIMAT
When STIOLTO RESPIMAT was administered by the inhalation route, the pharmacokinetic parameters for tiotropium and for olodaterol were similar to those
observed when each active substance was administered separately.
Tiotropium
Tiotropium is administered as an inhalation spray. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.
Olodaterol
Olodaterol showed linear pharmacokinetics. On repeated once-daily inhalation, steady-state of olodaterol plasma concentrations was achieved after 8 days, and the
extent of exposure was increased up to 1.8-fold as compared to a single dose.
Absorption
Tiotropium
Following inhalation of the solution by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic
circulation. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected to influence the absorption of tiotropium for the same
reason. Maximum tiotropium plasma concentrations were observed 5 to 7 minutes after inhalation.
Olodaterol
Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers the absolute bioavailability of
olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the
systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to
systemic exposure.
Distribution
Tiotropium
The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Local concentrations in the lung are not known, but the mode of
administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier.
Olodaterol
Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1,110 L),
suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.
Elimination
Metabolism
Tiotropium
The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers.
Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, both not binding to muscarinic receptors.
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted
unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of
Phase 2 metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6
and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver
microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
Olodaterol
Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites
identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the
recommended therapeutic dose.
Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine
diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.
Excretion
Tiotropium
The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was
880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After
inhalation of the solution by patients with COPD, urinary excretion is 18.6% (0.932 mcg) of the dose, the remainder being mainly non-absorbed drug in the gut that is
eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once-daily inhalation by
COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.
Olodaterol
Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is
22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination
processes. However, the effective half-life at daily dose of 5 mcg calculated from Cmax from COPD patients is 7.5 hours.
Following intravenous administration of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount
of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites
was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and
10
oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state
accounted for 5% to 7% of the dose.
Drug Interactions
STIOLTO RESPIMAT
Pharmacokinetic drug interaction studies with STIOLTO RESPIMAT have not been performed; however, such studies have been conducted with individual
components tiotropium and olodaterol.
When tiotropium and olodaterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those
observed when each active substance was administered separately.
Tiotropium
An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once-daily was
conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and
no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of
tiotropium.
Common concomitant medications (long-acting beta2-adrenergic agonists (LABA), inhaled corticosteroids (ICS)) used by patients with COPD were not found to alter
the exposure to tiotropium.
Olodaterol
Drug-drug interaction studies were carried out using fluconazole as a model inhibitor of CYP 2C9 and ketoconazole as a potent P-gp (and CYP3A4, 2C8, 2C9)
inhibitor.
Fluconazole: Co-administration of 400 mg fluconazole once a day for 14 days had no relevant effect on systemic exposure to olodaterol.
Ketoconazole: Co-administration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.
Tiotropium: Co-administration of tiotropium bromide, delivered as a fixed-dose combination with olodaterol, for 21 days had no relevant effect on systemic exposure to
olodaterol, and vice versa.
Specific Populations
Olodaterol
A pharmacokinetic meta-analysis showed that no dose adjustment is necessary based on the effect of age, gender, and weight on systemic exposure in COPD patients
after inhalation of olodaterol.
Geriatric Patients
Tiotropium: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (347 mL/min in
COPD patients <65 years to 275 mL/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values.
Renal Impairment
Tiotropium
Following inhaled administration of therapeutic doses of tiotropium to steady-state to patients with COPD, mild renal impairment (creatinine clearance 60 - <90
mL/min) resulted in 23% higher AUC0-6,ss and 17% higher Cmax,ss values. Moderate renal impairment (creatinine clearance 30 - <60 mL/min) resulted in 57% higher
AUC0-6,ss and 31% higher Cmax,ss values compared to COPD patients with normal renal function (creatinine clearance ≥90 mL/min). In COPD patients with severe renal
impairment (CLCR <30 mL/min), a single intravenous administration of tiotropium bromide resulted in 94% higher AUC0-4 and 52% higher Cmax compared to COPD
patients with normal renal function.
Olodaterol
Olodaterol levels were increased by approximately 40% in subjects with severe renal impairment. A study in subjects with mild and moderate renal impairment was not
performed.
Hepatic Impairment
Tiotropium
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.
Olodaterol
Subjects with mild and moderate hepatic impairment showed no changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically
impaired subjects and their healthy controls. A study in subjects with severe hepatic impairment was not performed.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
STIOLTO RESPIMAT
No studies of the carcinogenicity, in vitro mutagenicity, or impairment of fertility were conducted with STIOLTO RESPIMAT, however, studies are available for the
individual components, tiotropium and olodaterol.
Tiotropium
No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female
mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40,
and 0.5 times the recommended human daily inhalation dose (RHDID) on a mcg/m2 basis, respectively.
Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster
cell mutagenesis assay, the chromosomal aberration assay in human lymphocytes in vitro, the mouse micronucleus assay in vivo, and the unscheduled DNA synthesis
assay in primary rat hepatocytes in vitro.
In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately
35 times the RHDID on a mcg/m2 basis). No such effects were observed at 9 mcg/kg/day (approximately 4 times than the RHDID on a mcg/m2 basis). The fertility
index; however, was not affected at inhalation doses up to 1,689 mg/kg/day (approximately 760 times the RHDID on a mcg/m2 basis).
11
Olodaterol
Two-year inhalation studies were conducted in rats and mice to assess the carcinogenic potential of olodaterol. Lifetime treatment of female rats induced leiomyomas of
the mesovarium at doses of 25.8 and 270 mcg/kg/day (approximately 18- and 198-fold, respectively, the RHDID on an AUC basis). No tumor findings were observed
in male rats at doses up to 270 mcg/kg/day (approximately 230-fold the RHDID on an AUC basis). Lifetime treatment of female mice induced leiomyomas and
leiomyosarcomas of the uterus at doses ≥76.9 mcg/kg/day (approximately 106-fold the RHDID on an AUC basis). No tumor findings were observed in male mice at
doses up to 255 mcg/kg/day (approximately 455-fold the RHDID on an AUC basis). Increases in leiomyomas and leiomyosarcomas of the female rodent reproductive
tract have been similarly demonstrated with other beta2-adrenergic agonist drugs. The relevance of these findings to human use is unknown.
Olodaterol was not mutagenic in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of micronuclei in rats after
intravenous doses. The increased frequency of micronuclei was likely related to drug enhanced (compensatory) erythropoiesis. The mechanism for induction of
micronuclei formation is likely not relevant at clinical exposures.
Olodaterol did not impair male or female fertility in rats at inhalation doses up to 3,068 mcg/kg/day (approximately 2,322 times the RHDID on an AUC basis).
14
CLINICAL STUDIES
The safety and efficacy of STIOLTO RESPIMAT were evaluated in a clinical development program that included three dose ranging trials, two active-controlled trials,
three active- and placebo-controlled trials, and one placebo-controlled trial. The efficacy of STIOLTO RESPIMAT is based primarily on two 4-week dose-ranging trials
in 592 COPD patients and two confirmatory active-controlled 52-week trials (Trials 1 and 2) in 5,162 COPD patients.
Dose-Ranging Trials
Dose selection for STIOLTO RESPIMAT was primarily based on trials for the individual components, tiotropium bromide and olodaterol.
Dose selection was also supported by two randomized, double-blind, active-controlled, 4-week trials. In one trial in 232 patients with COPD, three tiotropium doses
(1.25, 2.5, and 5 mcg) were given in combination with olodaterol 5 or 10 mcg and were evaluated compared to olodaterol monotherapy. Results demonstrated
improvement in trough FEV1 for the combination when compared to olodaterol alone. The difference in trough FEV1 for the tiotropium bromide/olodaterol doses of
1.25/5, 2.5/5, and 5/5 mcg once daily from olodaterol 5 mcg were 0.054 L (95% CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084 L (0.046, 0.122), respectively. In
the second trial in 360 patients with COPD, three olodaterol doses (2, 5, and 10 mcg) were given in combination with tiotropium 5 mcg and were evaluated compared to
tiotropium monotherapy. The difference in trough FEV1 for the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg once daily from tiotropium 5 mcg were 0.024 L
(95% CI -0.029, 0.076), 0.033 L (-0.019, 0.085), and 0.057 L (0.004, 0.110), respectively. Results of these trials supported the evaluation of once-daily doses of
tiotropium bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.
Confirmatory Trials
A total of 5,162 COPD patients (1,029 receiving STIOLTO RESPIMAT, 1,038 receiving olodaterol 5 mcg, and 1,033 receiving tiotropium bromide 5 mcg) were
studied in two confirmatory trials of STIOLTO RESPIMAT. Trials 1 and 2 were 52-week, replicate, randomized, double-blind, active controlled, parallel group trials
that compared STIOLTO RESPIMAT to tiotropium 5 mcg and olodaterol 5 mcg. In these trials, all products were administered via the RESPIMAT inhaler.
The trials enrolled patients 40 years of age or older with a clinical diagnosis of COPD, a smoking history of more than 10 pack-years, and moderate to very severe
pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal [GOLD Stage 2-4]; post-bronchodilator FEV1 to FVC ratio of less than 70%). All
treatments were administered once daily in the morning. The primary endpoints were change from baseline in FEV1 AUC0-3hr and trough FEV1 after 24 weeks of
treatment.
The majority of the 5162 patients were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years. Mean post-bronchodilator FEV1 was 1.37 L (GOLD 2
[50%], GOLD 3 [39%], GOLD 4 [11%]). Mean beta2-agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy
included inhaled steroids [47%] and xanthines [10%].
In both Trials 1 and 2, STIOLTO RESPIMAT demonstrated significant improvements in FEV1 AUC0-3hr and trough FEV1 after 24 weeks compared to tiotropium 5 mcg
and olodaterol 5 mcg (Table 2). The increased bronchodilator effects of STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained
throughout the 52-week treatment period. STIOLTO RESPIMAT displayed a mean increase in FEV1 from baseline of 0.137 L (range: 0.133-0.140 L) within 5 minutes
after the first dose. Patients treated with STIOLTO RESPIMAT used less rescue medication compared to patients treated with tiotropium 5 mcg and olodaterol 5 mcg.
Table 2
FEV1 AUC0-3hr and Trough FEV1 response for STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg after 24 weeks
(primary endpoints; Trials 1 and 2)
Trial 1
Trial 2
n
Mean (L)
Difference (L)
(95% CI)
n
Mean (L)
Difference (L)
(95% CI)
FEV1 AUC0-3hr response
STIOLTO RESPIMAT
522
0.256
-
502
0.268
-
Tiotropium 5 mcg
526
0.139
0.117
(0.094, 0.140)
500
0.165
0.103
(0.078, 0.127)
Olodaterol 5 mcg
525
0.133
0.123
(0.100, 0.146)
507
0.136
0.132
(0.108, 0.157)
Trough FEV1 response
STIOLTO RESPIMAT
521
0.136
-
497
0.145
-
Tiotropium 5 mcg
520
0.065
0.071
(0.047, 0.094)
498
0.096
0.050
(0.024, 0.075)
Olodaterol 5 mcg
519
0.054
0.082
(0.059, 0.106)
503
0.057
0.088
(0.063, 0.113)
Pre-treatment baseline FEV1: Trial 1=1.16 L; Trial 2=1.15 L
p≤0.0001 for all comparisons between STIOLTO RESPIMAT and the monotherapies.
12
For the subset of patients (n=521) who completed extended lung function measurements up to 12 hours post-dose, STIOLTO RESPIMAT showed a significantly
greater FEV1 response compared to tiotropium 5 mcg and olodaterol 5 mcg over the full 24-hour dosing interval. Results from Trial 2 are shown in Figure 1.
Figure 1
FEV1 profile for STIOLTO RESPIMAT, tiotropium 5 mcg and olodaterol 5 mcg over a 24-hour dosing interval after 24 weeks (12 hr PFT subset
from Trial 2)
The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2 and in two additional 12-week placebo-controlled trials (Trials 3 and 4).
In the first 12-week trial, SGRQ responder rates at week 12 (defined as an improvement in score of 4 or more as a threshold) were 53%, 42%, and 31% for STIOLTO
RESPIMAT, tiotropium 5 mcg, and placebo, respectively, with odds ratios of 1.6 (95% CI 1.1, 2.4) and 2.5 (95% CI 1.6, 3.8) for STIOLTO RESPIMAT vs. tiotropium
5 mcg and STIOLTO RESPIMAT vs. placebo, respectively. In the second 12-week trial, results were similar with odds ratios of 1.5 (95% CI 1.0, 2.3) and 2.2 (95% CI
1.5, 3.4) for STIOLTO RESPIMAT vs. tiotropium 5 mcg and STIOLTO RESPIMAT vs. placebo, respectively. For the 52-week trials similar responder rates were seen.
In Trial 1, the odds ratios for STIOLTO vs. tiotropium 5 mcg and STIOLTO vs. olodaterol 5 mcg at week 24 were 1.6 (95% CI 1.2, 2.0) and 1.9 (95% CI 1.5, 2.4),
respectively. The results were similar in the 52-week Trial 2, with odds ratios for STIOLTO vs. tiotropium 5 mcg and STIOLTO vs. olodaterol 5 mcg of 1.3 (95% CI
1.0, 1.7) and 1.5 (95% CI 1.1, 1.9), respectively.
Exacerbations
Tiotropium 5 mcg Trials Evaluating Exacerbations
The effect of tiotropium 5 mcg inhalation spray on exacerbations was evaluated in three 48-week randomized, double-blind, placebo-controlled clinical trials that
included COPD exacerbations as the primary endpoint. Exacerbations of COPD were defined as a complex of lower respiratory events/symptoms (increase or new
onset) related to the underlying COPD, with duration of three days or more, requiring a prescription of antibiotics and/or systemic steroids and/or hospitalization. In a
pooled analysis of the first two trials, tiotropium 5 mcg significantly reduced the number of COPD exacerbations compared to placebo with a rate ratio of 0.78 (95% CI
0.67, 0.92). In the third trial, tiotropium 5 mcg delayed the time to first COPD exacerbation compared to placebo with a hazard ratio of 0.69 (95% CI 0.63, 0.77).
STIOLTO RESPIMAT Trial Evaluating Exacerbations
In a one-year, randomized, double-blind, active-controlled parallel group clinical trial (Trial 5), the effect of STIOLTO RESPIMAT on COPD exacerbations was
compared with tiotropium 5 mcg inhalation spray. Exacerbations were defined as above. Enrolled patients (3,939 patients receiving STIOLTO RESPIMAT and 3,941
patients receiving tiotropium 5 mcg inhalation spray) had a history of COPD exacerbation in the previous 12 months. The primary endpoint was the annualized rate of
moderate to severe COPD exacerbations. The majority of patients were male (71%) and Caucasian (79%). The mean age was 66 years, and mean post-bronchodilator
FEV1 percent predicted was 45%. STIOLTO RESPIMAT treatment did not demonstrate superiority to tiotropium 5 mcg inhalation spray for the primary endpoint, the
annualized rate of moderate to severe COPD exacerbations, with a rate ratio of 0.93 (99% CI, 0.85-1.02, p=0.0498). The study did not reach the pre-specified
significance level of 0.01.
16
HOW SUPPLIED/STORAGE AND HANDLING
STIOLTO RESPIMAT Inhalation Spray is supplied in a labeled carton containing one STIOLTO RESPIMAT cartridge and one STIOLTO RESPIMAT inhaler.
The STIOLTO RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The STIOLTO RESPIMAT cartridge is only
intended for use with the STIOLTO RESPIMAT inhaler and should not be interchanged with any other RESPIMAT device delivered product.
13
The STIOLTO RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the
cartridge. The inhaler contains a dose indicator. The light green-colored cap and the written information on the label of the gray inhaler body indicate that it is labeled
for use with the STIOLTO RESPIMAT cartridge.
STIOLTO RESPIMAT Inhalation Spray is available as:
•
STIOLTO RESPIMAT Inhalation Spray: 60 metered actuations (NDC 0597-0155-61)
•
STIOLTO RESPIMAT Inhalation Spray: 10 metered actuations (NDC 0597-0155-70) (institutional pack)
The STIOLTO RESPIMAT cartridge has a net fill weight of at least 4 grams and when used with the STIOLTO RESPIMAT inhaler, is designed to deliver the labeled
number of metered actuations after preparation for use.
When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be
dispensed.
After assembly, the STIOLTO RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever
comes first.
Keep out of reach of children. Do not spray into eyes.
Storage
Store at 20oC to 25oC (68oF to 77oF); excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature]. Avoid freezing.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Serious Asthma-Related Events
Inform patients that LABA, such as STIOLTO RESPIMAT, when used as monotherapy [without an inhaled corticosteroid], increase the risk of serious asthma-related
events, including asthma-related death. STIOLTO RESPIMAT is not indicated for the treatment of asthma.
Not for Acute Symptoms
STIOLTO RESPIMAT is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms
should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the
patient in how it should be used.)
Instruct patients to notify their physician immediately if they experience any of the following:
•
Worsening of symptoms
•
Decreasing effectiveness of inhaled, short-acting beta2-agonists
•
Need for more inhalations than usual of inhaled, short-acting beta2-agonists
•
Significant decrease in lung function as outlined by the physician
Instruct patients not to stop therapy with STIOLTO RESPIMAT without physician/provider guidance since symptoms may recur after discontinuation.
Do Not Use Additional Long-Acting Beta2-Agonists
Patients who have been taking inhaled, short-acting beta2-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them
only for the symptomatic relief of acute symptoms.
When patients are prescribed STIOLTO RESPIMAT, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more
than the recommended once-daily dosage of STIOLTO RESPIMAT. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be
fatal.
Risks Associated with Beta2-Agonist Therapy
Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
Immediate Hypersensitivity Reactions
Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration
of STIOLTO RESPIMAT. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.
Paradoxical Bronchospasm
Inform patients that STIOLTO RESPIMAT can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should
discontinue STIOLTO RESPIMAT.
Urinary Retention
Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a
physician immediately should any of these signs or symptoms develop.
Visual Effects
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of
acute narrow-angle glaucoma. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eye
drops alone are not considered to be effective treatment.
Inform patients that care must be taken not to allow the aerosol cloud to enter into the eyes as this may cause blurring of vision and pupil dilation.
Since dizziness and blurred vision may occur with the use of STIOLTO RESPIMAT, caution patients about engaging in activities such as driving a vehicle or operating
appliances or machinery.
14
Instructions for Administering STIOLTO RESPIMAT
It is important for patients to understand how to correctly administer STIOLTO RESPIMAT inhalation spray using the STIOLTO RESPIMAT inhaler. Instruct patients
that STIOLTO RESPIMAT inhalation spray should only be administered via the STIOLTO RESPIMAT inhaler and the STIOLTO RESPIMAT inhaler should not be
used for administering other medications.
Instruct patients that priming STIOLTO RESPIMAT is essential to ensure appropriate content of the medication in each actuation.
When using the unit for the first time, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and the unit is primed. STIOLTO
RESPIMAT patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to repeat the process three more times. The unit is then
considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21
days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
STIOLTO® and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH
Copyright © 202x Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
COL10537BH212024
1
PATIENT INFORMATION
STIOLTO® RESPIMAT® (sti-OL-to– RES peh mat)
(tiotropium bromide and olodaterol inhalation spray), for oral inhalation use
What is STIOLTO RESPIMAT?
•
STIOLTO RESPIMAT combines an anticholinergic, tiotropium bromide and a long-acting beta2-adrenergic agonist
(LABA) medicine, olodaterol.
•
Anticholinergic and LABA medicines such as STIOLTO RESPIMAT help the muscles around the airways in your
lungs stay relaxed to prevent symptoms, such as wheezing, cough, chest tightness, and shortness of breath. These
symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe.
•
STIOLTO RESPIMAT is a prescription medicine used to control the symptoms of COPD in adults with COPD.
COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both.
•
STIOLTO RESPIMAT is for long-term use and should be taken as 2 puffs 1 time each day, to improve the
symptoms of COPD for better breathing.
•
STIOLTO RESPIMAT is not used to treat sudden symptoms of COPD. Always have a beta2-agonist inhaler
medicine (rescue inhaler) with you to treat sudden symptoms of COPD. If you do not have a rescue inhaler, contact
your healthcare provider to have one prescribed for you.
•
STIOLTO RESPIMAT is not for the treatment of asthma. It is not known if STIOLTO RESPIMAT is safe and
effective in people with asthma.
•
STIOLTO RESPIMAT should not be used in children. It is not known if STIOLTO RESPIMAT is safe and
effective in children.
Do not use STIOLTO RESPIMAT if you:
•
have asthma.
•
are allergic to tiotropium, ipratropium, olodaterol, or any of the ingredients in STIOLTO RESPIMAT. See the end of
this Patient Information leaflet for a complete list of ingredients in STIOLTO RESPIMAT.
Before you use STIOLTO RESPIMAT, tell your healthcare provider about all of your medical conditions,
including if you:
•
have heart problems.
•
have high blood pressure.
•
have seizures.
•
have thyroid problems.
•
have diabetes.
•
have eye problems, such as glaucoma. STIOLTO RESPIMAT can make your glaucoma worse.
•
have prostate or bladder problems, or problems passing urine. STIOLTO RESPIMAT can make these problems
worse.
•
have kidney problems.
•
are pregnant or plan to become pregnant. It is not known if the medicines tiotropium or olodaterol in STIOLTO
RESPIMAT can harm your unborn baby.
•
are breastfeeding or plan to breastfeed. It is not known if the medicines tiotropium or olodaterol in STIOLTO
RESPIMAT passes into your breast milk and if it can harm your baby. You and your healthcare provider should
decide if you will take STIOLTO RESPIMAT while breastfeeding.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, eye drops, vitamins, and herbal supplements. STIOLTO RESPIMAT and certain other medicines may affect
each other. This may cause serious side effects.
Especially tell your healthcare provider if you take:
•
anticholinergics (including ipratropium, aclidinium, umeclidinium or another tiotropium-containing product such as
SPIRIVA RESPIMAT or SPIRIVA HANDIHALER)
•
atropine
Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist
each time you get a new medicine.
How should I use STIOLTO RESPIMAT?
Read the step-by-step instructions for using STIOLTO RESPIMAT at the end of this Patient Information leaflet.
•
Do not use STIOLTO RESPIMAT unless your healthcare provider has taught you how to use the inhaler and you
understand how to use it correctly. Ask your healthcare provider or pharmacist if you have any questions.
•
STIOLTO RESPIMAT inhaler has a slow-moving mist that helps you inhale the medicine.
•
Use STIOLTO RESPIMAT exactly as your healthcare provider tells you to use it. Do not use STIOLTO RESPIMAT
more often than prescribed.
•
Use 1 dose (2 puffs) of STIOLTO RESPIMAT, 1 time each day, at the same time of the day.
2
•
If you miss a dose of STIOLTO RESPIMAT, take it as soon as you remember. Do not take more than 1 dose (2
puffs) in 24 hours.
•
If you take too much STIOLTO RESPIMAT, call your healthcare provider or go to the nearest hospital
emergency room right away.
•
Do not spray STIOLTO RESPIMAT in your eyes. Your vision may become blurred and your pupils may become
larger (dilated).
•
STIOLTO RESPIMAT Inhalation Spray should only be given using the STIOLTO RESPIMAT inhaler. The STIOLTO
RESPIMAT inhaler should not be used to give other medicines.
•
Always use the new STIOLTO RESPIMAT inhaler that is provided with each new prescription.
•
STIOLTO RESPIMAT does not relieve sudden symptoms of COPD. You should not take extra doses of
STIOLTO RESPIMAT to relieve sudden symptoms of COPD. Always have a rescue inhaler medicine with you to
treat sudden symptoms. If you do not have a rescue inhaler medicine, call your healthcare provider to have one
prescribed for you.
•
If your COPD symptoms worsen over time, do not increase your dose of STIOLTO RESPIMAT, instead call your
healthcare provider.
•
Do not stop using STIOLTO RESPIMAT or other medicines to control or treat your COPD unless told to do so by
your healthcare provider because your symptoms might get worse. Your healthcare provider will change your
medicines as needed.
•
Do not use STIOLTO RESPIMAT:
o more often than prescribed for you,
o at a higher dose than prescribed for you, or
o with other medicines that contain LABA or an anticholinergic for any reason. Ask your healthcare provider or
pharmacist if any of your other medicines are LABA or anticholinergic medicines.
•
Call your healthcare provider or get emergency medical care right away if your breathing problems worsen
with STIOLTO RESPIMAT, you need to use your rescue inhaler medicine more often than usual, or your rescue
inhaler medicine does not work as well for you at relieving your symptoms.
What are the possible side effects with STIOLTO RESPIMAT?
STIOLTO RESPIMAT can cause serious side effects, including:
•
serious problems from asthma. People with asthma who take long-acting beta2-adrenergic agonist (LABA)
medicines, such as olodaterol (one of the medicines in STIOLTO RESPIMAT), without also using a medicine called
an inhaled corticosteroid, have an increased risk of serious problems from asthma, including being hospitalized,
needing a tube placed in their airway to help them breathe, or death.
•
call your healthcare provider if breathing problems worsen over time while using STIOLTO RESPIMAT. You
may need a different treatment.
Get emergency medical care if:
o your breathing problems worsen quickly
o you use your rescue inhaler medicine, but it does not relieve your breathing problems
•
using too much of a LABA medicine (one of the medicines in STIOLTO RESPIMAT) may cause:
o chest pain
o fast and irregular heartbeat
o tremor
o
increased blood pressure
o
headache
o
nervousness
•
COPD symptoms can get worse over time. If your COPD symptoms worsen over time, do not increase your dose
of STIOLTO RESPIMAT, instead call your healthcare provider.
•
serious allergic reactions including rash, hives, itching, swelling of the face, lips, tongue, throat, difficulties
in breathing or swallowing. Stop taking STIOLTO RESPIMAT and get emergency medical help right away if you
get any symptoms of a serious allergic reaction after using STIOLTO RESPIMAT.
•
sudden shortness of breath can happen immediately after using STIOLTO RESPIMAT. Sudden shortness of
breath may be life-threatening. Stop taking STIOLTO RESPIMAT and call your healthcare provider or get
emergency medical help right away if you get sudden shortness of breath after using STIOLTO RESPIMAT.
•
effects on your heart, including fast or irregular heartbeat, palpitations, chest pain, and increased blood pressure.
•
new or worsening eye problems including acute narrow-angle glaucoma. Symptoms of acute narrow-angle
glaucoma include eye pain or discomfort, blurred vision, seeing halos or colored images around lights, and red
eyes. Call your healthcare provider right away if you have any of these symptoms. Use caution as some of these
eye problems can affect your ability to drive and operate appliances and machinery.
•
new or worsening urinary retention. Symptoms of urinary retention may include difficulty urinating, painful
urination, urinating frequently, or urinating in a weak stream or drips. Call your healthcare provider right away if you
have any of these symptoms.
•
changes in laboratory blood levels including high blood sugar (hyperglycemia) and low levels of potassium
(hypokalemia), which may cause symptoms of muscle weakness or abnormal heart rhythm.
Common side effects of STIOLTO RESPIMAT include runny nose, cough, and back pain.
3
These are not all the side effects of STIOLTO RESPIMAT. Call your doctor for medical advice about side effects. You
may report side effects to FDA at 1-800-FDA-1088.
How should I store STIOLTO RESPIMAT?
•
Store STIOLTO RESPIMAT at room temperature, between 68°F to 77°F (20°C to 25°C).
•
Do not freeze your STIOLTO cartridge or RESPIMAT inhaler.
•
Keep your STIOLTO RESPIMAT inhaler, cartridge, and all medicines out of the reach of children.
General information about the safe and effective use of STIOLTO RESPIMAT
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
STIOLTO RESPIMAT for a condition for which it was not prescribed. Do not give STIOLTO RESPIMAT to other people,
even if they have the same symptoms that you have. It may harm them.
You can ask your healthcare provider or pharmacist for information about STIOLTO RESPIMAT that is written for
health professionals.
Active ingredients: tiotropium bromide and olodaterol
Inactive ingredients: benzalkonium chloride, edetate disodium, hydrochloric acid, and water for injection
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
SPIRIVA®, HANDIHALER®, STIOLTO® and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH
Copyright © 202x Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
COL10537BH212024
For more information about STIOLTO RESPIMAT, including current prescribing information, a video demonstration or a
Quick Start Guide on how to use STIOLTO RESPIMAT, go to www.STIOLTO.com, scan the code, or call 1-800-542-
6257.
This Patient Information has been approved by the U.S. Food and Drug Administration Revised: xx/202x
1
Instructions for Use
STIOLTO® RESPIMAT® (sti-OL-to- RES peh mat)
(tiotropium bromide and olodaterol inhalation spray), for oral inhalation use
For Oral Inhalation Only
Do not spray STIOLTO RESPIMAT into your eyes.
Read these Instructions for Use before you start using STIOLTO RESPIMAT and each time you get a refill. There may be
new information. This leaflet does not take the place of talking to your doctor about your medical condition or your
treatment.
You will need to use this inhaler 1 time each day, at the same time each day. Each time you use it take 2 puffs.
Do not turn the clear base before inserting the cartridge.
How to store your STIOLTO RESPIMAT inhaler
• Store STIOLTO RESPIMAT at room temperature between 68°F to 77°F (20°C to 25°C).
• Do not freeze your STIOLTO RESPIMAT cartridge and inhaler.
• If STIOLTO RESPIMAT has not been used for more than 3 days, release 1 puff towards the ground.
• If STIOLTO RESPIMAT has not been used for more than 21 days, repeat steps 4 to 6 under the “Prepare for first use”
until a mist is visible. Then repeat steps 4 to 6 three more times.
• Keep your STIOLTO RESPIMAT cartridge, inhaler, and all medicines out of the reach of children.
How to care for your STIOLTO RESPIMAT inhaler
Clean the mouthpiece, including the metal part inside the mouthpiece, with a damp cloth or tissue only, at least 1 time
each week. Any minor discoloration in the mouthpiece does not affect your STIOLTO RESPIMAT inhaler.
When to get a new STIOLTO RESPIMAT inhaler
• The scale on your inhaler will show the number of puffs you have, if used as indicated (2 puffs 1 time each day).
• The dose indicator will show you approximately how much medicine is left.
• When the dose indicator enters the red area of the scale, it will show you approximately how many puffs are left before
you need a refill or new prescription.
• When the dose indicator reaches the end of the red scale, your STIOLTO RESPIMAT is empty and automatically locks.
At this point, the clear base cannot be turned any further.
2
• Three months after insertion of cartridge, throw away the STIOLTO RESPIMAT even if it has not been used, or when
the inhaler is locked, or when it expires, whichever comes first.
Prepare for first use
1. Remove clear base
•
Keep the cap closed.
•
Press the safety catch while firmly pulling off the clear
base with your other hand. Be careful not to touch the
piercing element.
•
Write the discard by date on the label (3 months from the
date the cartridge is inserted).
2. Insert cartridge
•
Insert the narrow end of the cartridge into the inhaler.
•
Place the inhaler on a firm surface and push down firmly
until it clicks into place.
3. Replace clear base
•
Put the clear base back into place until it clicks.
•
Do not remove the clear base or the cartridge after it has
been put together.
4. Turn
•
Keep the cap closed.
•
Turn the clear base in the direction of the arrows on the
label until it clicks (half a turn).
5. Open
•
Open the cap until it snaps fully open.
6. Press
•
Point the inhaler toward the ground.
•
Press the dose-release button.
•
Close the cap.
•
If you do not see a mist, repeat steps 4 to 6 until a mist is
seen.
•
After a mist is seen, repeat steps 4 to 6 three more times.
•
After complete preparation of your inhaler, it will be
ready to deliver the number of puffs on the label.
3
Daily use (T O P)
Turn
•
Keep the cap closed.
•
Turn the clear base in the direction of the arrows on the
label until it clicks (half a turn).
Open
•
Open the cap until it snaps fully open.
Press
•
Breathe out slowly and fully.
•
Close your lips around the mouthpiece without covering the
air vents.
•
Point the inhaler to the back of your throat.
•
While taking a slow, deep breath through your mouth, Press
the dose-release button and continue to breathe in.
•
Hold your breath for 10 seconds or for as long as
comfortable.
•
Repeat Turn, Open, Press (TOP) for a total of 2 puffs.
•
Close the cap until you use your inhaler again.
Answers to Common Questions
It is difficult to insert the cartridge deep enough:
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, press the dose-release button,
then insert the cartridge.
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow end first.
I cannot press the dose-release button:
Did you turn the clear base? If not, turn the clear base in a continuous movement until it clicks (half a turn).
Is the dose indicator on the STIOLTO RESPIMAT pointing to 0 (zero)? The STIOLTO RESPIMAT inhaler is locked
after the labeled number of puffs have been used. Prepare and use your new STIOLTO RESPIMAT inhaler.
4
I cannot turn the clear base:
Did you turn the clear base already? If the clear base has already been turned, follow steps “Open” and “Press” under
“Daily use” to get your medicine.
Is the dose indicator on the STIOLTO RESPIMAT pointing to 0 (zero)? The STIOLTO RESPIMAT inhaler is locked
after the labeled number of puffs have been used. Prepare and use your new STIOLTO RESPIMAT inhaler.
The dose indicator on the STIOLTO RESPIMAT reaches 0 (zero) too soon:
Did you use STIOLTO RESPIMAT as indicated (2 puffs 1 time each day)? STIOLTO RESPIMAT will deliver the
labeled number of puffs if used at 2 puffs 1 time each day.
Did you turn the clear base before you inserted the cartridge? The dose indicator counts each turn of the clear base
regardless whether a cartridge has been inserted or not.
Did you spray in the air often to check whether the STIOLTO RESPIMAT is working? After you have prepared
STIOLTO RESPIMAT, no test-spraying is required if used daily.
Did you insert the cartridge into a used STIOLTO RESPIMAT? Always insert a new cartridge into a NEW STIOLTO
RESPIMAT.
My STIOLTO RESPIMAT sprays automatically:
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.
Did you press the dose-release button when turning the clear base? Close the cap, so the dose-release button is
covered, then turn the clear base.
Did you stop when turning the clear base before it clicked? Turn the clear base in a continuous movement until it
clicks (half a turn).
My STIOLTO RESPIMAT does not spray:
Did you insert a cartridge? If not, insert a cartridge.
Did you repeat Turn, Open, Press (TOP) less than 3 times after inserting the cartridge? Repeat Turn, Open, Press
(TOP) 3 times after inserting the cartridge as shown in steps 4 to 6 under “Prepare for first use”.
Is the dose indicator on the STIOLTO RESPIMAT pointing to 0 (zero)? You have used up all your medicine and the
inhaler is locked.
For more information about STIOLTO RESPIMAT, including current prescribing information, a video demonstration or a
Quick Start Guide on how to use STIOLTO RESPIMAT, go to www.STIOLTO.com, scan the code, or call 1-800-542-
6257.
This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
SPIRIVA®, HANDIHALER®, STIOLTO® and RESPIMAT® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH
Copyright © 202x Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
5
Revised: xxx 202x
COL10537BH212024
| custom-source | 2025-02-12T15:48:23.946370 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/206756Orig1s036lbl.pdf', 'application_number': 206756, 'submission_type': 'SUPPL ', 'submission_number': 36} |
80,798 |
For more information about
SPIRIVA RESPIMAT, including current
prescribing information, a video
demonstration or a Quick Start
Guide on how to use SPIRIVA RESPIMAT,
go to www.spiriva.com, scan the code, or
call 1-800-542-6257.
2.5 mcg/actuation*
2.5 mcg/actuation*
2.5 mcg/actuation*
2.5 mcg/actuation*
ABCD
4 Grams
10 Metered Inhalations
4 Grams
10 Metered Inhalations
CT8174E
316784-04
4 Grams
10 Metered Inhalations
4 Grams
10 Metered Inhalations
Package Contents:
1 Spiriva® Respimat® Inhaler
1 Spiriva® Respimat® Cartridge
1 Prescribing Information
1 Instructions for Use
Only use
Spiriva® Respimat® Inhaler
with
Spiriva® Respimat® Cartridge
Avoid spraying in eyes.
Keep out of reach of children.
Insert cartridge before use.
Discard 3 months after insertion
of the cartridge into inhaler.
FOR ORAL INHALATION ONLY
(Two inhalations equal one dose)
NDC 0597-0100-51
Institutional Pack
Spiriva® Respimat®
(tiotropium bromide inhalation spray)
Spiriva® Respimat®
(tiotropium bromide inhalation spray)
Spiriva® Respimat®
(tiotropium bromide inhalation spray)
Spiriva® Respimat®
(tiotropium bromide inhalation spray)
Spiriva® Respimat®
(tiotropium bromide inhalation spray)
Spiriva® Respimat®
(tiotropium bromide inhalation spray)
4 Grams
10 Metered Inhalations
2.5 mcg/actuation*
Distributed by:
Boehringer Ingelheim (BI)
Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Made in Germany
Product and trademark licensed from:
BI International GmbH
© 2024 BI International GmbH
ALL RIGHTS RESERVED
4 Grams
2.5 mcg/actuation*
10 Metered Inhalations
For more information about
SPIRIVA RESPIMAT, including current
prescribing information, a video
demonstration or a Quick Start Guide on
how to use SPIRIVA RESPIMAT, go to
www.spiriva.com, scan the code,
or call 1-800-542-6257.
ATTENTION PHARMACIST:
Dispense with Instructions for Use
Store at 20°C to 25°C (68°F to 77°F);
excursions permitted to 15°C to 30°C
(59°F to 86°F) [see USP Controlled
Room Temperature].
AVOID FREEZING.
Excipients: benzalkonium chloride,
edetate disodium, hydrochloric acid,
and water for injection.
Contents of unopened cartridge are
sterile.
Recommended Dosage: Two
inhalations once daily. See
Prescribing Information.
*Each actuation delivers 2.5 mcg
of tiotropium (equivalent to
3.124 mcg of tiotropium bromide
monohydrate) from the
mouthpiece.
GTIN
00305970100515
SN
12345678901234
EXP
YYYY-MMM-DD
LOT
123456A
For more information about
SPIRIVA RESPIMAT, including current
prescribing information, a video
demonstration or a Quick Start
Guide on how to use SPIRIVA RESPIMAT,
go to www.spiriva.com, scan the code, or
call 1-800-542-6257.
| custom-source | 2025-02-12T15:48:24.044362 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/021936Orig1s036lbl.pdf', 'application_number': 21936, 'submission_type': 'SUPPL ', 'submission_number': 36} |
80,800 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ATROVENT HFA safely and effectively. See full prescribing
information for ATROVENT HFA.
ATROVENT® HFA (ipratropium bromide HFA inhalation aerosol), for
oral inhalation use
Initial U.S. Approval: 2004
----------------------------INDICATIONS AND USAGE---------------------------
ATROVENT HFA is an anticholinergic indicated for the maintenance
treatment of bronchospasm associated with chronic obstructive pulmonary
disease (COPD), including chronic bronchitis and emphysema (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
For oral inhalation only
•
Two inhalations four times a day, not to exceed 12 inhalations in 24
hours (2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
•
Inhalation Aerosol: Each actuation of ATROVENT HFA Inhalation
Aerosol delivers 17 mcg of ipratropium bromide (monohydrate) from
the mouthpiece (3)
•
Supplied in a 12.9 g canister containing 200 actuations (3)
-------------------------------CONTRAINDICATIONS------------------------------
•
Hypersensitivity to ipratropium bromide or other ATROVENT HFA
components (4)
•
Hypersensitivity to atropine or any of its derivatives (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
•
Not indicated for the initial treatment of acute episodes of bronchospasm
where rescue therapy is required for rapid response (5.1)
•
Hypersensitivity reactions including anaphylaxis: Discontinue
ATROVENT HFA at once and consider alternative treatments (5.2)
•
Paradoxical bronchospasm: Discontinue ATROVENT HFA and
consider other treatments if paradoxical bronchospasm occurs (5.3)
•
Ocular effects: Use with caution in patients with narrow-angle glaucoma
and instruct patients to consult a physician immediately if signs or
symptoms of narrow-angle glaucoma develop (5.4)
•
Urinary retention: Use with caution in patients with prostatic hyperplasia
or bladder-neck obstruction and instruct patients to consult a physician
immediately if signs or symptoms of urinary retention develop (5.5)
------------------------------ADVERSE REACTIONS-------------------------------
Most common adverse reactions (>5% incidence in the 12-week placebo-
controlled trials) were bronchitis, COPD exacerbation, dyspnea, and headache
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Anticholinergics: May interact additively with concomitantly used
anticholinergic medications. Avoid administration of ATROVENT HFA with
other anticholinergic-containing drugs (7.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: X/202X
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Use for Maintenance Treatment Only
5.2 Hypersensitivity Reactions, Including Anaphylaxis
5.3 Paradoxical Bronchospasm
5.4 Ocular Effects
5.5 Urinary Retention
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Anticholinergic Agents
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
ATROVENT HFA Inhalation Aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary
disease (COPD), including chronic bronchitis and emphysema.
2
DOSAGE AND ADMINISTRATION
The usual starting dosage of ATROVENT HFA is two inhalations four times a day. Patients may take additional inhalations as required; however, the total number of
inhalations should not exceed 12 in 24 hours.
ATROVENT HFA is a solution aerosol that does not require shaking. However, as with any other metered-dose inhaler, some coordination is required between
actuating the canister and inhaling the medication.
Patients should “prime” or actuate ATROVENT HFA before using for the first time by releasing 2 test sprays into the air away from the face. In cases where the inhaler
has not been used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face. Patients should avoid spraying ATROVENT
HFA into their eyes.
Each inhaler provides sufficient medication for 200 actuations. The inhaler should be discarded after the labeled number of actuations has been used. The amount of
medication in each actuation cannot be assured after this point, even though the canister is not completely empty.
Patients should be instructed on the proper use of their inhaler [see Patient Counseling Information (17)].
3
DOSAGE FORMS AND STRENGTHS
ATROVENT HFA is an inhalation aerosol supplied in a pressurized stainless steel canister as a metered-dose inhaler with a white mouthpiece that has a clear, colorless
sleeve and a green protective cap. Each pressurized metered-dose aerosol unit for oral inhalation contains a 12.9 g solution of ipratropium bromide (monohydrate) that
provides sufficient medication for 200 actuations. After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide (monohydrate) from the valve
and delivers 17 mcg of ipratropium bromide (monohydrate) from the mouthpiece.
4
CONTRAINDICATIONS
ATROVENT HFA is contraindicated in the following conditions [see Warnings and Precautions (5.2)].
•
Hypersensitivity to ipratropium bromide or other ATROVENT HFA components
•
Hypersensitivity to atropine or any of its derivatives
5
WARNINGS AND PRECAUTIONS
5.1 Use for Maintenance Treatment Only
ATROVENT HFA is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute
episodes of bronchospasm where rescue therapy is required for rapid response.
5.2
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after the administration of
ATROVENT HFA. In clinical trials and postmarketing experience with ipratropium-containing products, hypersensitivity reactions such as skin rash, pruritus,
angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported [see Adverse Reactions (6.1,
6.2)]. If such a reaction occurs, therapy with ATROVENT HFA should be stopped at once and alternative treatment should be considered [see Contraindications (4)].
5.3
Paradoxical Bronchospasm
ATROVENT HFA can produce paradoxical bronchospasm that can be life threatening. If this occurs, treatment with ATROVENT HFA should be stopped and other
treatments considered.
5.4
Ocular Effects
ATROVENT HFA is an anticholinergic and its use may increase intraocular pressure. This may result in precipitation or worsening of narrow-angle glaucoma.
Therefore, ATROVENT HFA should be used with caution in patients with narrow-angle glaucoma [see Drug Interactions (7.1)].
Patients should avoid spraying ATROVENT HFA into their eyes. If a patient sprays ATROVENT HFA into their eyes, they may cause eye pain or discomfort,
temporary blurring of vision, mydriasis, visual halos or colored images in association with red eyes from conjunctival and corneal congestion. Advise patients to consult
their physician immediately if any of these symptoms develop while using ATROVENT HFA Inhalation Aerosol.
5.5
Urinary Retention
ATROVENT HFA is an anticholinergic and may cause urinary retention. Therefore, caution is advised when administering ATROVENT HFA Inhalation Aerosol to
patients with prostatic hyperplasia, or bladder-neck obstruction [see Drug Interactions (7.1)].
6
ADVERSE REACTIONS
The following adverse reactions are described, or described in greater detail, in other sections:
•
Hypersensitivity Reactions, Including Anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.2)]
•
Paradoxical Bronchospasm [see Warnings and Precautions (5.3)]
•
Ocular Effects [see Warnings and Precautions (5.4)]
•
Urinary Retention [see Warnings and Precautions (5.5)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates observed in patients.
6.1 Clinical Trials Experience
The adverse reaction information concerning ATROVENT HFA is derived from two 12-week, double-blind, parallel-group studies and one 1-year open-label, parallel
group study. These studies compared ATROVENT HFA Inhalation Aerosol, ATROVENT CFC Inhalation Aerosol, and placebo (in one study only) in 1,010 COPD
patients. The following table lists the incidence of adverse reactions that occurred at a rate of greater than or equal to 3% in any ipratropium bromide group and greater
than placebo in the 12-week study. The frequency of corresponding reactions in the 1-year open label study is included for comparison.
3
TABLE 1
Adverse Reactions (% Patients) in ATROVENT HFA Clinical Trials
Placebo-controlled 12-week Study 244.1405
and
Active-controlled 12-week Study 244.1408
Active-controlled 1-year Study
244.2453
ATROVENT
HFA
(N=243)
%
ATROVENT
CFC
(N=183)
%
Placebo
(N=128)
%
ATROVENT
HFA
(N=305)
%
ATROVENT
CFC
(N=151)
%
BODY AS A WHOLE - GENERAL DISORDERS
Back pain
2
3
2
7
3
Headache
6
9
8
7
5
Influenza-like symptoms
4
2
2
8
5
CENTRAL & PERIPHERAL NERVOUS SYSTEM DISORDERS
Dizziness
3
3
2
3
1
GASTROINTESTINAL SYSTEM DISORDERS
Dyspepsia
1
3
1
5
3
Mouth dry
4
2
2
2
3
Nausea
4
1
2
4
4
RESPIRATORY SYSTEM DISORDERS
Bronchitis
10
11
6
23
19
COPD exacerbation
8
14
13
23
23
Dyspnea
8
8
4
7
4
Sinusitis
1
4
3
11
14
URINARY SYSTEM DISORDERS
Urinary tract infection
2
3
1
10
8
Cough, rhinitis, and upper respiratory infection occurred in greater than or equal to 3% of patients in either ipratropium treatment group but not greater than placebo in
the 12-week study.
In the one open-label controlled study in 456 COPD patients, the overall incidence of adverse events was also similar between ATROVENT HFA and ATROVENT
CFC formulations.
Overall, in the above mentioned studies, 9.3% of the patients taking 42 mcg ATROVENT HFA and 8.7% of the patients taking 42 mcg ATROVENT CFC reported at
least one adverse event that was considered by the investigator to be related to the study drug. The most common drug-related adverse events were dry mouth (1.6% of
ATROVENT HFA and 0.9% of ATROVENT CFC patients), and taste perversion (bitter taste) (0.9% of ATROVENT HFA and 0.3% of ATROVENT CFC patients).
As an anticholinergic drug, cases of precipitation or worsening of narrow-angle glaucoma, glaucoma, halo vision, conjunctival hyperemia, corneal edema, mydriasis,
acute eye pain, dry throat, hypotension, palpitations, urinary retention, tachycardia, constipation, bronchospasm, including paradoxical bronchospasm have been
reported with the use of ATROVENT. Additional adverse reactions identified for ATROVENT seen in clinical trials include throat irritation, stomatitis, mouth edema,
and vision blurred.
Allergic-type reactions such as skin rash, pruritus, angioedema including that of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and
anaphylactic reactions have been reported [see Warnings and Precautions (5.2)].
6.2 Postmarketing Experience
In a 5-year, placebo-controlled trial, hospitalizations for supraventricular tachycardia and/or atrial fibrillation occurred with an incidence rate of 0.5% in COPD patients
receiving ATROVENT CFC.
In addition to the adverse reactions reported in the controlled clinical trials, adverse reactions have been identified during post-approval use of ATROVENT. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship
to drug exposure.
Allergic-type reactions such as skin rash, angioedema including that of tongue, lips and face, urticaria (including giant urticaria), laryngospasm, and anaphylactic
reactions have been reported, with positive rechallenge in some cases.
Additionally, urinary retention, mydriasis, gastrointestinal distress (diarrhea, nausea, vomiting), cough and bronchospasm, including paradoxical bronchospasm,
hypersensitivity reactions, intraocular pressure increased, accommodation disorder, heart rate increased, pharyngeal edema, and gastrointestinal motility disorders have
been reported during the postmarketing period with use of ATROVENT.
5
C20H30BrNO3•H2O
ipratropium bromide
Mol. Wt. 430.4
Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in ethanol, and insoluble in lipophilic solvents
such as ether, chloroform, and fluorocarbons.
ATROVENT HFA is a pressurized metered-dose aerosol unit for oral inhalation that contains a solution of ipratropium bromide. The 200 inhalation unit has a net
weight of 12.9 grams. After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide (monohydrate) from the valve in 56 mg of solution and
delivers 17 mcg of ipratropium bromide (monohydrate) from the mouthpiece. The actual amount of drug delivered to the lung may depend on patient factors, such as
the coordination between the actuation of the device and inspiration through the delivery system. The excipients are anhydrous citric acid, dehydrated alcohol, HFA-
134a (1,1,1,2-tetrafluoroethane) as propellant, and sterile water for irrigation. This product does not contain chlorofluorocarbons (CFCs) as propellants.
ATROVENT HFA should be primed before using for the first time by releasing 2 test sprays into the air away from the face. In cases where the inhaler has not been
used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the
action of acetylcholine, the transmitter agent released at the neuromuscular junctions in the lung. Anticholinergics prevent the increases in intracellular concentration of
Ca++ which is caused by interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle.
12.2
Pharmacodynamics
Cardiovascular effects
At recommended dosages, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.
Ocular effects
In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation, or visual acuity.
Mucociliary clearance and respiratory secretions
Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions.
12.3
Pharmacokinetics
Following administration by oral inhalation from a metered-dose inhaler, the majority of the delivered dose is deposited in the gastrointestinal tract and, to a lesser
extent, in the lung, the intended site of action. Ipratropium bromide is a quaternary amine and hence is not readily absorbed into the systemic circulation either from the
surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies.
The half-life of elimination is about 2 hours after inhalation or intravenous administration. Ipratropium bromide is minimally bound (0% to 9% in vitro) to plasma
albumin and α1-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the
dose is excreted unchanged in the urine.
A pharmacokinetic study with 29 chronic obstructive pulmonary disease (COPD) patients (48-79 years of age) demonstrated that mean peak plasma ipratropium
concentrations of 59±20 pg/mL were obtained following a single administration of 4 inhalations of ATROVENT HFA (84 mcg). Plasma ipratropium concentrations
declined to 24±15 pg/mL by six hours. When these patients were administered 4 inhalations QID (16 inhalations/day=336 mcg) for one week, the mean peak plasma
ipratropium concentration increased to 82±39 pg/mL with a trough (6 hour) concentration of 28±12 pg/mL at steady state.
Specific Populations
Geriatric Patients
In the pharmacokinetic study with 29 COPD patients, a subset of 14 patients were >65 years of age. Mean peak plasma ipratropium concentrations of 56±24 pg/mL
were obtained following a single administration of 4 inhalations (21 mcg/puff) of ATROVENT HFA (84 mcg). When these 14 patients were administered 4 inhalations
four times a day (16 inhalations/day) for one week, the mean peak plasma ipratropium concentration only increased to 84±50 pg/mL indicating that the pharmacokinetic
behavior of ipratropium bromide in the geriatric population is consistent with younger patients.
Renally Impaired Patients
The pharmacokinetics of ATROVENT HFA have not been studied in patients with renal insufficiency.
Hepatically Impaired Patients
The pharmacokinetics of ATROVENT HFA have not been studied in patients with hepatic insufficiency.
Drug-Drug Interaction
No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions with other medications.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg (approximately 240 and 120 times the maximum
recommended human daily inhalation dose (MRHDID) in adults on a mg/m2 basis, respectively). Results of various mutagenicity/clastogenicity studies (Ames test,
mouse dominant lethal test, mouse micronucleus test and chromosome aberrations of bone marrow in Chinese hamsters) were negative.
Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 2,000 times the MRHDID in adults on a mg/m2 basis) was unaffected by ipratropium
bromide administration. At an oral dose of 500 mg/kg (approximately 20,000 times the MRHDID in adults on a mg/m2 basis), ipratropium bromide produced a
decrease in the conception rate.
14
CLINICAL STUDIES
Conclusions regarding the efficacy of ATROVENT HFA were derived from two randomized, double-blind, controlled clinical studies. These studies enrolled males and
females ages 40 years and older, with a history of COPD, a smoking history of >10 pack-years, an FEV1 <65% and an FEV1/FVC <70%.
7
bromide (monohydrate) from the valve and 17 mcg from the mouthpiece. Each canister has a net weight of 12.9 grams and provides sufficient medication for 200
actuations. The inhaler should be discarded after the labeled number of actuations has been used when the indicator displays “0”. The amount of medication in each
actuation cannot be assured after this point, even though the canister is not completely empty.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. For optimal results, the canister
should be at room temperature before use.
Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw
the inhaler into a fire or incinerator.
Keep out of reach of children. Avoid spraying in eyes.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Appropriate and safe use of ATROVENT HFA includes providing the patient with the information listed below and an understanding of the way it should be
administered.
Advise patients that ATROVENT HFA is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the
initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema, may occur after the
administration of ATROVENT HFA. Advise patients to immediately discontinue ATROVENT HFA and consult a physician [see Warnings and Precautions (5.2)].
Paradoxical Bronchospasm
Inform patients that ATROVENT HFA can produce paradoxical bronchospasm that can be life-threatening. If paradoxical bronchospasm occurs, patients should
discontinue using ATROVENT HFA.
Ocular Effects
Caution patients to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis,
increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival
and corneal congestion. Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.
Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of ATROVENT HFA, patients should be cautioned about engaging in
activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.
Urinary Retention
Inform patients that ATROVENT HFA may cause urinary retention and should be advised to consult their physicians if they experience difficulty with urination.
Frequency of Use
The action of ATROVENT HFA should last 2 to 4 hours. Advise patients not to increase the dose or frequency of ATROVENT HFA without patients consulting their
physician. Advise patients to seek immediate medical attention if treatment with ATROVENT HFA becomes less effective for symptomatic relief, their symptoms
become worse, and/or patients need to use the product more frequently than usual.
Concomitant Drug Use
Advise patients on the use of ATROVENT HFA in relation to other inhaled drugs [see Drug Interactions (7.1)].
Use Only as Prescribed
Remind patients that ATROVENT HFA should be used consistently as prescribed throughout the course of therapy.
Preparation for Use and Priming
Instruct patients that priming ATROVENT HFA is essential to ensure appropriate content of the medication in each actuation. Patients do not have to shake the
ATROVENT HFA canister before use.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
ATROVENT® is a registered trademark of and used under license from Boehringer Ingelheim International GmbH
Copyright © 202X Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
COL9554BH212024
1
INSTRUCTIONS FOR USE
ATROVENT® HFA
(ipratropium bromide HFA)
Inhalation Aerosol, for oral inhalation use
Read this Instructions for Use before using your ATROVENT HFA and each time you get a refill. There may be new
information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or
your treatment.
Use ATROVENT HFA exactly as your healthcare provider tells you to. Do not change your dose or how often you use
ATROVENT HFA without talking with your healthcare provider.
Tell your doctor about all the medicines you take. ATROVENT HFA may affect the way some other medicines work
and some other medicines may affect the way ATROVENT HFA works.
Important information about using ATROVENT HFA
•
You do not have to shake ATROVENT HFA before using it.
•
ATROVENT HFA should be “primed” 2 times before you use the first dose of a new ATROVENT HFA inhaler
or when the inhaler has not been used for more than 3 days.
o
To prime, push the canister against the mouthpiece (see Figure 1), allowing the medicine to spray
into the air.
o
Do not spray the medicine into your eyes while priming ATROVENT HFA.
Inhaler Description
ATROVENT HFA Inhalation Aerosol (Figure 1) consists of a metal canister containing the medicine and a mouthpiece that
releases the medicine from the canister. The mouthpiece includes a clear colorless sleeve, a white plastic portion and a
green protective dust cap.
The inhaler comes with a dose indicator you can see through a small window on the plastic mouthpiece (see Figure 1). A
new inhaler first shows “200” in the dose indicator window. The dose indicator will show the approximate number of
actuations (sprays) of medicine remaining in the inhaler. As you use the inhaler, the dose indicator will typically rotate
during every 5 to 7 actuations (sprays) towards the next decreasing number (see Figure 2).
Figure 1
Figure 2
3
Mouthpiece Cleaning Instructions:
Step A. Remove and set aside the canister and dust cap from the mouthpiece (see Figure 1).
Step B. Wash the mouthpiece through the top and bottom with warm running water for at least 30 seconds (see
Figure 6). Do not use anything other than water to wash the mouthpiece.
Figure 6
Step C. Dry the mouthpiece by shaking off the excess water and allow it to air dry all the way.
Step D. When the mouthpiece is dry, replace the canister. Make sure the canister is fully and firmly inserted into the
mouthpiece.
Step E. Replace the green protective dust cap.
If little or no medicine comes out of the mouthpiece, wash the mouthpiece as described in Steps A to E under the
“Mouthpiece Cleaning Instructions”.
9. When to get a new ATROVENT HFA inhaler.
There are approximately 40 actuations (sprays) left when the dose indicator displays “40,” where the background
changes from green to red (see Figure 7a). This is when you need to refill your prescription or ask your doctor if you
need another prescription for ATROVENT HFA inhalation aerosol.
The background color will be all red when the indicator approaches 20. The indicator will stop moving at “0”. Discard
the inhaler once the dose indicator displays “0” (see Figure 7b). Even though the canister may not be empty, you
cannot be sure of the amount of medicine in each actuation (spray) once the dose indicator displays “0”.
Figure 7a
Figure 7b
This product does not contain any chlorofluorocarbon (CFC) propellants.
The contents of ATROVENT HFA are under pressure. Do not puncture the canister. Do not use or store near heat or open
flame. Exposure to temperatures above 120°F may cause bursting. Never throw the container into a fire or incinerator.
4
Keep ATROVENT HFA and all medicines out of the reach of children.
Store ATROVENT HFA at room temperature 68°F to 77°F (20°C to 25°C). Short-term exposure to higher or lower
temperatures [from 59ºF (15ºC) to 86ºF (30ºC)] is acceptable.
For more information about ATROVENT HFA including current prescribing information and Instructions for Use, go to
www.atrovent.com, scan the code, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
ATROVENT® is a registered trademark of and used under license from Boehringer Ingelheim International GmbH
Copyright © 202X Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
COL9554BH212024
Revised: X 202X
| custom-source | 2025-02-12T15:48:24.128414 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/021527Orig1s042lbl.pdf', 'application_number': 21527, 'submission_type': 'SUPPL ', 'submission_number': 42} |
80,812 |
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Injectafer safely and effectively. See full prescribing information for
Injectafer.
INJECTAFER® (ferric carboxymaltose injection), for intravenous use
Initial U.S. Approval: 2013
------------------------------RECENT MAJOR CHANGES------------------------
Warnings and Precautions, Symptomatic Hypophosphatemia (5.2) 11/2024
----------------------------INDICATIONS AND USAGE---------------------------
Injectafer is an iron replacement product indicated for the treatment of:
•
iron deficiency anemia (IDA) in:
o
adult and pediatric patients 1 year of age and older who have either
intolerance or an unsatisfactory response to oral iron. (1)
o
adult patients who have non-dialysis dependent chronic kidney
disease. (1)
•
iron deficiency in adult patients with heart failure and New York Heart
Association class II/III to improve exercise capacity. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
•
For patients weighing 50 kg or more, the recommended dosage is
Injectafer 750 mg intravenously in two doses separated by at least 7
days for a total cumulative dose of 1,500 mg of iron per course. For
adult patients weighing 50 kg or more, an alternative dose of Injectafer
15 mg/kg body weight up to a maximum of 1,000 mg intravenously
may be administered as a single-dose per course. (2.1)
•
For patients weighing less than 50 kg, the recommended dosage is
Injectafer 15 mg/kg body weight intravenously in two doses separated
by at least 7 days per course. (2.1)
•
See Section 2.1, Table 1 for dosage in patients with iron deficiency and
heart failure. (2.1)
Injectafer treatment may be repeated if IDA or iron deficiency in heart failure
reoccurs. (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Injection: 50 mg/mL (3)
•
100 mg iron/2 mL single-dose vial
•
750 mg iron/15 mL single-dose vial
•
1,000 mg iron/20 mL single-dose vial
-------------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity to Injectafer or any of its inactive components. (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
•
Hypersensitivity Reactions: Observe for signs and symptoms of
hypersensitivity during and after Injectafer administration for at least 30
minutes and until clinically stable following completion of each
administration. (5.1)
•
Symptomatic Hypophosphatemia: Monitor serum phosphate levels in
patients at risk for low serum phosphate who require a repeat course of
treatment. (5.2)
•
Hypertension: Monitor patients closely for signs and symptoms of
hypertension following each Injectafer administration. (5.3)
------------------------------ADVERSE REACTIONS-------------------------------
•
The most common adverse reactions in adult patients (>2%) are
nausea, hypertension, flushing, injection site reactions, erythema,
hypophosphatemia, and dizziness. (6.1)
•
The most common adverse reactions in pediatric patients (≥4%)
are hypophosphatemia, injection site reactions, rash, headache, and
vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American
Regent at 1-800-734-9236 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------USE IN SPECIFIC POPULATIONS----------------------
Pregnancy: Risk of hypersensitivity reactions which may have serious
consequences for the fetus. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 01/2025
____________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
2.2
Preparation and Administration
2.3
Repeat Treatment Monitoring Safety Assessment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
Symptomatic Hypophosphatemia
5.3
Hypertension
5.4
Laboratory Test Alterations
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Post-marketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.4
Pediatric Use
8.5
Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
14.1 Iron Deficiency Anemia
14.2 Iron Deficiency in Heart Failure
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
8.2
Lactation
* Sections or subsections omitted from the full prescribing information are not
listed.
___________________________________________________________________________________________________________________________________
Reference ID: 5505983
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Injectafer is indicated for the treatment of:
•
iron deficiency anemia (IDA) in:
o
adult and pediatric patients 1 year of age and older who have either intolerance or
an unsatisfactory response to oral iron.
o
adult patients who have non-dialysis dependent chronic kidney disease.
•
iron deficiency in adult patients with heart failure and New York Heart
Association class II/III to improve exercise capacity.
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
Recommended Dosage for Treatment of Iron Deficiency Anemia
For patients weighing 50 kg or more, the recommended dosage is:
• Injectafer 750 mg intravenously in two doses separated by at least 7 days for a
total cumulative dose of 1,500 mg of iron per course.
• In adult patients, Injectafer 15 mg/kg body weight up to a maximum of 1,000 mg
intravenously may be administered as a single-dose per course.
For patients weighing less than 50 kg, the recommended dosage is Injectafer 15 mg/kg
body weight intravenously in two doses separated by at least 7 days per course.
Recommended Dosage in Patients with Iron Deficiency with Heart Failure
See Table 1 for recommended dosage for treatment of iron deficiency in patients with
heart failure and New York Heart Association class II/III to improve exercise capacity.
Table 1:Recommended Dosage in Patients with Iron Deficiency with Heart Failure
Administer a maintenance dose of 500 mg at 12, 24 and 36 weeks if serum ferritin
<100 ng/mL or serum ferritin 100-300 ng/mL with transferrin saturation <20%. There are
no data available to guide dosing beyond 36 weeks or with Hb ≥15 g/dL.
2.2 Preparation and Administration
Administer Injectafer intravenously, either as an undiluted slow intravenous push or by
infusion. When administered via infusion, dilute up to 1,000 mg of iron in no more than
250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the
infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes.
Weight less than 70 kg
Weight 70 kg or more
Hb (g/dL)
Hb (g/dL)
< 10
10 to 14
> 14 to < 15
< 10
10 to 14
> 14 to < 15
Day 1
1,000 mg
1,000 mg
500 mg
1,000 mg
1,000 mg
500 mg
Week 6
500 mg
No dose
No dose
1,000 mg
500 mg
No dose
Reference ID: 5505983
3
When added to an infusion bag containing 0.9% sodium chloride injection, USP, at
concentrations ranging from 2 to 4 mg of iron per mL, Injectafer solution is physically
and chemically stable for 72 hours when stored at room temperature. To maintain
stability, do not dilute to concentrations less than 2 mg iron/mL.
Inspect parenteral drug products visually for the absence of particulate matter and
discoloration prior to administration. The product contains no preservatives. Each vial of
Injectafer is intended for a single dose.
When administering Injectafer 500 or 750 mg as a slow intravenous push, give at the rate
of approximately 100 mg (2 mL) per minute. For Injectafer 1,000 mg, administer as a
slow intravenous push over 15 minutes. Avoid extravasation of Injectafer since brown
discoloration of the extravasation site may be long lasting. Monitor for extravasation. If
extravasation occurs, discontinue the Injectafer administration at that site.
Discard unused portion.
2.3 Repeat Treatment Monitoring Safety Assessment
Injectafer treatment may be repeated if IDA or iron deficiency in heart failure reoccurs.
Check serum phosphate levels in patients at risk for low serum phosphate who require a
repeat course of treatment or for any patient who receives a repeat course of treatment
within three months [see Warnings and Precautions (5.2)]. Treat hypophosphatemia as
medically indicated.
3
DOSAGE FORMS AND STRENGTHS
Injection: 50 mg/mL, dark brown, non-transparent, sterile, aqueous solution.
• 100 mg iron/2 mL single-dose vial
• 750 mg iron/15 mL single-dose vial
• 1,000 mg iron/20 mL single-dose vial
4
CONTRAINDICATIONS
Injectafer is contraindicated in patients with a history of hypersensitivity to Injectafer or
any of its components [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which
have been life-threatening and fatal, have been reported in patients receiving Injectafer.
Patients may present with shock, clinically significant hypotension, loss of
consciousness, and/or collapse. Monitor patients for signs and symptoms of
hypersensitivity during and after Injectafer administration for at least 30 minutes and
until clinically stable following completion of the infusion. Only administer Injectafer
when personnel and therapies are immediately available for the treatment of serious
hypersensitivity reactions [see Adverse Reactions (6.1, 6.2)]. In clinical trials, serious
anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1,775) of subjects
receiving Injectafer. Other serious or severe adverse reactions potentially associated with
Reference ID: 5505983
4
hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or
hypotension were reported in 1.5% (26/1,775) of these subjects.
5.2 Symptomatic Hypophosphatemia
Symptomatic hypophosphatemia with serious outcomes including osteomalacia and
fractures requiring clinical intervention has been reported in patients treated with
Injectafer in the post-marketing setting. These cases have occurred mostly after repeated
exposure to Injectafer in patients with no reported history of renal impairment. However,
symptomatic hypophosphatemia has been reported after one dose. Possible risk factors
for hypophosphatemia include a history of gastrointestinal disorders associated with
malabsorption of fat-soluble vitamins or phosphate, inflammatory bowel disease,
concurrent or prior use of medications that affect proximal renal tubular function,
hyperparathyroidism, vitamin D deficiency, malnutrition, and hereditary hemorrhagic
telangiectasia (HHT or Osler-Weber-Rendu syndrome). In most cases,
hypophosphatemia resolved within three months.
Correct pre-existing hypophosphatemia prior to initiating therapy with Injectafer.
Monitor serum phosphate levels in patients at risk for chronic low serum phosphate.
Check serum phosphate levels prior to a repeat course of treatment in patients at risk for
low serum phosphate and in any patient who receives a second course of therapy within
three months [see Dosage and Administration (2.3)]. Treat hypophosphatemia as
medically indicated.
5.3 Hypertension
In clinical studies, hypertension was reported in 4% (67/1,775) of subjects in clinical
trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with
facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these
two clinical trials. These elevations generally occurred immediately after dosing and
resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension
following each Injectafer administration [see Dosage and Administration (2)].
5.4 Laboratory Test Alterations
In the 24 hours following administration of Injectafer, laboratory assays may
overestimate serum iron and transferrin bound iron by also measuring the iron in
Injectafer.
6
ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in
other sections of the labeling:
•
Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
•
Hypophosphatemia [see Warnings and Precautions (5.2)]
•
Hypertension [see Warnings and Precautions (5.3)]
•
Laboratory Test Alterations [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse
reaction rates observed cannot be directly compared to rates in other clinical trials and
may not reflect the rates observed in clinical practice.
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Adults
In two randomized clinical studies [Studies 1 and 2, see Clinical Studies (14)], a total of
1,775 patients were exposed to Injectafer 15 mg/kg body weight up to a maximum single
dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative
dose of 1,500 mg of iron.
Adverse reactions reported by ≥1% of treated patients are shown in the following table.
Table 2. Adverse reactions reported in ≥1% of Study Patients in Clinical Trials 1 and 2
Injectafer
(N=1,775)
%
Pooled
Comparatorsa
(N=1,783)
%
Oral
iron
(N=253)
%
Nausea
7.2
2
1.2
Hypertension*
4
2
0.4
Flushing*
4
0.2
0
Injection site reactions*
3
3.2
0
Erythema*
3
0.6
0
Hypophosphatemia
2.1
0.1
0
Dizziness*
2.1
1.3
0.4
Vomiting
2
1
0.4
Injection Site Discoloration**
1.4
0.3
0
Headache*
1.3
1.2
0.4
Hepatic enzyme increased*
1.2
0.2
0
Dysgeusia*
1.2
2.1
0
Hypotension
1
2
0
Rash*
1
0.3
0
Constipation
0.5
0.9
3.2
a Includes oral iron and all formulations of IV iron other than Injectafer
*Grouped Terms:
Hypertension includes hypertension, blood pressure increased, and hypertensive crisis.
Flushing includes flushing and hot flush.
Injection site reactions include injection site extravasation, injection site discoloration, injection site pain,
injection site irritation, injection site bruising, injection site reaction, injection site discomfort, injection site
erythema, injection site hematoma, injection site hemorrhage, injection site pruritus, injection site rash, and
injection site swelling.
Erythema includes erythema and injection site erythema.
Dizziness includes dizziness, balance disorder, and vertigo.
**Injection site discoloration was also included in the injection site local administration reactions grouped
term.
Headache includes headache and migraine.
Hepatic enzyme increased includes alanine aminotransferase increased and aspartate aminotransferase
increased.
Dysgeusia includes dysgeusia and ageusia.
Rash includes rash, urticaria, skin exfoliation, blister, erythema multiforme, injection site rash, rash
maculo-papular, and rash pruritic.
Other adverse reactions reported by ≥0.5% of treated patients include abdominal pain,
diarrhea, gamma glutamyl transferase increased, paresthesia, and sneezing. Transient
decreases in laboratory blood phosphorus levels (<2 mg/dL) have been observed in 27%
(440/1,638) of patients in clinical trials.
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Pooled data from two Phase 3 studies 1VIT09030 (NCT00981045) and 1VIT09031
(NCT00982007) with a dosing regimen of Injectafer 15 mg/kg up to a maximum of 750
mg x 2 doses to a cumulative dose of 1,500 mg of iron were analyzed to compare rates of
adverse reactions in two Phase 3 parallel group studies 1VIT07017 (NCT00548860) and
1VIT07018 (NCT00548691) with a dosing regimen of Injectafer 15 mg/kg up to a
maximum of 1,000 mg single dose (Table 3).
Table 3. Adverse Reactions (≥1% in any Treatment Group) In Patients Receiving
Two Doses of 15 mg/kg to a Maximum of 750 mg to a Cumulative Dose of 1,500 mg
or a Single Dose of Injectafer 15 mg/kg to a Maximum of 1,000 mg.
Injectafer 15 mg/kg to a
maximum of 750 mg x 2
doses to a cumulative dose of
1,500 mg
Injectafer 15 mg/kg to a
maximum of 1,000 mg
single dose
IVIT09030 and IVIT09031b
(N=1,775)
%
IVIT07017 and IVIT07018a
(N=1,200)
%
Any Adverse Reaction
24
12
Injection site reactions*
3
4
Injection site
extravasation**
0.2
2
Hepatic enzyme
increased*
1.2
1.2
Rash*
1
1.2
Headache*
1.3
1
Dizziness*
2.1
1
Dysgeusia*
1.2
1
Nausea
7.2
1
Hypertension*
4
1
Hypophosphatemia
2.1
1
Erythema*
3
0.3
Flushing*
4
0.3
Vomiting
2
0.2
Injection site
discoloration**
1.4
<0.1
Hypotension
1
<0.1
abIncluded studies 1VIT07017, 1VIT07018, 1VIT09030 and 1VIT09031
*Grouped Terms
**Injection site extravasation and injection site discoloration were also included in the injection site
reactions grouped term.
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Pediatric Patients
The safety of Injectafer in pediatric patients was evaluated in study 1VIT17044
(NCT03523117; Study 3). Study 1VIT17044 was a randomized, active-controlled study
in which 40 patients (1 to 12 years of age: 10 patients, 12 to 17 years of age: 30 patients)
received Injectafer 15 mg/kg to a maximum single dose of 750 mg (whichever was
smaller) on Days 0 and 7 for a maximum total dose of 1,500 mg; 38 patients evaluable
for safety in the control arm received an age-dependent formulation of oral ferrous sulfate
for 28 days. The median age of patients who received Injectafer was 14.5 years (range, 1-
17); 83% were female; 88% White and 13% Black. The most common adverse reactions
(≥4%) were hypophosphatemia, injection site reactions, rash, headache, and vomiting.
Table 4 summarizes the adverse reactions in Study 3.
Table 4. Adverse Reactions of any Grade in Pediatric Patients Receiving Injectafer
in Study 3
Injectafer
(N=40)
%
Oral Ferrous
Sulfate
(N=38)
%
Any Adverse Reactions
35
26
Hypophosphatemia*
13
0
Injection site reactions*
8
0
Rash*
8
0
Headache
5
3
Vomiting
5
3
Nasopharyngitis
3
5
Flushing
3
0
Gastrointestinal infections
3
0
Liver function test increased
3
0
Platelet count decreased
3
0
White blood cell count decreased
3
0
*Grouped Terms
Injection site reactions include infusion site hematoma, infusion site hypoesthesia and injection site pain.
Hypophosphatemia includes hypophosphatemia and blood phosphorus decreased.
Rash includes rash, exanthema and urticaria.
Patients with Iron Deficiency and Heart Failure
The safety of Injectafer was evaluated in adult patients with iron deficiency and heart
failure in randomized controlled trials FAIR-HF (NCT00520780), CONFIRM-HF
(NCT01453608) and AFFIRM-AHF (NCT02937454) in which 1,016 patients received
Injectafer versus 857 received placebo. The overall safety profile of Injectafer was
consistent across the studied indications.
6.2 Post-marketing Experience
The following adverse reactions have been identified during post approval use of
Injectafer. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
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The following adverse reactions have been reported from the post-marketing spontaneous
reports with Injectafer:
•
Cardiac disorders: Tachycardia
•
General disorders and administration site conditions: Chest discomfort, chills,
pyrexia
•
Metabolism and nutrition disorders: Hypophosphatemia
•
Musculoskeletal and connective tissue disorders: Arthralgia, back pain,
hypophosphatemic osteomalacia
•
Nervous system disorders: Syncope
•
Respiratory, thoracic and mediastinal disorders: Dyspnea
•
Skin and subcutaneous tissue disorders: Angioedema, erythema, pruritus, urticaria
•
Pregnancy: Fetal bradycardia
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Parenteral iron administration may be associated with hypersensitivity reactions [see
Warnings and Precautions (5.1)], which may have serious consequences, such as fetal
bradycardia (see Clinical Considerations). Advise pregnant women of the potential risk
to a fetus. Published studies and available data from postmarketing reports with
intravenous Injectafer are insufficient to assess the risk of major birth defects and
miscarriage.
There are risks to the mother and fetus associated with untreated IDA in pregnancy as
well as risks to the fetus associated with maternal severe hypersensitivity reactions (see
Clinical Considerations).
In animal reproduction studies, administration of ferric carboxymaltose to rabbits during
the period of organogenesis caused adverse developmental outcomes including fetal
malformations and increased implantation loss at maternally toxic doses of approximately
12% to 23% of the human weekly dose of 750 mg (based on body surface area).
The estimated background risk of major birth defects and miscarriage for the indicated
populations is unknown. All pregnancies have a background risk of birth defect, loss, or
other adverse outcomes. In the U.S. general population, the estimated background risk of
major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and
15% to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Untreated IDA in pregnancy is associated with adverse maternal outcomes such as post-
partum anemia. Adverse pregnancy outcomes associated with IDA include increased risk
for preterm delivery and low birth weight.
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Fetal/Neonatal adverse reactions
Severe adverse reactions including circulatory failure (severe hypotension, shock
including in the context of anaphylactic reaction) may occur in pregnant women with
parenteral iron products (such as Injectafer) which may cause fetal bradycardia,
especially during the second and third trimester.
Data
Human Data
Published data from randomized controlled studies, prospective observational studies and
retrospective studies on the use of ferric carboxymaltose in pregnant women have not
reported an association with intravenous ferric carboxymaltose and major birth defects
and miscarriage. However, these studies cannot establish or exclude the absence of any
drug-related risk during pregnancy.
Animal Data
Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to
30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryonic or fetal
findings. This daily dose in rats is approximately 40% of the human weekly dose of
750 mg based on body surface area. In rabbits, ferric carboxymaltose was administered
as a one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18
mg/kg/day. Malformations were seen starting at the daily dose of 9 mg/kg (23% of the
human weekly dose of 750 mg). Spontaneous abortions occurred starting at the daily
iron dose of 4.5 mg/kg (12% of the human weekly dose of 750 mg based on body surface
area). Pre-implantation loss was at the highest dose. Adverse embryonic or fetal effects
were observed in the presence of maternal toxicity.
A pre- and post-natal development study was conducted in rats at intravenous doses up to
18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg based on
body surface area). There were no adverse effects on survival of offspring, their
behavior, sexual maturation or reproductive parameters.
8.2 Lactation
Risk Summary
The available published data on the use of ferric carboxymaltose in lactating women
demonstrate that iron is present in breast milk. Among the breastfed infants, adverse
reactions included constipation and diarrhea but none of the adverse reactions reported
were considered related to ferric carboxymaltose exposure through breastmilk. There is
no information on the effects of ferric carboxymaltose on milk production. The
developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for Injectafer in addition to any potential adverse effects on the
breastfed child from the drug or from the underlying maternal condition.
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8.4 Pediatric Use
The safety and effectiveness of Injectafer for IDA in pediatric patients aged 1 year and
older who have normal kidney function and have either intolerance to oral iron or have
had unsatisfactory response to oral iron have been established. Use of Injectafer for this
indication in this age group is supported by evidence from adequate and well-controlled
studies of Injectafer in adults with additional pharmacodynamic and safety data in
pediatric patients aged 1 year and older [see Adverse Reactions (6.1) and Clinical
Pharmacology (12.3)].
Safety and effectiveness of Injectafer have not been established in pediatric patients less
than 1 year of age with IDA.
Safety and effectiveness of Injectafer have not been established to improve exercise
capacity in pediatric patients with ID and symptomatic heart failure.
8.5 Geriatric Use
Of the 1,775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while
25% were 75 years and over. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out.
10
OVERDOSAGE
Excessive dosages of Injectafer may lead to accumulation of iron in storage sites
potentially leading to hemosiderosis. A patient who received Injectafer 18,000 mg over 6
months developed hemosiderosis with multiple joint disorder, walking disability, and
asthenia. In the postmarketing setting, hypophosphatemic osteomalacia has been reported
in patients who have received repeated high-cumulative courses of Injectafer.
11
DESCRIPTION
Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex
with the chemical name of polynuclear iron (III)-hydroxide 4(R)-(poly-(1→4)-O--D-
glucopyranosyl)-oxy-2(R),3(R),5(R),6-tetrahydroxy-hexanoate. It has a relative
molecular weight of approximately 150,000 Da corresponding to the following empirical
formula:
[FeOx(OH)y(H2O)z]n [(C6H10O5)m (C6H12O7)l]k,
where n 103, m 8, l 11, and k 4
(l represents the mean branching degree of the ligand).
The chemical structure is presented below:
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Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic
colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric
carboxymaltose in water for injection. Injectafer is available in 2 mL, 15 mL and 20 mL
single-dose vials. Sodium hydroxide and/or hydrochloric acid may have been added to
adjust the pH to 5.0-7.0.
Vial closure is not made with natural rubber latex.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose,
a carbohydrate polymer that releases iron.
12.2 Pharmacodynamics
Using positron emission tomography (PET) it was demonstrated that red cell uptake of
59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patients with iron deficiency,
red cell uptake of radiolabeled iron ranged from 91% to 99% at 24 days after Injectafer
dose. In patients with renal anemia, red cell uptake of radiolabeled iron ranged from 61%
to 84% at 24 days after Injectafer dose.
12.3 Pharmacokinetics
After administration of a single dose of Injectafer of 100 to 1,000 mg of iron in iron
deficient adult patients, maximum iron concentration of 37 µg/mL to 333 µg/mL were
obtained respectively after 15 minutes to 1.21 hours post dose. The volume of
distribution was estimated to be 3 L.
The iron injected or infused was rapidly cleared from the plasma, the terminal half-life
ranged from 7 to 12 hours. Renal elimination of iron was negligible.
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After administration of a single dose of Injectafer 15 mg/kg in pediatric patients 1-17
years of age, the maximum concentrations ranged between 124 and 418.1 µg/mL and the
median time to maximum concentration was 7 minutes. The elimination half-life of
Injectafer in pediatric patients was approximately 9.7 hours. The total median 72-hour
exposure (AUC0-72h) after a single dose of Injectafer 15 mg/kg in pediatric patients was
4,529.7 µg∙h/mL while the median exposure after a single dose of 1,000 mg in adults was
5,875.3 µg∙h/mL.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies have not been performed with ferric carboxymaltose.
Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in
vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human
lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma
L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to
500 mg/kg.
In a combined male and female fertility study, ferric carboxymaltose was administered
intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg.
Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on
mating function, fertility or early embryonic development. Based on body surface area,
the dose of 30 mg/kg in animals is approximately 40% of the human dose of 750 mg.
14
CLINICAL STUDIES
14.1 Iron Deficiency Anemia
The safety and efficacy of Injectafer for treatment of IDA were evaluated in two
randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials,
Injectafer was administered at a dose of 15 mg/kg body weight up to a maximum single
dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative
dose of 1,500 mg of iron.
Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or Have Had
Unsatisfactory Response to Oral Iron
Trial 1: A Multi-center, Randomized, Active Controlled Study to Investigate the Efficacy
and Safety of Intravenous Ferric Carboxymaltose (FCM) in Patients with Iron Deficiency
Anemia (IDA), (NCT00982007) was a randomized, open-label, controlled clinical study
in patients with IDA who had an unsatisfactory response to oral iron (Cohort 1) or who
were intolerant to oral iron (Cohort 2) during the 14-day oral iron run-in period.
Inclusion criteria prior to randomization included hemoglobin (Hb) <12 g/dL, ferritin
≤100 ng/mL or ferritin ≤300 ng/mL when transferrin saturation (TSAT) ≤30%. Cohort 1
subjects were randomized to Injectafer or oral iron for 14 more days. Cohort 2 subjects
were randomized to Injectafer or another IV iron per standard of care [90% of subjects
received iron sucrose]. The mean age of study patients was 43 years (range, 18 to 94);
94% were female; 42% were Caucasian, 32% were African American, 24% were
Hispanic, and 2% were other races. The primary etiologies of IDA were heavy uterine
bleeding (47%) and gastrointestinal disorders (17%).
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Table 5 shows the baseline and the change in hemoglobin from baseline to highest value
between baseline and Day 35 or time of intervention.
Table 5. Mean Change in Hemoglobin From Baseline to the Highest Value
Between Day 35 or Time of Intervention (Modified Intent-to-Treat Population)
Hemoglobin (g/dL)
Mean (SD)
Cohort 1
Cohort 2
Injectafer
(N=244)
Oral Iron
(N=251)
Injectafer
(N=245)
IV SCa
(N=237)
Baseline
10.6 (1.0)
10.6 (1.0)
9.1 (1.6)
9.0 (1.5)
Highest Value
12.2 (1.1)
11.4 (1.2)
12.0 (1.2)
11.2 (1.3)
Change (from baseline to
highest value)
1.6 (1.2)
0.8 (0.8)
2.9 (1.6)
2.2 (1.3)
p-value
0.001
0.001
SD=standard deviation; aIntravenous iron per standard of care
Increases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in Cohort 1 and 218.2 ±
211.4 ng/mL in Cohort 2), and transferrin saturation (13 ± 16% in Cohort 1 and 20 ±
15% in Cohort 2) were observed at Day 35 in Injectafer-treated patients.
Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis Dependent Chronic
Kidney Disease
Trial 2: REPAIR-IDA, Randomized Evaluation of efficacy and safety of Ferric
Carboxymaltose in Patients with Iron Deficiency Anemia and Impaired Renal function,
(NCT00981045) was a randomized, open-label, controlled clinical study in patients with
non-dialysis dependent chronic kidney disease. Inclusion criteria included hemoglobin
(Hb) ≤11.5 g/dL, ferritin ≤100 ng/mL or ferritin ≤300 ng/mL when transferrin saturation
(TSAT) ≤30%. Study patients were randomized to either Injectafer or Venofer. The
mean age of study patients was 67 years (range, 19 to 101); 64% were female; 54% were
Caucasian, 26% were African American, 18% Hispanics, and 2% were other races.
Table 6 shows the baseline and the change in hemoglobin from baseline to highest value
between baseline and Day 56 or time of intervention.
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Table 6. Mean Change in Hemoglobin From Baseline to the Highest Value
Between Baseline and Day 56 or Time of Intervention (Modified Intent-to-Treat
Population)
Hemoglobin (g/dL)
Mean (SD)
Injectafer
(N=1,249)
Venofer
(N=1,244)
Baseline
10.3 (0.8)
10.3 (0.8)
Highest Value
11.4 (1.2)
11.3 (1.1)
Change (from baseline to highest
value)
1.1 (1.0)
0.9 (0.92)
Treatment Difference (95% CI)
0.21 (0.13, 0.28)
Increases from baseline in mean ferritin (734.7 ± 337.8 ng/mL) and transferrin
saturation (30 ± 17%) were observed prior to Day 56 in Injectafer-treated patients.
14.2 Iron Deficiency in Heart Failure
Trial 3: FER-CARS-05 (CONFIRM-HF) was a randomized, double-blind, placebo-
controlled, study in patients with iron deficiency and chronic heart failure with left
ventricular ejection fraction of < 45% and New York Heart Association (NYHA) class
II/III to determine whether intravenous Injectafer improves exercise capacity measured as
change from baseline to 24 weeks in 6-minute walk distance (6MWD).
Iron deficiency was defined as serum ferritin <100 ng/mL or 100 to 300 ng/mL with
TSAT <20%. Patients with Hb of ≥ 15 g/dl were excluded. Of the 304 patients, 150 were
randomized to Injectafer and 151 to placebo. The median age of study patients was 71
years (range, 35 to 88); 46% were female; 99% were Caucasian.
At baseline, mean (SD) Hb was 12 g/dl (1.4), ferritin 57 ng/mL (45), TSAT 19 % (13.7),
LVEF 37% (7), brain natriuretic peptide 770 pg/mL (973); and 57 and 43% were
classified as NYHA class II and III, respectively.
At baseline, 95% of patients were treated with angiotensin converting enzyme inhibitor
(ACEi) or angiotensin receptor blocker (ARB), 91% with beta-blocker, 59% with
aldosterone antagonists, and 90% with diuretic.
The mean change in 6MWD from Baseline to Week 24 in Injectafer-treated patients was
18 meters (95% CI 4, 32), and placebo-treated patients was -7 meters (95% CI -21, 7),
with between group difference of 25 meters (7, 43), p-value 0.007, favoring Injectafer.
Results were generally similar within age and sex subgroups.
In Injectafer-treated patients, change from Baseline to Week 24 in serum ferritin was
269 ng/mL (229, 309), in TSAT was 9% (7, 11), and in Hb was 0.6 g/dL (0.3, 0.8).
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16
HOW SUPPLIED/STORAGE AND HANDLING
Injectafer (ferric carboxymaltose injection) is a dark brown, non-transparent, sterile,
aqueous solution.
NDC 0517-0602-01
100 mg iron/2 mL Single-Dose Vial
Individually Boxed
NDC 0517-0650-01
750 mg iron/15 mL Single-Dose Vial
Individually Boxed
NDC 0517-0620-01 1,000 mg iron/20 mL Single-Dose Vial
Individually Boxed
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to
86°F). [See the USP controlled room temperature.] Do not freeze.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information) and
discuss with the patient the etiology of the iron deficiency anemia and the patient’s iron
deficiency anemia treatment options.
Prior History of Reactions to Parenteral Iron Products
Question patients regarding any prior history of reactions to parenteral iron products [see
Warnings and Precautions (5.1)].
Serious Hypersensitivity Reactions
Advise patients to report any signs and symptoms of hypersensitivity that may develop
during and following Injectafer administration, such as rash, itching, dizziness,
lightheadedness, swelling, and breathing problems [see Warnings and Precautions (5.1)].
Symptomatic Hypophosphatemia
Advise patients to report any signs or symptoms of hypophosphatemia such as fatigue,
muscle weakness or pain, bone and joint pain, or bone fractures [see Warnings and
Precautions (5.2)].
Pregnancy
Advise pregnant women about the risk of hypersensitivity reactions which may have
serious consequences for the fetus. Advise patients who may become pregnant to inform
their healthcare provider of a known or suspected pregnancy [see Use in Specific
Populations (8.1)].
Injectafer is manufactured under license from Vifor (International) Inc, Switzerland.
Distributed by:
RQ1052-I
Reference ID: 5505983
16
Patient Information
INJECTAFER (in-jekt-a-fer)
(ferric carboxymaltose injection)
What is INJECTAFER?
INJECTAFER is a prescription iron replacement medicine used for the treatment of:
•
iron deficiency anemia (IDA) in:
o adults and children 1 year of age and older who cannot tolerate iron taken by mouth (oral) or who have not
responded well to oral iron.
o adults who have chronic kidney disease who are not on dialysis (non-dialysis dependent chronic kidney
disease).
•
iron deficiency in adults with mild to moderate heart failure to improve the ability to exercise (improve exercise
capacity).
It is not known if INJECTAFER is safe and effective in children with IDA who are under 1 year of age.
It is not known if INJECTAFER is safe and effective in children with iron deficiency and mild to moderate heart failure
to improve exercise capacity.
Do not receive INJECTAFER.
Do not receive INJECTAFER if you are allergic to ferric carboxymaltose or any of the ingredients in INJECTAFER.
See the end of this Patient Information leaflet for a complete list of ingredients in INJECTAFER.
Before receiving INJECTAFER, tell your healthcare provider about all of your medical conditions, including if
you:
•
have had an allergic reaction to iron given into your vein
•
have a history of trouble absorbing certain vitamins or phosphate in your body
•
have inflammatory bowel disease
•
have hyperparathyroidism
•
have low vitamin D levels
•
have high blood pressure
•
have previously received INJECTAFER
•
are pregnant or plan to become pregnant. INJECTAFER may harm your unborn baby. Tell your healthcare
provider right away if you become pregnant or think you are pregnant during treatment with INJECTAFER.
•
are breastfeeding or plan to breastfeed. INJECTAFER passes into your breast milk. It is not known if
INJECTAFER will harm your baby. Talk to your healthcare provider about the best way to feed your baby during
treatment with INJECTAFER.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements.
How will I receive INJECTAFER?
•
INJECTAFER is given into your vein (intravenously) by your healthcare provider.
•
INJECTAFER is usually given in 2 doses at least 7 days apart for IDA, or 6 weeks apart for iron deficiency with
mild to moderate heart failure to improve exercise capacity.
•
If your healthcare provider decides it is right for you, INJECTAFER may be given intravenously by your
healthcare provider as a single-dose treatment.
•
INJECTAFER treatment may be repeated if your healthcare provider decides it is needed.
What are the possible side effects of INJECTAFER?
INJECTAFER may cause serious side effects, including:
•
Allergic reactions. Serious life-threatening allergic reactions that can lead to death have happened in people
who receive INJECTAFER and may include the following signs or symptoms:
o low blood pressure
o cold or clammy skin
Reference ID: 5505983
17
o feeling dizzy or lightheaded
o loss of consciousness
o trouble breathing
o swelling
o fast heartbeat
o feet or hands turn blue
o itching
o rash
o hives
o wheezing
Your healthcare provider will watch you during and for at least 30 minutes after you receive INJECTAFER. Tell
your healthcare provider right away if you develop any signs or symptoms of allergic reactions during or after
treatment with INJECTAFER.
•
Symptoms of low blood phosphate levels. INJECTAFER may cause low levels of phosphate in your blood that
may be serious and can lead to softening of your bones and broken bones (fractures), especially in people who
have received multiple INJECTAFER treatments. Your healthcare provider may check your blood phosphate
levels before a repeat treatment with INJECTAFER if you are at risk for low blood phosphate levels. If a repeat
treatment is needed within 3 months of your last treatment your healthcare provider should check your blood
phosphate levels. Tell your healthcare provider if you develop any of the following signs or symptoms of low
blood phosphate levels during treatment with INJECTAFER:
o feeling very tired
o muscle weakness or pain
o bone or joint pain
o broken bones
•
High blood pressure. High blood pressure, sometimes with redness and warmth of the face (facial flushing),
dizziness, or nausea, has happened during treatment with INJECTAFER. Your healthcare provider will check
your blood pressure and check for any signs and symptoms of high blood pressure after you receive
INJECTAFER.
The most common side effects of INJECTAFER in adults include:
•
nausea
•
high blood pressure
•
flushing
•
skin redness
•
low levels of phosphate in your blood
•
dizziness
•
injection site reactions
The most common side effects of INJECTAFER in children include:
•
low levels of phosphate in your blood
•
injection site reactions
•
rash
•
headache
•
vomiting
These are not all the possible side effects of INJECTAFER.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of INJECTAFER.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can
ask your pharmacist or healthcare provider for information about INJECTAFER that is written for health professionals.
What are the ingredients in INJECTAFER?
Active ingredient: ferric carboxymaltose.
Inactive ingredients: water for injection. Sodium hydroxide or hydrochloric acid may be added to adjust pH to 5.0-
7.0.
Distributed by:
INJECTAFER is manufactured under license from Vifor (International) Inc, Switzerland.
For more information go to www.injectafer.com or call 1-800-734-9236.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 05/2023
Reference ID: 5505983
| custom-source | 2025-02-12T15:48:24.322685 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/203565s027lbl.pdf', 'application_number': 203565, 'submission_type': 'SUPPL ', 'submission_number': 27} |
80,796 | custom-source | 2025-02-12T15:48:24.327525 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/203108Orig1s023lbl.pdf', 'application_number': 203108, 'submission_type': 'SUPPL ', 'submission_number': 23} | |
80,801 | 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
SPIRIVA HANDIHALER safely and effectively. See full prescribing
information for SPIRIVA HANDIHALER.
SPIRIVA® HANDIHALER® (tiotropium bromide inhalation powder),
for oral inhalation use
Initial U.S. Approval: 2004
----------------------------INDICATIONS AND USAGE---------------------------
SPIRIVA HANDIHALER is an anticholinergic indicated for the long-term,
once-daily, maintenance treatment of bronchospasm associated with chronic
obstructive pulmonary disease (COPD), and for reducing COPD
exacerbations (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
•
For oral inhalation only. DO NOT swallow SPIRIVA capsules. Only
use SPIRIVA capsules with the HANDIHALER device (2)
•
Two inhalations of the powder contents of a single SPIRIVA capsule
(18 mcg) once daily (2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Inhalation powder: SPIRIVA capsules contain 18 mcg tiotropium powder
(equivalent to 22.5 mcg tiotropium bromide monohydrate) for use with
HANDIHALER device (3)
-------------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity to tiotropium, ipratropium, or any components of SPIRIVA
capsules (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
•
Not for acute use: Not a rescue medication (5.1)
•
Immediate hypersensitivity reactions: Discontinue SPIRIVA
HANDIHALER at once and consider alternatives if immediate
hypersensitivity reactions, including angioedema, urticaria, rash,
bronchospasm, or anaphylaxis, occur. Use with caution in patients with
severe hypersensitivity to milk proteins. (5.2)
•
Paradoxical bronchospasm: Discontinue SPIRIVA HANDIHALER and
consider other treatments if paradoxical bronchospasm occurs (5.3)
•
Worsening of narrow-angle glaucoma may occur. Use with caution in
patients with narrow-angle glaucoma and instruct patients to consult a
physician immediately if this occurs. (5.4)
•
Worsening of urinary retention may occur. Use with caution in patients
with prostatic hyperplasia or bladder-neck obstruction and instruct
patients to consult a physician immediately if this occurs. (5.5)
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions (>5% incidence in the 1-year placebo-
controlled trials) were upper respiratory tract infection, dry mouth, sinusitis,
pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, and
rhinitis (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Anticholinergics: May interact additively with concomitantly used
anticholinergic medications. Avoid administration of SPIRIVA
HANDIHALER with other anticholinergic-containing drugs. (7.2)
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Patients with moderate to severe renal impairment should be monitored
closely for potential anticholinergic side effects (2, 8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: x/202x
_____________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Not for Acute Use
5.2 Immediate Hypersensitivity Reactions
5.3 Paradoxical Bronchospasm
5.4 Worsening of Narrow-Angle Glaucoma
5.5 Worsening of Urinary Retention
5.6 Renal Impairment
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Sympathomimetics, Methylxanthines, Steroids
7.2 Anticholinergics
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
_______________________________________________________________________________________________________________________________________
2
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
SPIRIVA HANDIHALER (tiotropium bromide inhalation powder) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with
chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA HANDIHALER is indicated to reduce exacerbations in COPD
patients.
2
DOSAGE AND ADMINISTRATION
For oral inhalation only. Do not swallow SPIRIVA capsules, as the intended effects on the lungs will not be obtained. The contents of the SPIRIVA capsules
should only be used with the HANDIHALER device [see Overdosage (10)].
The recommended dosage of SPIRIVA HANDIHALER is two inhalations of the powder contents of one SPIRIVA capsule, once-daily, with the HANDIHALER
device [see Patient Counseling Information (17)]. Do not take more than one dose in 24 hours.
For administration of SPIRIVA HANDIHALER, a SPIRIVA capsule is placed into the center chamber of the HANDIHALER device. The SPIRIVA capsule is pierced
by pressing and releasing the green piercing button on the side of the HANDIHALER device. The tiotropium formulation is dispersed into the air stream when the
patient inhales through the mouthpiece [see Patient Counseling Information (17)].
No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given
SPIRIVA HANDIHALER should be monitored closely for anticholinergic effects [see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and
Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Inhalation Powder: SPIRIVA HANDIHALER consists of SPIRIVA capsules containing tiotropium powder for oral inhalation and a HANDIHALER device. SPIRIVA
capsules contain 18 mcg of tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) in a light green, hard gelatin capsule with “TI 01” printed on one side
and Boehringer Ingelheim company symbol on the other side. The HANDIHALER device is only intended for use with the SPIRIVA capsules.
4
CONTRAINDICATIONS
SPIRIVA HANDIHALER is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product [see Warnings and
Precautions (5.2)]. In clinical trials and postmarketing experience with SPIRIVA HANDIHALER, immediate hypersensitivity reactions, including angioedema
(including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions (5.2)].
5
WARNINGS AND PRECAUTIONS
5.1 Not for Acute Use
SPIRIVA HANDIHALER is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e., as rescue therapy for
the treatment of acute episodes of bronchospasm.
5.2 Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching,
may occur after administration of SPIRIVA HANDIHALER. If such a reaction occurs, therapy with SPIRIVA HANDIHALER should be stopped at once and
alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to
atropine or its derivatives should be closely monitored for similar hypersensitivity reactions to SPIRIVA HANDIHALER. In addition, SPIRIVA HANDIHALER
should be used with caution in patients with severe hypersensitivity to milk proteins.
5.3 Paradoxical Bronchospasm
Inhaled medicines, including SPIRIVA HANDIHALER, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-
acting beta2-agonist such as albuterol. Treatment with SPIRIVA HANDIHALER should be stopped and other treatments considered.
5.4 Worsening of Narrow-Angle Glaucoma
SPIRIVA HANDIHALER should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of
acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and
corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
5.5 Worsening of Urinary Retention
SPIRIVA HANDIHALER should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary
retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a
physician immediately should any of these signs or symptoms develop.
5.6 Renal Impairment
As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA
HANDIHALER should be monitored closely for anticholinergic side effects [see Clinical Pharmacology (12.3)].
6
ADVERSE REACTIONS
The following adverse reactions are described, or described in greater detail, in other sections:
•
Immediate hypersensitivity reactions [see Warnings and Precautions (5.2)]
3
•
Paradoxical bronchospasm [see Warnings and Precautions (5.3)]
•
Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)]
•
Worsening of urinary retention [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly
compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice.
6-Month to 1-Year Trials
The data described below reflect exposure to SPIRIVA HANDIHALER in 2,663 patients. SPIRIVA HANDIHALER was studied in two 1-year placebo-controlled
trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1,308 patients were treated with SPIRIVA
HANDIHALER at the recommended dosage of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian,
and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle
glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran's
Affairs setting is not included in this safety database because only serious adverse events were collected.
The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions
reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or
worsening), dysuria, and urinary retention.
Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated SPIRIVA HANDIHALER in patients with COPD. Table 1 shows all adverse
reactions that occurred with a frequency of ≥3% in the SPIRIVA HANDIHALER group in the 1-year placebo-controlled trials where the rates in the SPIRIVA
HANDIHALER group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.
Table 1
Adverse Reactions (% Patients) in One-Year COPD Clinical Trials
Body System (Event)
Placebo-Controlled Trials
Ipratropium-Controlled Trials
SPIRIVA
Placebo
SPIRIVA
Ipratropium
(n = 550)
(n = 371)
(n = 356)
(n = 179)
Body as a Whole
Chest Pain (non-specific)
7
5
5
2
Edema, Dependent
5
4
3
5
Gastrointestinal System Disorders
Dry Mouth
16
3
12
6
Dyspepsia
6
5
1
1
Abdominal Pain
5
3
6
6
Constipation
4
2
1
1
Vomiting
4
2
1
2
Musculoskeletal System
Myalgia
4
3
4
3
Resistance Mechanism Disorders
Infection
4
3
1
3
Moniliasis
4
2
3
2
Respiratory System (Upper)
Upper Respiratory Tract Infection
41
37
43
35
Sinusitis
11
9
3
2
Pharyngitis
9
7
7
3
Rhinitis
6
5
3
2
Epistaxis
4
2
1
1
Skin and Appendage Disorders
Rash
4
2
2
2
Urinary System
Urinary Tract Infection
7
5
4
2
Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the SPIRIVA HANDIHALER treatment group, but were <1% in excess of the placebo
group.
Other reactions that occurred in the SPIRIVA HANDIHALER group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the
placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System
Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional
Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina
pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among
the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention.
In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [see Use in Specific Populations (8.5)].
4
Two multicenter, 6-month, controlled studies evaluated SPIRIVA HANDIHALER in patients with COPD. The adverse reactions and the incidence rates were similar to
those seen in the 1-year controlled trials.
4-Year Trial
The data described below reflect exposure to SPIRIVA HANDIHALER in 5,992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2,986 patients were
treated with SPIRIVA HANDIHALER at the recommended dosage of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90%
Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy
or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥3% in the SPIRIVA HANDIHALER
group where the rates in the SPIRIVA HANDIHALER group exceeded placebo by ≥1%, adverse reactions included (SPIRIVA HANDIHALER, placebo): pharyngitis
(12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%),
and arthralgia (4.2%, 3.1%).
Additional Adverse Reactions
Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with SPIRIVA HANDIHALER than placebo include:
dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.
6.2 Postmarketing Experience
Adverse reactions have been identified during worldwide post-approval use of SPIRIVA HANDIHALER. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions
are: application site irritation (glossitis, mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus paralytic,
intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria.
7
DRUG INTERACTIONS
7.1 Sympathomimetics, Methylxanthines, Steroids
SPIRIVA HANDIHALER has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral
and inhaled steroids without increases in adverse reactions.
7.2 Anticholinergics
There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SPIRIVA HANDIHALER with
other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions
(6)].
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
The limited human data with SPIRIVA HANDIHALER use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes.
Based on animal reproduction studies, no structural abnormalities were observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the
period of organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID). Increased post-implantation loss
was observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect,
loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and
8 times the MRHDID, respectively (on a mcg/m2 basis at inhalation doses of 1,471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural
abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean
pup weights, and a delay in pup sexual maturation at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m2 basis at a maternal inhalation dose of 78
mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m2 basis at a
maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the MRHDID, respectively (on a mcg/m2 basis at
inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).
8.2 Lactation
Risk Summary
There are no data on the presence of tiotropium in human milk, the effects on the breastfed infant, or the effects on milk production. Tiotropium is present in milk of
lactating rats; however, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear [see Data]. The developmental and
health benefits of breastfeeding should be considered along with the mother’s clinical need for SPIRIVA HANDIHALER and any potential adverse effects on the
breastfed child from SPIRIVA HANDIHALER or from the underlying maternal condition.
Data
The distribution of tiotropium bromide into milk was investigated after a single intravenous administration of 10 mg/kg to lactating rats. Tiotropium and/or its
metabolites are present in the milk of lactating rats at concentrations above those in plasma.
5
8.4 Pediatric Use
SPIRIVA HANDIHALER is not indicated for use in children. The safety and effectiveness of SPIRIVA HANDIHALER in pediatric patients have not been established.
8.5 Geriatric Use
Based on available data, no adjustment of SPIRIVA HANDIHALER dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].
Of the total number of patients who received SPIRIVA HANDIHALER in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75
years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the SPIRIVA HANDIHALER and the
comparator groups for most events. Dry mouth increased with age in the SPIRIVA HANDIHALER group (differences from placebo were 9.0%, 17.1%, and 16.2% in
the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the SPIRIVA HANDIHALER
group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from
placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups.
8.6 Renal Impairment
Patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with SPIRIVA HANDIHALER should be monitored closely for
anticholinergic side effects [see Dosage and Administration (2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.
10
OVERDOSAGE
High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled
dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-
daily inhalation of 141 mcg of tiotropium.
Treatment of overdosage consists of discontinuation of SPIRIVA HANDIHALER together with institution of appropriate symptomatic and/or supportive therapy.
Accidental Ingestion
Acute intoxication by inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is not well-absorbed systemically.
A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed
altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, SPIRIVA HANDIHALER was discontinued, and the constipation
was treated with an enema. The patient recovered and was discharged on the same day.
11
DESCRIPTION
SPIRIVA HANDIHALER consists of SPIRIVA capsules and a HANDIHALER device. Each light green, hard gelatin SPIRIVA capsule contains a dry powder
consisting of 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins).
The contents of SPIRIVA capsules are intended for oral inhalation only, and are intended for administration only with the HANDIHALER device.
The active component of SPIRIVA HANDIHALER is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for
muscarinic receptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane
bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble
in water and soluble in methanol.
The structural formula is:
Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O.
The HANDIHALER device is an inhalation device used to inhale the dry powder contained in the SPIRIVA capsule. The dry powder is delivered from the
HANDIHALER device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HANDIHALER device delivers a mean of 10.4 mcg tiotropium when
tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L
(range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the HANDIHALER device was 30.0 L/min (range 20.4
to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the
HANDIHALER device, which may vary from patient to patient, and may vary with the exposure time of the SPIRIVA capsule outside the blister pack.
6
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to
M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and
reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies,
prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of
tiotropium is predominantly a site-specific effect.
12.2 Pharmacodynamics
Cardiac Electrophysiology
In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes
from baseline-corrected QT interval of 30 to 60 msec was higher in the SPIRIVA HANDIHALER group as compared with placebo. This difference was apparent using
both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No
patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies with SPIRIVA HANDIHALER did not detect an effect of the drug on QTc
intervals.
The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy
volunteers. Subjects received tiotropium dry powder for inhalation 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were
performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from
baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium dry powder for inhalation 18 mcg and 54 mcg, respectively. No subject showed a new
onset of QTc >500 msec or QTc changes from baseline of ≥60 msec.
12.3 Pharmacokinetics
Tiotropium is administered by dry powder inhalation. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for
therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation
powder (18 mcg) from the HANDIHALER device resulted in a similar systemic exposure between the two products.
Absorption
Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable.
Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium. Maximum tiotropium plasma
concentrations were observed 7 minutes after inhalation.
Distribution
Tiotropium is 72% bound to plasma protein and had a volume of distribution of 32 L/kg after intravenous administration to young healthy volunteers. Local
concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that
tiotropium does not readily penetrate the blood-brain barrier.
Elimination
The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was
880 mL/min after intravenous administration in young healthy volunteers. After chronic once-daily dry powder inhalation by COPD patients, pharmacokinetic steady
state was reached by day 7 with no accumulation thereafter.
Metabolism
The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers.
Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted
unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of
Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450
2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver
microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
Excretion
Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation to COPD patients at steady state, urinary
excretion was 7% (1.3 mcg) of the unchanged dose over 24 hours. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.
Specific Populations
Geriatric Patients
As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (365 mL/min in COPD patients
<65 years to 271 mL/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values following administration via
HANDIHALER device.
Renal Impairment
Following 4-week SPIRIVA HANDIHALER or SPIRIVA RESPIMAT once daily dosing in patients with COPD, mild renal impairment (creatinine clearance 60-<90
mL/min) resulted in 6-23% higher AUC0-6,ss and 6-17% higher Cmax,ss values; moderate renal impairment (creatinine clearance 30-<60 mL/min) resulted in 54-57%
7
higher AUC0-6,ss and 15-31% higher Cmax,ss values compared to COPD patients with normal renal function (creatinine clearance ≥90 mL/min). There is insufficient data
for tiotropium exposure in patients with severe renal impairment (creatinine clearance <30 mL/min) following inhalation of SPIRIVA HANDIHALER or SPIRIVA
RESPIMAT. However AUC0-4 and Cmax were 94% and 52% higher, respectively, in patients with severe renal impairment following intravenous infusion of tiotropium
bromide.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.
Drug Interactions
An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once daily was
conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and
no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of
tiotropium.
Common concomitant medications (long-acting beta2-adrenergic agonists (LABA), inhaled corticosteroids (ICS)) used by patients with COPD were not found to alter
the exposure to tiotropium.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female
mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40,
and 0.5 times the recommended human daily inhalation dose (MRHDID) on a mcg/m2 basis, respectively.
Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster
cell mutagenesis assay, the chromosomal aberration assays in human lymphocytes in vitro and mouse micronucleus formation in vivo, and the unscheduled DNA
synthesis in primary rat hepatocytes in vitro assay.
In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately
40 times the MRHDID on a mcg/m2 basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on a mcg/m2 basis). The fertility
index, however, was not affected at inhalation doses up to 1,689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m2 basis).
14
CLINICAL STUDIES
The SPIRIVA HANDIHALER (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 2,663 patients with COPD
(1,308 receiving SPIRIVA HANDIHALER): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled
studies. These studies enrolled patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a
forced expiratory volume in one second (FEV1) less than or equal to 60% or 65% of predicted, and a ratio of FEV1/FVC of less than or equal to 0.7.
In these studies, SPIRIVA HANDIHALER, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within
3 hours following the first dose.
Two additional trials evaluated exacerbations: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1,829 COPD patients in a US
Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5,992 COPD patients. Long-term effects on lung
function and other outcomes, were also evaluated in the 4-year multicenter trial.
6-Month to 1-Year Effects on Lung Function
In the 1-year, placebo-controlled trials, the mean improvement in FEV1 at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to
baseline after the first dose (Day 1). Further improvements in FEV1 and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day
8 with once-daily treatment. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily
treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence
of tolerance.
In the two 6-month, placebo-controlled trials, serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in
Trial B. The serial FEV1 values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV1) with
SPIRIVA HANDIHALER, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month
treatment period.
8
Figure 1 Mean FEV1 Over Time (prior to and after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*
Day 1
Day 169
*Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the SPIRIVA HANDIHALER and placebo groups,
respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.
Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown
in Figure 2.
Figure 2 Mean FEV1 Over Time (0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the Two Ipratropium-Controlled Studies*
Day 1
Day 92
*Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the SPIRIVA HANDIHALER and
ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least
favorable observation carried forward.
A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval
in comparison to placebo, regardless of whether SPIRIVA HANDIHALER was administered in the morning or in the evening.
Throughout each week of the 1-year treatment period in the two placebo-controlled trials, patients taking SPIRIVA HANDIHALER had a reduced requirement for the
use of rescue short-acting beta2-agonists. Reduction in the use of rescue short-acting beta2-agonists, as compared to placebo, was demonstrated in one of the two 6-
month studies.
4-Year Effects on Lung Function
A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5,992 COPD patients was conducted to evaluate the long-term effects of
SPIRIVA HANDIHALER on disease progression (rate of decline in FEV1). Patients were permitted to use all respiratory medications (including short-acting and long-
acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 40 to 88 years of age, 75% male, and 90%
Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV1 of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the
groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV1, as demonstrated by similar slopes of FEV1 decline
over time (Figure 3).
SPIRIVA HANDIHALER maintained improvements in trough (pre-dose) FEV1 (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure
3).
10
Storage
Store at 20°C to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
The SPIRIVA capsules should not be exposed to extreme temperature or moisture. Do not store SPIRIVA capsules in the HANDIHALER device.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Not for Acute Use:
Instruct patients that SPIRIVA HANDIHALER is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a
rescue medication).
Immediate Hypersensitivity Reactions:
Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration
of SPIRIVA HANDIHALER. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.
Paradoxical Bronchospasm:
Inform patients that SPIRIVA HANDIHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should
discontinue SPIRIVA HANDIHALER.
Worsening of Narrow-Angle Glaucoma:
Instruct patients to be alert for signs and symptoms of narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association
with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs and symptoms develop.
Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.
Since dizziness and blurred vision may occur with the use of SPIRIVA HANDIHALER, caution patients about engaging in activities such as driving a vehicle or
operating appliances or machinery.
Worsening of Urinary Retention:
Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician
immediately should any of these signs or symptoms develop.
Instructions for Administering SPIRIVA HANDIHALER:
Instruct patients on how to correctly administer SPIRIVA capsules using the HANDIHALER device [see Patient Counseling Information (17)]. Instruct patients that
SPIRIVA capsules should only be administered via the HANDIHALER device and the HANDIHALER device should not be used for administering other medications.
Remind patients that the contents of SPIRIVA capsules are for oral inhalation only and must not be swallowed.
Instruct patients always to store SPIRIVA capsules in sealed blisters and to remove only one SPIRIVA capsule immediately before use or its effectiveness may be
reduced. Instruct patients to discard unused additional SPIRIVA capsules that are exposed to air (i.e., not intended for immediate use).
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
Address medical inquiries to: 1-800-542-6257.
SPIRIVA® and HANDIHALER® are registered trademarks of and are used under license from Boehringer Ingelheim International GmbH.
Copyright © 202x Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
COL10494BH212024
1
Patient Information
SPIRIVA (speh REE vah) HANDIHALER
(tiotropium bromide inhalation powder)
Do NOT swallow SPIRIVA capsules.
Important Information: Do not swallow SPIRIVA capsules. SPIRIVA capsules should only be used with the
HANDIHALER device and inhaled through your mouth (oral inhalation).
Read the information that comes with your SPIRIVA HANDIHALER before you start using it and each time you refill your
prescription. There may be new information. This leaflet does not take the place of talking with your doctor about your
medical condition or your treatment.
What is SPIRIVA HANDIHALER?
•
SPIRIVA HANDIHALER is a prescription medicine used each day (a maintenance medicine) to control symptoms of
chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
•
SPIRIVA HANDIHALER helps make your lungs work better for 24 hours. SPIRIVA HANDIHALER relaxes your
airways and helps keep them open. You may start to feel like it is easier to breathe on the first day, but it may take
longer for you to feel the full effects of the medicine. SPIRIVA HANDIHALER works best and may help make it easier
to breathe when you use it every day.
•
SPIRIVA HANDIHALER reduces the likelihood of flare-ups and worsening of COPD symptoms (COPD
exacerbations). A COPD exacerbation is defined as an increase or new onset of more than one COPD symptom
such as cough, mucus, shortness of breath, and wheezing that requires medicine beyond your rescue medicine.
SPIRIVA HANDIHALER is not a rescue medicine and should not be used for treating sudden breathing problems.
Your doctor may give you other medicine to use for sudden breathing problems.
It is not known if SPIRIVA HANDIHALER is safe and effective in children.
Who should not take SPIRIVA HANDIHALER?
Do not use SPIRIVA HANDIHALER if you:
• are allergic to tiotropium, ipratropium (Atrovent®), or any of the ingredients in SPIRIVA HANDIHALER. See the end of
this leaflet for a complete list of ingredients in SPIRIVA HANDIHALER.
Symptoms of a serious allergic reaction to SPIRIVA HANDIHALER may include:
o
raised red patches on your skin (hives)
o
itching
o
rash
o
swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing
If you have these symptoms of an allergic reaction, stop taking SPIRIVA HANDIHALER and call your doctor right away or
go to the nearest hospital emergency room.
2
What should I tell my doctor before using SPIRIVA HANDIHALER?
Before taking SPIRIVA HANDIHALER, tell your doctor about all your medical conditions, including if you:
• have kidney problems.
• have glaucoma. SPIRIVA HANDIHALER may make your glaucoma worse.
• have an enlarged prostate, problems passing urine, or a blockage in your bladder. SPIRIVA HANDIHALER may make
these problems worse.
• are pregnant or plan to become pregnant. It is not known if SPIRIVA HANDIHALER could harm your unborn baby.
• are breast-feeding or plan to breast-feed. It is not known if SPIRIVA HANDIHALER passes into breast milk. You and
your doctor will decide if SPIRIVA HANDIHALER is right for you while you breast-feed.
• have a severe allergy to milk proteins. Ask your doctor if you are not sure.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines and eye
drops, vitamins, and herbal supplements. Some of your other medicines or supplements may affect the way SPIRIVA
HANDIHALER works. SPIRIVA HANDIHALER is an anticholinergic medicine. You should not take other anticholinergic
medicines while using SPIRIVA HANDIHALER, including ipratropium. Ask your doctor or pharmacist if you are not sure if
one of your medicines is an anticholinergic.
Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist when you get a
new medicine.
How should I take SPIRIVA HANDIHALER?
•
Use SPIRIVA HANDIHALER exactly as prescribed. Use SPIRIVA HANDIHALER one time every day.
•
Read the “Instructions for Use” at the end of this leaflet before you use SPIRIVA HANDIHALER. Talk with your doctor
if you do not understand the instructions.
•
Do not swallow SPIRIVA capsules.
•
Only use SPIRIVA capsules with the HANDIHALER device.
•
Do not use the HANDIHALER device to take any other medicine.
•
SPIRIVA HANDIHALER comes as a powder in a SPIRIVA capsule that fits the HANDIHALER device. Each SPIRIVA
capsule, containing only a small amount of SPIRIVA powder, is one full dose of medicine.
•
Separate one blister from the blister card. Then take out one of the SPIRIVA capsules from the blister package right
before you use it.
•
After the capsule is pierced, take a complete dose of SPIRIVA HANDIHALER by breathing in the powder by mouth
two times, using the HANDIHALER device (take 2 inhalations from one SPIRIVA capsule). See the “Instructions for
Use” at the end of this leaflet.
• Throw away any SPIRIVA capsule that is not used right away after it is taken out of the blister package. Do not leave
the SPIRIVA capsules open to air; they may not work as well.
• If you miss a dose, take it as soon as you remember. Do not use SPIRIVA HANDIHALER more than one time every
24 hours.
• If you use more than your prescribed dose of SPIRIVA HANDIHALER, call your doctor or a poison control center.
What should I avoid while using SPIRIVA HANDIHALER?
•
Do not let the powder from the SPIRIVA capsule get into your eyes. Your vision may get blurry and the pupil in your
eye may get larger (dilate). If this happens, call your doctor.
•
SPIRIVA HANDIHALER can cause dizziness and blurred vision. Should you experience these symptoms you should
use caution when engaging in activities such as driving a car or operating appliances or other machines.
What are the possible side effects of SPIRIVA HANDIHALER?
SPIRIVA HANDIHALER can cause serious side effects, including: Allergic reaction. Symptoms may include:
o
raised red patches on your skin (hives)
o
itching
o
rash
o
swelling of the lips, tongue, or throat that may cause difficulty in breathing or swallowing
If you have these symptoms of an allergic reaction, stop taking SPIRIVA HANDIHALER and call your doctor right away or
3
go to the nearest hospital emergency room.
• Sudden narrowing and blockage of the airways into the lungs (bronchospasm). Your breathing suddenly gets
worse.
If you have these symptoms of bronchospasm, stop taking SPIRIVA HANDIHALER and call your doctor right away or go
to the nearest hospital emergency room.
• New or worsened increased pressure in the eyes (acute narrow-angle glaucoma). Symptoms of acute narrow-
angle glaucoma may include:
o
eye pain
o
blurred vision
o
seeing halos (visual halos) or colored images along with red eyes
Using only eye drops to treat these symptoms may not work. If you have these symptoms, stop taking SPIRIVA
HANDIHALER and call your doctor right away.
• New or worsened urinary retention. Symptoms of blockage in your bladder and/or enlarged prostate may include:
difficulty passing urine, painful urination.
If you have these symptoms of urinary retention, stop taking SPIRIVA HANDIHALER and call your doctor right away.
Other side effects with SPIRIVA HANDIHALER include:
•
upper respiratory tract infection
•
dry mouth
•
sinus infection
•
sore throat
•
non-specific chest pain
•
urinary tract infection
•
indigestion
•
runny nose
•
constipation
•
increased heart rate
•
blurred vision
These are not all the possible side effects with SPIRIVA HANDIHALER. Tell your doctor if you have any side effect that
bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How do I store SPIRIVA HANDIHALER?
•
Do not store SPIRIVA capsules in the HANDIHALER device.
•
Store SPIRIVA capsules in the sealed blister package at room temperature 68oF to 77oF (20oC to 25oC).
•
Keep SPIRIVA capsules away from heat and cold (do not freeze).
•
Store SPIRIVA capsules in a dry place. Throw away any unused SPIRIVA capsules that have been open to air.
Ask your doctor or pharmacist if you have any questions about storing your SPIRIVA capsules.
Keep SPIRIVA HANDIHALER, SPIRIVA capsules, and all medicines out of the reach of children.
General information about SPIRIVA HANDIHALER
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use
SPIRIVA HANDIHALER for a purpose for which it has not been prescribed. Do not give SPIRIVA HANDIHALER to other
people even if they have the same symptoms that you have. It may harm them.
For more information about SPIRIVA HANDIHALER, talk with your doctor. You can ask your doctor or pharmacist for
information about SPIRIVA HANDIHALER that is written for health professionals.
4
For current prescribing information for SPIRIVA HANDIHALER, scan the code or for additional information you may also
call Boehringer Ingelheim Pharmaceuticals, Inc., at 1-800-542-6257.
What are the ingredients in SPIRIVA HANDIHALER?
Active ingredient: tiotropium
Inactive ingredient: lactose monohydrate
What is COPD (Chronic Obstructive Pulmonary Disease)?
COPD is a serious lung disease that includes chronic bronchitis, emphysema, or both. Most COPD is caused by smoking.
When you have COPD, your airways become narrow. So, air moves out of your lungs more slowly. This makes it hard to
breathe.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
SPIRIVA® and HANDIHALER® are registered trademarks of and are used under license from Boehringer Ingelheim
International GmbH.
Copyright © 202x Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
Revised: xxx 202x
COL10494BH21202x
1
Instructions for Use
SPIRIVA® (speh REE vah) HANDIHALER®
(tiotropium bromide inhalation powder)
Do not swallow SPIRIVA
capsules.
Important Information about using your SPIRIVA HANDIHALER
•
Do not swallow SPIRIVA capsules.
•
SPIRIVA capsules should only be used with the HANDIHALER device and inhaled
through your mouth (oral inhalation).
•
Do not use your HANDIHALER device to take any other medicine.
First read the Patient Information, then read these Instructions for Use before you start to use
SPIRIVA HANDIHALER and each time you refill your prescription. There may be new
information.
Becoming familiar with your HANDIHALER device and SPIRIVA capsules:
Your SPIRIVA HANDIHALER comes with SPIRIVA capsules in blister packaging and a
HANDIHALER device. Use the new HANDIHALER device provided with your medicine.
Figure A
The parts of your HANDIHALER device include:
(See Figure A)
1. dust cap (lid)
2. mouthpiece
3. mouthpiece ridge
4. base
5. green piercing button
6. center chamber
7. air intake vents
2
Figure B
Each SPIRIVA capsule is packaged in a blister. (See Figure B)
Figure C
•
Each SPIRIVA capsule contains only a small amount of
powder. (See Figure C) This is 1 full dose.
•
Do not open the SPIRIVA capsule or it may not work.
Taking your full daily dose of medicine requires 4 main steps.
Step 1. Opening your HANDIHALER device:
Figure D
After removing your HANDIHALER device from the pouch:
•
Open the dust cap (lid) by pressing the green piercing button.
(See Figure D)
3
Figure E
•
Pull the dust cap (lid) upwards away from the base to expose
the mouthpiece. (See Figure E)
Figure F
•
Open the mouthpiece by pulling the mouthpiece ridge up and
away from the base so the center chamber is showing. (See
Figure F)
Step 2. Inserting the SPIRIVA capsule into your HANDIHALER device:
Figure G
Each day, separate only 1 of the blisters from the blister card by
tearing along the perforated line. (See Figure G)
4
Figure H
Remove the SPIRIVA capsule from the blister:
•
Do not cut the foil or use sharp instruments to take out the
SPIRIVA capsule from the blister.
•
Bend 1 of the blister corners with an arrow and separate the
aluminum foil layers.
•
Peel back the printed foil until you see the whole SPIRIVA
capsule. (See Figure H)
•
If you have opened more than 1 blister to the air, the extra
SPIRIVA capsule should not be used and should be thrown
away.
Figure I
Place the SPIRIVA capsule in the center chamber of your
HANDIHALER device. (See Figure I)
Figure J
Close the mouthpiece firmly against the gray base until you hear a
click. Leave the dust cap (lid) open. (See Figure J)
5
Step 3. Piercing the SPIRIVA capsule:
Figure K
•
Hold your HANDIHALER device with the mouthpiece pointed
up. (See Figure K)
•
Press the green piercing button once until it is flat (flush)
against the base, then release. This is how you make holes in
the SPIRIVA capsule so that you get your medicine when you
breathe in.
•
Do not press the green button more than one time.
•
Do not shake your HANDIHALER device.
•
The piercing of the SPIRIVA capsule may produce small
gelatin pieces. Some of these small pieces may pass through
the screen of your HANDIHALER device into your mouth or
throat when you breathe in your medicine. This is normal.
The small pieces of gelatin should not harm you.
Step 4. Taking your full daily dose (2 inhalations from the same SPIRIVA capsule):
Figure L
Breathe out completely in 1 breath, emptying your lungs of any
air. (See Figure L)
Important: Do not breathe into your HANDIHALER device.
Figure M
With your next breath, take your medicine:
•
Hold your head in an upright position while you are
looking straight ahead. (See Figure M)
•
Raise your HANDIHALER device to your mouth in a horizontal
position. Do not block the air intake vents.
•
Close your lips tightly around the mouthpiece.
•
Breathe in deeply until your lungs are full. You should
hear or feel the SPIRIVA capsule vibrate (rattle). (See
Figure M)
•
Hold your breath for a few seconds and, at the same time,
take your HANDIHALER device out of your mouth.
•
Breathe normally again.
The rattle tells you that you breathed in correctly. If you do not hear
or feel a rattle, see the section, “If you do not hear or feel the
6
SPIRIVA capsule rattle as you breathe in your medicine.”
Figure N
To get your full daily dose, you must again, breathe out
completely (See Figure N) and for a second time, breathe in
(See Figure O) from the same SPIRIVA capsule.
Important: Do not press the green piercing button again.
Figure O
Remember: To get your full medicine dose each day, you must
breathe in 2 times from the same SPIRIVA capsule. Make sure you
breathe out completely each time before you breathe in from your
HANDIHALER device.
Caring for and storing your SPIRIVA HANDIHALER:
Figure P
•
After taking your daily dose, open the mouthpiece and tip out
the used SPIRIVA capsule into your trash can, without
touching it.
•
Remove any SPIRIVA capsule pieces or SPIRIVA powder
buildup by turning your HANDIHALER device upside down and
gently, but firmly, tapping it. (See Figure P) Then, close the
mouthpiece and dustcap for storage.
•
Do not store your HANDIHALER device and SPIRIVA capsules
(blisters) in a damp moist place. Always store SPIRIVA
capsules in the sealed blisters.
7
If you do not hear or feel the SPIRIVA capsule rattle as you breathe in your medicine:
Figure Q
Do not press the green piercing button again.
Hold your HANDIHALER device with the mouthpiece pointed up and
tap your HANDIHALER device gently on a table. (See Figure Q)
Check to see that the mouthpiece is completely closed. Breathe out
completely before deeply breathing in again with the mouthpiece in
your mouth. (See Figure O)
If you still do not hear or feel the SPIRIVA capsule rattle after
repeating the above steps:
•
Throw away the SPIRIVA capsule.
•
Open the base by lifting the green piercing button and check
the center chamber for pieces of the SPIRIVA capsule.
SPIRIVA capsule pieces in the center chamber can cause a
SPIRIVA capsule not to rattle.
•
Turn your HANDIHALER device upside down and gently, but
firmly, tap to remove the SPIRIVA capsule pieces. Call your
doctor for instructions.
Cleaning your HANDIHALER device:
Figure R
Clean your HANDIHALER device as needed. (See Figure R)
•
It takes 24 hours to air dry your HANDIHALER device
after you clean it.
•
Do not use cleaning agents or detergents.
•
Do not place your HANDIHALER device in the dishwasher
for cleaning.
Cleaning Steps:
•
Open the dust cap and mouthpiece.
•
Open the base by lifting the green piercing button.
•
Look in the center chamber for SPIRIVA capsule pieces or
powder buildup. If seen, tap out.
•
Rinse your HANDIHALER device with warm water, pressing
the green piercing button a few times so that the center
chamber and the piercing needle is under the running
water. Check that any powder buildup or SPIRIVA capsule
pieces are removed.
•
Dry your HANDIHALER device well by tipping the excess
water out on a paper towel. Air-dry afterwards, leaving the
dust cap, mouthpiece, and base open by fully spreading it
out so that it dries completely.
•
Do not use a hair dryer to dry your HANDIHALER device.
•
Do not use your HANDIHALER device when it is wet. If
needed, you may clean the outside of the mouthpiece with
a clean damp cloth.
8
For current prescribing information for SPIRIVA HANDIHALER, scan the code or for additional
information you may also call Boehringer Ingelheim Pharmaceuticals, Inc., at 1-800-542-6257.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
SPIRIVA® and HANDIHALER® are registered trademarks of and are used under license from
Boehringer Ingelheim International GmbH.
Copyright © 202x Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
Revised: xxx 202x
COL10494BH212024
Helpful Hints to help ensure that you are properly taking your full daily dose of SPIRIVA HANDIHALER:
•
Press the green piercing button 1 time; Breathe in 2 times; Breathe out completely before each of the
2 inhalations.
•
Always use the new HANDIHALER device provided with your medicine.
•
Keep your HANDIHALER device with the mouthpiece pointed up when pressing the green piercing button.
•
Press the green piercing button 1 time to pierce the SPIRIVA capsule.
•
Do not breathe out into your HANDIHALER device.
•
Keep your HANDIHALER device in a horizontal position and keep your head upright, looking straight
ahead, when breathing in.
•
Check the center chamber of your HANDIHALER device for SPIRIVA capsule pieces or powder build-up.
If pieces or powder are seen, tap out before use.
•
Clean your HANDIHALER as needed and dry thoroughly.
| custom-source | 2025-02-12T15:48:24.507778 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/021395Orig1s078lbl.pdf', 'application_number': 21395, 'submission_type': 'SUPPL ', 'submission_number': 78} |
80,814 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
TURALIO safely and effectively. See full prescribing information
for TURALIO.
TURALIO® (pexidartinib) capsules, for oral use
Initial U.S. Approval: 2019
WARNING: HEPATOTOXICITY
See full prescribing information for complete boxed warning.
•
TURALIO can cause serious and potentially fatal liver
injury, including vanishing bile duct syndrome. (5.1)
•
Monitor liver tests prior to initiation of TURALIO and at
specified intervals during treatment. Withhold and dose
reduce or permanently discontinue TURALIO based on
severity of hepatotoxicity. Monitoring and prompt
cessation of TURALIO may not eliminate the risk of
serious and potentially fatal liver injury. (2.2, 5.1)
•
TURALIO is available only through a restricted program
called the TURALIO Risk Evaluation and Mitigation
Strategy (REMS) Program. (5.2)
-----------------------------RECENT MAJOR CHANGES------------------------
Boxed Warning
1/2025
Warnings and Precautions (5.1)
1/2025
-----------------------------INDICATIONS AND USAGE--------------------------
TURALIO is a kinase inhibitor indicated for the treatment of adult
patients with symptomatic tenosynovial giant cell tumor (TGCT)
associated with severe morbidity or functional limitations and not
amenable to improvement with surgery. (1)
------------------------DOSAGE AND ADMINISTRATION----------------------
• Recommended Dosage: 250 mg orally twice daily with a low-fat
meal (approximately 11 to 14 grams of total fat). (2.1)
• See full prescribing information for dosage modifications due to
adverse reactions, renal impairment and hepatic impairment. (2.2,
2.5, 2.6)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsules: 125 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
None. (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
• Embryo-Fetal Toxicity: May cause fetal harm. Advise patients of
reproductive potential of the potential risk to a fetus and to use an
effective non-hormonal method of contraception. (5.3, 7.3, 8.1, 8.3)
• Potential Risks Associated with a High-Fat Meal: May increase
incidence and severity of adverse reactions, including hepatotoxicity.
Avoid taking TURALIO with a high-fat meal (approximately 55 to 65
grams of total fat). (2.1, 5.4)
-------------------------------ADVERSE REACTIONS-----------------------------
Most common adverse reactions (>20%) were increased lactate
dehydrogenase, increased aspartate aminotransferase, hair color
changes, fatigue, increased alanine aminotransferase, decreased
neutrophils, increased cholesterol, increased alkaline phosphatase,
decreased lymphocytes, eye edema, decreased hemoglobin, rash,
dysgeusia, and decreased phosphate. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi
Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
• Use with Hepatotoxic Products: Avoid coadministration of TURALIO
with other products known to cause hepatotoxicity. (7.1)
• Moderate or Strong CYP3A Inhibitors: Reduce the dose of TURALIO
if concomitant use of moderate or strong CYP3A inhibitors cannot
be avoided. (2.3, 7.2)
• Strong CYP3A Inducers: Avoid concomitant use of strong CYP3A
inducers. (7.2)
• UGT Inhibitors: Reduce the dose of TURALIO if concomitant use of
UGT inhibitors cannot be avoided. (2.3, 7.2)
• Acid-Reducing Agents: Avoid concomitant use of proton pump
inhibitors. Use histamine-2 receptor antagonists or antacids if
needed. (2.4, 7.2)
• High-Fat Meal: Avoid taking TURALIO with a high-fat meal. (2.1, 5.4,
7.2).
• CYP3A Substrates: Avoid concomitant use with CYP3A substrates
where minimal concentration changes may lead to serious
therapeutic failure. (7.3)
--------------------------USE IN SPECIFIC POPULATIONS--------------------
• Lactation: Advise not to breastfeed. (8.2)
• Renal Impairment: Reduce the dosage for patients with mild to
severe renal impairment. (2.5, 8.6)
• Hepatic Impairment: Reduce the dosage for patients with moderate
hepatic impairment. (2.6, 8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 1/2025
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: HEPATOTOXICITY
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Dosage Modifications for Adverse Reactions
2.3 Concomitant Use of Moderate or Strong CYP3A Inhibitors or
UGT Inhibitors
2.4 Concomitant Use of Acid-Reducing Agents
2.5 Dosage Modification for Renal Impairment
2.6 Dosage Modification for Hepatic Impairment
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
5.2 TURALIO REMS Program
5.3 Embryo-Fetal Toxicity
5.4 Potential Risks Associated with a High-Fat Meal
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Use with Hepatotoxic Products
7.2 Effect of Other Drugs or Food on TURALIO
7.3 Effect of TURALIO on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Tenosynovial Giant Cell Tumor
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
Reference ID: 5506007
* Sections or subsections omitted from the full prescribing information
are not listed.
2
Reference ID: 5506007
FULL PRESCRIBING INFORMATION
WARNING: HEPATOTOXICITY
• TURALIO can cause serious and potentially fatal liver injury, including
vanishing bile duct syndrome [see Warnings and Precautions (5.1)].
• Monitor liver tests prior to initiation of TURALIO and at specified intervals
during treatment. Withhold and dose reduce or permanently discontinue
TURALIO based on severity of hepatotoxicity. Monitoring and prompt
cessation of TURALIO may not eliminate the risk of serious and potentially
fatal liver injury [see Dosage and Administration (2.2), Warnings and
Precautions (5.1)].
• TURALIO is available only through a restricted program called the TURALIO
Risk Evaluation and Mitigation Strategy (REMS) Program [see Warnings and
Precautions (5.2)].
1 INDICATIONS AND USAGE
TURALIO is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell
tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to
improvement with surgery.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of TURALIO is 250 mg taken orally twice daily with a low-fat meal
(approximately 11 to 14 grams of total fat) until disease progression or unacceptable toxicity [see
Clinical Pharmacology (12.3)]. Taking TURALIO with a high-fat meal (approximately 55 to 65 grams
of total fat) increases pexidartinib concentrations and may increase the risk of adverse reactions,
including hepatotoxicity [see Warnings and Precautions (5.1, 5.4), Drug Interactions (7.2), Clinical
Pharmacology (12.2, 12.3)].
Swallow TURALIO capsules whole. Do not open, break, or chew the capsules.
If a patient vomits or misses a dose of TURALIO, instruct the patient to take the next dose at its
scheduled time.
2.2 Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions are provided in Table 1.
Table 1: Recommended Dose Reductions for TURALIO for Adverse Reactions
Dose Reduction
Total Daily Dose
Administration of Total Daily Dose with Low-Fat
Meal
First
375 mg
125 mg in the morning and 250 mg in the evening
Second
250 mg
125 mg twice daily
Permanently discontinue TURALIO in patients who are unable to tolerate 125 mg orally twice daily.
The recommended dosage modifications for adverse reactions are summarized in Table 2.
Table 2: Recommended Dosage Modifications for TURALIO for Adverse Reactions
3
Reference ID: 5506007
Adverse
Reaction
Severity
TURALIO Dosage Modifications
Hepatotoxicity [see Warnings and Precautions (5.1)]
Increased ALT
and/or AST
Greater than 3 to 5 times
ULN
•
Withhold and monitor liver tests weekly.
•
If AST and ALT are less than or equal to 3 times ULN
within 4 weeks, resume at reduced dose.
•
If AST or ALT is not less than or equal to 3 times
ULN in 4 weeks, permanently discontinue TURALIO.
Greater than 5 to 10
times ULN
•
Withhold and monitor liver tests twice weekly.
•
If AST and ALT are less than or equal to 3 times ULN
within 4 weeks, resume at reduced dose.
•
If AST or ALT is not less than or equal to 3 times
ULN in 4 weeks, permanently discontinue TURALIO.
Greater than 10 times
ULN
•
Permanently discontinue TURALIO.
•
Monitor liver tests twice weekly until AST or ALT is
less than or equal to 5 times ULN, then weekly until
less than or equal to 3 times ULN.
Increased ALPa
ALP greater than 2 times
•
Permanently discontinue TURALIO. Monitor liver
and GGT
ULN with GGT greater
than 2 times ULN
tests twice weekly until ALP is less than or equal to 5
times ULN, then weekly until less than or equal to 2
times ULN.
Increased
bilirubin
TB greater than ULN to
less than 2 times ULN
or
DB greater than ULN
and less than 1.5 times
ULN
•
Withhold and monitor liver tests twice weekly.
•
If an alternate cause for increased bilirubin is
confirmed and bilirubin is less than ULN within 4
weeks, resume at reduced dose.
•
If bilirubin is not less than ULN in 4 weeks,
permanently discontinue TURALIO.
TB greater or equal to 2
times ULN
or
DB greater than 1.5
times ULN
•
Permanently discontinue TURALIO.
•
Monitor liver tests twice weekly until bilirubin is less
than or equal to ULN.
Adverse Reactions or Other Laboratory Abnormalities [see Adverse Reactions (6.1)]
Any
Severe or intolerable
•
Withhold until improvement or resolution.
•
Resume at a reduced dose upon improvement or
resolution.
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; DB =
direct bilirubin; GGT = gamma-glutamyl transferase; TB = total bilirubin; ULN = upper limit of normal
a Confirm ALP elevations as liver isozyme fraction.
2.3 Concomitant Use of Moderate or Strong CYP3A Inhibitors or UGT Inhibitors
Avoid concomitant use of TURALIO with moderate or strong CYP3A inhibitors or UGT inhibitors
during treatment with TURALIO. If concomitant use with a moderate or strong CYP3A inhibitor or
UGT inhibitor cannot be avoided, reduce the TURALIO dose according to the recommendations in
Table 3.
If concomitant use of a moderate or strong CYP3A inhibitor or UGT inhibitor is discontinued, increase
the TURALIO dose (after 3 plasma half-lives of the moderate or strong CYP3A inhibitor or UGT
inhibitor) to the dose that was used before starting the inhibitor [see Clinical Pharmacology (12.3)].
4
Reference ID: 5506007
Table 3: Recommended Dosage Reductions for TURALIO for Concomitant Use of Moderate or
Strong CYP3A Inhibitors or UGT Inhibitors
Total Daily Dose*
Modified Total Daily Dose for
Concomitant Use with
Dosing Schedule for
Modified Total Daily Dose for
Moderate or Strong CYP3A
Use with Moderate or Strong
Inhibitors or UGT Inhibitors
CYP3A Inhibitors or UGT
Inhibitors
Administer with Low-Fat Meal
500 mg
250 mg
125 mg twice daily
375 mg
250 mg
125 mg twice daily
250 mg
125 mg
125 mg once daily
* The Total Daily Dose represents the recommended dose (row one) and the recommended dose after modifications due
to adverse reactions, renal impairment, or moderate hepatic impairment (rows two and three) [see Dosage and
Administration (2.2, 2.5, 2.6)].
2.4 Concomitant Use of Acid-Reducing Agents
Avoid the concomitant use of proton pump inhibitors (PPI) while taking TURALIO. As an alternative to
a PPI, administer TURALIO 2 hours before or 2 hours after taking a locally-acting antacid, or if using
a histamine 2 (H2)-receptor antagonist, administer TURALIO at least 2 hours before or 10 hours after
taking an H2-receptor antagonist [see Clinical Pharmacology (12.3)].
2.5 Dosage Modification for Renal Impairment
The recommended dosage of TURALIO for patients with mild to severe renal impairment (creatinine
clearance [CLcr] 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight) is 125 mg
in the morning and 250 mg in the evening with a low-fat meal [see Clinical Pharmacology (12.3)].
2.6 Dosage Modification for Hepatic Impairment
The recommended dosage of TURALIO for patients with moderate hepatic impairment (total bilirubin
>1.5 to 3 × upper limit of normal (ULN), not due to Gilbert’s syndrome, with any AST) is 125 mg twice
daily with a low-fat meal [see Clinical Pharmacology (12.3)]. TURALIO has not been studied in
patients with severe hepatic impairment (total bilirubin >3 to 10 × ULN and any AST).
3 DOSAGE FORMS AND STRENGTHS
Capsules: 125 mg, size 1 with white opaque body and powder blue opaque cap with black print
“DSC521”
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
TURALIO can cause serious and potentially fatal liver injury and is available only through a restricted
program under a Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions
(5.2)].
Hepatotoxicity, including liver failure and life-threatening vanishing bile duct syndrome (VBDS),
ductopenia, and symptomatic cholestasis (including severe pruritis) can occur in patients treated with
TURALIO and can occur despite monitoring and prompt drug cessation. The mechanism of
5
Reference ID: 5506007
cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether
liver injury can also occur in the absence of increased transaminases.
Of the first 609 patients who received TURALIO under the REMS program, 32 (5.3%) developed a
liver injury event of concern (LIEC), defined as any serious liver-related outcome or any liver
abnormality that triggers drug discontinuation per the US Prescribing Information [see Dosage and
Administration (2.2)]. These 32 patients developed liver toxicity within 71 days of the first dose of
TURALIO; ten required hospitalization, and two developed VBDS. Sixteen of the 32 patients had not
fully recovered at the time of the analysis, including 6 patients followed for at least 6 months after
discontinuation.
Among 768 patients who received TURALIO in clinical trials, there were two irreversible cases of
cholestatic liver injury. One patient with advanced cancer and ongoing liver toxicity died and one
patient with a confirmed case of VBDS required a liver transplant.
In ENLIVEN, 3 of 61 (5%) patients who received TURALIO developed signs of serious liver injury,
defined as ALT or AST ≥3 × ULN with total bilirubin ≥2 × ULN. In these patients, peak ALT ranged
from 6 to 9 × ULN, peak total bilirubin ranged from 2.5 to 15 × ULN, and alkaline phosphatase (ALP)
was ≥2 × ULN. ALT, AST, and total bilirubin improved to <2 × ULN in these three patients 1 to 7
months after discontinuing TURALIO.
Avoid TURALIO in patients with pre-existing increased serum transaminases; total bilirubin or direct
bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP. Monitor liver tests,
including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT) prior
to initiation of TURALIO, weekly for the first 8 weeks, every 2 weeks for the next month and every 3
months thereafter. Withhold and dose reduce, or permanently discontinue TURALIO based on the
severity of the hepatotoxicity [see Dosage and Administration (2.2)]. Refer patients to a hepatologist if
liver tests do not return to normal. Rechallenge with a reduced dose of TURALIO may result in a
recurrence of increased serum transaminases, bilirubin, ALP, or other signs of liver injury. Monitor
liver tests weekly for the first month after rechallenge.
5.2 TURALIO REMS Program
TURALIO is only available through a restricted program under a REMS, because of the risk of
hepatotoxicity [see Warnings and Precautions (5.1)].
Notable requirements of the TURALIO REMS Program include the following:
• Prescribers must be certified with the program by enrolling and completing training.
• Patients must complete and sign an enrollment form for inclusion in a patient registry.
• Pharmacies must be certified with the program and must only dispense to patients who are
authorized to receive TURALIO.
Further information is available at www.TURALIOREMS.com or 1-833-887-2546.
5.3 Embryo-Fetal Toxicity
Based on animal studies and its mechanism of action, TURALIO may cause fetal harm when
administered to a pregnant woman. Oral administration of pexidartinib to pregnant rats and rabbits
during the period of organogenesis resulted in malformations, increased post-implantation loss, and
abortion at exposures approximately equal to the human exposure at the recommended dose based
on area under the curve (AUC).
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to
use effective non-hormonal contraception, since TURALIO can render hormonal contraceptives
ineffective, during treatment with TURALIO and for 1 month after the final dose. Advise males with
female partners of reproductive potential to use effective contraception during treatment with
6
Reference ID: 5506007
TURALIO and for 1 week after the final dose [see Drug Interactions (7.3), Use in Specific Populations
(8.1, 8.3)].
5.4 Potential Risks Associated with a High-Fat Meal
Taking TURALIO with a high-fat meal increases pexidartinib concentrations, which may increase the
incidence and severity of adverse reactions, including hepatotoxicity [see Clinical Pharmacology
(12.2, 12.3)].
Instruct patients to take TURALIO with a low-fat meal (approximately 11 to 14 grams of total fat) and
to avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat). Consider
referring patients to a dietician as deemed necessary [see Dosage and Administration (2.1),
Warnings and Precautions (5.1), Drug Interactions (7.2)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Hepatotoxicity [see Warnings and Precautions (5.1)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The safety of TURALIO 250 mg orally twice daily administered with a low-fat meal has been
established based on adequate and well-controlled studies of TURALIO 400 mg orally twice daily
administered on an empty stomach and additional pharmacokinetic data that indicate there is no
clinically significant difference in the relative exposure between the two dosages [see Clinical
Pharmacology (12.3)].
The safety of TURALIO was evaluated in ENLIVEN [see Clinical Studies (14.1)]. ENLIVEN excluded
patients with ALT, AST, or total bilirubin >1.5 × ULN; and known active or chronic infection with
hepatitis B or C virus, or human immunodeficiency virus. Patients received TURALIO without food at
a dose of 400 mg in the morning and 600 mg in the evening orally for 2 weeks followed by 400 mg
orally twice daily until disease progression or unacceptable toxicity. Seventy-nine percent of patients
received TURALIO for 6 months or longer and 66% for greater than one year.
The median age of TURALIO-treated patients was 44 years (range: 22-75), 57% were females, and
85% were White.
Serious adverse reactions were reported in 13% of patients who received TURALIO. Most frequent
(occurring in >1 patient) serious adverse reactions included abnormal liver tests (3.3%) and
hepatotoxicity (3.3%).
Permanent discontinuation due to an adverse reaction occurred in 13% of patients who received
TURALIO. Most frequent adverse reactions (occurring in >1 patient) requiring permanent
discontinuation included increased ALT (4.9%), increased AST (4.9%) and hepatotoxicity (3.3%).
Dose reductions or interruptions occurred in 38% of patients who received TURALIO. Most frequent
adverse reactions (occurring in >1 patient) requiring a dosage reduction or interruption were
increased ALT (13%), increased AST (13%), nausea (8%), increased ALP (7%), vomiting (4.9%),
increased bilirubin (3.3%), increased GGT (3.3%), dizziness (3.3%), and abdominal pain (3.3%).
The most common (>20%) adverse reactions, including laboratory abnormalities, in patients who
received TURALIO were: increased lactate dehydrogenase (LDH), increased AST, hair color
changes, fatigue, increased ALT, decreased neutrophils, increased cholesterol, increased ALP,
7
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decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased
phosphate.
Tables 4, 5, and 6 summarize the adverse reactions and laboratory abnormalities in ENLIVEN during
the randomized phase (Week 25).
Table 4: Adverse Reactions (≥10% All Grades or >2% Grade ≥ 3) in Patients Receiving
TURALIO with a Difference Between Arms of >5% Compared to Placebo Through Week 25 in
ENLIVEN
TURALIO
N=61
Placebo
N=59
Adverse Reaction
All Grades
(%)
Grade ≥ 3
(%)
All Grades
(%)
Grade ≥ 3
(%)
Skin and subcutaneous tissue
Hair color changes
67
0
3.4
0
Rasha
28
1.6
7
0
Pruritusb
18
0
3.4
0
General
Fatiguec
64
0
41
0
Peripheral edemad
20
0
7
0
Eye
Eye edemae
30
1.6
5
0
Nervous system
Dysgeusiaf
26
0
1.7
0
Neuropathyg
10
0
5
0
Gastrointestinal
Vomiting
20
1.6
5
0
Constipation
12
0
5
0
Metabolism and nutrition
Decreased appetite
16
0
10
0
Vascular
Hypertension
15
4.9
10
0
a Rash includes rash, maculo-papular rash, rash pruritic, urticaria, erythema, dermatitis acneiform,
dermatitis allergic.
b Pruritis includes pruritus, pruritus generalized.
c Fatigue includes fatigue, asthenia, malaise.
d Peripheral edema includes face edema, localized edema, edema peripheral, peripheral swelling.
e Eye edema includes periorbital edema, eye edema, eyelid edema, papilledema.
f Dysgeusia includes dysgeusia, ageusia.
g Neuropathy includes neuropathy peripheral, paresthesia, hypoesthesia, burning sensation.
Table 5: Hepatic Laboratory Abnormalities (≥10% All Grades or >2% Grade ≥ 3) Worsening from
Baseline in Patients Receiving TURALIO with a Difference Between Arms of >5% Compared to
Placebo Through Week 25 in ENLIVEN
TURALIOa
Placeboa
Laboratory
Abnormalityb
Grade 1
(%)
Grade 2
(%)
Grade ≥ 3
(%)
Grade 1
(%)
Grade 2
(%)
Grade ≥ 3
(%)
Liver Tests
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TURALIOa
Placeboa
Increased AST
61
15
12
15
0
0
Increased ALT
31
13
20
22
0
0
Increased ALP
31
3.3
4.9
1.7
0
0
Increased bilirubin
3.3
3.3
3.3
0
0
0
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase
a Each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement
TURALIO (n=61) and placebo (n=59).
b Graded per NCI CTCAE v 4.03
Table 6: Other Laboratory Abnormalities Worsening from Baseline (≥10% All Grades or >2% of
Grade ≥ 3) in Patients Receiving TURALIO with a Difference Between Arms of >5% Compared to
Placebo Through Week 25 in ENLIVEN
TURALIOa
Placeboa
Laboratory Abnormalityb
All Grades
(%)
Grade ≥3
(%)
All Grades
(%)
Grade ≥3
(%)
Chemistry
Increased LDHc
92
0
5
0
Increased cholesterol
44
4.9
25
0
Decreased phosphate
25
3.3
5
0
Hematology
Decreased neutrophils
44
3.3
9
0
Decreased lymphocytes
38
1.6
3.4
0
Decreased hemoglobin
30
0
14
1.7
Decreased platelets
15
0
5
0
LDH=Lactate Dehydrogenase
a Each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement
TURALIO (n = 61) and placebo (n = 58-59).
b Graded per NCI CTCAE v 4.03 except for LDH
c LDH: Grade 1 >ULN to ≤2.5 x ULN; Grade 2 >2.5 to ≤5 x ULN; Grade 3 >5 to ≤20 x ULN; Grade 4 >20 x ULN
Clinically relevant adverse reactions occurring in <10% of patients were:
Eye: blurred vision, photophobia, diplopia, reduced visual acuity
Gastrointestinal: dry mouth, stomatitis, mouth ulceration
General: pyrexia
Hepatobiliary: cholangitis, hepatotoxicity, liver disorder
Neurological: cognitive disorders (memory impairment, amnesia, confusional state, disturbance in
attention, attention deficit/hyperactivity disorder)
Skin and subcutaneous tissue: alopecia, skin pigment changes (hypopigmentation, depigmentation,
discoloration, hyperpigmentation), photosensitivity reactions.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of TURALIO. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
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Investigations: Blood creatine phosphokinase increased
7 DRUG INTERACTIONS
7.1 Use with Hepatotoxic Products
TURALIO can cause hepatotoxicity. In patients with increased serum transaminases, total bilirubin, or
direct bilirubin (>ULN) or active liver or biliary tract disease, avoid coadministration of TURALIO with
other products known to cause hepatotoxicity [see Warnings and Precautions (5.1)].
7.2 Effect of Other Drugs or Food on TURALIO
Table 7: Effect of Other Drugs or Food on TURALIO
Moderate or Strong CYP3A Inhibitors
Clinical Impact
•
Concomitant use of a moderate or strong CYP3A inhibitor may increase
pexidartinib concentrations [see Clinical Pharmacology (12.3)], which may
increase the incidence and severity of adverse reactions of TURALIO.
Management
•
Reduce TURALIO dosage if concomitant use of moderate or strong
CYP3A inhibitors, including grapefruit or grapefruit juice, cannot be
avoided [see Dosage and Administration (2.3)].
Strong CYP3A Inducers
Clinical Impact
•
Concomitant use of a strong CYP3A inducer decreases pexidartinib
concentrations [see Clinical Pharmacology (12.3)], which may decrease
the efficacy of TURALIO.
Management
•
Avoid concomitant use of strong CYP3A inducers, including St John’s
wort.
UGT Inhibitors
Clinical Impact
•
Concomitant use of a UGT inhibitor increases pexidartinib concentrations
[see Clinical Pharmacology (12.3)], which may increase the incidence
and severity of adverse reactions of TURALIO.
Management
•
Reduce TURALIO dosage if concomitant use of UGT inhibitors cannot be
avoided [see Dosage and Administration (2.3)].
Acid-Reducing Agents
Clinical Impact
•
Concomitant use of a PPI decreases pexidartinib concentrations [see
Clinical Pharmacology (12.3)], which may decrease the efficacy of
TURALIO.
Management
•
Avoid concomitant use of PPIs with TURALIO. As an alternative to PPIs,
use locally-acting antacids or H2-receptor antagonists [see Dosage and
Administration (2.4)].
High-Fat Meal
Clinical Impact
•
Taking TURALIO with a high-fat meal increased pexidartinib
concentrations [see Clinical Pharmacology (12.3)], which may increase
the incidence and severity of TURALIO adverse reactions, including
hepatotoxicity [see Warnings and Precautions (5.1, 5.4)].
Management
•
Take TURALIO with a low-fat meal (approximately 11 to 14 grams of total
fat). Avoid taking TURALIO with a high-fat meal (approximately 55 to 65
grams of total fat) [see Dosage and Administration (2.1)].
7.3 Effect of TURALIO on Other Drugs
Reference ID: 5506007
10
Table 8: Effect of TURALIO on Other Drugs
CYP3A Substrates
Clinical Impact
•
TURALIO is a moderate CYP3A inducer. Concomitant use of TURALIO
decreases the concentration of CYP3A substrates [see Clinical
Pharmacology (12.3)], which may reduce the efficacy of these substrates.
Management
•
Avoid coadministration of TURALIO with hormonal contraceptives [see
Warnings and Precautions (5.3), Use in Specific Populations (8.3)].
•
Avoid concomitant use of TURALIO with other CYP3A substrates, where
minimal concentration changes may lead to serious therapeutic failures. If
concomitant use is unavoidable, increase the CYP3A substrate dosage in
accordance with approved product labeling.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology
(12.1)], TURALIO may cause embryo-fetal harm when administered to a pregnant woman. The
available human data do not establish the presence or absence of major birth defects or miscarriage
related to the use of TURALIO. Oral administration of pexidartinib to pregnant animals during the
period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal
exposures that were approximately equal to the human exposure at the recommended dose (see
Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage
in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
Embryo-fetal development studies investigating the administration of pexidartinib during the period of
organogenesis were conducted in rats and rabbits. In rats, pexidartinib resulted in increased post-
implantation loss and fetal malformations including localized fetal edema, absence of kidney and
ureter, abnormalities of the reproductive tract, and developmental variations including misshapen
kidney, decreased skeletal ossification and higher mean litter proportions of slightly or moderately
malaligned sternebrae at doses of 40 mg/kg (approximately equal to the human exposure at the
recommended dose). In rabbits, administration of pexidartinib resulted in increased post-implantation
loss, abortion, and fetal malformations including absence of kidney or ureter, rudimentary, misshapen
or malpositioned kidney, rib abnormalities, and skeletal variations of accessory skull bones at doses
of 60 mg/kg (approximately equal to the human exposure at the recommended dose).
8.2 Lactation
Risk Summary
There are no data on the presence of pexidartinib or its metabolites in either human or animal milk or
its effects on a breastfed child or on milk production. Because of the potential for serious adverse
reactions in the breastfed child, advise women not to breastfeed during treatment with TURALIO and
for at least 1 week after the final dose.
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8.3 Females and Males of Reproductive Potential
TURALIO may cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to the initiation of TURALIO [see
Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective non-hormonal contraception during
treatment with TURALIO and for 1 month after the final dose. Counsel patients to use non-hormonal
method(s) of contraception, since TURALIO can render hormonal contraceptives ineffective [see
Drug Interactions (7.3), Nonclinical Toxicology (13.1)].
Males
Advise male patients with female partners of reproductive potential to use effective contraception
during treatment with TURALIO and for 1 week after the final dose [see Nonclinical Toxicology
(13.1)].
Infertility
Based on findings from animal studies, TURALIO may impair both male and female fertility [see
Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of TURALIO in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of TURALIO did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects.
8.6 Renal Impairment
Reduce the dosage when administering TURALIO to patients with mild to severe renal impairment
(CLcr 15 to 89 mL/min, estimated by Cockcroft-Gault [C-G]) [see Dosage and Administration (2.5),
Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤
upper limit of normal [ULN] with AST > ULN or total bilirubin >1 to 1.5 × ULN with any AST) [see
Clinical Pharmacology (12.3)].
Reduce the dosage of TURALIO for patients with moderate hepatic impairment (total bilirubin >1.5 to
3 × ULN, not due to Gilbert’s syndrome, with any AST) [see Dosage and Administration (2.6), Clinical
Pharmacology (12.3)].
TURALIO has not been studied in patients with severe hepatic impairment (total bilirubin >3 to 10 ×
ULN and any AST).
10 OVERDOSAGE
Due to the high plasma protein binding, TURALIO is not expected to be dialyzable [see Clinical
Pharmacology (12.3)].
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.. HCI
Cl
11 DESCRIPTION
Pexidartinib is a kinase inhibitor. The chemical name of pexidartinib hydrochloride is 5-[(5-Chloro-1H
pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine
monohydrochloride. Pexidartinib hydrochloride is an off-white to white solid. The molecular formula
for pexidartinib hydrochloride is C20H15ClF3N5•HCl. The molecular weight is 454.28 for the
hydrochloride salt and 417.81 for the free base. The chemical structure is:
The solubility of pexidartinib hydrochloride in aqueous solutions decreases with increasing pH. The
pKa1 and pKa2 were determined to be 2.6 and 5.4 respectively for the conjugate acids. Pexidartinib
hydrochloride is soluble in methanol, slightly soluble in water and ethanol, and practically insoluble in
heptane.
TURALIO (pexidartinib) capsules are for oral use. Each capsule contains 125 mg pexidartinib which
is equivalent to 135.9 mg pexidartinib hydrochloride. The capsule contains the following inactive
ingredients: poloxamer 407, mannitol, crospovidone, and magnesium stearate. The hypromellose
capsule shell contains hypromellose, titanium dioxide and FD&C Blue No. 1.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Pexidartinib is a small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1
receptor (CSF1R), KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3
(FLT3) harboring an internal tandem duplication (ITD) mutation. Overexpression of the CSF1R ligand
promotes cell proliferation and accumulation in the synovium. In vitro, pexidartinib inhibited
proliferation of cell lines dependent on CSF1R and ligand-induced autophosphorylation of CSF1R.
Pexidartinib also inhibited the proliferation of a CSF1R dependent cell line in vivo.
12.2 Pharmacodynamics
Exposure-Response Relationships
There is an exposure response relationship between pexidartinib steady state exposure and serum
transaminase levels (ALT and AST) with a higher risk of increased serum transaminases at higher
exposure. Additionally, increased transaminases occurred more frequently with higher pexidartinib
doses between 200 to 1200 mg per day administered on an empty stomach (0.25 to 1.5 times the
exposure from the recommended dose).
Cardiac Electrophysiology
At two times the mean maximum exposure of the recommended dosage, TURALIO does not prolong
the QTc interval to any clinically relevant extent.
12.3 Pharmacokinetics
The pharmacokinetics of TURALIO was evaluated following single doses in healthy subjects and
following multiple doses in patients as summarized in Table 9.
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Table 9: TURALIO Exposure and Pharmacokinetic Parameters
General Information
Steady state exposure [Mean (SD)]a
Cmax
8625 (2746) ng/mL
AUC0-12h
77465 (24975) ng•h/mL
Dose proportionality
Pexidartinib exposure (Cmax and AUC0-INF) increased linearly
over the single oral dose range of 200 to 2400 mg
administered on an empty stomach (0.5 to 6 times the
exposure from the recommended dose).
Time to steady stateb
Approximately 7 days
Accumulation ratio (AUC) [Median]b
3.6
Absorption
Tmax [Median]a
2.5 hours
Effect of food
TURALIO 400 mg with a high-
fat mealc
Compared to an empty stomach:
•
Increased pexidartinib Cmax and AUC0-INF by 100%
•
Delayed Tmax by 2.5 hours
TURALIO 400 mg with a low-fat
meald
Compared to an empty stomach:
•
Increased pexidartinib Cmax by 56% and AUC0-INF by 59%
•
Delayed Tmax by 1.5 hours
Predicted relative AUC0-24h of
TURALIO 250 mg with a low-fat
meal to that of TURALIO
400 mg on an empty stomach
•
No clinically significant difference
Distribution
In vitro plasma protein binding
•
Greater than 99%
•
Human serum albumin: 99.9%
•
α-1 acid glycoprotein: 89.9%
Apparent volume of distribution
(Vz/F) [Mean (CV%)]e
•
187 L (27%)
Elimination
Apparent clearance [Mean (CV%)]e
•
5.1 L/h (36%)
t1/2 [Mean (SD)]
•
26.6 (6.5) hours
Metabolism
Primary pathway
• Oxidation: CYP3A4
• Glucuronidation: UGT1A4
N-glucuronide metabolite
• Major inactive metabolite formed by UGT1A4
• Approximately 10% higher exposure than pexidartinib after a
single dose
Excretionf
• Feces: 65% (44% as unchanged)
• Urine: 27% as metabolites (≥10% as N-glucuronide)
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a Pexidartinib 400 mg twice daily on an empty stomach (similar exposure to that of the recommended
dosage)
b Estimated based on half life
c The high-fat meal comprised 800 to 1000 calories with approximately 50% from fat (approximately 55
to 65 grams of total fat).
d The low-fat meal comprised approximately 400 calories with 25% from fat (approximately 11 to
14 grams of total fat).
e After a single oral dose of pexidartinib
f After a single oral dose of radiolabeled pexidartinib
Specific Populations
No clinically meaningful differences in the pharmacokinetics of pexidartinib were observed based on
age (18 to 84 years), sex, race (White and Black), or mild hepatic impairment (total bilirubin ≤ ULN
with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST).
Patients with Renal Impairment
Mild (CLcr 60 to 89 mL/min), moderate (CLcr 30 to 59 mL/min) and severe (CLcr 15 to 29 mL/min)
renal impairment increased pexidartinib exposure (AUC) by approximately 30%, relative to that in
patients with normal renal function (CLcr ≥90 mL/min).
Patients with Hepatic Impairment
Moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN, not due to Gilbert’s syndrome, with any
AST) increased pexidartinib exposure (AUC) by 43% relative to exposure in patients with normal
hepatic function (total bilirubin and AST ≤ ULN).
The pharmacokinetics of pexidartinib have not been studied in patients with severe hepatic
impairment (total bilirubin > 3 to 10 × ULN with any AST).
Drug Interaction Studies
Clinical Studies
Effects of Other Drugs on Pexidartinib
Strong or Moderate CYP3A Inducers: Coadministration of rifampicin (strong CYP3A inducer)
decreased pexidartinib Cmax by 33% and AUC0-INF by 65%. Coadministration of efavirenz (moderate
CYP3A inducer) is predicted to have no clinically significant differences in pexidartinib
pharmacokinetics.
Strong or Moderate CYP3A Inhibitors: Coadministration of itraconazole (strong CYP3A inhibitor)
increased pexidartinib Cmax by 48% and AUC0-INF by 70%. Coadministration of fluconazole (moderate
CYP3A inhibitor) is predicted to increase pexidartinib Cmax by 41% and AUC by 67% at steady state.
UGT Inhibitors: Coadministration of probenecid (UGT inhibitor) increased pexidartinib AUC0-INF by
60% with no effect on Cmax.
Acid-Reducing Agents: Coadministration of esomeprazole (proton pump inhibitor) decreased
pexidartinib Cmax by 55% and AUC0-INF by 50%. The effects of H2-receptor antagonists and locally-
acting antacids on pexidartinib pharmacokinetics have not been studied.
Effects of Pexidartinib on Other Drugs
CYP3A Substrates: Coadministration of TURALIO at the approved recommended dosage decreased
midazolam (CYP3A substrate) Cmax by 28% and AUC0-INF by 59%.
Other Drugs: When coadministered with omeprazole (CYP2C19 substrate), tolbutamide (CYP2C9
substrate), digoxin (P-gp substrate), or CYP2C8 substrate with TURALIO, no clinically significant
differences in their pharmacokinetics were observed or predicted.
15
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In Vitro Studies
CYP/UGT Enzymes: Pexidartinib inhibited and induced CYP2B6 at clinically relevant concentrations.
Pexidartinib inhibited UGT1A1 at clinically relevant concentrations.
Transporters: Pexidartinib is not a substrate for P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1,
OATP1B3, OATP2B1, and BSEP.
Pexidartinib is an inhibitor of MATE1, MATE2-K, OATP1B1, OATP1B3 and OATP2B1.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were performed in mice and rats. Both studies were negative for carcinogenic
findings at exposures up to 9 times the human exposure at the recommended daily dose based on
AUC.
Pexidartinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic
in either an in vitro human peripheral blood lymphocyte chromosomal aberrations assay or in an in
vivo mouse bone marrow micronucleus assay.
Based on nonclinical findings, TURALIO may impair male and female fertility. In a fertility study in
which pexidartinib was administered orally to male and female rats, there were reductions in
pregnancy, as well as increases in pre- and post-implantation loss with a corresponding reduction in
viable embryos at 40 mg/kg (approximately 1.3 times the human exposure at the recommended
dose). Males at this dose level displayed reductions in spermatogenic parameters and adverse
effects on sperm concentration, production, motility, and morphology. Lower testicular and epididymal
weights occurred in this study at doses of ≥10 mg/kg/day (approximately 0.3 times the human
exposure at the recommended dose). This is consistent with findings in chronic toxicology studies of
germ cell depletion of the testes and hypospermia and cellular debris in the epididymis in male
reproductive tissues of both rats and dogs at respective doses as low as 20 and 30 mg/kg/day
(approximately 0.6 and 0.1 times the human exposure at the recommended dose). In rats, these
changes persisted following a 16-week recovery period at the 60 mg/kg/day dose level
(approximately 1.5 times the human exposure at the recommended dose).
In female rats, necrosis of corpora lutea occurred at doses ≥0.5 mg/kg/day (approximately 0.01 times
the human exposure at the recommended dose) with pigment deposition within the interstitium of the
ovaries, an increased incidence of luteal cysts and incidence/severity of hemorrhage of corpora lutea,
and a decreased incidence of retained antral follicles and decreased corpora lutea at 60 mg/kg
(approximately 1.8 times the human exposure at the recommended dose). In female dogs there were
decreased follicle numbers and moderate atrophy of the oviduct, uterus, and cervix at doses as low
as 1 mg/kg (approximately 0.01 times the human exposure at the recommended dose).
13.2 Animal Toxicology and/or Pharmacology
In repeat dose toxicity studies of up to 26 weeks in rats, there were findings of myxomatous change in
the skin, tongue, and gastrointestinal tract, lymphoid depletion of the bone marrow and thymus, and
chronic progressive nephropathy of the kidney at 20 mg/kg/day (approximately 0.6 times the human
exposure at the recommended dose). Similar changes occurred in the rat carcinogenicity study along
with alterations in the tunica intima of the aorta. Vascular inflammation consistent with polyarteritis
nodosa occurred in male rats at 60 mg/kg/day (approximately 1.5 times the human exposure at the
recommended dose). There were also dose-dependent findings of minimal to moderate subphyseal
or cortical hyperostosis and physeal hypertrophy in the femur that correlated with decreased systemic
phosphate levels at doses ≥ 60 mg/kg.
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14 CLINICAL STUDIES
14.1 Tenosynovial Giant Cell Tumor
The efficacy of TURALIO 250 mg orally twice daily administered with a low-fat meal has been
established based on adequate and well-controlled studies of TURALIO 400 mg orally twice daily
administered on an empty stomach and additional pharmacokinetic data that indicate there is no
clinically significant difference in the relative exposure between the two dosages.
The efficacy of TURALIO was evaluated in ENLIVEN (NCT02371369), a double-blind, randomized
(1:1), placebo-controlled, multicenter trial in patients with symptomatic TGCT [also referred to as giant
cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS)] for whom
surgical removal of the tumor would be associated with worsening functional limitation or severe
morbidity. Eligible patients were required to have measurable disease per the Response Evaluation
Criteria in Solid Tumors (RECIST) v1.1. Patients were randomized to placebo or TURALIO
administered on an empty stomach: 400 mg in the morning and 600 mg in the evening for 2 weeks
followed by 400 mg twice daily until unacceptable toxicity or disease progression. Randomization was
stratified by geographic region (US vs. non-US countries) and disease location (upper extremity vs.
lower extremity involvement). Patients who completed treatment in the double-blind, randomized part
of the trial were eligible to advance to an open-label extension part in which all patients were given
the option to receive pexidartinib.
The major efficacy outcome measure was overall response rate (ORR) as assessed by blinded
independent central review (BICR) at Week 25 using RECIST v1.1. Additional efficacy outcome
measures were mean change from baseline in range of motion of the affected joint at Week 25 and
ORR as assessed by BICR at Week 25 using tumor volume score (TVS). Range of motion was
measured as a percent of normal reference range for the affected joint. Range of motion
assessments were performed by a third-party clinical assessor using a goniometer. TVS was defined
in ENLIVEN as the estimated volume of the maximally distended synovial cavity or tendon sheath
involved, measured in 10% increments. Patients in the placebo arm were offered TURALIO at Week
25 beginning with a 400 mg twice daily dose, as permitted by the study protocol.
A total of 120 patients were randomized, 61 to the TURALIO arm and 59 to the placebo arm. The
median age was 44 years (range: 18-79); 59% were females; 88% were White; 53% had prior
surgery; 88% were diagnosed with diffuse TGCT; and 9% had previously been treated with systemic
therapy. Disease locations were knee (61%), ankle (18%), hip (11%), wrist (3%), foot (3%) and other
(5%).
ENLIVEN demonstrated a statistically significant improvement in ORR in patients randomized to
TURALIO compared with placebo. Efficacy results are summarized in Table 10.
Table 10: Efficacy Results Assessed at Week 25 for ENLIVEN
Efficacy Parameter
TURALIO
N=61
Placebo
N=59
Overall Response Rate (ORR)a,b
ORR
(95% CI)
38%
(27%, 50%)
0
(0, 6%)
Complete Response
15%
0
Partial Response
23%
0
P-valuec
<0.0001
Duration of Response (DOR)b
17
Reference ID: 5506007
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TURALIO (N=45)
Placebo (N=43)
t
t
Improvement
Improvement
-40
Tumor Responset I Responder
□ Non-Responder
Patient
*Percent of normal reference range for the affected joint.
tTumor Response by RECIST v1 .1 .
TURALIO
Placebo
Efficacy Parameter
N=61
N=59
Range (months)
6.9+, 24.9+
NA
CI: confidence interval; NA: not applicable; SD: standard deviation; LS: least
squares; +: denotes ongoing at last assessment
a Blinded independent central review
b Data cut-off date January 31, 2018
c Fisher’s exact test
The analysis of mean change from baseline in range of motion at Week 25 demonstrated a
statistically significant improvement in patients randomized to TURALIO compared to placebo. Figure
1 shows the change from baseline in range of motion for each patient at Week 25 (TURALIO N=45,
placebo N=43). Results were excluded for 1 patient with missing baseline and 31 patients with a
missing range of motion assessment at Week 25.
Figure 1: Change from Baseline in Range of Motion at Week 25 for ENLIVEN
ORR by TVS was 56% (95% CI: 43%, 67%) in patients randomized to the TURALIO arm and 0% in
patients randomized to the placebo arm; p < 0.0001.
At completion of the open-label extension part of the study in which all patients received TURALIO,
the ORR using RECIST v1.1 was 61% (95% CI: 48%, 72%) in the 61 patients originally randomized
to the TURALIO arm. The median duration of response was not reached (range: 4.6+, 63.4+ months)
in the 37 responders.
18
Reference ID: 5506007
16 HOW SUPPLIED/STORAGE AND HANDLING
TURALIO 125 mg capsules are supplied as size 1 with white opaque body and powder blue opaque
cap with black print “DSC521”, available in:
•
28 count bottle
NDC#: 65597-407-28
•
120 count bottle
NDC#: 65597-407-20
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP
Controlled Room Temperature].
Keep containers closed and do not remove desiccant from bottles.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Hepatotoxicity
Advise patients of the risk of hepatotoxicity that could be fatal and that they will need to undergo
monitoring for liver injury. Advise patients to immediately report any signs or symptoms of severe liver
injury to their healthcare provider and that liver testing and prompt cessation of TURALIO may not
eliminate the risk of severe or life-threatening liver injury [see Warnings and Precautions (5.1)].
TURALIO REMS Program
• TURALIO is available only through a restricted program called TURALIO REMS Program and
patients are required to be part of the patient registry [see Warnings and Precautions (5.2)].
• TURALIO is available only from certified pharmacies participating in the program. Therefore,
provide patients with the telephone number and website for information on how to obtain the
product.
Embryo-Fetal Toxicity
• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known or
suspected pregnancy [see Warnings and Precautions (5.3), Use in Specific Populations (8.1,
8.3)].
• Advise females of reproductive potential to use effective non-hormonal contraception during
treatment with TURALIO and for 1 month after the final dose [see Drug Interactions (7.3), Use in
Specific Populations (8.3)].
• Advise male patients with female partners of reproductive potential to use effective contraception
during treatment and for 1 week after the final dose [see Use in Specific Populations (8.3),
Nonclinical Toxicology (13.1)].
Lactation
Advise females not to breastfeed during treatment with TURALIO and for 1 week after the final dose
[see Use in Specific Populations (8.2)].
Infertility
Advise females and males of reproductive potential that TURALIO may impair fertility [see Use in
Specific Populations (8.3), Nonclinical Toxicology (13.1)].
Administration
• Instruct patients to take TURALIO with a low-fat meal (approximately 11 to 14 grams of total fat)
and to avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat).
19
Reference ID: 5506007
Consider referring patients to a dietician as deemed necessary [see Dosage and Administration
(2.1), Warnings and Precautions (5.4), Drug Interactions (7.2)].
• Instruct patients to swallow capsules whole (do not open, break, or chew) [see Dosage and
Administration (2.1)].
Drug Interactions
Advise patients to inform their healthcare providers of all concomitant products, including over-the
counter products and supplements [see Dosage and Administration (2), Drug Interactions (7)].
Photosensitivity
Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun
exposure and to use sunscreen and protective clothing during treatment with TURALIO [see Adverse
Reactions (6.1)].
Manufactured for: Daiichi Sankyo, Inc.
Basking Ridge, NJ 07920
TURALIO® is a registered trademark of Daiichi Sankyo Company, Limited.
©202x, Daiichi Sankyo, Inc.
USPI-TUR125-Cx-xxxx-rxxx
20
Reference ID: 5506007
Medication Guide
TURALIO® (tur-a-lee-oh)
(pexidartinib)
capsules
What is the most important information I should know about TURALIO?
TURALIO can cause serious side effects, including:
Serious liver problems which may be severe and can lead to death, including liver failure and a liver injury
called vanishing bile duct syndrome (VBDS) that can cause the loss of bile ducts in the liver. Severe or life-
threatening liver problems can happen with TURALIO even if your healthcare provider monitors liver blood tests during
treatment and stops treatment with TURALIO.
Your healthcare provider will do blood tests to check for liver problems:
• before starting treatment with TURALIO,
• every week for the first 8 weeks during treatment,
• every 2 weeks for the next month,
• then, every 3 months after that.
If you develop liver problems during treatment with TURALIO, your healthcare provider may do blood tests more often
to monitor you or refer you to a liver specialist (hepatologist). It is important to stay under the care of your healthcare
provider during treatment with TURALIO.
Stop taking TURALIO and call your healthcare provider right away if you develop:
• yellowing of your skin and whites of your eyes
• dark urine
Tell your healthcare provider right away if you have any of these symptoms of liver problems during treatment with
TURALIO:
•
lack or loss of appetite
•
vomiting
• right upper stomach-area (abdomen) pain or
• fever
tenderness
• rash
• feeling overly tired
• itching
• nausea
TURALIO Risk Evaluation and Mitigation Strategy (REMS). Because of the risk of serious liver problems, TURALIO
is available only through a restricted program called the TURALIO REMS Program. Your healthcare provider must be
enrolled in the program in order for you to be prescribed TURALIO. There is a registry that collects information about
the effects of taking TURALIO over time. You must complete and sign an enrollment form for the TURALIO REMS
Program and the registry. Ask your healthcare provider for more information.
See “What are the possible side effects of TURALIO?” for more information about side effects.
What is TURALIO?
TURALIO is a prescription medicine used to treat certain adults who have tenosynovial giant cell tumor (TGCT) that is
not likely to improve with surgery. TGCT is also known as giant cell tumor of the tendon sheath (GCT-TS) or pigmented
villonodular synovitis (PVNS).
It is not known if TURALIO is safe and effective in children.
Before taking TURALIO, tell your healthcare provider about all of your medical conditions, including if you:
• have or had liver problems.
•
have kidney problems.
• are pregnant or plan to become pregnant. TURALIO may harm your unborn baby.
If you are a female who is able to become pregnant:
o
Your healthcare provider will do a pregnancy test before you start treatment with TURALIO.
o
Females who are able to become pregnant should use effective non-hormonal birth control (contraception)
during treatment with TURALIO and for 1 month after your final dose of TURALIO. Birth control pills (oral
contraceptives) and other hormonal forms of birth control may not be effective if used during treatment with
TURALIO. Talk with your healthcare provider about birth control methods you can use during this time.
o
Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with
TURALIO.
If you are a male with a female partner who is able to become pregnant:
o
Use effective birth control (contraception) during treatment and for 1 week after your final dose of TURALIO.
o
Tell your healthcare provider right away if your female partner becomes pregnant or thinks she is pregnant
during your treatment with TURALIO.
• are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with TURALIO and for at least 1 week
after your final dose of TURALIO.
Reference ID: 5506007
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. Certain medicines may affect the way TURALIO works and TURALIO
may affect how other medicines work. Taking TURALIO with certain medicines may increase the amount of
TURALIO in your blood. This may make it more likely for you to develop side effects and may cause more
severe side effects.
• Avoid taking the following medicines or supplements during treatment with TURALIO because they can affect how
TURALIO works:
o
Proton Pump Inhibitor medicines (PPIs)
o
St. John’s wort
How should I take TURALIO?
• Your healthcare provider will explain to you how you will receive your TURALIO.
• Take TURALIO exactly as your healthcare provider tells you to.
• TURALIO is usually taken 2 times a day. Your healthcare provider will tell you how much TURALIO to take and when
to take it.
• Take TURALIO with a low-fat meal (about 11 to 14 grams of total fat). Taking TURALIO with a high-fat meal
increases the amount of TURALIO in your blood. This may make it more likely for you to develop side
effects and may cause more severe side effects, including serious liver problems. See “What are the
possible side effects of TURALIO?”
o Talk with your healthcare provider about examples of foods that you can eat for a low-fat meal that
contains about 11 to 14 grams of total fat.
o Your healthcare provider may refer you to a dietician, if needed.
• Swallow TURALIO capsules whole.
• Do not open, break, or chew TURALIO capsules.
• If you need to take an acid-reducing medicine, follow your healthcare provider’s instructions for which medicine to
take and when to take it.
o If you take an antacid medicine: Take TURALIO either 2 hours before or 2 hours after taking an antacid
medicine.
o If you take an H2 receptor blocker medicine: Take TURALIO at least 2 hours before or 10 hours after taking an
H2 receptor blocker medicine.
• Tell your healthcare provider about all the medicines you take. See the section “Before taking TURALIO, tell
your healthcare provider about all of your medical conditions, including if you:”
• If you vomit after taking a dose, or if you miss a dose of TURALIO, take your next dose at your regular time.
What should I avoid while taking TURALIO?
• Avoid grapefruit or drinking grapefruit juice during treatment with TURALIO. Grapefruit or grapefruit juice can cause
you to have too much TURALIO in your blood and may lead to increased side effects and more severe side effects.
• Avoid spending prolonged time in sunlight. TURALIO can make your skin sensitive to the sun (photosensitivity), and
you may burn more easily. You should use sunscreen and wear protective clothing that covers your skin to help
protect against sunburn if you have to be in the sunlight during treatment with TURALIO.
What are the possible side effects of TURALIO?
TURALIO can cause serious side effects.
• See "What is the most important information I should know about TURALIO?"
• There are possible risks if TURALIO is taken with a high-fat meal. Avoid taking TURALIO with a high-fat meal
(about 55 to 65 grams of total fat). Taking TURALIO with a high-fat meal increases the amount of medicine in your
blood. This may make it more likely for you to develop side effects and may cause more severe side effects,
including serious liver problems. Take TURALIO with a low-fat meal (about 11 to 14 grams of total fat). See
“How should I take TURALIO?”
The most common side effects of TURALIO include:
•
changes in blood liver tests
•
decreased white blood cells and red blood cells
• hair color changes
•
swelling in or around your eyes
•
tiredness
•
rash, itching, hives, skin redness, and acne
•
increased cholesterol level in your blood
•
loss of taste or changes in the way things taste
•
decreased phosphate in your blood
TURALIO may affect fertility in females and males, which may affect your ability to have children. Talk to your
healthcare provider if you have concerns about fertility.
These are not all of the possible side effects of TURALIO.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TURALIO?
Reference ID: 5506007
• Store TURALIO at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the TURALIO container closed tightly.
• TURALIO comes with a drying agent (desiccant) in the container. Keep the desiccant in the container.
Keep TURALIO and all medicines out of the reach of children.
General information about the safe and effective use of TURALIO
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TURALIO
for a condition for which it was not prescribed. Do not give TURALIO to other people, even if they have the same
symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about
TURALIO that is written for health professionals.
What are the ingredients in TURALIO?
Active Ingredient: pexidartinib
Inactive Ingredients: poloxamer 407, mannitol, crospovidone, and magnesium stearate. Capsule shell: hypromellose,
titanium dioxide, and FD&C Blue No. 1
Manufactured for: Daiichi Sankyo, Inc., Basking Ridge, NJ 07920
TURALIO® is a registered trademark of Daiichi Sankyo Company, Limited. ©202x, Daiichi Sankyo, Inc.
USMG-TUR125-Cx-xxxx-r10x
For more information, call 1-877-437-7763 or go to https://www.turalio.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 1/2025
Reference ID: 5506007
| custom-source | 2025-02-12T15:48:24.933783 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211810s013lbl.pdf', 'application_number': 211810, 'submission_type': 'SUPPL ', 'submission_number': 13} |
80,819 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PYRUKYND safely and effectively. See full prescribing information for
PYRUKYND.
PYRUKYND® (mitapivat) tablets, for oral use
Initial U.S. Approval: 2022
----------------------------RECENT MAJOR CHANGES---------------------------
Warnings and Precautions, Hepatocellular Injury in Another Condition (5.2)
01/2025
---------------------------INDICATIONS AND USAGE----------------------------
PYRUKYND is a pyruvate kinase activator indicated for the treatment of
hemolytic anemia in adults with pyruvate kinase (PK) deficiency. (1)
-----------------------DOSAGE AND ADMINISTRATION-----------------------
• Starting dosage: 5 mg orally twice daily with or without food. (2.1)
• See Full Prescribing Information for dose titration and taper schedule. (2.1,
2.3)
• The tablet should be swallowed whole. (2.1)
----------------------DOSAGE FORMS AND STRENGTHS---------------------
Tablets: 5 mg, 20 mg, and 50 mg. (3)
-------------------------------CONTRAINDICATIONS------------------------------
None. (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Acute Hemolysis: Avoid abrupt interruption or abrupt discontinuation of
PYRUKYND to minimize the risk of acute hemolysis. A gradual reduction
in dosing rather than abrupt cessation is recommended when possible. (5.1)
• Hepatocellular Injury in Another Condition: Obtain liver tests prior to the
initiation of PYRUKYND and monthly thereafter for the first 6 months and
as clinically indicated. Interrupt PYRUKYND if clinically significant
increases in liver tests are observed or alanine aminotransferase is >5 times
the upper limit of normal (ULN). Discontinue PYRUKYND if hepatic
injury due to PYRUKYND is suspected. (5.2)
-------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions including laboratory abnormalities
(≥ 10%) in patients with PK deficiency were estrone decreased (males),
increased urate, back pain, estradiol decreased (males), and arthralgia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Agios
Pharmaceuticals at 1-833-228-8474 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS------------------------------
• Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. (7.1)
• Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg
twice daily. (7.1)
• Moderate CYP3A Inducers: Consider alternatives that are not moderate
inducers. If there are no alternatives, adjust PYRUKYND dosage. (7.1)
• Sensitive CYP3A, CYP2B6, CYP2C substrates including hormonal
contraceptives: Avoid concomitant use with substrates that have narrow
therapeutic index. (7.2)
• UGT1A1 Substrates: Avoid concomitant use with substrates that have
narrow therapeutic index. (7.2)
• P-gp Substrates: Avoid concomitant use with substrates that have narrow
therapeutic index. (7.2)
--------------------------USE IN SPECIFIC POPULATIONS---------------------
Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate or
severe hepatic impairment. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 1/2025
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
2.2 Missed Dose
2.3 Interruption or Discontinuation
2.4 Recommended Dosage for Hepatic Impairment
2.5 Recommended Dosage for Drug Interactions
2.6 Dose Modifications for Adverse Reactions and Hemoglobin Levels
Above Normal
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Acute Hemolysis with Abrupt Treatment Interruption
5.2 Hepatocellular Injury in Another Condition
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
7
DRUG INTERACTIONS
7.1 Effect of Other Drugs on PYRUKYND
7.2 Effect of PYRUKYND on Other Drugs
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5505232
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
PYRUKYND is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK)
deficiency.
2
DOSAGE AND ADMINISTRATION
2.1
Recommended Dosage
PYRUKYND is taken with or without food and swallowed whole. Do not split, crush, chew, or
dissolve the tablets.
The starting dosage for PYRUKYND is 5 mg orally twice daily. To gradually increase hemoglobin
(Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum
recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks (see Table
1). Assess Hb and transfusion requirement before increasing to the next dose level, as some patients
may reach and maintain normal Hb at 5 mg twice daily or 20 mg twice daily.
Discontinue PYRUKYND if no benefit has been observed by 24 weeks, based on the hemoglobin and
hemolysis laboratory results and transfusion requirements.
Table 1: Dose Titration Schedule
Duration
Dosage
Week 1 through Week 4
5 mg twice daily
Week 5 through Week 8
If Hb is below normal range or patient has required a transfusion
within the last 8 weeks:
• Increase to 20 mg twice daily and maintain for 4 weeks. If
Hb is within normal range and patient has not required a transfusion
within the last 8 weeks:
• Maintain 5 mg twice daily.
Week 9 through Week 12
If Hb is below normal range or patient has required a transfusion
within the last 8 weeks:
• Increase to 50 mg twice daily and maintain thereafter. If
Hb is within normal range and patient has not required a transfusion
within the last 8 weeks:
• Maintain current dose (5 mg twice daily or 20 mg twice
daily).
Maintenance
If Hb decreases, consider up-titration to the maximum of 50 mg
twice daily as per the above schedule.
2.2
Missed Dose
If a dose of PYRUKYND is missed by 4 hours or less, administer the dose as soon as possible. If a
dose of PYRUKYND is missed by more than 4 hours, do not administer a replacement dose, and wait
until the next scheduled dose. Subsequently, return to the normal dosing schedule.
2.3
Interruption or Discontinuation
To reduce the risk of acute hemolysis, avoid abrupt interruption or abrupt discontinuation of
PYRUKYND when possible [see Warnings and Precautions (5.1)]. Taper the dose to gradually
Reference ID: 5505232
discontinue the medication (see Table 2). Monitor patients for signs of acute hemolysis and worsening
of anemia.
Table 2: Dose Taper Schedule
Current Dose
Dose Taper Schedule
Day 1-7
Day 8-14
Day 15
5 mg twice daily
5 mg once daily
Discontinue
N/A
20 mg twice daily
20 mg once daily
5 mg once daily
Discontinue
50 mg twice daily
50 mg once daily
20 mg once daily
Discontinue
Abbreviations: N/A = not applicable.
2.4
Recommended Dosage for Hepatic Impairment
Avoid use of PYRUKYND in patients with moderate or severe hepatic impairment [see Use in Special
Populations (8.6) and Clinical Pharmacology (12.3)].
2.5
Recommended Dosage for Drug Interactions
Strong CYP3A Inhibitors
Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Drug Interactions (7.1)
and Clinical Pharmacology (12.3)].
Moderate CYP3A Inhibitors
Monitor Hb and for increased risks of adverse reactions from PYRUKYND. When used with a
moderate CYP3A inhibitor, do not titrate PYRUKYND beyond 20 mg twice daily [see Drug
Interactions (7.1) and Clinical Pharmacology (12.3)].
Strong CYP3A Inducers
Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Drug Interactions (7.1)
and Clinical Pharmacology (12.3)].
Moderate CYP3A Inducers
Consider alternative therapies that are not moderate CYP3A inducers during treatment with
PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond the 50 mg twice
daily dose, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see
Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
2.6
Dose Modifications for Adverse Reactions and Hemoglobin Levels Above Normal
If a dose reduction is required because of an adverse reaction or tolerability, or for Hb above normal,
the dose may be reduced to the next lower dose level, 20 mg twice daily or 5 mg twice daily.
If a patient needs to discontinue PYRUKYND, the dose taper schedule (Table 2) should be followed.
In situations where the risk to the patient due to the adverse reaction or Hb above normal is greater
than the risk of acute hemolysis due to sudden withdrawal of the drug, treatment may be stopped
without taper and patients should be monitored for signs of acute hemolysis.
3
DOSAGE FORMS AND STRENGTHS
• 5 mg tablets: round, blue, film-coated tablets with "M5" printed on one side.
• 20 mg tablets: round, blue, film-coated tablets with "M20" printed on one side.
Reference ID: 5505232
• 50 mg tablets: oblong, blue, film-coated tablets with "M50" printed on one side.
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Acute Hemolysis with Abrupt Treatment Interruption
Acute hemolysis with subsequent anemia has been observed following abrupt interruption or
discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND.
Gradually taper the dose of PYRUKYND to discontinue treatment if possible [see Dosage and
Administration (2.3, 2.6)]. When discontinuing treatment, monitor patients for signs of acute
hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or
shortness of breath.
5.2
Hepatocellular Injury in Another Condition
In patients with another condition treated with PYRUKYND at a higher dose than that recommended
for patients with PK deficiency, liver injury has been observed. These events were characterized by a
time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of
>5×ULN with or without jaundice. All patients discontinued treatment with PYRUKYND, and these
events improved upon treatment discontinuation.
Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months
and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are
observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Discontinue
PYRUKYND if hepatic injury due to PYRUKYND is suspected.
6
ADVERSE REACTIONS
The following clinically significant adverse reaction is described elsewhere in labeling:
• Acute Hemolysis with Abrupt Treatment Discontinuation [see Warnings and Precautions
(5.1)].
• Hepatocellular Injury in Another Condition [see Warnings and Precautions (5.2)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
A total of 155 patients received PYRUKYND, 79% of whom were exposed for longer than 24 weeks.
PYRUKYND was administered up to 50 mg orally twice daily in 67 patients with PK deficiency in the
ACTIVATE trial (N=40) and the ACTIVATE-T trial (N=27) [see Clinical Studies (14)].
ACTIVATE Trial
In the ACTIVATE trial patients with PK deficiency who were not regularly transfused received
PYRUKYND in incremental doses up to 50 mg twice daily (N=40) or placebo (N=39).
Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE
Trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, which each
occurred in 1 patient.
In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities
(≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain,
Reference ID: 5505232
estradiol decreased (males), and arthralgia.
Table 3 summarizes the adverse reactions in the ACTIVATE trial.
Table 3: Adverse Reactions (≥ 5%) in Patients Receiving PYRUKYND in ACTIVATE
Adverse Reactions
PYRUKYND
(N=40)
Placebo
(N=39)
All Grades
(%)
Grade ≥3
(%)
All Grades
(%)
Grade ≥3
(%)
Back paina
15%
0
8%
0
Arthralgiab
10%
0
5%
0
Hypertriglyceridemiac
8%
5%
3%
0
Gastroenteritis
8%
3%
0
0
Hot flushd
8%
0
0
0
Oropharyngeal pain
8%
0
5%
0
Hypertension
5%
5%
0
0
Arrhythmiae
5%
0
0
0
Breast discomfort
5%
0
0
0
Constipation
5%
0
0
0
Dry mouthf
5%
0
0
0
Paresthesia
5%
0
0
0
Grades: Per the CTCAE definition.
Grouped Term Definitions
a Includes back pain, sciatica, and flank pain.
b Includes arthralgia and joint swelling.
c Includes hypertriglyceridemia and blood triglycerides increased.
d Includes hot flush and flushing.
e Includes arrhythmia, tachycardia, heart rate increased and atrial fibrillation.
f Includes dry mouth and dry lip.
Laboratory abnormalities of PYRUKYND included increased urate (15%).
Variations in Reproductive Hormones
In ACTIVATE, increases in serum testosterone and decreases in serum estrone and estradiol were
observed in men receiving PYRUKYND (Table 4). These changes in hormones persisted throughout
the study period. In patients who discontinued PYRUKYND and had follow-up hormone
measurements, the hormone changes returned close to the baseline levels 28 days after discontinuing
PYRUKYND. In female patients, sex hormone analysis was limited due to physiologic variations in
hormones during the menstrual cycle and the use of hormonal contraceptives.
Reference ID: 5505232
Table 4: Laboratory Abnormalities in Reproductive Hormones in Men Receiving PYRUKYND
ACTIVATE
Parameter
PYRUKYND
(16 males)
n (%)
Placebo
(15 males) n
(%)
Reproductive hormone analysesa
Estrone decreased (males)
Estradiol decreased (males)
Blood testosterone increased (males)
9 (56.3)
2 (12.5)
1 (6.3)
0
1 (6.7)
1 (6.7)
a Decreases in estrone and estradiol to below the lower limit of the reference range and increases in testosterone to above
the upper limit of the reference range where baseline was within normal limits.
ACTIVATE-T Trial
The adverse reactions reported in the population of patients who were regularly transfused
(ACTIVATE-T) were consistent with that seen in ACTIVATE.
7
DRUG INTERACTIONS
7.1
Effect of Other Drugs on PYRUKYND
Strong CYP3A Inhibitors
Clinical Impact
• Co-administration of PYRUKYND with strong CYP3A
inhibitors increased mitapivat plasma concentrations [see
Clinical Pharmacology (12.3)].
• Increased mitapivat plasma concentrations may increase the risks
of adverse reactions of PYRUKYND.
Prevention or Management
• Avoid co-administration of strong CYP3A inhibitors with
PYRUKYND [see Dosage and Administration (2.5)].
Moderate CYP3A Inhibitors
Clinical Impact
• Co-administration of PYRUKYND with moderate CYP3A
inhibitors will increase mitapivat plasma concentrations [see
Clinical Pharmacology (12.3)].
Prevention or Management
• Monitor Hb and for increased risks of adverse reactions with
PYRUKYND.
• Do not titrate PYRUKYND beyond 20 mg twice daily [see
Dosage and Administration (2.5)].
Strong CYP3A Inducers
Clinical Impact
• Co-administration of PYRUKYND with strong CYP3A
inducers decreased mitapivat plasma concentrations [see
Clinical Pharmacology (12.3)].
• Decreased mitapivat plasma concentrations will reduce the
efficacy of PYRUKYND.
Reference ID: 5505232
Prevention or Management
• Avoid co-administration of strong CYP3A inducers with
PYRUKYND [see Dosage and Administration (2.5)].
Moderate CYP3A Inducers
Clinical Impact
• Co-administration of PYRUKYND with moderate CYP3A
inducers will decrease mitapivat plasma concentrations [see
Clinical Pharmacology (12.3)].
Prevention or Management
• Consider alternative therapies that are not moderate CYP3A
inducers during treatment with PYRUKYND. If there are no
alternative therapies, monitor Hb and titrate beyond 50 mg twice
daily, if necessary, but do not exceed a maximum recommended
dose of 100 mg twice daily [see Dosage and Administration
(2.5)].
7.2
Effect of PYRUKYND on Other Drugs
CYP3A Substrates
Clinical Impact
• PYRUKYND induces CYP3A. Co-administration of
PYRUKYND will decrease systemic concentrations of
drugs that are sensitive CYP3A substrates, including
hormonal contraceptives (e.g., ethinyl estradiol) [see
Clinical Pharmacology (12.3)].
Prevention or Management
• Monitor patients for loss of therapeutic effect of sensitive
CYP3A substrates with narrow therapeutic index when co-
administered with PYRUKYND.
• Advise patients using hormonal contraceptives to use an
alternative non-hormonal contraceptive method or add a
barrier method of contraception during treatment with
PYRUKYND.
CYP2B6 and CYP2C Substrates
Clinical Impact
• PYRUKYND induces CYP2B6, CYP2C8, CYP2C9, and
CYP2C19 enzymes in vitro, and may decrease systemic
concentrations of drugs that are sensitive substrates of these
enzymes [see Clinical Pharmacology (12.3)].
Prevention or Management
• Monitor patients for loss of therapeutic effect of sensitive
substrates of these enzymes with narrow therapeutic index
when co-administered with PYRUKYND.
UGT1A1 Substrates
Clinical Impact
• PYRUKYND induces UGT1A1 in vitro and may decrease
systemic concentrations of drugs that are UGT1A1 substrates
[see Clinical Pharmacology (12.3)].
Reference ID: 5505232
Prevention or Management
• Monitor patients for loss of therapeutic effect of UGT1A1
substrates with narrow therapeutic index when co-administered
with PYRUKYND.
P-gp Substrates
Clinical Impact
• PYRUKYND inhibits the P-gp transporter in vitro and may
increase systemic concentrations of drugs that are P-gp substrates
[see Clinical Pharmacology (12.3)].
Prevention or Management
• Monitor patients for adverse reactions of P-gp substrates with
narrow therapeutic index when co-administered with
PYRUKYND.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Available data from clinical trials of PYRUKYND are insufficient to evaluate for a drug- associated
risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.
In animal reproduction studies, mitapivat orally administered twice daily to pregnant rats and rabbits
during organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended
human dose (MRHD) of 50 mg twice daily, respectively. Mitapivat administered orally to pregnant
rats twice daily during organogenesis through lactation did not result in adverse developmental effects
at doses up to 13 times the MRHD (see Data).
The estimated background risk of major birth defects for the indicated population is unknown.
Estimated frequencies for other important background risks in the population are as follows:
miscarriage 18%, growth retardation 24%, preterm birth 56%. All pregnancies have a background risk
of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to
4% and 15% to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal Risk
Untreated PK deficiency in pregnant women may precipitate acute hemolysis, pre-term labor,
miscarriage and severe anemia requiring frequent transfusion. Additionally, preeclampsia and severe
hypertension have been reported.
Data
Animal Data
In an embryo-fetal development study in rats, mitapivat was administered at doses of 5, 10, 25, and
100 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 6 to 17).
There was a statistically significant 14% decrease in maternal net body weight gain at the high dose
with associated decrease in food consumption. Enlarged or fused placenta and/or a distended amniotic
sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of
viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were
observed at the high dose (100 mg/kg twice daily, 63 times the MRHD, based on area under the plasma
drug concentration-time curve [AUC]). No maternal or embryo-fetal toxicity was observed up to 25
Reference ID: 5505232
mg/kg twice daily (13 times the MRHD, based on AUC).
In an embryo-fetal development study in rabbits, mitapivat was administered at doses of 12.5, 30, and
62.5 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 7 to 20).
Lower fetal weight was observed at 62.5 mg/kg twice daily (3 times MRHD, based on AUC) and
correlated with reduced maternal body weight gain. No effects on fetal morphology were observed.
In a pre- and post-natal development study in rats, mitapivat was administered at doses of 5, 10, 25,
and 100 mg/kg twice daily by oral gavage during the period of organogenesis and continuing to
weaning (gestation day 7 to lactation day 20). Dystocia was observed at ≥25 mg/kg twice daily (≥13x
MRHD, based on AUC). At 100 mg/kg twice daily (63x MRHD, based on AUC) decreased maternal
body weight gain, prolonged parturition, and dystocia occurred and resulted in maternal mortality,
complete litter loss, decreased pup viability and decreased pup body weight. No adverse effects on pup
growth and development, and reproductive performance were observed up to 50 mg/kg (13 times the
MRHD, based on AUC).
8.2
Lactation
Risk Summary
There are no data on the presence of PYRUKYND or its metabolites in human or animal milk, the
effects on the breastfed child, or the effects on milk production. The developmental and health benefits
of breastfeeding should be considered along with the mother’s clinical need for PYRUKYND and any
potential adverse effects on the breastfed child from PYRUKYND or from the underlying maternal
condition.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5
Geriatric Use
Clinical studies of PYRUKYND did not include sufficient numbers of subjects aged 65 years and over
to determine whether they respond differently from younger subjects.
8.6
Hepatic Impairment
Mitapivat undergoes extensive hepatic metabolism. Moderate and severe hepatic impairment is
expected to increase the systemic exposure of mitapivat. Avoid use of PYRUKYND in patients with
moderate and severe hepatic impairment [see Dosage and Administration (2.4), Warnings and
Precautions (5.2), and Clinical Pharmacology (12.3)].
11
DESCRIPTION
The active ingredient of PYRUKYND is mitapivat, a pyruvate kinase activator, present as mitapivat
sulfate. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4-
(cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]-, sulfate, hydrate (2:1:3). The chemical structure
of mitapivat sulfate is:
The molecular formula is (C24H26N4SO3)2 • H2SO4 • 3H2O, and the molecular weight is 1053.23 for
mitapivat sulfate. Mitapivat sulfate is a white to off-white solid and is slightly soluble in water.
PYRUKYND is available as 5 mg, 20 mg, and 50 mg tablets for oral administration. Each tablet
Reference ID: 5505232
contains 5 mg, 20 mg, or 50 mg mitapivat free base, provided as 5.85 mg, 23.4 mg, or 58.5 mg,
respectively, of the sulfate hydrate salt, and the following inactive ingredients: croscarmellose sodium,
mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating contains the
inactive ingredients FD&C Blue No. 2, hypromellose, lactose monohydrate, titanium dioxide, and
triacetin. The tablets are imprinted with black ink containing the inactive ingredients ammonium
hydroxide, ferrosoferric oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase
tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate
kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP),
shortened RBC lifespan, and chronic hemolysis.
12.2
Pharmacodynamics
Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers.
Cardiac Electrophysiology
At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any
clinically relevant extent.
12.3
Pharmacokinetics
Mitapivat exposure increased in an approximately dose proportional manner over the clinically
relevant dose range of 5 mg to 50 mg twice daily.
The population pharmacokinetic model simulated Cmax, Ctrough, AUC0-12 and accumulation ratio of
mitapivat at recommended dosages are listed in the table below.
Table 5:
Steady State Mitapivat Exposure at Recommended Dosagesa
Mitapivat Dosage
Cmax
(ng/mL)
Ctrough
(ng/mL)
AUC0-12
(ng*h/mL)
Accumulation
Ratio
5 mg twice daily
101.2 (17%)
10.1 (74%)
450.4 (28%)
1.2
20 mg twice daily
389.9 (18%)
32.3 (77%)
1623.8 (28%)
1.1
50 mg twice daily
935.2 (18%)
62.1 (80%)
3591.4 (28%)
1.0
a Pharmacokinetic parameters are presented as geometric mean (CV%). The simulations were performed until 100 days
after first dose. The interval of the last 12 hours was selected for steady state PK parameters calculation.
Residual error was not included during simulation.
Absorption
Median tmax values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50
mg twice daily.
The absolute bioavailability after a single dose was approximately 73%.
Effect of Food
Following administration of a single dose of PYRUKYND in healthy subjects, a high-fat meal
(approximately 900 to 1,000 total calories, with 500 to 600 calories from fat, 250 calories from
carbohydrate, and 150 calories from protein) did not change the exposure (AUCinf) of mitapivat, but
reduced the rate of mitapivat absorption, with a 42% reduction in Cmax and a delay in tmax of 2.3 hours
when compared to dosing under fasted conditions.
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Distribution
Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution (RBC-to-plasma ratio
of 0.37). The mean volume of distribution at steady state (Vss) was 42.5 L.
Elimination
The mean effective half-life (t1/2) of mitapivat ranged from 3 to 5 hours following multiple dose
administrations of 5 mg twice daily to 20 mg twice daily in patients with PK deficiency.
Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the
5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively.
Metabolism
In vitro studies showed that mitapivat is primarily metabolized by CYP3A4. Following a single oral
dose of 120 mg of radiolabeled mitapivat to healthy subjects, unchanged mitapivat was the major
circulating component.
Excretion
After a single oral administration of radiolabeled mitapivat to healthy subjects, the total recovery of
administered radioactive dose was 89.2%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the
feces (<1% unchanged).
Specific Populations
No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age,
sex, race, or body weight.
Pediatric Population
The pharmacokinetics of mitapivat in children and adolescents (˂18 years old) have not been studied.
Hepatic Impairment
Mitapivat undergoes extensive hepatic metabolism. Moderate and severe hepatic impairment is
expected to increase the systemic exposure of mitapivat. The pharmacokinetics of mitapivat in patients
with hepatic impairment have not been studied.
Renal Impairment
The effects of renal impairment on mitapivat pharmacokinetics were assessed with population
pharmacokinetic analyses. Steady state AUC of mitapivat in patients with eGFR 60 to <90
mL/min/1.73 m2 was not significantly different compared to patients with eGFR ≥90 mL/min/1.73 m2.
There are limited data available in patients with eGFR 30 to <60 mL/min/1.73 m2 and no data available
in patients with eGFR <30 mL/min/1.73 m2.
Drug Interaction Studies
Clinical Studies and Model-Based Approaches
Effect of Strong CYP3A Inhibitors on PYRUKYND
Itraconazole (a strong CYP3A inhibitor) increased mitapivat AUCinf and Cmax by 4.9-fold and 1.7-
fold, respectively, following a single PYRUKYND dose of 20 mg. Itraconazole increased mitapivat
AUC0-12 and Cmax by 3.6-fold and 2.2-fold, respectively, following PYRUKYND 50 mg twice daily.
Ketoconazole (a strong CYP3A inhibitor) increased mitapivat AUC0-12 and Cmax by approximately 3.9-
fold and 2.4-fold, respectively, following PYRUKYND doses of 5, 20 or 50 mg twice daily.
Effect of Moderate CYP3A Inhibitors on PYRUKYND
Reference ID: 5505232
Fluconazole (a moderate CYP3A inhibitor) increased mitapivat AUC0-12 and Cmax by approximately
2.6-fold and 1.6-fold, respectively, following PYRUKYND doses of 5, 20 or 50 mg twice daily.
Effect of Strong CYP3A Inducers on PYRUKYND
Rifampin (a strong CYP3A inducer) decreased mitapivat AUCinf and Cmax by 91% and 77%,
respectively, following a single PYRUKYND dose of 50 mg. Rifampin decreased mitapivat AUC0-12
and Cmax by approximately 95% and 85%, respectively, following PYRUKYND doses of 5, 20 or 50
mg twice daily.
Effect of Moderate CYP3A Inducers on PYRUKYND
Efavirenz (a moderate CYP3A4 inducer) decreased mitapivat AUC0-12 and Cmax by approximately 60%
and 30%, respectively, following PYRUKYND doses of 5 or 20 mg twice daily. Efavirenz decreased
mitapivat AUC0-12 and Cmax by 55% and 24%, respectively, following PYRUKYND doses of 50 mg
twice daily.
Effect of PYRUKYND on CYP3A substrates
Midazolam (a CYP3A substrate) AUCinf and Cmax decreased by 21% and 19%, respectively, following
co-administration of midazolam with PYRUKYND 5 mg twice daily. Midazolam AUCinf and Cmax
decreased by 43% and 39%, respectively, following co-administration with PYRUKYND 20 mg twice
daily, and 57% and 52%, respectively, with PYRUKYND 50 mg twice daily.
Effect of PYRUKYND on P-gp Substrates
Co-administration of PYRUKYND with drugs that are substrates of P-gp may result in a clinically
relevant increase in plasma concentrations of these substrates.
In vitro Studies
CYP450 and UGT Enzymes
Mitapivat induces CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT1A1.
Drug Transporter Systems
Mitapivat is a substrate and an inhibitor of P-gp.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Mitapivat was not carcinogenic in transgenic rasH2 mice up to the highest doses tested at 500
mg/kg/day in males and at 250 mg/kg/day in females when given orally for 26 weeks.
Mitapivat was not carcinogenic in rats when given orally up to 300 mg/kg/day in males and 200
mg/kg/day in females, at systemic exposures 47 times and >100 times the MRHD, respectively, based
on AUC.
Mutagenesis
Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not
clastogenic in an in vitro human lymphocyte micronucleus assay or in an in vivo rat bone marrow
micronucleus assay.
Fertility
In a fertility and early embryonic development study, oral administration of mitapivat twice daily in
Reference ID: 5505232
male rats prior to and during mating at doses up to 300 mg/kg/day, which represents 45 times the
MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or
reproductive function. In female rats, twice daily oral administration of mitapivat prior to mating and
continuing through organogenesis, at doses up to 200 mg/kg/day, which represents 48 times the
MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or
reproductive function.
14
CLINICAL STUDIES
Patients with PK Deficiency
Patients Not Regularly Transfused
The efficacy of PYRUKYND was evaluated in ACTIVATE, a multinational, randomized, double-
blind, placebo-controlled clinical study (NCT03548220) of 80 adults with PK deficiency who were not
regularly transfused, defined as having had no more than 4 transfusions in the 52- week period prior to
treatment and no transfusions in the 3-month period prior to treatment.
Patients were included if they had documented presence of at least 2 variant alleles in the pyruvate
kinase liver and red blood cell (PKLR) gene, of which at least 1 was a missense variant, and Hb less
than or equal to 10 g/dL. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had
2 non-missense variants (without the presence of another missense variant) in the PKLR gene were
excluded because these patients did not achieve Hb response (change from baseline in Hb ≥1.5 g/dL at
>50% assessments) in the dose-ranging study.
Randomization was stratified by average screening Hb (<8.5 vs ≥8.5 g/dL) and PKLR gene variant
category (missense/missense vs. missense/non-missense).
Among the 80 patients with PK deficiency, 40 patients were randomized to PYRUKYND. Following a
period of dose titration up to 50 mg twice daily, patients continued a fixed dose of PYRUKYND for 12
weeks. Eighty-eight percent of patients were maintained on 50 mg twice daily.
The median duration of treatment with PYRUKYND was 24.1 weeks (range 23.6 to 27.4 weeks).
Overall, 30 (75%) patients were exposed to PYRUKYND for >24 weeks and <28 weeks. Among the
80 randomized patients, the median age was 33 years (range 18 to 78) and 40% were male; race was
reported in 88% of patients: 75% were White, 10% Asian, 1.3% Native Hawaiian/Other Pacific
Islander and 1.3% were other races. The median baseline hemoglobin was 8.5 g/dL (range: 6.4 to 10.2
g/dL). There were 55 patients (69%) with the missense/missense PKLR gene variant category, and 25
patients (31%) with the missense/non-missense PKLR gene variant category. There were 58 patients
(73%) who had a history of splenectomy. Complications and comorbidities associated with PK
deficiency included iron overload with a median baseline ferritin of 479 ng/mL (range: 21 to 5890
ng/mL), chelation therapy use in the year before the first dose of study treatment in 15 patients (19%),
decreased bone mineral density in 64 patients (80%) who had a baseline femoral neck T-score or
lumbar spine T-score <-1.0, and history of cholecystectomy in 58 patients (73%).
Efficacy was based upon Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline sustained at
2 or more scheduled assessments (Weeks 16, 20, and 24) during the fixed dose period without
transfusions. The efficacy results, including changes in markers of hemolysis are shown in Table 6.
Reference ID: 5505232
Table 6:
Efficacy Results in Patients with PK Deficiency Who Were Not Regularly
Transfused (ACTIVATE)
Endpoint
PYRUKYND
N=40
Placebo
N=40
Difference1, 2
p-value
Hb Response, n (%)
16 (40%)
0
39 (24, 55)
<0.0001
Hemoglobin (g/dL)
Baseline Mean (SD)
LS Mean Change (95% CI)
8.6 (1.0)
1.7 (1.3, 2.1)
8.5 (0.8)
-0.1 (-0.6, 0.3)
1.8 (1.2, 2.4)
<0.0001
Indirect bilirubin
(mg/dL)
Baseline Mean (SD)
LS Mean Change (95% CI)
4.8 (3.6)
-1.2 (-1.7, -0.7)
5.2 (3.6)
0.3 (-0.2, 0.8)
-1.5 (-2.2, -0.9)
<0.0001
Reticulocyte
(fraction of 1)
Baseline Mean (SD)
LS Mean Change (95% CI)
0.37 (0.24)
-0.10 (-0.13, -0.07)
0.40 (0.22)
0 (-0.02, 0.03)
-0.10 (-0.14, -0.06)
<0.0001
LDH (U/L)
Baseline Mean (SD)
LS Mean Change (95% CI)
348 (276)
-92 (-124, -60)
260 (140)
-21 (-53, 11)
-71 (-116, -26)
0.003
Haptoglobin (mg/dL)
Baseline Mean (SD)
LS Mean Change (95% CI)
8.2 (10.7)
16.9 (8.8, 25.1)
8.3 (13.8)
1.2 (-7.0, 9.4)
15.8 (4.3, 27.3)
0.008
CI: confidence interval, Hb: hemoglobin, LDH: lactate dehydrogenase, LS Mean Change: least square mean change from
baseline, SD: standard deviation
1 All results are statistically significant.
2 For Hb response, the difference is adjusted for randomization stratification factors, which included average screening Hb
(<8.5, ≥8.5 g/dL) and PKLR gene variant category (missense/missense, missense/non-missense). The two-sided p-value is
based on the Mantel-Haenszel stratum weighted method adjusting for the randomization stratification factors.
For the endpoints of average change from baseline at Weeks 16, 20, and 24 for hemoglobin, indirect bilirubin, reticulocytes,
LDH, and haptoglobin, the two-sided p-value is based on the mixed-effect model repeat measurement (MMRM) method,
which included change from baseline as the dependent variable, baseline as a covariate, and treatment arm, visit, treatment-
by-visit interaction, and the randomization stratification factors as fixed factors and subject as the random effect. All
scheduled visits were included in the model.
In ACTIVATE, the LS Mean change from baseline with PYRUKYND compared to placebo was -0.4
(standard error [SE] 0.1) for jaundice (scale: 0-4), -1.1 (SE 0.4) for tiredness (scale: 0-10), and -0.3 (SE
0.3) for shortness of breath (scale: 0-10), assessed with the daily Pyruvate Kinase Deficiency Diary
(PKDD) where lower scores represent less sign/symptom severity.
In ACTIVATE, the majority of PYRUKYND-treated patients experienced an increase in Hb, while the
Reference ID: 5505232
majority of patients in the placebo arm experienced a decrease in Hb as measured by average change
from baseline at weeks 16, 20, and 24 (Figure 1).
Figure 1:
Average Change at Weeks 16, 20, and 24 from Baseline in Hemoglobin (Hb) by
Patient - All Randomized Patients (ACTIVATE)a
aApproximately 99% of all randomized patients completed 24 weeks of treatment.
Figure 2:
LS Mean Change from Baseline in Hemoglobin Over Time - All Randomized
Patients (ACTIVATE)
CI: confidence interval, Hb: hemoglobin, LS: least square
Fifteen of the 16 patients with a Hb response in ACTIVATE continued in a long-term extension study
and were evaluable for maintenance of response. Thirteen maintained increases in Hb concentration
from baseline above the response threshold of ≥1.5 g/dL at the last available Hb assessment without
Reference ID: 5505232
requiring any transfusions. The median duration of response for the 16 patients with Hb response was
6.9 months (range: 3.3, 18.4+).
Patients Who Were Regularly Transfused
The efficacy of PYRUKYND in patients with PK deficiency who were regularly transfused was
evaluated in ACTIVATE-T, a multinational single-arm clinical trial (NCT03559699) of 27 adults with
PK deficiency who had a minimum of 6 transfusion episodes in the 52-week period prior to informed
consent. Patients were included if they had documented presence of at least 2 variant alleles in the
PKLR gene, of which at least 1 was a missense variant. Patients who were homozygous for the
c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another
missense variant) in the PKLR gene were excluded. Following a period of dose titration up to 50 mg
twice daily, patients continued on a fixed dose of PYRUKYND for 24 weeks.
The median duration of treatment with PYRUKYND was 40.3 weeks (range 16.3 to 46.3 weeks).
Overall, 20 (74%) patients were exposed to PYRUKYND for >40 weeks and <47 weeks. The median
age was 36 years (range 18 to 68) and 26% were male; race was reported in 85% of patients: 74% were
White and 11% Asian. The median baseline hemoglobin was 9.1 g/dL (range: 7.4 to 10.9 g/dL).
Patients had a median of 9 transfusion episodes (range: 6 to 17 episodes) in the 52 weeks before the
first dose of study treatment and a median of 7 red blood cell units transfused (range: 3 to 20 units)
standardized to 24 weeks. There were 20 patients (74%) with the missense/missense PKLR gene
variant category, and 7 patients (26%) with the missense/non-missense PKLR gene variant category.
There were 21 patients (78%) who had a history of splenectomy. Patients had evidence of
complications and comorbidities associated with PK deficiency including iron overload (median
baseline ferritin was 1324 ug/L; range: 163 to 5357 ng/mL), chelation therapy use in the year before
the first dose of study treatment in 24 patients (89%), decreased bone mineral density in 20 patients
(74%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of
cholecystectomy in 23 patients (85%).
Efficacy was based on transfusion reduction response and was defined as ≥33% reduction in the
number of red blood cell (RBC) units transfused during the fixed dose period compared with the
patient’s historical transfusion burden.
Efficacy results for patients with PK deficiency who were regularly transfused are presented in Table
7.
Table 7:
Efficacy Results in Patients with PK Deficiency Who Were Regularly Transfused
(ACTIVATE-T)
Endpoints
PYRUKYND
N=27
Patients with Transfusion Reduction Response
n (%)
9 (33)
95% CI
(17, 54)
Patients who were Transfusion Free
n (%)
6 (22)
95% CI
(9, 42)
CI: confidence interval, RBC: red blood cell CI is based on Clopper-Pearson method.
All 6 (22%) patients who were transfusion free in ACTIVATE-T remained transfusion free in a long-
term extension study. The median duration of response for the 6 patients was 17 months (range: 11.5+,
21.8+).
Reference ID: 5505232
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
PYRUKYND 28-Day Packs
Tablet
Strength
Description
Imprint
NDC
5 mg
Round, blue, film-coated tablets
"M5" printed on one side
71334-205-05
20 mg
Round, blue, film-coated tablets
"M20" printed on one side
71334-210-20
50 mg
Oblong, blue, film-coated tablets
"M50" printed on one side
71334-215-50
PYRUKYND Taper Packs
Tablet
strength(s)
Blister Wallet
Configuration
Tablet Description
Imprint
NDC
5 mg
• 5 mg blister wallet
containing 7 tablets
round, blue, film-coated
tablets
"M5" printed
on one side
71334-220-11
20 mg and
5 mg
• 20 mg blister wallet
containing 7 tablets
• 5 mg blister wallet
containing 7 tablets
round, blue, film-coated
tablets
"M20"
printed on
one side
71334-225-12
round, blue, film-coated
tablets
"M5" printed
on one side
50 mg and
20 mg
• 50 mg blister wallet
containing 7 tablets
oblong, blue, film-
coated tablets
"M50"
printed on
one side
71334-230-13
• 20 mg blister wallet
containing 7 tablets
round, blue, film-coated
tablets
"M20"
printed on
one side
Storage
Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and
86°F) [see USP Controlled Room Temperature]. Store the blister wallets in the original carton until
use.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Acute Hemolysis with Abrupt Treatment Interruption
Inform patients of the risk of developing acute hemolysis and subsequent anemia following abrupt
interruption or discontinuation of PYRUKYND. Inform patients to follow their healthcare provider’s
instructions for discontinuing PYRUKYND. Upon discontinuing PYRUKYND, tell patients to
immediately report any symptoms suggestive of acute hemolysis including jaundice, scleral icterus,
Reference ID: 5505232
dark urine, dizziness, confusion, fatigue, or shortness of breath to their healthcare provider for further
evaluation [see Warnings and Precautions (5.1)].
Hepatocellular Injury in Another Condition
Inform patients of the risk of hepatocellular injury observed in patients with another condition during
the first 6 months of treatment with PYRUKYND at a higher dose than that recommended for patients
with PK deficiency. Tell patients to immediately report any symptoms suggestive of liver injury
including jaundice, dark urine, right upper quadrant pain, nausea, vomiting, or loss of appetite to their
healthcare provider for further evaluation [see Warnings and Precautions (5.2)].
Drug Interactions
Advise patients to inform their healthcare providers of all concomitant medications, including over-
the-counter medications, vitamins, and herbal products [see Drug Interactions (7)].
Dosing and Storage Instructions
• Instruct patients to swallow the tablets whole with or without food and not to split, crush,
chew, or dissolve the tablets.
• Advise patients if a dose of PYRUKYND is missed by 4 hours or less, to take the
scheduled dose as soon as possible. If a dose of PYRUKYND is missed by more than 4
hours, advise the patient to not take a replacement dose and wait until the next scheduled
dose.
PYRUKYND® is a registered trademark of Agios Pharmaceuticals, Inc.
© 2022 Agios Pharmaceuticals, Inc.
Manufactured for and Distributed by:
Agios Pharmaceuticals, Inc.
Cambridge, MA 02139
AG-PI-00X
Reference ID: 5505232
PATIENT INFORMATION
PYRUKYND (pye roo’ kind)
(mitapivat)
tablets, for oral use
What is PYRUKYND?
PYRUKYND is a prescription medicine used to treat low red blood cell counts caused by the early breakdown of
red blood cells (hemolytic anemia) in adults with pyruvate kinase deficiency (PK Deficiency).
It is not known if PYRUKYND is safe and effective in children.
Before taking PYRUKYND, tell your healthcare provider about all your medical conditions, including if
you:
•
have liver problems.
•
are pregnant or plan to become pregnant. It is not known if PYRUKYND will harm your unborn baby. Tell
your healthcare provider right away if you become pregnant or think that you are pregnant during treatment
with PYRUKYND.
•
are breastfeeding or plan to breastfeed. It is not known if PYRUKYND passes into your breast milk. Talk to
your healthcare provider about the best way to feed your baby during treatment with PYRUKYND.
Tell your healthcare provider about all the medicines that you take, including prescription and over-the-
counter medicines, vitamins, and herbal supplements.
PYRUKYND and certain other medicines may affect each other causing side effects. PYRUKYND may affect the
way other medicines work, and other medicines may affect how PYRUKYND works.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get
a new medicine.
How should I take PYRUKYND?
•
Take PYRUKYND exactly as your healthcare provider tells you to take it.
•
Take PYRUKYND with or without food.
•
Swallow PYRUKYND tablets whole. Do not split, chew, crush, or dissolve the tablets.
•
Do not change your dose or stop taking PYRUKYND without talking to your healthcare provider. Your
healthcare provider will give you instructions for stopping PYRUKYND. See “What are the possible side
effects of PYRUKYND?”
•
If you miss a dose of PYRUKYND by 4 hours or less, take your dose as soon as possible. If more than 4
hours have passed since your regularly scheduled dose, wait for the next dose. Return to your normal
schedule at the next dose.
What are the possible side effects of PYRUKYND?
PYRUKYND may cause serious side effects, including:
•
Rapid breakdown of red blood cells (acute hemolysis) has happened after suddenly interrupting or
stopping treatment with PYRUKYND. You should not suddenly stop taking PYRUKYND. If you have to
stop your treatment with PYRUKYND, your healthcare provider should monitor you closely. Tell your
healthcare provider right away if you develop any signs or symptoms of breakdown of red blood cells
including:
o
yellowing of your skin or the whites of your eyes (jaundice)
o feeling tired
o
dark colored urine
o shortness of breath
o
dizziness o confusion
•
Liver injury has happened in people with another condition during the first 6 months of treatment with
PYRUKYND when given at a dose higher than recommended for people with PK deficiency. Your
healthcare provider will do blood tests to check your liver before you start treatment with PYRUKYND,
monthly for the first 6 months of treatment, and as needed. Your healthcare provider may temporarily or
permanently stop your treatment with PYRUKYND if you have abnormal liver tests. Tell your healthcare
provider right away if you develop any signs or symptoms of liver problems including:
o
yellowing of your skin or the whites of your eyes (jaundice)
o nausea
o
dark colored urine
o vomiting
o
pain in the upper right side of your stomach area
o loss of appetite
Reference ID: 5505232
The most common side effects of PYRUKYND include:
•
decrease in reproductive hormone (estrone)
•
decrease in reproductive hormone (estradiol)
in men
in men
•
increased salt from uric acid (urate) blood
•
joint pain (arthralgia)
test
•
back pain
These are not all of the possible side effects of PYRUKYND.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store PYRUKYND?
•
Store PYRUKYND at room temperature between 68°F to 77°F (20°C to 25°C).
•
Store the blister wallets in the original carton until use.
Keep PYRUKYND and all medicines out of the reach of children.
General information about the safe and effective use of PYRUKYND.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not
use PYRUKYND for a condition for which it was not prescribed. Do not give PYRUKYND to other people, even if
they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or
pharmacist for information about PYRUKYND that is written for healthcare professionals.
What are the ingredients in PYRUKYND?
Active ingredient: mitapivat
Inactive ingredients: croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate.
The tablet film coating contains: FD&C Blue No. 2, hypromellose, lactose monohydrate, titanium dioxide, and
triacetin.
The tablets printed with black ink contains: ammonium hydroxide, ferrosoferric oxide, isopropyl alcohol, n-butyl
alcohol, propylene glycol, and shellac glaze.
Manufactured for and Distributed by:
Agios Pharmaceuticals, Inc.
Cambridge, MA 02139
PYRUKYND® is a trademark of Agios Pharmaceuticals, Inc.
© 2022 Agios Pharmaceuticals, Inc. All rights reserved.
For more information, visit www.pyrukynd.com or call 1-833-228-8474.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 1/2025
Reference ID: 5505232
| custom-source | 2025-02-12T15:48:25.359900 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2025/216196s004lbl.pdf', 'application_number': 216196, 'submission_type': 'SUPPL ', 'submission_number': 4} |
80,824 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use METHYLIN® Chewable Tablets safely and effectively. See
full prescribing information for METHYLIN® Chewable Tablets.
METHYLIN® Chewable Tablets (methylphenidate hydrochloride),
for oral use, CII
Initial U.S. Approval: 1955
WARNING: ABUSE, MISUSE, AND ADDICTION
See full prescribing information for complete boxed warning.
Methylin has a high potential for abuse and misuse, which can
lead to the development of a substance use disorder, including
addiction. Misuse and abuse of CNS stimulants, including
Methylin, can result in overdose and death (5.1, 9.2, 10):
•
Before prescribing Methylin, assess each patient’s risk for
abuse, misuse, and addiction.
•
Educate patients and their families about these risks,
proper storage of the drug, and proper disposal of any
unused drug.
•
Throughout treatment, reassess each patient’s risk and
frequently monitor for signs and symptoms of abuse,
misuse, and addiction.
----------------------------INDICATIONS AND USAGE ------------------------
Methylin Chewable Tablets are a central nervous system (CNS)
stimulant indicated for the treatment of:
•
Attention Deficit Hyperactivity Disorder (ADHD) in patients
6 years of age and older (1)
•
Narcolepsy (1)
----------------------- DOSAGE AND ADMINISTRATION -------------------
•
Pediatric Patients 6 Years and Older: Start with 5 mg twice daily
(before breakfast and lunch); titrate the dose in weekly increments
of 5 mg to 10 mg. Daily dosages above 60 mg are not
recommended. (2.2)
•
Adults: Administer in divided doses 2 or 3 times daily, preferably
30 to 45 minutes before meals. Maximum recommended daily
dosage is 60 mg. (2.2)
•
Administer with at least 8 ounces (a full glass) of water or other
fluid. (2.2)
--------------------- DOSAGE FORMS AND STRENGTHS -----------------
Chewable tablets: 2.5 mg, 5 mg, and 10 mg. (3)
------------------------------- CONTRAINDICATIONS ---------------------------
•
Known hypersensitivity to methylphenidate or other components
of Methylin (4)
•
Concurrent treatment with a monoamine oxidase inhibitor
(MAOI), or use of an MAOI within the preceding 14 days (4)
----------------------- WARNINGS AND PRECAUTIONS --------------------
•
Risks to Patients with Serious Cardiac Disease: Avoid use in
patients
with
known
structural
cardiac
abnormalities,
cardiomyopathy, serious cardiac arrhythmias, coronary artery
disease, or other serious cardiac disease. (5.2)
•
Increased Blood Pressure and Heart Rate: Monitor blood
pressure and pulse. (5.3)
•
Psychiatric Adverse Reactions: Prior to initiating Methylin,
screen patients for risk factors for developing a manic episode.
If new psychotic or manic symptoms occur, consider
discontinuing Methylin. (5.4)
•
Priapism: If abnormally sustained or frequent and painful
erections occur, patients should seek immediate medical
attention. (5.5)
•
Peripheral Vasculopathy, including Raynaud’s Phenomenon:
Careful observation for digital changes is necessary during
Methylin
treatment.
Further
clinical
evaluation
(e.g.,
rheumatology referral) may be appropriate for patients who
develop signs or symptoms of peripheral vasculopathy. (5.6)
•
Long-Term Suppression of Growth in Pediatric Patients:
Closely monitor growth (height and weight) in pediatric
patients. Pediatric patients not growing or gaining height or
weight as expected may need to have their treatment
interrupted. (5.7)
•
Acute Angle Closure Glaucoma: Methylin-treated patients
considered at risk for acute angle closure glaucoma (e.g.,
patients with significant hyperopia) should be evaluated by an
ophthalmologist. (5.8)
•
Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe
Methylin to patients with open-angle glaucoma or abnormally
increased IOP only if the benefit of treatment is considered to
outweigh the risk. Closely monitor patients with a history of
increased IOP or open-angle glaucoma. (5.9)
•
Motor and Verbal Tics, and Worsening of Tourette’s Syndrome:
Before initiating Methylin, assess the family history and
clinically evaluate patients for tics or Tourette’s syndrome.
Regularly monitor patients for the emergence or worsening of
tics or Tourette’s syndrome. Discontinue treatment if clinically
appropriate. (5.10)
•
Risk of Choking: Taking this product without enough liquid may
cause choking. Discontinue Methylin Chewable Tablets and
seek immediate medical attention if chest pain, vomiting,
difficulty in swallowing, or difficulty in breathing occur after
administration. (5.11)
•
Risks in Patients with Phenylketonuria: Methylin Chewable
Tablets contains phenylalanine which can be harmful to
patients with phenylketonuria. (5.12)
------------------------------ ADVERSE REACTIONS ---------------------------
Common adverse reactions: tachycardia, palpitations, headache,
insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite,
dry mouth, nausea, and abdominal pain. (6)
To
report
SUSPECTED
ADVERSE
REACTIONS,
contact
Mallinckrodt at 1-800-778-7898 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS ---------------------------
•
Antihypertensive Drugs: Monitor blood pressure. Adjust dosage
of antihypertensive drug as needed. (7.1)
See 17 for PATIENT COUNSELING INFORMATION and
Medication Guide.
Revised: 1/2025
Reference ID: 5507795
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ABUSE, MISUSE, AND ADDICTION
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Pretreatment Screening
2.2
Recommended Dosage and Administration Information
2.3
Dosage Reduction and Discontinuation
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Abuse, Misuse, and Addiction
5.2
Risks to Patients with Serious Cardiac Disease
5.3
Increased Blood Pressure and Heart Rate
5.4
Psychiatric Adverse Reactions
5.5
Priapism
5.6
Peripheral Vasculopathy, including Raynaud’s
Phenomenon
5.7
Long-Term Suppression of Growth in Pediatric Patients
5.8
Acute Angle Closure Glaucoma
5.9
Increased Intraocular Pressure and Glaucoma
5.10 Motor and Verbal Tics, and Worsening of Tourette’s
Syndrome
5.11 Risk of Choking
5.12 Risks in Patients with Phenylketonuria
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
7.1 Clinically Important Drug Interactions
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
Reference ID: 5507795
FULL PRESCRIBING INFORMATION
WARNING: ABUSE, MISUSE, AND ADDICTION
Methylin has a high potential for abuse and misuse, which can lead to the
development of a substance use disorder, including addiction. Misuse and abuse
of CNS stimulants, including Methylin, can result in overdose and death [see
Overdosage (10)], and this risk is increased with higher doses or unapproved
methods of administration, such as snorting or injection.
Before prescribing Methylin, assess each patient’s risk for abuse, misuse, and
addiction. Educate patients and their families about these risks, proper storage of
the drug, and proper disposal of any unused drug. Throughout Methylin
treatment, reassess each patient’s risk of abuse, misuse, and addiction and
frequently monitor for signs and symptoms of abuse, misuse, and addiction [see
Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].
1
INDICATIONS AND USAGE
Methylin Chewable Tablets is indicated for the treatment of:
• Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and
older
• Narcolepsy
2
DOSAGE AND ADMINISTRATION
2.1
Pretreatment Screening
Prior to treating patients with Methylin Chewable Tablets, assess:
• for the presence of cardiac disease (i.e., perform a careful history, family history
of sudden death or ventricular arrhythmia, and physical exam) [see Warnings
and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or
Tourette’s syndrome before initiating Methylin Chewable Tablets [see Warnings
and Precautions (5.10)].
2.2
Recommended Dosage and Administration Information
Pediatric Patients 6 years and Older
The recommended starting dosage is 5 mg orally twice daily before breakfast and lunch
(preferably 30 to 45 minutes before meals). Increase the dosage gradually, in
increments of 5 mg to 10 mg weekly. Daily dosage above 60 mg is not recommended.
Adults
Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before
meals. The maximum recommended dosage is 60 mg daily. The average dosage is 20
to 30 mg daily. For adult patients who are unable to sleep if medication is taken late in
the day, administer the last dose before 6 p.m.
Reference ID: 5507795
Administer Methylin Chewable Tablets with at least 8 ounces (a full glass) of water or
other fluid. Do not swallow whole. Taking this product without enough liquid may cause
choking [see Warnings and Precautions (5.11)].
2.3
Dosage Reduction and Discontinuation
If paradoxical aggravation of symptoms or other adverse reactions occur, reduce
dosage, or, if necessary, discontinue Methylin Chewable Tablets. If improvement is not
observed after appropriate dosage adjustment over a one-month period, discontinue
Methylin Chewable Tablets.
3
DOSAGE FORMS AND STRENGTHS
Chewable tablets:
•
2.5 mg of methylphenidate hydrochloride, white to cream colored, grape flavored,
rounded square tablet with a convex surface, debossed with a “2.5” and “CHEW”
below it on one side, and a debossed
on the other side
•
5 mg of methylphenidate hydrochloride, a white to cream colored, grape flavored,
rounded square tablet with a convex surface, debossed with a “5” and “CHEW”
below it on one side, and a debossed
on the other side
•
10 mg of methylphenidate hydrochloride, white to cream colored, grape flavored,
scored rounded square tablet with a convex surface, debossed with a “10” and
“CHEW” below it on one side, and a debossed
on the other side
4
CONTRAINDICATIONS
Methylin Chewable Tablets is contraindicated in patients:
•
with a known hypersensitivity to methylphenidate or other components of
Methylin Chewable Tablets. Hypersensitivity reactions such as angioedema and
anaphylactic
reactions
have
been
reported
in
patients
treated
with
methylphenidate [see Adverse Reactions (6)].
•
receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs),
and also within 14 days following discontinuation of treatment with a MAOI,
because of the risk of hypertensive crisis [see Drug Interactions (7.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Abuse, Misuse, and Addiction
Methylin has a high potential for abuse and misuse. The use of Methylin exposes
individuals to the risks of abuse and misuse, which can lead to the development of a
substance use disorder, including addiction. Methylin can be diverted for non-medical
use into illicit channels or distribution [see Drug Abuse and Dependence (9.2, 9.3)].
Misuse and abuse of CNS stimulants, including Methylin, can result in overdose and
Reference ID: 5507795
death [see Overdosage (10)], and this risk is increased with higher doses or
unapproved methods of administration, such as snorting or injection.
Before prescribing Methylin, assess each patient’s risk for abuse, misuse, and
addiction. Educate patients and their families about these risks and proper disposal of
any unused drug. Advise patients to store Methylin in a safe place, preferably locked,
and instruct patients to not give Methylin to anyone else. Throughout Methylin
treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently
monitor for signs and symptoms of abuse, misuse, and addiction.
5.2
Risks to Patients with Serious Cardiac Disease
Sudden death has been reported in patients with structural cardiac abnormalities or
other serious cardiac disease who were taking CNS stimulants at the recommended
ADHD dosage.
Avoid Methylin use in patients with known structural cardiac abnormalities,
cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious
cardiac disease.
5.3
Increased Blood Pressure and Heart Rate
CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to
4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may
have larger increases.
Monitor all Methylin-treated patients for hypertension and tachycardia.
5.4
Psychiatric Adverse Reactions
Exacerbation of Pre-Existing Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought
disorder in patients with a pre-existing psychotic disorder.
Induction of a Manic Episode in Patients with Bipolar Disorder
CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating
Methylin treatment, screen patients for risk factors for developing a manic episode (e.g.,
comorbid or history of depressive symptoms or a family history of suicide, bipolar
disorder, and depression).
New Psychotic or Manic Symptoms
CNS stimulants, at the recommended dosage, may cause psychotic or manic
symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior
history of psychotic illness or mania. In a pooled analysis of multiple short-term,
placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in
approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-
treated patients. If such symptoms occur, consider discontinuing Methylin.
5.5
Priapism
Reference ID: 5507795
Prolonged and painful erections, sometimes requiring surgical intervention, have been
reported with methylphenidate use in both adult and pediatric male patients. Although
priapism was not reported with methylphenidate initiation, it developed after some time
on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred
during a methylphenidate withdrawal (drug holidays or during discontinuation).
Methylin-treated patients who develop abnormally sustained or frequent and painful
erections should seek immediate medical attention.
5.6
Peripheral Vasculopathy, including Raynaud’s Phenomenon
CNS stimulants, such as Methylin, used to treat ADHD are associated with peripheral
vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually
intermittent and mild; however, sequelae have included digital ulceration and/or soft
tissue
breakdown.
Effects
of
peripheral
vasculopathy,
including
Raynaud’s
phenomenon, were observed in postmarketing reports and at the therapeutic dosages
of CNS stimulants in all age groups throughout the course of treatment. Signs and
symptoms generally improved after reduction or discontinuation of the CNS stimulant.
Careful observation for digital changes is necessary during Methylin treatment. Further
clinical evaluation (e.g., rheumatology referral) may be appropriate for Methylin-treated
patients who develop signs or symptoms of peripheral vasculopathy.
5.7
Long-Term Suppression of Growth in Pediatric Patients
CNS stimulants have been associated with weight loss and slowing of growth rate in
pediatric patients.
Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were
randomized to either methylphenidate or non-medication treatment groups over 14
months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-
medication treated pediatric patients over 36 months (to the ages of 10 to 13 years),
suggests that pediatric patients who received methylphenidate for 7 days per week
throughout the year) had a temporary slowing in growth rate (on average, a total
of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years),
without evidence of growth rebound during this development period.
Closely monitor growth (weight and height) in Methylin-treated pediatric patients.
Pediatric patients who are not growing or gaining height or weight as expected may
need to have their treatment interrupted.
5.8
Acute Angle Closure Glaucoma
There have been reports of angle closure glaucoma associated with methylphenidate
treatment. Although the mechanism is not clear, Methylin-treated patients considered at
risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should
be evaluated by an ophthalmologist.
5.9
Increased Intraocular Pressure and Glaucoma
Reference ID: 5507795
There have been reports of an elevation of intraocular pressure (IOP) associated with
methylphenidate treatment [see Adverse Reactions (6)].
Prescribe Methylin to patients with open-angle glaucoma or abnormally increased IOP
only if the benefit of treatment is considered to outweigh the risk. Closely monitor
Methylin-treated patients with a history of abnormally increased IOP or open angle
glaucoma.
5.10 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
CNS stimulants, including methylphenidate, have been associated with the onset or
exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been
reported [see Adverse Reactions (6)].
Before initiating Methylin, assess the family history and clinically evaluate patients for
tics or Tourette’s syndrome. Regularly monitor Methylin-treated patients for the
emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if
clinically appropriate.
5.11 Risk of Choking
Methylin Chewable Tablets may swell and block the throat or esophagus which can
cause the patient to choke. Avoid use of Methylin Chewable Tablets in patients who
have difficulty swallowing. Administer with at least 8 ounces of fluid [see Dosage and
Administration (2.2)]. Discontinue Methylin Chewable Tablets and seek immediate
medical attention if chest pain, vomiting, difficulty in swallowing, or difficulty in breathing
occur after administration.
5.12 Risks in Patients with Phenylketonuria
Phenylalanine can be harmful to patients with phenylketonuria (PKU). Methylin
Chewable Tablets contain phenylalanine, a component of aspartame. Each 2.5 mg
Methylin Chewable Tablet contains 0.42 mg of phenylalanine; each 5.0 mg Methylin
Chewable Tablet contains 0.84 mg of phenylalanine and each 10.0 mg Methylin
Chewable Tablet contains 1.68 mg of phenylalanine. Before prescribing Methylin
Chewable Tablets to a patient with PKU, consider the combined daily amount of
phenylalanine from all sources, including Methylin Chewable Tablets.
6
ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions
(5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Known hypersensitivity to methylphenidate or other ingredients of Methylin [see
Contraindications (4)]
• Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors
[see Contraindications (4), Drug Interactions (7)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions
(5.2)]
Reference ID: 5507795
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Priapism [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and
Precautions (5.6)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and
Precautions (5.7)]
• Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8)]
• Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions
(5.9)]
• Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings
and Precautions (5.10)]
• Risk of Choking [see Warnings and Precautions (5.11)]
• Risks in Patients with Phenylketonuria [see Warnings and Precautions (5.12)]
The following adverse reactions associated with the use of methylphenidate containing
products were identified in other clinical studies, postmarketing reports, or literature.
Because some of these reactions were reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Infections and infestations: nasopharyngitis
Blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia,
pancytopenia
Immune system disorders: hypersensitivity reactions, including angioedema and
anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas
Metabolism and nutrition disorders: decreased appetite, reduced weight gain and
suppression of growth during prolonged use in pediatric patients
Psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes
with visual and tactile hallucinations), depressed mood, affect lability, mania,
disorientation, libido changes
Nervous system disorders: headache, dizziness, tremor, dyskinesia including
choreoathetoid movements, drowsiness, convulsions, cerebral arteritis and/or
occlusion, serotonin syndrome in combination with serotonergic drugs, migraine, motor
and verbal tics
Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis,
increased intraocular pressure
Reference ID: 5507795
Cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias,
angina pectoris, sudden cardiac death, myocardial infarction, bradycardia, extrasystole
Respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain,
dyspnea
Gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia,
diarrhea
General disorders: fatigue, hyperpyrexia
Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to
severe hepatic injury
Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative
dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura,
angioneurotic edema, erythema, fixed drug eruption
Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps,
rhabdomyolysis, myalgia, muscle twitching
Renal and urinary disorders: hematuria
Reproductive system and breast disorders: gynecomastia
Urogenital disorders: priapism
Vascular disorders: peripheral coldness, Raynaud’s phenomenon
Investigations: weight loss
7
DRUG INTERACTIONS
7.1
Clinically Important Drug Interactions
Table 1 presents clinically important drug interactions with Methylin.
Table 1:
Drugs Having Clinically Important Interactions with Methylin
Monoamine Oxidase Inhibitors (MAOI)
Clinical Impact:
Concomitant use of MAOIs and CNS stimulants, including
Methylin, can cause hypertensive crisis. Potential outcomes
include death, stroke, myocardial infarction, aortic dissection,
ophthalmological complications, eclampsia, pulmonary edema,
and renal failure [see Contraindications (4)].
Reference ID: 5507795
Intervention:
Concomitant use of Methylin with monoamine oxidase inhibitors
(MAOIs) or within 14 days after discontinuing MAOI treatment is
contraindicated.
Antihypertensive Drugs
Clinical Impact:
Methylin may decrease the effectiveness of drugs used to treat
hypertension [see Warnings and Precautions (5.3)].
Intervention:
Monitor blood pressure and adjust the dosage of the
antihypertensive drug as needed.
Halogenated Anesthetics
Clinical Impact:
Concomitant use of halogenated anesthetics and Methylin may
increase the risk of sudden blood pressure and heart rate
increase during surgery.
Intervention:
Avoid use of Methylin in patients being treated with anesthetics
on the day of surgery.
Risperidone
Clinical Impact:
Combined use of methylphenidate with risperidone when there
is a change, whether an increase or decrease, in dosage of
either or both medications, may increase the risk of
extrapyramidal symptoms (EPS).
Intervention:
Monitor for signs of EPS.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to ADHD medications, including Methylin, during pregnancy. Healthcare
providers are encouraged to advise patients to register by calling the National
Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting online at
www.womensmentalhealth.org/research/pregnancyregistry/adhd-medications/.
Risk Summary
Published studies and postmarketing reports on methylphenidate use during pregnancy
have not identified a drug-associated risk of major birth defects, miscarriage or adverse
maternal or fetal outcomes. There may be risks to the fetus associated with the use of
CNS stimulants use during pregnancy (see Clinical Considerations).
No effects on morphological development were observed in embryo-fetal development
studies with oral administration of methylphenidate to pregnant rats and rabbits during
organogenesis at doses up to 12 and 19 times, respectively, the maximum
recommended human dose (MRHD) of 60 mg/day given to adults on a mg/m2 basis.
However, spina bifida was observed in rabbits at a dose 65 times the MRHD given to
adults. A decrease in pup body weight was observed in a pre- and post-natal
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development study with oral administration of methylphenidate to rats throughout
pregnancy and lactation at doses 7 times the MRHD given to adults (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss, or
other adverse outcomes. In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%
and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
CNS stimulants, such as Methylin, can cause vasoconstriction and thereby decrease
placental perfusion. No fetal and/or neonatal adverse reactions have been reported with
the use of therapeutic doses of methylphenidate during pregnancy; however, premature
delivery and low birth weight infants have been reported in amphetamine-dependent
mothers.
Data
Animal Data
In embryo-fetal development studies conducted in rats and rabbits, methylphenidate
was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during
the period of organogenesis. Malformations (increased incidence of fetal spina bifida)
were observed in rabbits at the highest dose, which is approximately 65 times the
MRHD of 60 mg/day given to adults on a mg/m2 basis. The no effect level for embryo-
fetal development in rabbits was 60 mg/kg/day (19 times the MRHD given to adults on a
mg/m2 basis). There was no evidence of morphological development effects in rats,
although increased incidences of fetal skeletal variations were seen at the highest dose
level (12 times the MRHD of 60 mg/day given to adults on a mg/m2 basis), which was
also maternally toxic. The no effect level for embryo-fetal development in rats was 25
mg/kg/day (4 times the MRHD on a mg/m2 basis). When methylphenidate was
administered to rats throughout pregnancy and lactation at doses of up to 45
mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the
MRHD of 60 mg/day given to adults on a mg/m2 basis), but no other effects on postnatal
development were observed. The no effect level for pre- and postnatal development in
rats was 15 mg/kg/day (approximately 2 times the MRHD given to adults on a mg/m2
basis).
8.2
Lactation
Risk Summary
Limited published literature, based on milk sampling from seven mothers reports that
methylphenidate is present in human milk, which resulted in infant doses of 0.16% to
0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between
1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no
effects on milk production. Long-term neurodevelopmental effects on infants from
stimulant exposure are unknown. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for Methylin
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and any potential adverse effects on the breastfed infant from Methylin or from the
underlying maternal condition.
Clinical Considerations
Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia,
anorexia, and reduced weight gain.
8.4
Pediatric Use
The safety and effectiveness of Methylin for the treatment of ADHD have been
established in pediatric patients six years of age and older. The safety and
effectiveness of Methylin in pediatric patients under six years of age have not been
established. The long-term efficacy of methylphenidate in pediatric patients has not
been established.
Long-Term Suppression of Growth
Growth should be monitored during treatment with stimulants, including Methylin.
Pediatric patients who are not growing or gaining weight as expected may need to have
their treatment interrupted [see Warnings and Precautions (5.7), Adverse Reactions
(6.1)].
Juvenile Animal Toxicity Data
In a study conducted in young rats, methylphenidate was administered orally at doses
of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day
7) and continuing through sexual maturity (postnatal Week 10). When these animals
were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor
activity was observed in males and females previously treated with 50 mg/kg/day
(approximately 4 times the MRHD of 60 mg/day given to children on a mg/m2 basis) or
greater, and a deficit in the acquisition of a specific learning task was seen in females
exposed to the highest dose (8 times the MRHD given to children on a mg/m2 basis).
The no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is
less than the MRHD given to children on a mg/m2 basis. The clinical significance of the
long-term behavioral effects observed in rats is unknown.
8.5
Geriatric Use
Methylin has not been studied in the geriatric population.
8.6
Renal Impairment
Methylin has not been studied in patients with renal impairment.
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
Methylin Chewable Tablets contains methylphenidate, a Schedule II controlled
substance.
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9.2
Abuse
Methylin has a high potential for abuse and misuse which can lead to the development
of a substance use disorder, including addiction [see Warnings and Precautions (5.1)].
Methylin can be diverted for non-medical use into illicit channels or distribution.
Abuse is the intentional, non-therapeutic use of a drug, even once, to achieve a desired
psychological or physiological effect. Misuse is the intentional use, for therapeutic
purposes, of a drug by an individual in a way other than prescribed by a healthcare
provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral,
cognitive, and physiological phenomena that may include a strong desire to take the
drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful
consequences, giving a higher priority to drug use than other activities and obligations),
and possible tolerance or physical dependence.
Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate,
or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia;
decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or
abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal
ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse
and abuse of CNS stimulants, including Methylin, can result in overdose and death [see
Overdosage (10)], and this risk is increased with higher doses or unapproved methods
of administration, such as snorting or injection.
9.3
Dependence
Physical Dependence
Methylin may produce physical dependence. Physical dependence is a state that
develops as a result of physiological adaptation in response to repeated drug use,
manifested by withdrawal signs and symptoms after abrupt discontinuation or a
significant dose reduction of a drug.
Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following
prolonged use of CNS stimulants including Methylin include dysphoric mood;
depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased
appetite; and psychomotor retardation or agitation.
Tolerance
Methylin may produce tolerance. Tolerance is a physiological state characterized by a
reduced response to a drug after repeated administration (i.e., a higher dose of a drug
is required to produce the same effect that was once obtained at a lower dose).
10
OVERDOSAGE
Clinical Effects of Overdose
Overdose of CNS stimulants is characterized by the following sympathomimetic effects:
Reference ID: 5507795
• Cardiovascular effects including tachyarrhythmias, and hypertension or
hypotension. Vasospasm, myocardial infarction, or aortic dissection may
precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations.
Serotonin syndrome, seizures, cerebral vascular accidents, and coma may
occur.
• Life-threatening
hyperthermia
(temperatures
greater
than
104°F)
and
rhabdomyolysis may develop.
Overdose Management
Consider the possibility of multiple drug ingestion. Because methylphenidate has a
large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider
contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional
overdose management recommendations.
11
DESCRIPTION
Methylin® Chewable Tablets contain methylphenidate, a CNS stimulant, in the
hydrochloride salt form. The chemical name of methylphenidate hydrochloride is methyl
α-phenyl-2-piperidineacetate hydrochloride. The molecular weight is 269.77. Its
molecular formula is C14H19NO2 • HCl, and it has the following chemical structure.
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its
solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in
alcohol, and slightly soluble in chloroform and in acetone.
Methylin Chewable Tablets are for oral administration, and each tablet contains 2.5 mg,
5 mg or 10 mg of methylphenidate hydrochloride USP (equivalent to 2.2 mg, 4.3 mg, or
8.6 mg of methylphenidate respectively).
Methylin Chewable Tablets contain the following inactive ingredients: aspartame,
maltose, microcrystalline cellulose, guar gum, grape flavor, pregelatinized starch, and
stearic acid.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode
of therapeutic action in ADHD and narcolepsy is not known.
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12.2 Pharmacodynamics
Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The
d-threo enantiomer is more pharmacologically active than the l-threo enantiomer.
Methylphenidate blocks the reuptake of norepinephrine and dopamine into the
presynaptic neuron and increases the release of these monoamines into the
extraneuronal space.
Cardiac Electrophysiology
A formal QT study has not been conducted in subjects taking Methylin.
The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of
Methylin, on the QT interval was evaluated in a double-blind, placebo- and open-label
active
(moxifloxacin)-controlled
study
following
single
doses
of
40
mg
dexmethylphenidate hydrochloride extended-release capsule in 75 healthy volunteers.
Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for
heart rate correction was employed to derive the corrected QT interval (QTcF). The
maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit
of the 90% confidence interval was below 10 ms for all time-matched comparisons
versus placebo. This was below the threshold of clinical concern and there was no
evident exposure response relationship.
12.3 Pharmacokinetics
Absorption
Following
oral
administration
of
Methylin
Chewable
Tablets,
peak
plasma
methylphenidate concentrations are achieved at about 1 to 2 hours. The mean Cmax
following a 20 mg dose is approximately 10 ng/mL.
No clinically significant difference in methlyphenidate pharmacokinetics was observed
between
Methylin
Chewable
Tablets
and
immediate-release
methylphenidate
hydrochloride tablet.
Effect of Food
In a study in adult volunteers investigating the effects of a high-fat meal on the
bioavailability of Methylin Chewable Tablets at a dose of 20 mg, the presence of food
delayed the peak concentrations by approximately 1 hour (1.5 hours, fasted and
2.4 hours, fed). Overall, a high-fat meal increased the AUC of Methylin Chewable
Tablets by about 20%, on average.
Distribution
Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg
for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate.
Elimination
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The mean terminal half-life (t½) of methylphenidate was 3 hours following administration
of 20 mg Methylin Chewable Tablet. The systemic clearance is 0.40 ± 0.12 L/h/kg for d-
methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate.
Metabolism
In humans, methylphenidate is metabolized primarily via deesterification to
alpha-phenylpiperidine acetic acid (PPA, ritalinic acid). The metabolite has little or no
pharmacologic activity.
Excretion
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the
radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting
for approximately 80% of the dose.
The pharmacokinetics of the Methylin Chewable Tablets have been studied in healthy
adult volunteers. The mean terminal half-life (t½) of methylphenidate following
administration of 20 mg Methylin Chewable Tablets is 3 hours.
Specific Populations
Male and Female Patients, Racial Groups, and Age
The effect of gender, race, and age on the pharmacokinetics of methylphenidate after
Methylin administration have not been studied.
Patients with Renal Impairment
There is no experience with the use of Methylin Chewable Tablets in patients with renal
insufficiency. After oral administration of radiolabeled methylphenidate in humans,
methylphenidate was extensively metabolized and approximately 80% of the
radioactivity was excreted in the urine in the form of ritalinic acid. Since renal clearance
is not an important route of methylphenidate clearance, renal insufficiency is expected
to have little effect on the pharmacokinetics of Methylin Chewable Tablets.
Patients with Hepatic Impairment
There is no experience with the use of Methylin Chewable Tablets in patients with
hepatic insufficiency.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused
an increase in hepatocellular adenomas and, in males only, an increase in
hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is
approximately 5 times the maximum recommended human dose (MRDH) given to
adults on a mg/m2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor
type. There was no increase in total malignant hepatic tumors. The mouse strain used
is sensitive to the development of hepatic tumors, and the significance of these results
to humans is unknown.
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Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study
carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which
is approximately 7 times the MRHD (adults) on a mg/m2 basis.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is
sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and
female mice were fed diets containing the same concentration of methylphenidate as in
the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74
mg/kg/day of methylphenidate.
Mutagenesis
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the
in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal
aberration assay using human lymphocytes. Sister chromatid exchanges and
chromosome aberrations were increased, indicative of a weak clastogenic response, in
an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was
negative in vivo in males and females in the mouse bone marrow micronucleus assay.
Impairment of Fertility
No human data on the effect of methylphenidate on fertility are available.
Methylphenidate did not impair fertility in male or female mice that were fed diets
containing the drug in an 18-week continuous breeding study. The study was conducted
at doses up to 160 mg/kg/day, approximately 13 times the maximum recommended
human dose of 60 mg/day given to adults on a mg/m2 basis.
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Each Methylin Chewable Tablet 2.5 mg of methylphenidate hydrochloride is available
as a white to cream colored, grape flavored, rounded square tablet with a convex
surface, debossed with a “2.5” and “CHEW” below it on one side, and a debossed
on
the other side.
Bottles of 100……………….NDC 59630-760-10
Each Methylin Chewable Tablet 5 mg of methylphenidate hydrochloride is available as
a white to cream colored, grape flavored, rounded square tablet with a convex surface,
debossed with a “5” and “CHEW” below it on one side, and a debossed
on the other
side.
Bottles of 100……………….NDC 59630-761-10
Each Methylin Chewable Tablet 10 mg of methylphenidate hydrochloride is available as
a white to cream colored, grape flavored, scored rounded square tablet with a convex
surface, debossed with a “10” and “CHEW” below it on one side, and a debossed
on
the other side.
Bottles of 100……………….NDC 59630-762-10
Reference ID: 5507795
Storage and Handling
Protect from moisture. Dispense in tight container with child-resistant closure.
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15°C and 30°C (59°F
and 86°F) [see USP Controlled Room Temperature].
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Abuse, Misuse, and Addiction
Educate patients and their families about the risks of abuse, misuse, and addiction of
Methylin, which can lead to overdose and death, and proper disposal of any unused
drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2),
Overdosage (10)]. Advise patients to store Methylin in a safe place, preferably locked,
and instruct patients to not give Methylin to anyone else.
Risks to Patients with Serious Cardiac Disease
Advise patients that there are potential risks to patients with serious cardiac disease,
including sudden death with Methylin use. Instruct patients to contact a healthcare
provider immediately if they develop symptoms such as exertional chest pain,
unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings
and Precautions (5.2)].
Increased Blood Pressure and Heart Rate
Advise patients and their caregivers that Methylin can cause elevations of their blood
pressure and pulse rate [see Warnings and Precautions (5.3)].
Psychiatric Adverse Reactions
Advise patients and their caregivers that Methylin, at recommended doses, can cause
psychotic or manic symptoms, even in patients without prior history of psychotic
symptoms or mania [see Warnings and Precautions (5.4)].
Priapism
Advise patients, caregivers, and family members of the possibility of painful or
prolonged penile erections (priapism). Instruct the patient to seek immediate medical
attention in the event of priapism [see Warnings and Precautions (5.5)].
Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including
Raynaud’s Phenomenon] [see Warnings and Precautions (5.6)]
• Instruct patients beginning treatment with Methylin about the risk of peripheral
vasculopathy, including Raynaud’s phenomenon, and associated signs and
symptoms: fingers or toes may feel numb, cool, painful, and/or may change color
from pale, to blue, to red.
• Instruct patients to report to their healthcare provider any new numbness, pain, skin
color change, or sensitivity to temperature in fingers or toes.
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• Instruct patients to call their physician immediately with any signs of unexplained
wounds appearing on fingers or toes while taking Methylin.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for
certain patients.
Long-Term Suppression of Growth in Pediatric Patients
Advise patients, families and caregivers that Methylin can cause slowing of growth and
weight loss [see Warnings and Precautions (5.7)].
Increased Intraocular Pressure (IOP) and Glaucoma
Advise patients that IOP and glaucoma may occur during treatment with Methylin [see
Warnings and Precautions (5.10)].
Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
Advise patients that motor and verbal tics and worsening of Tourette’s syndrome may
occur during treatment with Methylin. Instruct patients to notify their healthcare provider
if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see
Warnings and Precautions (5.11)].
Administration Information
Advise patients to take Methylin Chewable Tablets with at least 8 ounces (a full glass)
of water or other fluid because the tablet may swell and block the throat or esophagus
which may result in choking. Advise patients to discontinue Methylin Chewable Tablets
and seek immediate medical attention if they experience chest pain, vomiting, difficulty
in swallowing, or difficulty in breathing [see Dosage and Administration (2.2) and
Warnings and Precautions (5.11)].
Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy
outcomes in women exposed to Methylin during pregnancy [see Use in Specific
Populations (8.1)].
Methylin is a trademark of Mallinckrodt LLC.
Distributed by:
Shionogi Inc.
Florham Park, NJ 07932
Manufactured by:
MCT-PI-06
SpecGx LLC
L20M18
Webster Groves, MO 63119 USA
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MEDICATION GUIDE
METHYLIN® Chewable Tablets
(METH il in)
(methylphenidate hydrochloride), CII
What is the most important information I should know about Methylin Chewable Tablets?
Methylin Chewable Tablets may cause serious side effects, including:
•
Abuse, misuse, and addiction. Methylin Chewable Tablets has a high chance for abuse and misuse and may lead
to substance use problems, including addiction. Misuse and abuse of Methylin Chewable Tablets, other
methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death.
The risk of overdose and death is increased with higher doses of Methylin Chewable Tablets or when it is used in
ways that are not approved, such as snorting or injection.
o
Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting
treatment with Methylin Chewable Tablets and will monitor you or your child during treatment.
o
Methylin Chewable Tablets may lead to physical dependence after prolonged use, even if taken as directed by
your healthcare provider.
o
Do not give Methylin Chewable Tablets to anyone else. See “What is Methylin Chewable Tablets?” for more
information.
o
Keep Methylin Chewable Tablets in a safe place and properly dispose of any unused medicine. See “How
should I store Methylin Chewable Tablets?” for more information.
o
Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription
medicines, or street drugs.
•
Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or
other serious heart disease.
Your healthcare provider should check you or your child carefully for heart problems before starting and during
treatment with Methylin Chewable Tablets. Tell your healthcare provider if you or your child have any heart
problems, heart disease, or heart defects.
Call your healthcare provider right away or go to the nearest hospital emergency room right away if you or
your child have any signs of heart problems, such as chest pain, shortness of breath, or fainting during
treatment with Methylin Chewable Tablets.
•
Increased blood pressure and heart rate.
Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment
with Methylin Chewable Tablets.
•
Mental (psychiatric) problems, including:
o
new or worse behavior or thought problems
o
new or worse bipolar illness
o
new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic
symptoms
Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide,
bipolar illness, or depression.
Call your healthcare provider right away if you or your child have any new or worsening mental symptoms
or problems during treatment with Methylin Chewable Tablets, especially hearing voices, seeing or
believing things that are not real, or new manic symptoms.
What is Methylin Chewable Tablets?
Methylin Chewable Tablets is a central nervous system (CNS) stimulant prescription medicine used for the treatment of:
•
Attention Deficit Hyperactivity Disorder (ADHD) in people 6 years of age and older. Methylin Chewable Tablets
may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD.
•
a sleep disorder called narcolepsy.
It is not known if Methylin Chewable Tablets is safe and effective in children under 6 years of age.
Methylin Chewable Tablets is a federally controlled substance (CII) because it contains methylphenidate that
can be a target for people who abuse prescription medicines or street drugs. Keep Methylin Chewable Tablets in a
Reference ID: 5507795
safe place to protect it from theft. Never give your Methylin Chewable Tablets to anyone else, because it may cause
death or harm them. Selling or giving away Methylin Chewable Tablets may harm others and is against the law.
Do not take Methylin Chewable Tablets if you or your child:
• are allergic to methylphenidate or any of the ingredients in Methylin Chewable Tablets. See the end of this
Medication Guide for a complete list of ingredients in Methylin Chewable Tablets.
• are taking or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI).
Before taking Methylin Chewable Tablets tell your healthcare provider about all of your or your child’s medical
conditions, including if you or your child:
•
have heart problems, heart disease, heart defects, or high blood pressure
•
have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide,
bipolar illness, or depression
•
have circulation problems in fingers or toes
•
have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision
(farsightedness)
•
have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or
Tourette’s syndrome
•
have trouble swallowing
•
have phenylketonuria (PKU). The artificial sweetener aspartame in Methylin Chewable Tablets contains
phenylalanine, which can be harmful to people with PKU.
•
are pregnant or plan to become pregnant. It is not known if Methylin Chewable Tablets will harm your unborn baby.
o
There is a pregnancy registry for women who are exposed to Methylin Chewable Tablets during pregnancy. The
purpose of the registry is to collect information about the health of women exposed to Methylin Chewable
Tablets and their baby. If you or your child becomes pregnant during treatment with Methylin Chewable Tablets,
talk to your healthcare provider about registering with the National Pregnancy Registry for ADHD Medications at
1-866-961-2388 or visit online at www.womensmentalhealth.org/research/pregnancyregistry/adhd-medications/.
•
are breastfeeding or plan to breastfeed. Methylin passes into breast milk. Talk to your healthcare provider about the
best way to feed the baby during treatment with Methylin Chewable Tablets.
Tell your healthcare provider about all of the medicines that you or your child take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
Methylin Chewable Tablets and some medicines may interact with each other and cause serious side effects.
Sometimes the doses of other medicines will need to be during treatment with Methylin Chewable Tablets. Your
healthcare provider will decide whether Methylin Chewable Tablets can be taken with other medicines.
Especially tell your healthcare provider if you or your child take an monoamine oxidase inhibitor (MAOI).
Know the medicines that you or your child take. Keep a list of your or your child’s medicines with you to show your or
your child’s healthcare provider and pharmacist when you or your child get a new medicine. Do not start any new
medicine during treatment with Methylin Chewable Tablets without talking to your or your child’s healthcare
provider first.
How should I take Methylin Chewable Tablets?
• Take Methylin Chewable Tablets exactly as prescribed by your healthcare provider. Your healthcare provider
may change the dose if needed.
• For children 6 years of age and older:
o
Take Methylin Chewable Tablets 2 times a day, 30 to 45 minutes before breakfast and lunch.
• For adults:
o
Take Methylin Chewable tablets 2 or 3 times a day, 30 to 45 minutes before a meal.
o
If you have trouble sleeping when Methylin Chewable Tablets is taken late in the day, take your last dose before
6 p.m.
• Chew Methylin Chewable Tablets well and swallow with at least 8 ounces (a full glass) of water or other liquid.
o
Do not swallow Methylin Chewable Tablets whole.
o
If you do not take enough liquid with Methylin Chewable Tablets, this can cause you to choke. Stop taking
Methylin Chewable Tablets and get medical help right away if you or your child have chest pain, vomiting,
trouble swallowing, or trouble breathing after taking Methylin Chewable Tablets.
• If you or your child takes too much Methylin Chewable Tablets, call your healthcare provider or Poison Help line at 1-
800-222-1222 or go to the nearest hospital emergency room right away.
Reference ID: 5507795
What are the possible side effects of Methylin Chewable Tablets?
Methylin Chewable Tablets may cause serious side effects, including:
• See “What is the most important information I should know about Methylin Chewable Tablets?”
• Painful and prolonged erections (priapism). Priapism that may require surgery has happened in males who take
products that contain methylphenidate. If you or your child develops priapism, get medical help right away.
• Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon).
Signs and symptoms may include:
o fingers or toes may feel numb, cool, or painful
o fingers or toes may change color from pale, to blue, to red
Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to
temperature in the fingers or toes or if you or your child have any signs of unexplained wounds appearing on fingers
or toes during treatment with Methylin Chewable Tablets.
• Slowing of growth (height and weight) in children. Children should have their height and weight checked often
during treatment with Methylin Chewable Tablets. Your healthcare provider may stop your child’s treatment with
Methylin Chewable Tablets if your child is not growing or gaining weight as expected.
• Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or
your child develop changes in your vision or eye pain, swelling, or redness.
• New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get
any new or worsening tics or worsening Tourette’s syndrome during treatment with Methylin Chewable Tablets.
The most common side effects of Methylin Chewable Tablets include:
• increased heart rate
• irregular heartbeat (palpitations)
• headache
• trouble sleeping
• anxiety
• sweating
•
weight loss
•
decreased appetite
•
dry mouth
•
nausea
•
stomach (abdominal) pain
These are not all possible side effects of Methylin Chewable Tablets.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Methylin Chewable Tablets?
• Store Methylin Chewable Tablets at room temperature between 68° to 77°F (20° to 25°C).
• Store Methylin Chewable Tablets in a safe place, like a locked cabinet.
• Protect Methylin Chewable Tablets from moisture.
• Dispose of remaining, unused, or expired Methylin Chewable Tablets by a medicine take-back program at a U.S.
Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized
collector is available, mix Methylin Chewable Tablets with an undesirable, nontoxic substance such as dirt, cat litter,
or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a
sealed plastic bag and throw away Methylin Chewable Tablets in the household trash. Visit ww.fda.gov/drugdisposal
for additional information on disposal of unused medicines.
Keep Methylin Chewable Tablets and all medicines out of the reach of children.
General information about the safe and effective use of Methylin Chewable Tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Methylin
Chewable Tablets for a condition for which it was not prescribed. Do not give Methylin Chewable Tablets to other
people, even if they have the same symptoms. It may harm them, and it is against the law. You can ask your pharmacist
or healthcare provider for information about Methylin Chewable Tablets that is written for health professionals.
What are the ingredients in Methylin Chewable Tablets?
Active Ingredient: methylphenidate hydrochloride
Inactive Ingredients: aspartame, maltose, microcrystalline cellulose, guar gum, grape flavor, pregelatinized starch, and
stearic acid.
Distributed by: Shionogi Inc., Florham Park, NJ 07932
Manufactured by: SpecGx LLC, Webster Groves, MO 63119 USA
For more information, you may also contact Shionogi Inc. at 1-800-849-9707 or visit the website at www.methylinrx.com.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised 1/2025
Reference ID: 5507795
| custom-source | 2025-02-12T15:48:25.404698 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2025/21475s013lbl.pdf', 'application_number': 21475, 'submission_type': 'SUPPL ', 'submission_number': 13} |
80,821 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEMEROL™ INJECTION safely and effectively. See full prescribing
information for DEMEROL INJECTION.
DEMEROL™ (meperidine hydrochloride injection), for subcutaneous,
intramuscular, and intravenous use, CII
Initial U.S. Approval: 1942
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM
USE OF DEMEROL INJECTION
See full prescribing information for complete boxed warning.
• DEMEROL Injection exposes users to risks of addiction, abuse, and
misuse, which can lead to overdose and death. Assess patient’s risk
before prescribing and reassess regularly for these behaviors and
conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur
with use of DEMEROL Injection, especially during initiation or
following a dosage increase. To reduce the risk of respiratory
depression, proper dosing and titration of DEMEROL Injection are
essential. (5.2)
• Concomitant use of opioids with benzodiazepines or other central
nervous system (CNS) depressants, including alcohol, may result in
profound sedation, respiratory depression, coma, and death. Reserve
concomitant prescribing for use in patients for whom alternative
treatment options are inadequate. (5.3, 7)
• If opioid use is required for an extended period of time in a pregnant
woman, advise the patient of the risk of Neonatal Opioid Withdrawal
Syndrome, which may be life-threatening if not recognized and
treated. Ensure that management by neonatology experts will be
available at delivery. (5.4)
• Concomitant use with CYP3A4 inhibitors (or discontinuation of
CYP3A4 inducers) can result in a fatal overdose of meperidine. (5.5, 7)
• Concomitant use of DEMEROL Injection with Monoamine oxidase
(MAO) inhibitors can result in coma, severe respiratory depression,
cyanosis and hypotension. Use of DEMEROL Injection with MAO
inhibitors is contraindicated. (4, 5.6, 7)
-------------------------- RECENT MAJOR CHANGES --------------------------
Boxed Warning
12/2023
Indications and Usage (1)
12/2023
Dosage and Administration (2.1, 2.2)
12/2023
Warnings and Precautions (5.7)
12/2023
--------------------------- INDICATIONS AND USAGE --------------------------
DEMEROL Injection is indicated for preoperative medication, support of
anesthesia, for obstetrical analgesia, and for the management of pain severe
enough to require an opioid analgesic and for which alternative treatments are
inadequate. (1)
Limitations of Use (1)
Because of the risks of addiction, abuse, and misuse with opioids, which can
occur at any dosage or duration (5.1), reserve DEMEROL Injection for use in
patients for whom alternative treatment options [e.g., non-opioid analgesics or
opioid combination products]:
•
Have not been tolerated or are not expected to be tolerated,
•
Have not provided adequate analgesia or are not expected to provide
adequate analgesia.
DEMEROL Injection should not be used for an extended period of time unless
the pain remains severe enough to require an opioid analgesic and for which
alternative treatment options continue to be inadequate.
Use of DEMEROL Injection for an extended period of time may increase the
risk of toxicity (e.g., seizures) from the accumulation of the meperidine
metabolite, normeperidine.
----------------------- DOSAGE AND ADMINISTRATION ---------------------
• DEMEROL Injection should be prescribed only by healthcare professionals
who are knowledgeable about the use of opioids and how to mitigate the
associated risks. (2.1)
• Use the lowest effective dosage for the shortest duration of time consistent
with individual patient treatment goals. Reserve titration to higher doses of
DEMEROL Injection for patients in whom lower doses are insufficiently
effective and in whom the expected benefits of using a higher dose opioid
clearly outweigh the substantial risks. (2.1, 5)
• Many acute pain conditions (e.g., the pain that occurs with a number of
surgical procedures or acute musculoskeletal injuries) require no more than
a few days of an opioid analgesic. Clinical guidelines on opioid prescribing
for some acute pain conditions are available. (2.1)
• Initiate the dosing regimen for each patient individually, taking into
account the patient’s underlying cause and severity of pain, prior analgesic
treatment and response, and risk factors for addiction, abuse, and misuse.
(2.1, 5.2)
• Respiratory depression can occur at any time during opioid therapy,
especially when initiating and following dosage increases with DEMEROL
Injection. Consider this risk when selecting an initial dose and when
making dose adjustments. (2.2, 5.3)
• For Relief of Pain:
Titrate the dose based upon the individual patient’s response to their initial
dose of DEMEROL Injection. (2.2, 5)
Adults: 50 mg to 150 mg intramuscularly or subcutaneously every 3 to
4 hours. (2.2)
Children: 0.5 mg/lb to 0.8 mg/lb intramuscularly or subcutaneously up to
the adult dose every 3 to 4 hours. (2.2)
• Preoperative Medication:
Adults: 50 mg to 100 mg intramuscularly or subcutaneously, 30 to
90 minutes before beginning anesthesia. (2.3)
Children: 0.5 mg/lb to 1 mg/lb intramuscularly or subcutaneously up to the
adult dose, 30 to 90 minutes before beginning anesthesia. (2.3)
• Obstetrical Analgesia:
50 mg to 100 mg intramuscularly or subcutaneously; may be repeated at
1 to 3 hour intervals. (2.4)
• Do not abruptly discontinue DEMEROL Injection in a physically-
dependent patient. (2.2)
------------------------ DOSAGE FORMS AND STRENGTHS -----------------
• Injectable, Carpuject™ Single-Dose cartridge with Luer Lock for the
Carpuject Syringe System, to be used ONLY with Carpuject™ Holder: 25
mg/mL, 50 mg/mL, 75 mg/mL, and 100 mg/mL. (3)
• Injectable, Multiple-dose vials: 1,500 mg/30 mL (50 mg/mL). (3)
• Injectable, NexJect™ Single-dose Prefilled Syringe with Luer Lock: 25
mg/mL and 50 mg/mL. (3)
----------------------------- CONTRAINDICATIONS -----------------------------
• Significant respiratory depression. (4)
• Acute or severe bronchial asthma in an unmonitored setting or in absence
of resuscitative equipment. (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of
MAOIs within the last 14 days. (7)
• Known or suspected gastrointestinal obstruction, including paralytic
ileus. (4)
• Hypersensitivity to meperidine or to any other ingredients of the product.
(4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia
(OIH) occurs when an opioid analgesic paradoxically causes an increase in
pain, or an increase in sensitivity to pain. If OIH is suspected, carefully
consider appropriately decreasing the dose of the current opioid analgesic
or opioid rotation. (5.7)
• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs:
Potentially life-threatening condition could result from concomitant
serotonergic drug administration. Discontinue DEMEROL Injection if
serotonin syndrome is suspected. (5.8)
• Life-Threatening Respiratory Depression in Patients with Chronic
Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:
Monitor closely, particularly during initiation and titration. (5.9)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of
corticosteroids, and wean patient off of the opioid. (5.10)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid
use of DEMEROL Injection in patients with circulatory shock. (5.11)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain
Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and
respiratory depression. Avoid use of DEMEROL Injection in patients with
impaired consciousness or coma. (5.12)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions were lightheadedness, dizziness, sedation,
nausea, vomiting and sweating. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc.
at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Reference ID: 5507521
• Geriatric Patients: Use caution during dose selection, starting at the low
------------------------------ DRUG INTERACTIONS ------------------------------
end of the dosing range while carefully monitoring for side effects. (8.5)
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid
use with DEMEROL Injection because they may reduce analgesic effect of
See 17 for PATIENT COUNSELING INFORMATION.
DEMEROL Injection or precipitate withdrawal symptoms. (7)
Revised: 10/2024
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
• Pregnancy: May cause fetal harm. (8.1)
Reference ID: 5507521
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM
USE OF DEMEROL
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage and Administration Instructions
2.2
For Management of Pain
2.3
For Preoperative Medication
2.4
For Support of Anesthesia
2.5
For Obstetrical Analgesia
2.6
Dosage Modifications with Concomitant Phenothiazines
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Addiction, Abuse, and Misuse
5.2
Life-Threatening Respiratory Depression
5.3
Risks from Concomitant Use with Benzodiazepines or Other
CNS Depressants
5.4
Neonatal Opioid Withdrawal Syndrome
5.5
Risks of Concomitant Use or Discontinuation of Cytochrome
P450 3A4 Inhibitors and Inducers
5.6
Fatal Interaction with Monoamine Oxidase Inhibitors
5.7
Opioid-Induced Hyperalgesia and Allodynia
5.8
Serotonin Syndrome with Concomitant Use of Serotonergic
Drugs
5.9
Life-Threatening Respiratory Depression in Patients with
Chronic Pulmonary Disease or in Elderly, Cachectic, or
Debilitated Patients
5.10
Adrenal Insufficiency
5.11
Severe Hypotension
5.12
Risks of Use in Patients with Increased Intracranial Pressure,
Brain Tumors, Head Injury, or Impaired Consciousness
5.13
Risks of Use in Patients with Gastrointestinal Conditions
5.14
Increased Risk of Seizures in Patients with Seizure Disorders
5.15
Withdrawal
5.16
Risks of Driving and Operating Machinery
5.17
Risks in Patients with Pheochromocytoma
5.18
Risk of Use in Patients with Atrial Flutter and Other
Supraventricular Tachycardias
5.19
Intravenous Use
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 5507521
FULL PRESCRIBING INFORMATION
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF DEMEROL
Addiction, Abuse, and Misuse
Because the use of DEMEROL Injection exposes patients and other users to the risks of opioid
addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior
to prescribing and reassess all patients regularly for the development of these behaviors and
conditions [see Warnings and Precautions (5.1)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of DEMEROL
Injection, especially during initiation or following a dosage increase. To reduce the risk of
respiratory depression, proper dosing and titration of DEMEROL Injection are essential [see
Warnings and Precautions (5.2)].
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)
depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and
death. Reserve concomitant prescribing of DEMEROL Injection and benzodiazepines or other CNS
depressants for use in patients for whom alternative treatment options are inadequate [see
Warnings and Precautions (5.3), Drug Interactions (7)].
Neonatal Opioid Withdrawal Syndrome (NOWS)
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of
the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized
and treated. Ensure that management by neonatology experts will be available at delivery [see
Warnings and Precautions (5.4)].
Cytochrome P450 3A4 Interaction
The concomitant use of DEMEROL Injection with all cytochrome P450 3A4 inhibitors may result
in an increase in meperidine plasma concentrations, which could increase or prolong adverse
reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a
concomitantly used cytochrome P450 3A4 inducer may result in an increase in meperidine plasma
concentration. Monitor patients receiving DEMEROL Injection and any CYP3A4 inhibitor or
inducer [see Warnings and Precautions (5.5), Drug Interactions (7)].
Concomitant Use of DEMEROL Injection with Monoamine Oxidase (MAO) Inhibitors
Concomitant use of DEMEROL Injection with monoamine oxidase (MAO) inhibitors can result in
coma, severe respiratory depression, cyanosis, and hypotension. Use of DEMEROL Injection with
MAO inhibitors within last 14 days is contraindicated [see Contraindications (4), Warnings and
Precautions (5.6), Drug Interactions (7)].
1
INDICATIONS AND USAGE
DEMEROL Injection is indicated for preoperative medication, support of anesthesia, and obstetrical
analgesia.
Reference ID: 5507521
DEMEROL Injection is indicated for the management of pain severe enough to require an opioid
analgesic and for which alternative treatments are inadequate.
Limitations of Use:
Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or
duration [see Warnings and Precautions (5.1)], reserve DEMEROL Injection for use in patients for whom
alternative treatment options (e.g., non-opioid analgesics or opioid combination products):
• Have not been tolerated or are not expected to be tolerated,
• Have not provided adequate analgesia or are not expected to provide adequate analgesia.
DEMEROL Injection should not be used for an extended period of time unless the pain remains severe
enough to require an opioid analgesic and for which alternative treatment options continue to be
inadequate.
Use of DEMEROL Injection for an extended period of time may increase the risk of toxicity (e.g.,
seizures) from the accumulation of the meperidine metabolite, normeperidine.
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage and Administration Instructions
•
DEMEROL Injection should be prescribed only by healthcare professionals who are knowledgeable
about the use of opioids and how to mitigate the associated risks.
•
Use the lowest effective dosage for the shortest duration of time consistent with individual patient
treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid
doses increase, reserve titration to higher doses of DEMEROL Injection for patients in whom lower
doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid
clearly outweigh the substantial risks.
•
Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute
musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines
on opioid prescribing for some acute pain conditions are available.
•
There is variability in the opioid analgesic dose and duration needed to adequately manage pain due
both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient
individually, taking into account the patient's underlying cause and severity of pain, prior analgesic
treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and
Precautions (5.1)].
•
Respiratory depression can occur at any time during opioid therapy, especially when initiating and
following dosage increases with DEMEROL Injection. Consider this risk when selecting an initial
dose and when making dose adjustments [see Warnings and Precautions (5)].
•
Inspect DEMEROL Injection for particulate matter and discoloration prior to administration. Do not
use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a
precipitate.
2.2
For Management of Pain
Initial Dosage
Dosage should be adjusted according to the severity of the pain and the response of the patient. While
subcutaneous administration is suitable for occasional use, intramuscular administration is preferred when
Reference ID: 5507521
repeated doses are required. If intravenous administration is required, dosage should be decreased and the
injection made very slowly, preferably utilizing a diluted solution.
Adults: Initiate treatment in a dosing range of 50 mg to 150 mg intramuscularly or subcutaneously every 3
to 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Elderly
patients should usually be given meperidine at the lower end of the dose range and observed closely.
Children: Initiate treatment in a dosing range of 0.5 mg/lb to 0.8 mg/lb intramuscularly or subcutaneously
up to the adult dose, every 3 to 4 hours as necessary, and at the lowest dose necessary to achieve adequate
analgesia.
Titration and Maintenance of Therapy
Titrate the dose based upon the individual patient’s response to their initial dose of DEMEROL Injection.
Individually titrate DEMEROL Injection to a dose that provides adequate analgesia and minimizes
adverse reactions. Continually reevaluate patients receiving DEMEROL Injection to assess the
maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as
well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions
(5.1, 5.15)]. Frequent communication is important among the prescriber, other members of the health and
care team, the patient, and the caregiver/family during periods of changing analgesic requirements,
including initial titration.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain
before increasing the DEMEROL Injection dosage. If after increasing the dosage, unacceptable opioid-
related adverse reactions are observed (including an increase in pain after a dosage increase), consider
reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate
balance between management of pain and opioid-related adverse reactions.
Discontinuation of DEMEROL Injection
When a patient who has been taking DEMEROL Injection regularly and may be physically-dependent no
longer requires therapy with DEMEROL Injection, taper the dose gradually, by 25% to 50% every 2 to
4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these
signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the
interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue
DEMEROL Injection in a physically-dependent patient [see Warnings and Precautions (5.15), Drug
Abuse and Dependence (9.3)].
2.3
For Preoperative Medication
Adults: The usual dosage is 50 mg to 100 mg intramuscularly or subcutaneously, 30 to 90 minutes before
the beginning of anesthesia. Elderly patients should usually be given meperidine at the lower end of the
dose range and observed closely.
Children: The usual dosage is 0.5 mg/lb to 1 mg/lb intramuscularly or subcutaneously up to the adult
dose, 30 to 90 minutes before the beginning of anesthesia.
2.4
For Support of Anesthesia
Repeated slow intravenous Injections of fractional doses (e.g., 10 mg/mL) or continuous intravenous
infusion of a more dilute solution (e.g., 1 mg/mL) should be used. The dose should be titrated to the needs
of the patient and will depend on the premedication and type of anesthesia being employed, the
characteristics of the particular patient, and the nature and duration of the operative procedure. Elderly
patients should usually be given meperidine at the lower end of the dose range and observed closely.
Reference ID: 5507521
2.5
For Obstetrical Analgesia
The usual dosage is 50 mg to 100 mg intramuscularly or subcutaneously when pain becomes regular, and
may be repeated at 1- to 3-hour intervals.
2.6
Dosage Modifications with Concomitant Phenothiazines
The dose of DEMEROL Injection should be proportionately reduced (usually by 25 to 50 percent) when
administered concomitantly with phenothiazines and many other tranquilizers since they potentiate the
action of DEMEROL Injection.
3
DOSAGE FORMS AND STRENGTHS
DEMEROL Injection is a clear, colorless, sterile aqueous solution, available in the following dosage
forms and strengths:
•
Single-dose Carpuject™ cartridge with Luer Lock for the Carpuject Syringe System, ONLY to be
used with Carpuject™ Holder, and available in the following strengths: 25 mg/mL, 50 mg/mL,
75 mg/mL, and 100 mg/mL.
•
Multiple-dose vials containing 0.1% metacresol as a preservative, available in the following
strength: 1,500 mg/30 mL (50 mg/mL).
•
Single-dose NexJectTM Prefilled Syringe with Luer Lock, available in the following strengths:
25 mg/mL and 50 mg/mL.
4
CONTRAINDICATIONS
DEMEROL Injection is contraindicated in patients with:
•
Significant respiratory depression [see Warnings and Precautions (5.2)]
•
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment [see Warnings and Precautions (5.9)]
•
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
[see Warnings and Precautions (5.6), Drug Interactions (7)]
•
Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and
Precautions (5.13)]
•
Hypersensitivity to meperidine (e.g., anaphylaxis) [see Adverse Reactions (6)]
5
WARNINGS AND PRECAUTIONS
5.1
Addiction, Abuse, and Misuse
DEMEROL Injection contains meperidine, a Schedule II controlled substance. As an opioid, DEMEROL
Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence
(9)].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed DEMEROL Injection. Addiction can occur at recommended dosages and if the drug is misused
or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing DEMEROL
Injection, and monitor all patients receiving DEMEROL Injection for the development of these behaviors
and conditions. Risks are increased in patients with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for
Reference ID: 5507521
these risks should not, however, prevent the proper management of pain in any given patient. Patients at
increased risk may be prescribed opioids such as DEMEROL Injection but use in such patients
necessitates intensive counseling about the risks and proper use of DEMEROL Injection along with
intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.
Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact
local state professional licensing board or state-controlled substances authority for information on how to
prevent and detect abuse or diversion of this product.
5.2
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even
when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead
to respiratory arrest and death. Management of respiratory depression may include close observation,
supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see
Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can
exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of
DEMEROL Injection, the risk is greatest during the initiation of therapy or following a dosage increase.
To reduce the risk of respiratory depression, proper dosing and titration of DEMEROL Injection are
essential [see Dosage and Administration (2.3)]. Overestimating the DEMEROL Injection dosage when
converting patients from another opioid product can result in a fatal overdose with the first dose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related
hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present
with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and
Administration (2.2)].
5.3
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of
DEMEROL Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non
benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for
use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines
increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar
pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS
depressant drugs with opioid analgesics [see Drug Interactions (7)].
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an
opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In
patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or
other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If
an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant,
prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor
patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when
DEMEROL Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit
Reference ID: 5507521
drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the
benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use
disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated
with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].
5.4
Neonatal Opioid Withdrawal Syndrome
Use of DEMEROL Injection for an extended period of time during pregnancy can result in withdrawal in
the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be
life-threatening if not recognized and treated, and requires management according to protocols developed
by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage
accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal
opioid withdrawal syndrome and ensure that management by neonatology experts will be available at
delivery [see Use in Specific Populations (8.1)].
5.5
Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and
Inducers
Concomitant use of DEMEROL Injection with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g.,
erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may
increase plasma concentrations of meperidine and prolong opioid adverse reactions, which may cause
potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an
inhibitor is added after a stable dose of DEMEROL Injection is achieved. Similarly, discontinuation of a
CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in DEMEROL Injection treated
patients may increase meperidine plasma concentrations and prolong opioid adverse reactions. When
using DEMEROL Injection with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in DEMEROL
Injection treated patients, monitor patients closely at frequent intervals and consider dosage reduction of
DEMEROL Injection until stable drug effects are achieved [see Drug Interactions (7)].
Concomitant use of DEMEROL Injection with CYP3A4 inducers or discontinuation of a CYP3A4
inhibitor could decrease meperidine plasma concentrations, decrease opioid efficacy or, possibly, lead to a
withdrawal syndrome in a patient who had developed physical dependence to meperidine. When using
DEMEROL Injection with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients
closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate
analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].
5.6
Fatal Interaction with Monoamine Oxidase Inhibitors
Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or
those who have recently received such agents. Therapeutic doses of meperidine have occasionally
precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such
agents within 14 days. The mechanism of these reactions is unclear but may be related to a preexisting
hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis,
and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with
agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors, and impaired consciousness may also
occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions,
tachycardia, hyperpyrexia, and hypertension.
Do not use DEMEROL Injection in patients taking MAOIs or within 14 days of stopping such treatment.
Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of
intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and
safety of narcotic antagonists in the treatment of these reactions is unknown.
Reference ID: 5507521
5.7
Opioid-Induced Hyperalgesia and Allodynia
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in
pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for
increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH
include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels
of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These
symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid
tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though
the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.
Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and
allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the
dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid
moiety) [see Dosage and Administration (2), Warnings and Precautions (5.15)].
5.8
Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during
concomitant use of meperidine with serotonergic drugs. Serotonergic drugs include selective serotonin
reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic
antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic
neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants
(i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO
inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and
intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage
range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma),
autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting,
diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of
concomitant use but may occur later than that. Discontinue DEMEROL Injection if serotonin syndrome is
suspected.
5.9
Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in
Elderly, Cachectic, or Debilitated Patients
The use of DEMEROL Injection in patients with acute or severe bronchial asthma in an unmonitored
setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: DEMEROL Injection treated patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory
reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased
respiratory drive including apnea, even at recommended dosages of DEMEROL Injection [see Warnings
and Precautions (5.2)].
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur
in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered
clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].
Reference ID: 5507521
Monitor such patients closely, particularly when initiating and titrating DEMEROL Injection and when
DEMEROL Injection is given concomitantly with other drugs that depress respiration [see Warnings and
Precautions (5.2)].
Alternatively, consider the use of non-opioid analgesics in these patients.
5.10
Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one
month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs
including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal
insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal
insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient
off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal
function recovers. Other opioids may be tried as some cases reported use of a different opioid without
recurrence of adrenal insufficiency. The information available does not identify any particular opioids as
being more likely to be associated with adrenal insufficiency.
5.11
Severe Hypotension
DEMEROL Injection may cause severe hypotension including orthostatic hypotension and syncope in
ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has
already been compromised by a reduced blood volume or concurrent administration of certain CNS
depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these
patients for signs of hypotension after initiating or titrating the dosage of DEMEROL Injection. In
patients with circulatory shock, DEMEROL Injection may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of DEMEROL Injection in patients with circulatory
shock.
5.12
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury,
or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of
increased intracranial pressure or brain tumors), DEMEROL Injection may reduce respiratory drive, and
the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for worsening
of signs of increasing intracranial pressure. Monitor such patients for signs of sedation and respiratory
depression, particularly when initiating therapy with DEMEROL Injection.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of DEMEROL
Injection in patients with impaired consciousness or coma.
5.13
Risks of Use in Patients with Gastrointestinal Conditions
DEMEROL Injection is contraindicated in patients with known or suspected gastrointestinal obstruction,
including paralytic ileus.
The meperidine in DEMEROL Injection may cause spasm of the sphincter of Oddi. Opioids may cause
increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for
worsening symptoms.
5.14
Increased Risk of Seizures in Patients with Seizure Disorders
The meperidine in DEMEROL Injection may increase the frequency of seizures in patients with seizure
disorders and may increase the risk of seizures occurring in other clinical settings associated with
seizures. Monitor patients with a history of seizure disorders for worsened seizure control during
Reference ID: 5507521
-
DEMEROL Injection therapy. Prolonged meperidine use may increase the risk of toxicity (e.g., seizures)
from the accumulation of the meperidine metabolite, normeperidine.
5.15
Withdrawal
Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial
agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic,
including DEMEROL Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics
may reduce the analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing DEMEROL Injection, gradually taper the dosage [see Dosage and Administration
(2.2)]. Do not abruptly discontinue DEMEROL Injection [see Drug Abuse and Dependence (9.3)].
5.16
Risks of Driving and Operating Machinery
DEMEROL Injection may impair the mental or physical abilities needed to perform potentially hazardous
activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous
machinery unless they are tolerant to the effects of DEMEROL Injection and know how they will react to
the medication.
5.17
Risks in Patients with Pheochromocytoma
In patients with pheochromocytoma, meperidine has been reported to provoke hypertension.
5.18
Risk of Use in Patients with Atrial Flutter and Other Supraventricular Tachycardias
DEMEROL Injection should be used with caution in patients with atrial flutter and other supraventricular
tachycardias because of a possible vagolytic action which may produce a significant increase in the
ventricular response rate.
5.19
Intravenous Use
If necessary, meperidine may be given intravenously, but the injection should be given very slowly,
preferably in the form of a diluted solution. Rapid intravenous injection of narcotic analgesics, including
meperidine, increases the incidence of adverse reactions; severe respiratory depression, apnea,
hypotension, peripheral circulatory collapse, and cardiac arrest have occurred. Meperidine should not be
administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled
respiration are immediately available. When meperidine is given parenterally, especially intravenously,
the patient should be lying down.
6
ADVERSE REACTIONS
The following serious adverse reactions are described, or described in greater detail, in other sections:
• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7)]
• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions
(5.8)]
• Adrenal Insufficiency [see Warnings and Precautions (5.10)]
• Severe Hypotension [see Warnings and Precautions (5.11)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)]
Reference ID: 5507521
• Seizures [see Warnings and Precautions (5.14)]
• Withdrawal [see Warnings and Precautions (5.15)]
The following adverse reactions associated with the use of meperidine were identified in clinical studies
or postmarketing reports. Because some of these reactions were reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
The major hazards of meperidine, as with other opioid analgesics, are respiratory depression and, to a
lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have occurred.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea,
vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those
who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse
reactions in ambulatory patients may be alleviated if the patient lies down.
Other adverse reactions include:
Nervous System: Mood changes (e.g., euphoria, dysphoria), weakness, headache, agitation, tremor,
involuntary muscle movements (e.g., muscle twitches, myoclonus), severe convulsions, transient
hallucinations and disorientation, confusion, delirium, visual disturbances.
Inadvertent injection about a nerve trunk may result in sensory-motor paralysis which is usually, though
not always, transitory.
Gastrointestinal: Dry mouth, constipation, biliary tract spasm.
Cardiovascular: Flushing of the face, tachycardia, bradycardia, palpitation, hypotension [see Warnings
and Precautions (5.18)], syncope, phlebitis following intravenous injection.
Genitourinary: Urinary retention.
Allergic: Pruritus, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection.
Hypersensitivity reactions, anaphylaxis.
Histamine release leading to hypotension and/or tachycardia, flushing, sweating, and pruritus.
Other: Pain at injection site; local tissue irritation and induration following subcutaneous injection,
particularly when repeated; antidiuretic effect.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been
reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often
following greater than one month of use.
Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended
period of time [see Clinical Pharmacology (12.2)].
Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy
of any duration [see Warnings and Precautions (5.7)].
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were
in patients with at least one predisposing risk factor (e.g., diabetes).
Reference ID: 5507521
7
DRUG INTERACTIONS
Table 1 includes clinically significant drug interactions with DEMEROL Injection.
Table 1: Clinically Significant Drug Interactions with DEMEROL Injection
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:
Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAO)
inhibitors or those who have recently received such agents. Therapeutic doses of meperidine have
occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who
have received such agents within 14 days. The mechanism of these reactions is unclear but may
be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma,
severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of
acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia,
sweating, tremors, and impaired consciousness may also occur. In other reactions the
predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia,
and hypertension [see Warnings and Precautions (5.6)].
Intervention:
Do not use DEMEROL Injection in patients taking MAOIs or within 14 days of stopping such
treatment.
Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the
addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia.
The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.
Examples:
Phenelzine, tranylcypromine, linezolid
Inhibitors of CYP3A4 and CYP2B6
Clinical Impact:
The concomitant use of DEMEROL Injection and CYP3A4 or CYP2B6 inhibitors can increase
the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These
effects could be more pronounced with concomitant use of DEMEROL Injection and CYP2B6
and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of DEMEROL
Injection is achieved [see Warnings and Precautions (5.5)].
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the meperidine plasma
concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased
opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to
meperidine.
Intervention:
If concomitant use is necessary, consider dosage reduction of DEMEROL Injection until stable
drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent
intervals.
If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the DEMEROL Injection
dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal.
Examples:
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconizole), protease
inhibitors (e.g., ritonavir)
CYP3A4 and CYP2B6 Inducers
Clinical Impact:
The concomitant use of DEMEROL Injection and CYP3A4 inducers or CYP2B6 inducers can
decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3)], resulting in
decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical
dependence to meperidine [see Warnings and Precautions (5.5)].
After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the
meperidine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could
increase or prolong both the therapeutic effects and adverse reactions and may cause serious
respiratory depression.
Intervention:
If concomitant use is necessary, consider increasing the DEMEROL Injection dosage until stable
drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6
inducer is discontinued, consider DEMEROL Injection dosage reduction and monitor for signs of
respiratory depression.
Examples:
Rifampin, carbamazepine, phenytoin
Reference ID: 5507521
Table 1: Clinically Significant Drug Interactions with DEMEROL Injection
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS
depressants, including alcohol, can increase the risk of hypotension respiratory depression,
profound sedation, coma, and death [see Warnings and Precautions (5.3)].
Intervention:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum required. Monitor patients
closely for signs of respiratory depression and sedation.
Examples:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants,
general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter
system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention:
If concomitant use is warranted, carefully observe the patient, particularly during treatment
initiation and dose adjustment. Discontinue DEMEROL Injection if serotonin syndrome is
suspected.
Examples:
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors
(SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect
the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle
relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those
intended to treat psychiatric disorders and also others, such as linezolid and intravenous
methylene blue).
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:
May reduce the analgesic effect of DEMEROL Injection and/or precipitate withdrawal
symptoms.
Intervention:
Avoid concomitant use.
Examples:
Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:
Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and
produce an increased degree of respiratory depression.
Intervention:
Monitor patients for signs of respiratory depression that may be greater than otherwise expected
and decrease the dosage of DEMEROL Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the
dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe
constipation, which may lead to paralytic ileus.
Intervention:
Monitor patients for signs of urinary retention or reduced gastric motility when DEMEROL
Injection is used concomitantly with anticholinergic drugs.
Acyclovir
Clinical Impact:
The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its
metabolite, normeperidine.
Intervention:
If concomitant use of acyclovir and DEMEROL Injection is necessary, monitor patients for
respiratory depression and sedation at frequent intervals.
Cimetidine
Clinical Impact:
The concomitant use of cimetidine may reduce the clearance and volume of distribution of
meperidine also the formation of the metabolite, normeperidine, in healthy subjects
Intervention:
If concomitant use cimetidine and DEMEROL Injection is necessary, monitor patients for
respiratory depression and sedation at frequent intervals.
Reference ID: 5507521
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid
withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with DEMEROL Injection
are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse
maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see
Clinical Considerations). Formal animal reproduction studies have not been conducted with meperidine.
Neural tube defects (exencephaly and cranioschisis) have been reported in hamsters administered a single
bolus dose of meperidine during a critical period of organogenesis at 0.85 and 1.5 times the total human
daily dose of 1200 mg [see Data].
The background risk of major birth defects and miscarriage for the indicated population is unknown. All
pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical
purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome
shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern,
high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity
of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing
and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns
for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and
Precautions (5.4)].
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in
neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced
respiratory depression in the neonate. DEMEROL Injection is not recommended for use in pregnant
women during or immediately prior to labor, when other analgesic techniques are more appropriate.
Opioid analgesics, including DEMEROL Injection, can prolong labor through actions which temporarily
reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent
and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates
exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Data
Animal Data
Formal reproductive and developmental toxicology studies for meperidine have not been completed.
In a published study, neural tube defects (exencephaly and cranioschisis) were noted following
subcutaneous administration of meperidine hydrochloride (127 and 218 mg/kg, respectively) on Gestation
Day 8 to pregnant hamsters (0.85 and 1.5 times the total daily dose of 1200 mg/day based on body surface
area). The findings cannot be clearly attributed to maternal toxicity.
Reference ID: 5507521
8.2
Lactation
Risk Summary
Meperidine appears in the milk of nursing mothers receiving the drug. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical need for DEMEROL
Injection and any potential adverse effects on the breastfed infant from DEMEROL Injection or from the
underlying maternal condition.
Clinical Considerations
Monitor infants exposed to DEMEROL Injection through breast milk for excess sedation and respiratory
depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an
opioid analgesic is stopped, or when breastfeeding is stopped.
8.3
Females and Males of Reproductive Potential
Infertility
Use of opioids for an extended period of time may cause reduced fertility in females and males of
reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse
Reactions (6), Clinical Pharmacology (12.2), Nonclinical Pharmacology (13.1)].
8.4
Pediatric Use
The safety and efficacy of DEMEROL Injection in patients less than 18 years of age have not been
established.
The safety and effectiveness of meperidine in pediatric patients has not been established. Literature reports
indicate that meperidine has a slower elimination rate in neonates and young infants compared to older
children and adults. Neonates and young infants may also be more susceptible to the effects, especially the
respiratory depressant effects. If meperidine use is contemplated in neonates or young infants, any potential
benefits of the drug need to be weighed against the relative risk of the patient.
8.5
Geriatric Use
Elderly patients (aged 65 years or older) may have increased sensitivity to meperidine. In general, use
caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant
disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large
initial doses were administered to patients who were not opioid-tolerant or when opioids were
co-administered with other agents that depress respiration. Titrate the dosage of DEMEROL Injection
slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory
depression [see Warnings and Precautions (5.2)].
Meperidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and it may be useful to monitor
renal function.
8.6
Hepatic Impairment
Accumulation of meperidine and/or its active metabolite, normeperidine, can also occur in patients with
hepatic impairment. Elevated serum levels have been reported to cause central nervous system excitatory
effects. Meperidine should therefore be used with caution in patients with hepatic impairment. Titrate the
Reference ID: 5507521
dosage of DEMEROL Injection slowly in patients with hepatic impairment and monitor closely for signs
of central nervous system and respiratory depression.
8.7
Renal Impairment
Accumulation of meperidine and/or its active metabolite, normeperidine, can occur in patients with renal
impairment. Meperidine should therefore be used with caution in patients with renal impairment. Titrate
the dosage of DEMEROL Injection slowly in patients with renal impairment and monitor closely for signs
of central nervous system and respiratory depression.
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
DEMEROL Injection contains meperidine, a Schedule II controlled substance.
9.2
Abuse
DEMEROL Injection contains meperidine, a substance with high potential for misuse and abuse, which
can lead to the development of substance use disorder, including addiction [see Warnings and
Precautions (5.1)].
Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than
prescribed by a healthcare provider or for whom it was not prescribed.
Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or
physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a
strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite
harmful consequences, giving a higher priority to drug use than other activities and obligations), and
possible tolerance or physical dependence.
Misuse and abuse of DEMEROL Injection increases risk of overdose, which may lead to central nervous
system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent
abuse of DEMEROL Injection with alcohol and/or other CNS depressants. Abuse of and addiction to
opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical
dependence. In addition, abuse of opioids can occur in the absence of addiction.
All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse and
addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate
medical use. Patients at high risk of DEMEROL Injection abuse include those with a history of prolonged
use of any opioid, including products containing meperidine, those with a history of drug or alcohol
abuse, or those who use DEMEROL Injection in combination with other abused drugs.
“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics
include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination,
testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to
provide prior medical records or contact information for other treating healthcare provider(s). “Doctor
shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who
abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief
can be appropriate behavior in a patient with inadequate pain control.
Reference ID: 5507521
DEMEROL Injection, like other opioids, can be diverted for nonmedical use into illicit channels of
distribution. Careful record-keeping of prescribing information, including quantity, frequency, and
renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and
proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of DEMEROL Injection
Abuse of DEMEROL Injection poses a risk of overdose and death. The risk is increased with concurrent
abuse of DEMEROL Injection with alcohol and/or other CNS depressants.
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis
and HIV.
9.3
Dependence
Both tolerance and physical dependence can develop during use of opioid therapy.
Tolerance is a physiological state characterized by a reduced response to a drug after repeated
administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained
at a lower dose).
Physical dependence is a state that develops as a result of a physiological adaptation in response to
repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a
significant dose reduction of a drug.
Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g.,
naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial
agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until
after several days to weeks of continued use.
DEMEROL Injection should not be abruptly discontinued in a physically-dependent patient [see Dosage
and Administration (2.4)]. If DEMEROL Injection is abruptly discontinued in a physically-dependent
patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation,
rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop,
including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea,
anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically-dependent on opioids will also be physically-dependent and may
exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
10
OVERDOSAGE
Clinical Presentation
Acute overdose with meperidine can be manifested by respiratory depression, somnolence progressing to
stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases,
pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction,
atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose
situations [see Clinical Pharmacology (12.2)]. In severe overdose, particularly by the intravenous route,
apnea, circulatory collapse, cardiac arrest, and death may occur.
Accumulation of normeperidine as in chronic use or possibly following introduction of a concomitant
CYP3A4 inducer presents as excitatory syndrome including hallucinations, tremors, muscle twitches,
dilated pupils, hyperactive reflexes, and convulsions.
Reference ID: 5507521
•
IHIC!I
Treatment of Overdose
In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of
assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and
vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest
or arrhythmias will require advanced life-support measures.
Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from
opioid overdose. For clinically significant respiratory or circulatory depression secondary to meperidine
overdose, administer an opioid antagonist.
Because the duration of opioid reversal is expected to be less than the duration of action of meperidine in
DEMEROL Injection, carefully monitor the patient until spontaneous respiration is reliably
re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer
additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of
the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms
experienced will depend on the degree of physical dependence and the dose of the antagonist
administered. If a decision is made to treat serious respiratory depression in the physically-dependent
patient, administration of the antagonist should be begun with care and by titration with smaller than
usual doses of the antagonist.
11
DESCRIPTION
DEMEROL (meperidine hydrochloride injection) is an opioid agonist available as a sterile aqueous
solution, for intramuscular, intravenous, or subcutaneous administration. It contains meperidine
hydrochloride as the active pharmaceutical ingredient. Meperidine hydrochloride chemical name is
4-Piperidinecarboxylic acid, 1-methyl-4-phenyl-,ethyl ester, hydrochloride. The molecular weight is
283.79 g/mol. Its molecular formula is C15H21NO2·HCl, and it has the following chemical structure.
Meperidine hydrochloride is a white crystalline substance with a melting point of 186° C to 189° C, and it
is readily soluble in water.
DEMEROL (meperidine hydrochloride injection) is available as:
Single-dose Carpuject cartridge with Luer Lock for the Carpuject Syringe System: 25 mg/mL, 50 mg/mL,
75 mg/mL, and 100 mg/mL. Each mL of Single-dose cartridge contains 25 mg, 50 mg, 75 mg or 100 mg
of meperidine hydrochloride USP (equivalent to 21.79 mg, 43.58 mg, 65.36 mg or 87.15 mg of
meperidine), respectively, and sodium hydroxide NF, and hydrochloric acid NF as pH adjusters, in water
for injection. Only the 25 mg strength contains 3.8 mg of sodium chloride USP as isotonicity agent.
Multiple-dose vials: 1,500 mg/30 mL (50 mg/mL) strength. Each mL of vial contains 50 mg of
meperidine hydrochloride USP (equivalent to 43.58 mg of meperidine), 1 mg of meta-cresol USP, as a
preservative, and sodium hydroxide NF, and hydrochloric acid NF as pH adjusters, in water for injection.
Reference ID: 5507521
Single-dose NexJect™ Prefilled Syringe with Luer Lock: 25 mg/mL and 50 mg/mL strengths. Each mL
contains 25 mg or 50 mg of meperidine hydrochloride USP (equivalent to 21.79 mg or 43.58 mg of
meperidine), respectively, and sodium hydroxide NF, and hydrochloric acid NF as pH adjusters, in water
for injection. Only the 25 mg strength contains 3.8 mg of sodium chloride USP as isotonicity agent.
The pH of DEMEROL (meperidine hydrochloride injection) solutions is between 3.5 and 6.0.
DEMEROL (meperidine hydrochloride injection) 5 percent solution has a specific gravity of 1.0086 at
20°C, and the 10 percent solution has a specific gravity of 1.0165 at 20°C.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Meperidine hydrochloride is an opioid agonist with multiple actions qualitatively similar to those of
morphine; the most prominent of these involve the central nervous system and organs composed of
smooth muscle. The principal actions of therapeutic value are analgesia and sedation.
12.2
Pharmacodynamics
Effects on the Central Nervous System
Meperidine produces respiratory depression by direct action on brain stem respiratory centers. The
respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to
both increases in carbon dioxide tension and electrical stimulation.
Meperidine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not
pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings).
Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Meperidine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum
of the stomach duodenum. Digestion of food in the small intestine is delayed and propulsive contractions
are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the
point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary
and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects of the Cardiovascular System
Meperidine produces peripheral vasodilation which may result in orthostatic hypotension or syncope.
Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red
eyes, and sweating and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormones
(LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH)
secretion, and pancreatic secretion of insulin and glucagon.
Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis,
leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction,
amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is
unknown because the various medical, physical, lifestyle, and psychological stressors that may influence
Reference ID: 5507521
gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse
Reactions (6)].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and
animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids
appear to be modestly immunosuppressive.
Concentration–Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among
patients who have been previously treated with opioid agonists. The minimum effective analgesic
concentration of meperidine for any individual patient may increase over time due to an increase in pain,
the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and
Administration (2.1, 2.2)].
Meperidine, in 60 mg to 80 mg parenteral doses, is approximately equivalent in analgesic effect to 10 mg
of morphine. The onset of action is slightly more rapid than with morphine, and the duration of action is
slightly shorter. Meperidine is significantly less effective by the oral than by the parenteral route, but the
exact ratio of oral to parenteral effectiveness is unknown.
Concentration–Adverse Reaction Relationships
There is a relationship between increasing meperidine plasma concentration and increasing frequency of
dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.
In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related
adverse reactions [see Dosage and Administration (2.1, 2.2)].
12.3
Pharmacokinetics
Elimination
The half-life of meperidine is 2 to 5 hours, and the half-life of normeperidine is 15 to 30 hours.
Metabolism
Meperidine is metabolized through biotransformation. In vitro data show meperidine is metabolized to
normeperidine in liver mainly by CYP3A4 and CYP2B6.
Excretion
Meperidine and normeperidine are excreted by kidneys.
Specific Population
Hepatic Impairment
The elimination half-life is 3 to 8 hours in healthy volunteers and is 1.3 to 2 times greater in
post-operative or cirrhotic patients.
Age
In clinical studies reported in the literature, changes in several pharmacokinetic parameters with
increasing age have been observed. The initial volume of distribution and steady-state volume of
distribution may be higher in elderly patients than in younger patients. The free fraction of meperidine in
plasma may be higher in patients over 45 years of age than in younger patients.
Drug Interactions Studies
Phenytoin: The hepatic metabolism of meperidine may be enhanced by phenytoin. Concomitant
administration resulted in reduced half-life and bioavailability with increased clearance of meperidine in
Reference ID: 5507521
healthy subjects; however, blood concentrations of normeperidine were increased [see Drug
Interactions (7)].
Ritonavir: Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir
[see Drug Interactions (7)].
Acyclovir: Plasma concentrations of meperidine and its metabolite, normeperidine, may be increased by
acyclovir [see Drug Interactions (7)].
Cimetidine: Cimetidine reduced the clearance and volume of distribution of meperidine and also the
formation of the metabolite, normeperidine, in healthy subjects [see Drug Interactions (7)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of meperidine have not been
conducted.
Mutagenesis
Studies in animals to evaluate the mutagenic potential of meperidine have not been conducted.
Impairment of Fertility
Studies to determine the effect of meperidine on fertility have not been conducted.
16
HOW SUPPLIED/STORAGE AND HANDLING
For Parenteral Use
DEMEROL (meperidine hydrochloride injection) is clear and colorless.
DEMEROL (meperidine hydrochloride injection) is supplied as a sterile solution in a multiple-dose vial,
single-dose Carpuject™ cartridges for use ONLY with the Carpuject™ Holders and NexJect™ prefilled
syringes for subcutaneous, intramuscular, and intravenous administration, and available as follows:
Unit of Sale
Concentration
(per total
volume)
NDC 0409-1181-30
Carton of 1
30 mL fill in 30 mL Multiple-dose
Vial
1,500 mg/30 mL
(50 mg/mL)
NDC 0409-1176-30
Carton of 10
1 mL fill in 2.5 mL Carpuject™
Single-dose cartridge with Luer Lock
25 mg/mL
NDC 0409-1178-30
Carton of 10
1 mL fill in 2.5 mL Carpuject™
Single-dose cartridge with Luer Lock
50 mg/mL
NDC 0409-1179-30
75 mg/mL
Reference ID: 5507521
Unit of Sale
Concentration
(per total
volume)
Carton of 10
1 mL fill in 2.5 mL Carpuject™
Single-dose cartridge with Luer Lock
NDC 0409-1180-69
Carton of 10
1 mL fill in 2.5 mL Carpuject™
Single-dose cartridge with Luer Lock
100 mg/mL
NDC 0409-1362-01
Clamshell of 10
1 mL fill in 1.5 mL NexJect™
Single-dose Prefilled Syringe with
Luer Lock
25 mg/mL
NDC 0409-1418-01
Clamshell of 10
1 mL fill in 1.5 mL NexJect™
Single-dose Prefilled Syringe with
Luer Lock
50 mg/mL
Carpuject™ Single-dose cartridges are packaged in a Slim-Pak tamper detection package.
Note that a needle is not included with Carpuject™ Single-dose cartridges and Nexject™ Single-dose
Prefilled Syringes.
Carpuject and NexJectTM Single-dose products: Discard unused portion.
Multiple-dose vials: Discard unused portion after 28 days.
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F). [See
USP Controlled Room Temperature.]
17
PATIENT COUNSELING INFORMATION
Addiction, Abuse, and Misuse
Inform patients that the use of DEMEROL Injection, even when taken as recommended, can result in
addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions
(5.1)]. Instruct patients not to share DEMEROL Injection with others and to take steps to protect
DEMEROL Injection from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is
greatest when DEMEROL Injection or when the dosage is increased, and that it can occur even at
recommended dosages [see Warnings and Precautions (5.2)].
Hyperalgesia and Allodynia
Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia,
including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7),
Adverse Reactions (6)].
Reference ID: 5507521
f,
Hosp1ra
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin
syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the
symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after
discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking, or plan
to take serotonergic medications [see Warnings and Precautions (5.8), Drug Interactions (7)].
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to
seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.1)].
Distributed by Hospira, Inc., Lake Forest, IL 60045 USA
For Medical Information about DEMEROL Injection, please visit www.pfizermedinfo.com or
call 1-800-438-1985.
LAB-0846-11.0
Reference ID: 5507521
Instructions for use
Prior to use,
visually inspect the product for.
Confirm medication order matches the following:
NexJect 1 ml Prefilled Syringe
Do not use If
seals are broken
■ drug name
■ drug strength
■ dose
■ route of administration
If any of the above does not match the order, obtain the appropriate medication.
Notes:
■ Do not place the syringe in a sterile field.
1
Twist off the plunger rod cover to break the
tam))E'r ev1derrt seal and discard the cowr
• If a needle is utilized, do not recap the needle.
INSTRUCTIONS FOR USE
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if
it is discolored in any other way, or if it contains a precipitate.
Instructions for use - Carpuject™ Single-dose Cartridge
Carpuject™ Single-dose cartridges with Luer Lock are packaged in a Slim-Pak™ tamper detection
package. Note that a needle is not included.
Before use, read all instructions for using the Carpuject™ Syringe, which are contained in the product
insert for the reusable Carpuject™ Holder before use.
Carpuject™ Single-dose cartridges are to be used ONLY with Carpuject™ Holders.
NOTE: To prevent needlestick injuries, do not recap, purposely bend, or break by hand used needles. Do
not recap, purposely bend, or break by hand blunt Cannulas.
Instructions for use - NexJect™ Single-dose Prefilled Syringe
Reference ID: 5507521
Exl)E'I air by
AdJust dose by expelling extra
3 gently advancing 4 volume from the synnge (When
the plunger rod,
clinically relevant), based on
your fac1l1ty protocol,
After appropriately prepanng the adm1n1strat1on
5
site, connect the luer to an access device or attach
a needle / blunt cannula 1f n~ded Ensure the
connection 1s secure and dehwr the med1cat1on, •
• A~r u~ discard th;> pr«luct 1ntoan appropn«te reoeptad,;,
~
Hosp,ra
NOTE: To prevent needlestick injuries, do not recap, purposely bend, or break by hand used needles. Do
not recap, purposely bend, or break by hand blunt Cannulas.
Distributed by Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1387-2.0
Revised: 12/2023
Reference ID: 5507521
| custom-source | 2025-02-12T15:48:25.449860 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2025/021171s060lbl.pdf', 'application_number': 21171, 'submission_type': 'SUPPL ', 'submission_number': 60} |
80,837 |
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This is a representation of an electronic record that was signed
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electronic signatures for this electronic record.
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/s/
------------------------------------------------------------
MARTHA K LENHART
01/10/2025 01:39:10 PM
Signature Page 1 of 1
Reference ID: 5508194
(
| custom-source | 2025-02-12T15:48:25.701892 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/022051Orig1s024,205434Orig1s017lbl.pdf', 'application_number': 205434, 'submission_type': 'SUPPL ', 'submission_number': 17} |
80,841 |
--------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically. Following this are manifestations of any and all
electronic signatures for this electronic record.
--------------------------------------------------------------------------------------------
/s/
------------------------------------------------------------
MARTHA K LENHART
01/10/2025 01:39:10 PM
Signature Page 1 of 1
Reference ID: 5508194
(
| custom-source | 2025-02-12T15:48:25.717564 | {'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/022051Orig1s024,205434Orig1s017lbl.pdf', 'application_number': 22051, 'submission_type': 'SUPPL ', 'submission_number': 24} |
80,843 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
IBSRELA® safely and effectively. See full prescribing information for
IBSRELA.
IBSRELA (tenapanor) tablets, for oral use
Initial U.S. Approval: 2019
WARNING: RISK OF SERIOUS DEHYDRATION IN
PEDIATRIC PATIENTS
See full prescribing information for complete boxed warning.
• IBSRELA is contraindicated in patients less than 6 years of age; in
young juvenile rats, tenapanor caused death presumed to be due to
dehydration. (4, 8.4)
• Avoid use of IBSRELA in patients 6 years to less than 12 years of
age. (5.1, 8.4)
• The safety and effectiveness of IBSRELA have not been established
in pediatric patients less than 18 years of age. (8.4)
------------------------INDICATIONS AND USAGE-------------------------------
IBSRELA is a sodium/hydrogen exchanger 3 (NHE3) inhibitor indicated for
treatment of irritable bowel syndrome with constipation (IBS-C) in adults. (1)
-------------------DOSAGE AND ADMINISTRATION---------------------------
• The recommended dosage in adults is 50 mg, orally twice daily. (2)
• Take immediately prior to breakfast or the first meal of the day and
immediately prior to dinner. (2)
------------------DOSAGE FORMS AND STRENGTHS----------------
Tablets: 50 mg tenapanor. (3)
--------------------------CONTRAINDICATIONS-------------------------
• Pediatric patients less than 6 years of age. (4, 5.1, 8.4)
• Patients with known or suspected mechanical gastrointestinal
obstruction. (4)
--------------------WARNINGS AND PRECAUTIONS------------------
Diarrhea: Patients may experience severe diarrhea. If severe diarrhea
occurs, suspend dosing and rehydrate patient. (5.2)
---------------------------ADVERSE REACTIONS-------------------------
Most common adverse reactions (≥2%) are diarrhea, abdominal
distension, flatulence and dizziness. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
Ardelyx at 1-844-427-7352 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
---------------------------DRUG INTERACTIONS-------------------------
OATP2B1 Substrates: Potential for reduced exposure of the
concomitant drug (e.g., enalapril). Monitor for signs related to loss of
efficacy and adjust the dosage of the concomitantly administered drug
as needed. (7.1)
See 17 for PATIENT COUNSELING INFORMATION and
Medication Guide.
Revised: 1/2025
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC
PATIENTS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Risk of Serious Dehydration in Pediatric Patients
5.2 Diarrhea
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 OATP2B1 Substrates
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED / STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed
Page 1
Reference ID: 5509314
<5
FULL PRESCRIBING INFORMATION
WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS
• IBSRELA is contraindicated in patients less than 6 years of age; in nonclinical
studies in young juvenile rats administration of tenapanor caused deaths
presumed to be due to dehydration [see Contraindications (4), Use in Specific
Populations (8.4)].
• Avoid use of IBSRELA in patients 6 years to less than 12 years of age
[see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].
•
The safety and effectiveness of IBSRELA have not been established in patients
less than 18 years of age [see Use in Specific Populations (8.4)].
1 INDICATIONS AND USAGE
IBSRELA is indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in adults.
2 DOSAGE AND ADMINISTRATION
The recommended dosage of IBSRELA in adults is 50 mg orally twice daily.
Administration Instructions
• Take IBSRELA immediately prior to breakfast or the first meal of the day and immediately
prior to dinner [see Clinical Pharmacology (12.2)].
• If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not
take 2 doses at the same time.
3 DOSAGE FORMS AND STRENGTHS
Tablets: 50 mg tenapanor supplied as an oval, white to off-white tablet debossed with “ 50” on one
side and “5791” on the other side.
4 CONTRAINDICATIONS
IBSRELA is contraindicated in:
• Patients less than 6 years of age due to the risk of serious dehydration [see Warnings and
Precautions (5.1), Use in Specific Populations (8.4)].
• Patients with known or suspected mechanical gastrointestinal obstruction.
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Serious Dehydration in Pediatric Patients
IBSRELA is contraindicated in patients below 6 years of age. The safety and effectiveness of
IBSRELA in patients less than 18 years of age have not been established. In young juvenile rats
(less than 1 week old; approximate human age equivalent of less than 2 years of age), decreased
body weight and deaths occurred, presumed to be due to dehydration, following oral administration
Page 2
Reference ID: 5509314
of tenapanor. There are no data available in older juvenile rats (human age equivalent 2 years to less
than 12 years).
Avoid the use of IBSRELA in patients 6 years to less than 12 years of age. Although there are no
data in older juvenile rats, given the deaths in younger rats and the lack of clinical safety and
efficacy data in pediatric patients, avoid the use of IBSRELA in patients 6 years to less than 12 years
of age [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations
(8.4)].
5.2 Diarrhea
Diarrhea was the most common adverse reaction in two randomized, double-blind,
placebo-controlled trials of IBS-C. Severe diarrhea was reported in 2.5% of IBSRELA-treated
patients [see Adverse Reactions (6.1)]. If severe diarrhea occurs, suspend dosing and rehydrate
patient.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The safety data described below reflect data from 1203 adult patients with IBS-C in two randomized,
double-blind, placebo-controlled clinical trials (Trial 1 and Trial 2). Patients were randomized to
receive placebo or IBSRELA 50 mg twice daily for up to 52 weeks. Demographic characteristics
were comparable between treatment groups in the two trials [see Clinical Studies (14)].
Most Common Adverse Reactions
The most common adverse reactions reported in at least 2% of patients in IBSRELA-treated patients
and at an incidence greater than placebo during the 26-week double-blind placebo-controlled
treatment period of Trial 1 are shown in Table 1.
Table 1:
Most Common Adverse Reactions* in Patients with IBS-C in Trial 1 (26 Weeks)
Adverse Reactions
IBSRELA
N=293
%
Placebo
N=300
%
Diarrhea
16
4
Abdominal Distension
3
<1
Flatulence
3
1
Dizziness
2
<1
* Reported in at least 2% of patients in IBSRELA-treated patients and at an incidence greater than placebo
The adverse reaction profile was similar during the 12-week double-blind placebo-controlled
treatment period of Trial 2 (610 patients: 309 IBSRELA-treated and 301 placebo-treated) with
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diarrhea (15% with IBSRELA vs 2% with placebo) and abdominal distension (2% with IBSRELA
vs 0% with placebo) as the most common adverse reactions.
Adverse Reaction of Special Interest – Severe Diarrhea
Severe diarrhea was reported in 2.5% of IBSRELA-treated patients compared to 0.2% of
placebo-treated patients during the 26 weeks of Trial 1 and the 12 weeks of Trial 2
[see Warnings and Precautions (5.2)].
Patients with Renal Impairment
In Trials 1 and 2, there were 368 patients (31%) with baseline renal impairment (defined as eGFR
less than 90 mL/min/1.73m2). In patients with renal impairment, diarrhea, including severe diarrhea,
was reported in 20% (39/194) of IBSRELA-treated patients and 0.6% (1/174) of placebo-treated
patients. In patients with normal renal function at baseline, diarrhea, including severe diarrhea, was
reported in 13% (53/407) of IBSRELA-treated patients and 3.5% (15/426) of placebo-treated
patients. No other differences in the safety profile were reported in the renally impaired subgroup.
The incidence of diarrhea and severe diarrhea in IBSRELA-treated patients did not correspond to the
severity of renal impairment.
Adverse Reactions Leading to Discontinuation
Discontinuations due to adverse reactions occurred in 7.6% of IBSRELA-treated patients and 0.8%
of placebo-treated patients during the 26 weeks of Trial 1 and the 12 weeks of Trial 2. The most
common adverse reaction leading to discontinuation was diarrhea: 6.5% of IBSRELA-treated
patients compared to 0.7% of placebo-treated patients.
Less Common Adverse Reactions
Adverse reactions reported in less than 2% of IBSRELA-treated patients and at an incidence greater
than placebo during the 26 weeks of Trial 1 and the 12 weeks of Trial 2 were: rectal bleeding and
abnormal gastrointestinal sounds.
Hyperkalemia
In a trial of another patient population with chronic kidney disease (defined by eGFR from 25 to
70 mL/min/1.73m2) and Type 2 diabetes mellitus, three serious adverse reactions of hyperkalemia
resulting in hospitalization were reported in 3 patients (2 IBSRELA-treated patients and
1 placebo-treated patient).
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of IBSRELA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions: pruritis, rash, and urticaria
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7 DRUG INTERACTIONS
7.1 OATP2B1 Substrates
Tenapanor is an inhibitor of intestinal uptake transporter, OATP2B1 [see Clinical Pharmacology
(12.3)]. Drugs which are substrates of OATP2B1 may have reduced exposures when concomitantly
taken with IBSRELA. Monitor for signs related to loss of efficacy and adjust the dosage of
concomitantly administered drug as needed.
Enalapril is a substrate of OATP2B1. When enalapril was coadministered with tenapanor (30 mg
twice daily for five days, a dosage 0.6 times the recommended dosage), the peak exposure (Cmax) of
enalapril and its active metabolite, enalaprilat, decreased by approximately 70% and total systemic
exposures (AUC) decreased by approximately 50% to 65% compared to when enalapril was
administered alone [see Clinical Pharmacology (12.3)].
Monitor blood pressure and increase the dosage of enalapril, if needed, when IBSRELA is
coadministered with enalapril.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Tenapanor is minimally absorbed systemically, with plasma concentrations below the limit of
quantification (less than 0.5 ng/mL) following oral administration [see Clinical Pharmacology
(12.3)]. Therefore, maternal use is not expected to result in fetal exposure to the drug. The available
data on IBSRELA exposure from a small number of pregnant women have not identified any drug
associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In reproduction studies with tenapanor in pregnant rats and rabbits, no adverse fetal effects were
observed in rats at 0.1 times the maximum recommended human dose and in rabbits at doses up to
8.8 times the maximum recommended human dose (based on body surface area).
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the United States general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In an embryofetal development study in rats, tenapanor was administered orally to pregnant rats
during the period of organogenesis at dose levels of 1, 10 and 30 mg/kg/day. Tenapanor doses of
10 and 30 mg/kg/day were not tolerated by the pregnant rats and was associated with mortality and
moribundity with body weight loss. The 10 and 30 mg/kg dose group animals were sacrificed early,
and the fetuses were not examined for intrauterine parameters and fetal morphology. No adverse
fetal effects were observed in rats at 1 mg/kg/day (approximately 0.1 times the maximum
recommended human dose) and in rabbits at doses up to 45 mg/kg/day (approximately 8.8 times the
maximum recommended human dose, based on body surface area).
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In a pre- and post-natal developmental study in mice, tenapanor at doses up to 200 mg/kg/day
(approximately 9.7 times the maximum recommended human dose, based on body surface area) had
no effect on pre- and post-natal development.
8.2 Lactation
Risk Summary
There are no data available on the presence of tenapanor in either human or animal milk, its effects
on milk production or its effects on the breastfed infant. Tenapanor is minimally absorbed
systemically, with plasma concentrations below the limit of quantification (less than 0.5 ng/mL)
following oral administration [see Clinical Pharmacology (12.3)]. The minimal systemic absorption
of tenapanor will not result in a clinically relevant exposure to breastfed infants. The developmental
and health benefits of breastfeeding should be considered along with the mother’s clinical need for
IBSRELA and any potential adverse effects on the breastfed infant from IBSRELA or from the
underlying maternal condition.
8.4 Pediatric Use
IBSRELA is contraindicated in patients less than 6 years of age. Avoid IBSRELA in patients 6 years
to less than 12 years of age [see Contraindications (4), Warnings and Precautions (5.1)].
The safety and effectiveness of IBSRELA in patients less than 18 years of age have not been
established.
In nonclinical studies, deaths occurred in young juvenile rats (less than 1 week-old-rats approximate
human age equivalent of less than 2 years of age) following oral administration of tenapanor, as
described below in Juvenile Animal Toxicity Data.
Juvenile Animal Toxicity Data
In a 21-day oral dose range finding toxicity study in juvenile rats, tenapanor was administered to
neonatal rats (post-natal day (PND) 5) at doses of 5 and 10 mg/kg/day. Tenapanor was not tolerated
in male and female pups and the study was terminated on PND 16 due to mortalities and decreased
body weight (24% to 29% reduction in females at the respective dose groups and 33% reduction in
males in the 10 mg/kg/day group, compared to control).
In a second dose range finding study, tenapanor doses of 0.1, 0.5, 2.5, or 5 mg/kg/day were
administered to neonatal rats from PND 5 through PND 24. Treatment-related mortalities were
observed at 0.5, 2.5, and 5 mg/kg/day doses. These premature deaths were observed as early as
PND 8, with majority of deaths occurring between PND 15 and 25. In the 5 mg/kg/day group, mean
body weights were 47% lower for males on PND 23 and 35% lower for females on PND 22 when
compared to the controls. Slightly lower mean tibial lengths (5% to 11%) were noted in males and
females in the 0.5, 2.5, and 5 mg/kg/day dose groups on PND 25 and correlated with the decrements
in body weight noted in these groups. Lower spleen, thymus, and/or ovarian weights were noted at
the 0.5, 2.5 and 5 mg/kg/day doses. Tenapanor-related gastrointestinal distension and microscopic
bone findings of increased osteoclasts, eroded bone, and/or decreased bone in sternum and/or
femorotibial joint were noted in males and females in the 0.5, 2.5 and 5 mg/kg/day dose groups
[see Contraindications (4), Warnings and Precautions (5.1)].
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-
d'''. ~~~I(~
)l ~ ~ ~ ;,p
8.5 Geriatric Use
Of the 1203 patients in placebo-controlled clinical trials of IBSRELA, 100 (8%) were 65 years of
age and older. No overall differences in safety or effectiveness were observed between elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
10 OVERDOSAGE
Based on nonclinical data, overdose of IBSRELA may result in gastrointestinal adverse effects such
as diarrhea as a result of exaggerated pharmacology with a risk for dehydration if diarrhea is severe
or prolonged [see Warnings and Precautions (5.1)].
11 DESCRIPTION
IBSRELA (tenapanor) tablets contain tenapanor hydrochloride as an active ingredient. Tenapanor
hydrochloride is a sodium/hydrogen exchanger 3 (NHE3) inhibitor for oral use. The chemical name
for tenapanor hydrochloride is 12,15-Dioxa-2,7,9-triazaheptadecanamide, 17-[[[3-[(4S)-6,8
dichloro-1,2,3,4-tetrahydro-2-methyl-4-isoquinolinyl]phenyl]sulphonyl]amino]-N-[2-[2-[2-[[[3
[(4S)-6,8-dichloro-1,2,3,4-tetrahydro-2-methyl-4
isoquinolinyl]phenyl]sulphonyl]amino]ethoxy]ethoxy]ethyl]-8-oxo-, hydrochloride (1:2). Tenapanor
hydrochloride has the molecular formula of C50H68Cl6N8O10S2, the molecular weight of 1218
Daltons, and the chemical structure below:
Cl
HCl N
Cl
O
O
O
H
H
H
S
O
N
N
O
N
N
O
N
N
O
S
H
H
H
O
O
O
Cl
HCl
N
Cl
Tenapanor hydrochloride is a white to off-white to light brown hygroscopic amorphous solid. It is
practically insoluble in water.
IBSRELA tablets contain 50 mg of tenapanor (equivalent to 53.2 mg of tenapanor hydrochloride).
Inactive ingredients in the tablet are colloidal silicon dioxide, low-substituted hydroxypropyl
cellulose, microcrystalline cellulose, propyl gallate, stearic acid, tartaric acid, and the coating agent
OPADRY®, which consists of hypromellose, titanium dioxide and triacetin.
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12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tenapanor is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter
expressed on the apical surface of the small intestine and colon primarily responsible for the
absorption of dietary sodium. In vitro and animal studies indicate its major metabolite, M1, is not
active against NHE3. By inhibiting NHE3 on the apical surface of the enterocytes, tenapanor reduces
absorption of sodium from the small intestine and colon, resulting in an increase in water secretion
into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool
consistency.
Tenapanor has also been shown to reduce abdominal pain by decreasing visceral hypersensitivity
and by decreasing intestinal permeability in animal models. In rat model of colonic hypersensitivity,
tenapanor reduced visceral hyperalgesia and normalized colonic sensory neuronal excitability.
12.2 Pharmacodynamics
Cardiac Electrophysiology
At 3 times the mean maximum exposure of M1 at the recommended dosage, there were no clinically
relevant effects on the QTc interval.
Food Effect
Administration of IBSRELA 5 to 10 minutes before a meal increased the 24-hour stool sodium
excretion compared to taking IBSRELA in the fed or fasting condition [see Dosage and
Administration (2)]. In clinical trials, IBSRELA was administered immediately prior to the first meal
of the day and immediately prior to dinner.
12.3 Pharmacokinetics
Absorption
Tenapanor is minimally absorbed following repeated twice daily oral administration. Plasma
concentrations of tenapanor were below the limit of quantitation (less than 0.5 ng/mL) in the
majority of samples from healthy subjects following single and repeated oral administration of
IBSRELA 50 mg twice daily. Therefore, standard pharmacokinetic parameters such as area under
the curve (AUC), maximum concentration (Cmax), and half-life (t1/2) could not be determined.
Distribution
Plasma protein binding of tenapanor and its major metabolite, M1, is approximately 99% and 97%,
respectively, in vitro.
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Elimination
Metabolism
Tenapanor is metabolized primarily by CYP3A4/5 and low levels of its major metabolite, M1, are
detected in plasma. The Cmax of M1 is approximately 13 ng/mL after single dose of IBSRELA 50 mg
and 15 ng/mL at steady state following repeated dosing of IBSRELA 50 mg twice daily in healthy
subjects.
Excretion
Following administration of a single 15 mg radiolabeled 14C-tenapanor dose to healthy subjects,
approximately 70% of the radioactivity was excreted in feces within 120 hours post-dose and 79%
within 240 hours post-dose, mostly as the parent drug accounting for 65% of dose within 144 hours
post-dose. Approximately 9% of the administered dose was recovered in urine, primarily as
metabolites. M1 is excreted in urine unchanged accounting for 1.5% of dose within 144 hours
post-dose.
Specific Populations
Patients with Hepatic Impairment
Following a single dose of tenapanor 100 mg in patients with moderate hepatic impairment
(Child-Pugh B), plasma concentrations of tenapanor were mostly below the limit of quantitation
(< 0.5 ng/mL) and the pharmacokinetic parameters for tenapanor could not be determined. The
geometric mean AUC and Cmax of the major metabolite, M1, were approximately 33% and 27%
lower, respectively, in patients with moderate hepatic impairment compared to those of healthy
subjects. The decrease in M1 systemic exposure is not clinically relevant.
Patients with Renal Impairment
Based on a cross-study comparison, plasma concentrations of M1 in end-stage renal disease patients
on hemodialysis (eGFR less than 15 mL/min/1.73m2) was not notably different from those of
healthy subjects given comparable doses of IBSRELA.
Drug Interaction Studies
CYP Metabolism Mediated Drug Interactions
Tenapanor and M1 did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6
in vitro.
Tenapanor and M1 did not induce CYP1A2 and CYP2B6 in vitro.
No significant inhibition or induction of CYP3A4 enzyme using midazolam as a substrate was
observed when IBSRELA 50 mg was administered twice a day for 13 days in healthy subjects.
Following co-administration of a single dose of IBSRELA 50 mg with repeated doses of
itraconazole 200 mg, a CYP3A4 inhibitor, the mean AUC and Cmax of M1 was decreased 50% in
healthy subjects. The decrease in M1 systemic exposure is not clinically relevant. Plasma
concentrations of tenapanor were mostly below the limit of quantitation (less than 0.5 ng/mL) after
co-administration of itraconazole.
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No significant effect on CYP2C9 activity using warfarin as a substrate was observed when tenapanor
30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in
healthy subjects.
Membrane Transporter Mediated Drug Interactions
Tenapanor inhibited OATP2B1, but is not an inhibitor of P-gp, BCRP, OATP1B1, and OATP1B3.
M1 did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and
MATE2-K.
M1 is a substrate of P-gp. Tenapanor is not a substrate of P-gp, BCRP, OATP1B1, and OATP1B3.
M1 is not a substrate of BCRP, OAT1, OAT3, OCT2, MATE1 and MATE2-K.
No significant effect on PepT1 activity using cefadroxil as a substrate was observed when IBSRELA
50 mg was administered twice a day for 12 days in healthy subjects.
No significant effect on P-gp activity using digoxin as a substrate was observed when tenapanor
30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in
healthy subjects.
Following administration of a single 20 mg dose of enalapril (OATP2B1 substrate) with tenapanor
30 mg administered twice a day (a dosage 0.6 times the recommended dosage) at steady state in
healthy subjects, the mean AUC and Cmax of enalapril was decreased by 64% and 69%, respectively.
The mean AUC and Cmax of enalaprilat was decreased by 52% and 68%, respectively [see Drug
Interactions (7.1)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of tenapanor was assessed in a 6-month carcinogenicity study in Tg
rasH2 mice and in a 2-year carcinogenicity study in rats.
Tenapanor was not tumorigenic at oral doses up to 100 mg/kg/day (approximately 4.5 times the
recommended human dose, based on the body surface area) in male mice and 800 mg/kg/day
(approximately 39 times the maximum recommended human dose, based on the body surface area)
for female mice. Tenapanor was not tumorigenic in male and female rats at oral doses up to
5 mg/kg/day (approximately 0.5 times the recommended human dose, based on the body surface
area). The major metabolite of tenapanor, M1, was not tumorigenic in Tg rasH2 mice at oral doses
up to 165 mg/kg/day (approximately 8 times the maximum recommended human dose, based on the
body surface area)
Mutagenesis
Tenapanor was not genotoxic in the in vitro bacterial reverse mutation (Ames) assays, an in vitro
chromosomal aberration assay in cultured human peripheral blood lymphocytes or the in vivo
micronucleus assays in mice and rats.
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Impairment of Fertility
Tenapanor had no effect on fertility or reproductive function in male rats at oral doses up to
10 mg/kg/day (approximately 0.97 times the recommended human dose, based on the body surface
area) and in female mice at oral doses up to 50 mg/kg/day (approximately 2.4 times the
recommended human dose, based on the body surface area).
14 CLINICAL STUDIES
The efficacy of IBSRELA for the treatment of IBS-C was established in two double-blind,
placebo-controlled, randomized, multicenter trials in adult patients: Trial 1 (TEN-01-302;
NCT02686138) and Trial 2 (TEN-01-301; NCT02621892). The intent-to-treat (ITT) analysis
population included 620 patients in Trial 1 and 606 patients in Trial 2 with mean age of 46 years
(range 18 to 75 years), 80% females, 64% White and 31% Black/African American. In these clinical
trials, IBSRELA was administered immediately prior to breakfast or the first meal of the day and
immediately prior to dinner.
To enter the trials, all patients met Rome III criteria for IBS-C and were required to meet the
following clinical criteria during the 2-week baseline run-in period:
• a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale where a
score of 0 indicates no pain and 10 indicates very severe pain
• less than 3 complete spontaneous bowel movements (CSBMs) per week, where a CSBM is
defined as a spontaneous bowel movement (SBM) that is associated with a sense of complete
evacuation (an SBM is a bowel movement occurring in the absence of laxative use)
• less than or equal to 5 SBMs per week
The trial designs were identical through the first 12 weeks of treatment, and thereafter differed in
that Trial 1 continued for an additional 14 weeks of treatment (26 weeks double-blind treatment),
whereas Trial 2 included a 4-week randomized withdrawal (RW) period.
Efficacy of IBSRELA was assessed using responder analyses based on daily diary entries.
In both trials, the primary endpoint was the proportion of responders, where a responder was defined
as a patient achieving both the stool frequency and abdominal pain intensity responder criteria in the
same week for at least 6 of the first 12 weeks of treatment. The stool frequency (CSBM) and
abdominal pain responder criteria assessed each week were defined as:
• CSBM responder: a patient who experienced an increase of at least 1 CSBM in weekly
average from baseline.
• Abdominal pain responder: a patient who experienced at least a 30% reduction in the weekly
average of abdominal pain score compared with baseline.
The responder rates for the primary endpoint and components of the primary endpoint (CSBM and
abdominal pain), which were pre-specified key secondary endpoints, are shown in Table 2.
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<5
Table 2:
Efficacy Responder Rates in Placebo-Controlled Trials (Trial 1 and Trial 2) in
Adults with IBS-C: Responder for at least 6 of the First 12 Weeks of Treatment
Trial 1
IBSRELA
N=293
Placebo
N=300
Treatment Difference
[95% CIa]
Responderb
Components of Responder Endpoint:
CSBM Responderc
Abdominal Pain Responderd
37%
47%
50%
24%
33%
38%
13%
[6%, 20%]
Trial 2
Responder Rates
IBSRELA
N=307
Placebo
N=299
Treatment Difference
[95% CIa]
Responderb
Components of Responder Endpoint:
CSBM Responderc
Abdominal Pain Responderd
27%
34%
44%
19%
29%
33%
8%
[2%, 15%]
a CI: Confidence Interval
b A responder for these trials was defined as a patient who met both the abdominal pain and CSBM weekly responder
criteria for at least 6 of the first 12 weeks.
c A CSBM responder was defined as a patient who achieved an increase in at least 1 CSBM per week, from baseline,
for a least 6 of at least 12 weeks.
d An abdominal pain responder was defined as a patient who met the criteria of at least 30% reduction from baseline
in weekly average of the worst daily abdominal pain, for at least 6 of the first 12 weeks.
In Trials 1 and 2, the proportion of responders for 9 out of the first 12 weeks, including at least 3 of
the last 4 weeks, was greater in IBSRELA-treated patients compared to placebo-treated patients.
In addition, in Trial 1, the proportion of responders for 13 out of 26 weeks was greater in
IBSRELA-treated patients compared to placebo-treated patients.
In both trials, improvements from baseline in average weekly CSBMs and abdominal pain were
observed by Week 1, with improvement maintained through the end of treatment.
In IBSRELA-treated patients re-randomized to placebo in Trial 2, CSBM frequency and abdominal
pain severity worsened on average over the 4-week period but remained improved compared to
baseline. Patients who continued on IBSRELA maintained their response to therapy on average over
the additional 4 weeks. Patients on placebo who were re-randomized to IBSRELA had an average
increase in CSBM frequency and a decrease in abdominal pain.
16
HOW SUPPLIED/STORAGE AND HANDLING
IBSRELA tablets contain 50 mg tenapanor and are oval, white to off-white, debossed with “ 50” on
one side and “5791” on the other side.
IBSRELA is supplied in a white, opaque, high-density polyethylene bottle containing 60 tablets with
a silica gel canister (as the desiccant) and screw-top polypropylene child-resistant cap lined and
induction-activated aluminum foil liner (NDC 73154-050-60).
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Storage
Store at room temperature, between 68°F and 77°F (20°C and 25°C).
Keep in original container and protect from moisture. Keep the container of IBSRELA tightly closed
and in a dry place.
Do not remove desiccant from the bottle. Do not subdivide or repackage.
17
PATIENT COUNSELING INFORMATION
Advise the patients to read the FDA-approved patient labeling (Medication Guide).
Diarrhea
Instruct patients to stop IBSRELA and contact their healthcare provider if they experience severe
diarrhea [see Warnings and Precautions (5.2)].
Accidental Ingestion
Accidental ingestion of IBSRELA in children, especially children less than 6 years of age, may
result in severe diarrhea and dehydration. Instruct patients to store IBSRELA securely and out of
reach of children [see Contraindications (4), Warnings and Precautions (5.1)].
Administration and Handling Instructions
Instruct Patients:
•
To take IBSRELA immediately prior to breakfast or the first meal of the day and
immediately before dinner [see Dosage and Administration (2)].
•
If a dose is missed, skip the missed dose and take the next dose at the regular time.
Do not take 2 doses at the same time [see Dosage and Administration (2)].
•
To keep IBSRELA in a dry place. Protect from moisture. Keep in the original bottle. Do not
remove desiccant from the bottle. Do not subdivide or repackage. Keep bottles tightly closed
[see How Supplied/Storage and Handling (16)].
Manufactured for and distributed by Ardelyx, Inc.
Waltham, MA 02451 USA
IBSRELA® is a registered trademark of Ardelyx, Inc.
Patent: www.IBSRELA-patents.com
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Medication Guide
IBSRELA® (ibs rel`a)
(tenapanor)
tablets, for oral use
What is the most important information I should know about IBSRELA?
•
Do not give IBSRELA to children who are less than 6 years of age. It may harm them.
•
You should not give IBSRELA to patients 6 years to less than 18 years of age. It may harm them.
IBSRELA can cause severe diarrhea and your child could get severe dehydration (loss of a large amount of body water
and salt).
See “What are the possible side effects of IBSRELA?” for more information about side effects.
What is IBSRELA?
IBSRELA is a prescription medicine used in adults to treat:
•
Irritable bowel syndrome with constipation (IBS-C).
It is not known if IBSRELA is safe and effective in children less than 18 years of age.
Who should not take IBSRELA?
•
Do not give IBSRELA to children who are less than 6 years of age. IBSRELA can cause severe diarrhea and
your child could get severe dehydration (loss of a large amount of body water and salt).
•
Do not take IBSRELA if a doctor has told you that you have a bowel blockage (intestinal obstruction).
Before you take IBSRELA, tell your doctor about all your medical conditions, including if you:
•
are pregnant or plan to become pregnant. It is not known if IBSRELA will harm your unborn baby.
•
are breastfeeding or plan to breastfeed. It is not known if IBSRELA passes into your breast milk. Talk with your
doctor about the best way to feed your baby if you take IBSRELA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins
and herbal supplements.
How should I take IBSRELA?
•
Take IBSRELA exactly as your doctor tells you to take it.
•
Take 1 IBSRELA tablet by mouth, 2 times each day.
•
Take IBSRELA immediately before breakfast or the first meal of the day and immediately before dinner.
•
If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the
same time.
What are the possible side effects of IBSRELA?
IBSRELA can cause serious side effects, including:
•
See “What is the most important information I should know about IBSRELA?”
•
Diarrhea is the most common side effect of IBSRELA, and it can sometimes be severe. Stop taking
IBSRELA and call your doctor if you develop severe diarrhea.
The other most common side effects of IBSRELA include:
•
swelling, or a feeling of fullness or pressure in your abdomen (distension).
•
gas (flatulence).
•
dizziness.
These are not all the possible side effects of IBSRELA. Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088. You may also report side effects to www.fda.gov/medwatch.
How should I store IBSRELA?
•
Store IBSRELA at room temperature, between 68°F and 77°F (20°C and 25°C).
•
Keep IBSRELA in the original container and protect from moisture. Keep the container of IBSRELA tightly closed
and in a dry place.
•
Do not put IBSRELA in another container (repackage).
•
The IBSRELA bottle contains a desiccant canister to help keep your medicine dry (protect it from moisture). Do not
remove the desiccant from the bottle.
Keep IBSRELA and all medicines out of the reach of children.
General information about the safe and effective use of IBSRELA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use IBSRELA
for a condition for which it was not prescribed. Do not give IBSRELA to other people, even if they have the same
symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about
IBSRELA that is written for health professionals.
What are the ingredients in IBSRELA?
Active ingredient: tenapanor hydrochloride
Inactive ingredients: colloidal silicon dioxide, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline
cellulose, propyl gallate, stearic acid, tartaric acid, titanium dioxide, and triacetin.
Manufactured for and distributed by Ardelyx, Inc. Waltham, MA 02451 USA
IBSRELA® is a registered trademark of Ardelyx, Inc.
Patent: www.IBSRELA-patents.com
For more information, go to www.ardelyx.com or call 1-844-427-7352
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: May 2021
Reference ID: 5509314
| custom-source | 2025-02-12T15:48:26.040342 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211801s012lbl.pdf', 'application_number': 211801, 'submission_type': 'SUPPL ', 'submission_number': 12} |
80,842 |
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
VEKLURY safely and effectively. See full prescribing information
for VEKLURY.
VEKLURY® (remdesivir) for injection, for intravenous use
VEKLURY® (remdesivir) injection, for intravenous use
Initial U.S. Approval: 2020
---------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
02/2024
Dosage and Administration
Dosage and Administration Overview (2.1)
02/2024
Recommended Dosage in Adults and Pediatric Patients
(Birth to Less than 18 Years of Age Weighing at Least
1.5 kg) (2.3)
02/2024
Dosage Preparation and Administration in Pediatric
Patients (Birth to Less than 18 Years of Age) Weighing
1.5 kg to Less than 40 kg (2.6)
02/2024
---------------------------INDICATIONS AND USAGE----------------------------
VEKLURY is a severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) nucleotide analog RNA polymerase inhibitor indicated
for the treatment of coronavirus disease 2019 (COVID-19) in adults
and pediatric patients (birth to less than 18 years of age weighing at
least 1.5 kg) who are:
• Hospitalized, or
• Not hospitalized and have mild-to-moderate COVID-19, and are at
high risk for progression to severe COVID-19, including
hospitalization or death. (1)
------------------------DOSAGE AND ADMINISTRATION----------------------
• The only approved dosage form of VEKLURY for pediatric patients
weighing 1.5 kg to less than 40 kg is VEKLURY for injection
(supplied as 100 mg lyophilized powder in vial). (2.1)
• Testing: In all patients, before starting VEKLURY and during
treatment as clinically appropriate, perform hepatic laboratory
testing. Assess prothrombin time before starting VEKLURY and
monitor as clinically appropriate. (2.2)
• Recommended dosage:
o Adults and pediatric patients weighing at least 40 kg: a single
loading dose of VEKLURY 200 mg on Day 1 followed by once-
daily maintenance doses of VEKLURY 100 mg from Day 2 via
intravenous infusion. (2.3)
o Pediatric patients (birth to less than 18 years of age) weighing
1.5 kg to less than 40 kg: Recommended dosage is based on
weight. Refer to Table 1 of the full prescribing information for
specific dosing guidelines based on body weight. (2.3)
• Hospitalized patients: The treatment course of VEKLURY should be
initiated as soon as possible after diagnosis of symptomatic COVID
19 has been made. (2.3)
o For hospitalized patients requiring invasive mechanical
ventilation and/or ECMO, the recommended total treatment
duration is 10 days. (2.3)
o For hospitalized patients not requiring invasive mechanical
ventilation and/or ECMO, the recommended treatment duration
is 5 days. If a patient does not demonstrate clinical improvement,
treatment may be extended for up to 5 additional days for a total
treatment duration of up to 10 days. (2.3)
• Non-hospitalized patients: The treatment course of VEKLURY
should be initiated as soon as possible after diagnosis of
symptomatic COVID-19 has been made and within 7 days of
symptom onset. (2.3)
o For non-hospitalized patients diagnosed with mild-to-moderate
COVID-19 who are at high risk for progression to severe COVID
19, including hospitalization or death, the recommended total
treatment duration is 3 days (2.3).
• Renal impairment: No dosage adjustment of VEKLURY is
recommended in patients with any degree of renal impairment,
including those on dialysis. (2.4)
• Administer VEKLURY via intravenous (IV) infusion over 30 to 120
minutes. (2.5, 2.6)
• Dose preparation and administration: Refer to the full prescribing
information for further details for both formulations. (2.5, 2.6)
• Storage of prepared dosages: VEKLURY contains no preservative.
(2.7)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
• For injection: 100 mg of remdesivir as a lyophilized powder, in a
single-dose vial. (3)
• Injection: 100 mg/20 mL (5 mg/mL) remdesivir, in a single-dose vial.
(3)
-------------------------------CONTRAINDICATIONS------------------------------
VEKLURY is contraindicated in patients with a history of clinically
significant hypersensitivity reactions to VEKLURY or any components
of the product. (4)
--------------------------WARNINGS AND PRECAUTIONS--------------------
• Hypersensitivity including infusion-related and anaphylactic
reactions: Hypersensitivity reactions have been observed during and
following administration of VEKLURY. Slower infusion rates, with a
maximum infusion time of up to 120 minutes, can be considered to
potentially prevent signs and symptoms of hypersensitivity. Monitor
patients during infusion and observe patients for at least one
hour after infusion is complete for signs and symptoms of
hypersensitivity as clinically appropriate. If signs and symptoms of a
clinically significant hypersensitivity reaction occur, immediately
discontinue administration of VEKLURY and initiate appropriate
treatment. (5.1)
• Increased risk of transaminase elevations: Transaminase elevations
have been observed in healthy volunteers and have also been
reported in patients with COVID-19 who received VEKLURY.
Perform hepatic laboratory testing in all patients before starting
VEKLURY and while receiving VEKLURY as clinically appropriate.
Consider discontinuing VEKLURY if ALT levels increase to greater
than 10 times the upper limit of normal. Discontinue VEKLURY if
ALT elevation is accompanied by signs or symptoms of liver
inflammation. (5.2)
• Risk of reduced antiviral activity when coadministered with
chloroquine phosphate or hydroxychloroquine sulfate:
Coadministration of VEKLURY and chloroquine phosphate or
hydroxychloroquine sulfate is not recommended based on data from
cell culture experiments demonstrating a potential antagonistic
effect of chloroquine on the intracellular metabolic activation and
antiviral activity of VEKLURY. (5.3)
------------------------------ ADVERSE REACTIONS -----------------------------
The most common adverse reactions (incidence greater than or equal
to 5%, all grades) observed with treatment with VEKLURY are nausea,
ALT increased, and AST increased. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead
Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 01/2025
1
Reference ID: 5508433
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1
Dosage and Administration Overview
2.2
Testing Before Starting and During Treatment with
VEKLURY
2.3
Recommended Dosage in Adults and Pediatric Patients
(Birth to Less than 18 Years of Age Weighing at Least
1.5 kg)
2.4
Renal Impairment
2.5
Dosage Preparation and Administration in Adults and
Pediatric Patients Weighing at Least 40 kg
2.6
Dosage Preparation and Administration in Pediatric Patients
(Birth to Less than 18 Years of Age) Weighing 1.5 kg to Less
than 40 kg
2.7
Storage of Prepared Dosages
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Including Infusion-related and Anaphylactic
Reactions
5.2
Increased Risk of Transaminase Elevations
5.3
Risk of Reduced Antiviral Activity When Coadministered with
Chloroquine Phosphate or Hydroxychloroquine Sulfate
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
7 DRUG INTERACTIONS
7.1
Effects of Other Drugs on VEKLURY
7.2
Effects of VEKLURY on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Description of Clinical Trials
14.2 NIAID ACTT-1 Study in Hospitalized Subjects with
Mild/Moderate and Severe COVID-19
14.3 Study GS-US-540-5773 in Hospitalized Subjects with Severe
COVID-19
14.4 Study GS-US-540-5774 in Hospitalized Subjects with
Moderate COVID-19
14.5 Study GS-US-540-9012 in Non-Hospitalized Subjects with
Mild-to-Moderate COVID-19 and at High Risk for
Progression to Severe Disease
14.6 Study GS-US-540-5823 in Hospitalized Pediatric Subjects
with COVID-19
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
2
Reference ID: 5508433
1
2
FULL PRESCRIBING INFORMATION
INDICATIONS AND USAGE
VEKLURY is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and
pediatric patients (birth to less than 18 years of age weighing at least 1.5 kg) who are [see Clinical
Studies (14)]:
• Hospitalized, or
• Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to
severe COVID-19, including hospitalization or death.
DOSAGE AND ADMINISTRATION
2.1 Dosage and Administration Overview
• VEKLURY may only be administered in settings in which healthcare providers have immediate
access to medications to treat a severe infusion or hypersensitivity reaction, such as anaphylaxis,
and the ability to activate the emergency medical system (EMS), as necessary [see Dosage and
Administration (2.5, 2.6), Warnings and Precautions (5.1)].
• Administer VEKLURY for the treatment of COVID-19 in adults and pediatric patients (birth to less
than 18 years of age weighing at least 1.5 kg) by intravenous infusion only. Do not administer by
any other route.
• There are TWO different formulations of VEKLURY:
o VEKLURY for injection (supplied as 100 mg lyophilized powder in vial) must be reconstituted
with Sterile Water for Injection prior to diluting with 0.9% sodium chloride injection.
•
The only approved dosage form of VEKLURY for pediatric patients weighing 1.5 kg
to less than 40 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder
in vial).
o VEKLURY injection (supplied as 100 mg/20 mL [5 mg/mL] solution in vial) must be further
diluted in 250 mL of 0.9% sodium chloride injection infusion bag.
• There are differences in the way the two formulations are prepared. Carefully follow the product-
specific preparation instructions below [see Dosage and Administration (2.5, 2.6)].
2.2 Testing Before Starting and During Treatment with VEKLURY
Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving
VEKLURY as clinically appropriate [see Warnings and Precautions (5.2) and Use in Specific
Populations (8.7)].
Determine prothrombin time in all patients before starting VEKLURY and monitor while receiving
VEKLURY as clinically appropriate [see Adverse Reactions (6.1)].
3
Reference ID: 5508433
2.3 Recommended Dosage in Adults and Pediatric Patients (Birth to Less than 18 Years of
Age Weighing at Least 1.5 kg)
• The recommended dosage for adults and pediatric patients weighing at least 40 kg is a single
loading dose of VEKLURY 200 mg on Day 1 via intravenous infusion followed by once-daily
maintenance doses of VEKLURY 100 mg from Day 2 via intravenous infusion.
• The recommended dosage for pediatric patients weighing 1.5 kg to less than 40 kg is presented in
Table 1.
Table 1
Recommended Dosage in Pediatric Patients Including Terma Neonates and
Infants Weighing 1.5 kg to Less than 40 kg
Pediatric Patient Population
Loading Dose
Via Intravenous Infusion
Maintenance Dose
Via Intravenous Infusion
Less than 28 days old
and at least 1.5 kg
VEKLURY 2.5 mg/kg on Day 1
VEKLURY 1.25 mg/kg
once daily from Day 2
At least 28 days old
and 1.5 kg to less than 3 kg
At least 28 days old
and 3 kg to less than 40 kg
VEKLURY 5 mg/kg on Day 1
VEKLURY 2.5 mg/kg once
daily from Day 2
a.
Gestational age greater than 37 weeks.
The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of
symptomatic COVID-19 has been made.
• The recommended total treatment duration for hospitalized patients requiring invasive mechanical
ventilation and/or extracorporeal membrane oxygenation (ECMO) is 10 days.
• The recommended treatment duration for hospitalized patients not requiring invasive mechanical
ventilation and/or ECMO is 5 days. If a patient does not demonstrate clinical improvement,
treatment may be extended for up to 5 additional days for a total treatment duration of up to 10
days.
Non-hospitalized patients:
The treatment course of VEKLURY should be initiated as soon as possible after diagnosis of
symptomatic COVID-19 has been made and within 7 days of symptom onset.
• The recommended total treatment duration for non-hospitalized patients diagnosed with mild-to
moderate COVID-19 who are at high risk for progression to severe COVID-19, including
hospitalization or death, is 3 days.
VEKLURY must be diluted prior to intravenous infusion. Refer to Dosage and Administration (2.5, 2.6)
for detailed preparation and administration instructions.
4
Reference ID: 5508433
2.4 Renal Impairment
No dosage adjustment of VEKLURY is recommended in patients with any degree of renal
impairment, including patients on dialysis. VEKLURY may be administered without regard to the
timing of dialysis [see Dosage and Administration (2.3) and Use in Specific Populations (8.4, 8.6)].
2.5 Dosage Preparation and Administration in Adults and Pediatric Patients Weighing at
Least 40 kg
There are differences in the way the two formulations are prepared. Carefully follow the
product-specific preparation instructions below.
VEKLURY for Injection (Supplied as 100 mg Lyophilized Powder in Vial)
Reconstitution Instructions
Remove the required number of single-dose vial(s) from storage. For each vial:
• Aseptically reconstitute VEKLURY lyophilized powder by adding 19 mL of Sterile Water for
Injection using a suitably sized syringe and needle per vial, and insert the needle in the center of
the vial stopper.
• Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder.
• Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial.
• Immediately shake the vial for 30 seconds.
• Allow the contents of the vial to settle for 2 to 3 minutes. A clear, colorless to yellow solution, free
of visible particles, should result.
• If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and
allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the
contents of the vial are completely dissolved. Discard the vial if the contents are not completely
dissolved.
• Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution.
• Use reconstituted product immediately to prepare the diluted drug product [see Dosage and
Administration (2.7)].
Dilution Instructions
Care should be taken during admixture to prevent inadvertent microbial contamination. As
there is no preservative or bacteriostatic agent present in this product, aseptic technique must be
used in preparation of the final parenteral solution. It is always recommended to administer
intravenous medication immediately after preparation when possible.
• Reconstituted VEKLURY for injection, containing 100 mg/20 mL remdesivir solution, must be
further diluted in either a 100 mL or 250 mL 0.9% sodium chloride injection infusion bag. Refer to
Table 2 for instructions.
5
Reference ID: 5508433
Table 2
Recommended Dilution Instructions—Reconstituted VEKLURY for Injection
Lyophilized Powder in Adults and Pediatric Patients Weighing at Least 40 kg
VEKLURY dose
0.9% sodium
chloride
injection
infusion bag
volume to be
used
Volume to be withdrawn
and discarded from
0.9% sodium chloride
injection infusion bag
Required volume of
reconstituted VEKLURY
for injection
Loading dose
200 mg
(2 vials)
250 mL
40 mL
40 mL (2 × 20 mL)
100 mL
40 mL
40 mL (2 × 20 mL)
Maintenance dose
100 mg
(1 vial)
250 mL
20 mL
20 mL
100 mL
20 mL
20 mL
• Withdraw and discard the required volume of 0.9% sodium chloride injection from the bag
following instructions in Table 2, using an appropriately sized syringe and needle.
• Withdraw the required volume of reconstituted VEKLURY for injection from the VEKLURY vial
following instructions in Table 2, using an appropriately sized syringe. Discard any unused portion
remaining in the reconstituted vial.
• Transfer the required volume of reconstituted VEKLURY for injection to the selected infusion bag.
• Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
• The prepared infusion solution can be stored for 24 hours at room temperature (20°C to 25°C
[68°F to 77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]) prior to
administration.
Administration Instructions
Do not administer the prepared diluted solution simultaneously with any other medication. The
compatibility of VEKLURY injection with intravenous solutions and medications other than 0.9%
sodium chloride injection, USP is not known. Administer VEKLURY via intravenous infusion over 30
to 120 minutes.
Administration should be under conditions where management of severe hypersensitivity reactions,
such as anaphylaxis, is possible. Monitor patients during infusion and observe patients for at least
one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically
appropriate [see Warnings and Precautions (5.1)].
Administer the diluted solution with the infusion rate described in Table 3.
6
Reference ID: 5508433
Table 3
Recommended Rate of Infusion—Diluted VEKLURY for Injection Lyophilized
Powder in Adults and Pediatric Patients Weighing at Least 40 kg
Infusion bag volume
Infusion time
Rate of infusion
30 min
8.33 mL/min
250 mL
60 min
4.17 mL/min
120 min
2.08 mL/min
30 min
3.33 mL/min
100 mL
60 min
1.67 mL/min
120 min
0.83 mL/min
VEKLURY Injection (Supplied as 100 mg/20 mL [5 mg/mL] Solution in Vial)
Dilution Instructions
Care should be taken during admixture to prevent inadvertent microbial contamination. As
there is no preservative or bacteriostatic agent present in this product, aseptic technique must be
used in preparation of the final parenteral solution. It is always recommended to administer
intravenous medication immediately after preparation when possible.
• Remove the required number of single-dose vial(s) from storage. Each vial contains 100 mg/20
mL of remdesivir. For each vial:
• Equilibrate to room temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to
12 hours at room temperature prior to dilution.
• Inspect the vial to ensure the container closure is free from defects and the solution is free of
particulate matter.
• VEKLURY injection must be diluted in an infusion bag containing 250 mL of 0.9% sodium chloride
injection only. Refer to Table 4 for instructions.
7
Reference ID: 5508433
Table 4
Recommended Dilution Instructions—VEKLURY Injection (Supplied as Solution
in Vial) in Adults and Pediatric Patients Weighing at Least 40 kg
0.9% sodium
Volume to be
chloride
withdrawn and
VEKLURY dose
injection
infusion bag
volume to be
used
discarded from
0.9% sodium
chloride injection
infusion bag
Required volume of
VEKLURY injection
Loading dose
200 mg
(2 vials)
250 mL
40 mL
40 mL (2 × 20 mL)
Maintenance dose
100 mg
(1 vial)
20 mL
20 mL
• Withdraw and discard the required volume of 0.9% sodium chloride injection from the bag
following instructions in Table 4, using an appropriately sized syringe and needle.
• Withdraw the required volume of VEKLURY injection from the VEKLURY vial following instructions
in Table 4, using an appropriately sized syringe.
• Pull the syringe plunger rod back to fill the syringe with approximately 10 mL of air.
• Inject the air into the VEKLURY injection vial above the level of the solution.
• Invert the vial and withdraw the required volume of VEKLURY injection solution into the syringe.
The last 5 mL of solution requires more force to withdraw.
• Transfer the required volume of VEKLURY injection to the infusion bag.
• Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
• The prepared infusion solution is stable for 24 hours at room temperature (20°C to 25°C [68°F to
77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
Administration Instructions
Do not administer the prepared diluted solution simultaneously with any other medication. The
compatibility of VEKLURY injection with intravenous solutions and medications other than 0.9%
sodium chloride injection, USP is not known. Administer VEKLURY via intravenous infusion over 30
to 120 minutes.
Administration should be under conditions where management of severe hypersensitivity reactions,
such as anaphylaxis, is possible. Monitor patients during infusion and observe patients for at least
one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically
appropriate [see Warnings and Precautions (5.1)].
Administer the diluted solution with the infusion rate described in Table 5.
8
Reference ID: 5508433
Table 5
Recommended Rate of Infusion—Diluted VEKLURY Injection Solution in Adults
and Pediatric Patients Weighing at Least 40 kg
Infusion bag volume
Infusion time
Rate of infusion
30 min
8.33 mL/min
250 mL
60 min
4.17 mL/min
120 min
2.08 mL/min
2.6 Dosage Preparation and Administration in Pediatric Patients (Birth to Less than 18 Years
of Age) Weighing 1.5 kg to Less than 40 kg
The only approved dosage form of VEKLURY for pediatric patients weighing 1.5 kg to less
than 40 kg is VEKLURY for injection (supplied as 100 mg lyophilized powder in vial). Carefully
follow the product-specific preparation instructions below.
Use VEKLURY for Injection (Supplied as 100 mg Lyophilized Powder in Vial) only.
Reconstitution Instructions
Remove the required number of single-dose vial(s) from storage. For each vial:
• Aseptically reconstitute VEKLURY lyophilized powder by adding 19 mL of Sterile Water for
Injection using a suitably sized syringe and needle per vial, and insert the needle in the center of
the vial stopper.
• Only use Sterile Water for Injection to reconstitute VEKLURY lyophilized powder.
• Discard the vial if a vacuum does not pull the Sterile Water for Injection into the vial.
• Immediately shake the vial for 30 seconds.
• Allow the contents of the vial to settle for 2 to 3 minutes. A clear, colorless to yellow solution, free
of visible particles, should result.
• If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and
allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the
contents of the vial are completely dissolved. Discard the vial if the contents are not completely
dissolved.
• Following reconstitution, each vial contains 100 mg/20 mL (5 mg/mL) of remdesivir solution.
• Use reconstituted product immediately to prepare the diluted drug product [see Dosage and
Administration (2.7)].
Dilution Instructions
• For pediatric patients (birth to less than 18 years of age) weighing 1.5 kg to less than 40 kg, the
100 mg/20 mL (5 mg/mL) remdesivir reconstituted solution should be further diluted to a fixed
concentration of 1.25 mg/mL using 0.9% sodium chloride injection.
• The final required infusion volume concentration of 1.25 mg/mL remdesivir diluted solution for
infusion is based on the pediatric weight-based dosing regimens.
• Small 0.9% sodium chloride injection infusion bags (e.g., 25, 50, or 100 mL) or an appropriately
sized syringe should be used for pediatric dosing. The recommended dose is administered via
9
Reference ID: 5508433
intravenous infusion in a total volume dependent on the dose to yield the target remdesivir
concentration of 1.25 mg/mL.
• A syringe and syringe pump may be used for infusion volumes less than 50 mL.
Infusion with IV Bag
• Determine the total infusion volume needed to achieve a final infusion volume concentration of
1.25 mg/mL of remdesivir diluted solution based on the patient’s calculated dose.
• Select an appropriately sized infusion bag (either prefilled with 0.9% sodium chloride injection or
empty) to prepare VEKLURY diluted solution.
• If using a prefilled 0.9% sodium chloride injection infusion bag, withdraw and discard the amount
of diluent equal to the volume of reconstituted VEKLURY solution needed per patient’s dose plus
a quantity sufficient to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted
solution.
• Withdraw the required volume of reconstituted VEKLURY solution into an appropriately sized
syringe.
• Transfer the required volume of reconstituted VEKLURY solution to the 0.9% sodium chloride
injection infusion bag.
• Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
• If using an empty infusion bag, transfer the required volume of reconstituted VEKLURY solution to
the bag, followed by a volume of 0.9% sodium chloride injection sufficient to achieve a 1.25
mg/mL final volume concentration of remdesivir diluted solution.
• The prepared infusion solution is stable for 24 hours at room temperature (20°C to 25°C [68°F to
77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
Infusion with Syringe
• Determine the total infusion volume needed to achieve a final infusion volume concentration of
1.25 mg/mL of remdesivir diluted solution based on patient’s calculated dose.
• Select an appropriately sized syringe equal to or larger than the calculated total infusion volume of
1.25 mg/mL remdesivir solution needed.
• Withdraw the required volume of reconstituted VEKLURY solution from the vial into the syringe
based on patient’s calculated dose, followed by the required volume of 0.9% sodium chloride
injection needed to achieve a 1.25 mg/mL final volume concentration of remdesivir diluted
solution.
• Gently invert the syringe 20 times to mix the solution in the syringe. Do not shake.
• The prepared diluted solution should be used immediately.
Administration Instructions
The prepared diluted solution should not be administered simultaneously with any other medication.
The compatibility of VEKLURY with IV solutions and medications other than 0.9% sodium chloride
injection, USP is not known. Administer VEKLURY via intravenous infusion over 30 to 120 minutes.
The rate of infusion (mL/min) should be calculated based on the total infusion volume and total
infusion time.
Administration should be under conditions where management of severe hypersensitivity reactions,
such as anaphylaxis, is possible. Monitor patients during infusion and observe patients for at least
10
Reference ID: 5508433
one hour after infusion is complete for signs and symptoms of hypersensitivity as clinically
appropriate [see Warnings and Precautions (5.1)].
2.7 Storage of Prepared Dosages
VEKLURY for Injection (Supplied as Lyophilized Powder in Vial)
After reconstitution, use vials immediately to prepare diluted solution. The diluted VEKLURY solution
in the infusion bags can be stored up to 24 hours at room temperature (20°C to 25°C [68°F to 77°F])
prior to administration or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
VEKLURY Injection (Supplied as Solution in Vial)
Store VEKLURY injection after dilution in the infusion bags up to 24 hours at room temperature (20°C
to 25°C [68°F to 77°F]) or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
IMPORTANT:
This product contains no preservative. Any unused portion of a single-dose VEKLURY vial should be
discarded after a diluted solution is prepared.
3
DOSAGE FORMS AND STRENGTHS
• VEKLURY for injection, 100 mg, available as a sterile, preservative-free white to off-white to
yellow lyophilized powder in single-dose vial for reconstitution.
• VEKLURY injection, 100 mg/20 mL (5 mg/mL), available as a clear, colorless to yellow solution,
free of visible particles in single-dose vial.
4
CONTRAINDICATIONS
VEKLURY is contraindicated in patients with a history of clinically significant hypersensitivity reactions
to VEKLURY or any components of the product [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Including Infusion-related and Anaphylactic Reactions
Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observed
during and following administration of VEKLURY; most occurred within one hour. Signs and
symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea,
wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slower infusion rates, with a
maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs
and symptoms. Monitor patients during infusion and observe patients for at least one hour after
infusion is complete for signs and symptoms of hypersensitivity as clinically appropriate. If signs and
symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue
administration of VEKLURY and initiate appropriate treatment. The use of VEKLURY is
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6
contraindicated in patients with known hypersensitivity to VEKLURY or any components of the
product [see Contraindications (4)].
5.2 Increased Risk of Transaminase Elevations
Transaminase elevations have been observed in healthy volunteers who received 200 mg of
VEKLURY followed by 100 mg doses for up to 10 days; the transaminase elevations were mild
(Grade 1) to moderate (Grade 2) in severity and resolved upon discontinuation of
VEKLURY. Transaminase elevations have also been reported in patients with COVID-19 who
received VEKLURY [see Adverse Reactions (6.1)]. Because transaminase elevations have been
reported as a clinical feature of COVID-19, and the incidence was similar in patients receiving
placebo versus VEKLURY in clinical trials of VEKLURY, discerning the contribution of VEKLURY to
transaminase elevations in patients with COVID-19 can be challenging.
Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving
VEKLURY as clinically appropriate [see Dosage and Administration (2.1) and Use in Specific
Populations (8.7)].
• Consider discontinuing VEKLURY if ALT levels increase to greater than 10 times the upper limit of
normal.
• Discontinue VEKLURY if ALT elevation is accompanied by signs or symptoms of liver
inflammation.
5.3 Risk of Reduced Antiviral Activity When Coadministered with Chloroquine Phosphate or
Hydroxychloroquine Sulfate
Coadministration of VEKLURY and chloroquine phosphate or hydroxychloroquine sulfate is not
recommended based on data from cell culture experiments demonstrating a potential antagonistic
effect of chloroquine on the intracellular metabolic activation and antiviral activity of VEKLURY [see
Drug Interactions (7) and Microbiology (12.4)].
ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
• Hypersensitivity Including Infusion-related and Anaphylactic Reactions [see Warnings and
Precautions (5.1)]
• Increased Risk of Transaminase Elevations [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
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Clinical Trials in Adult Subjects
The safety of VEKLURY is based on data from four Phase 3 studies in 1,476 hospitalized adult
subjects with COVID-19, one Phase 3 study in 279 non-hospitalized adult and pediatric subjects (12
years of age and older weighing at least 40 kg) with mild-to-moderate COVID-19, four Phase 1
studies in 131 healthy adults, and from patients with COVID-19 who received VEKLURY under the
Emergency Use Authorization or in a compassionate use program.
Clinical Trials Experience in Adults with COVID-19
NIAID ACTT-1 was a randomized, double-blind, placebo-controlled clinical trial in hospitalized
subjects with mild, moderate, and severe COVID-19 treated with VEKLURY (n=532) or placebo
(n=516) for up to 10 days. Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg
once daily on subsequent days [see Clinical Studies (14.1)]. The collection of adverse event data in
this trial was limited to severe (Grade 3) or potentially life-threatening (Grade 4) adverse events,
serious adverse events, adverse events leading to study drug discontinuation, and moderate (Grade
2) severity or higher hypersensitivity reactions. Rates of adverse reactions (≥ Grade 3), serious
adverse reactions, and adverse reactions leading to treatment discontinuation are presented in
Table 6.
Table 6
Summary of Adverse Reaction Rates in Hospitalized Subjects with Mild,
Moderate, or Severe COVID-19 in NIAID ACTT-1
Types of Adverse Reactions
VEKLURY
N=532
n (%)
Placebo
N=516
n (%)
Adverse reactions, Grades ≥3
41 (8%)
46 (9%)
Serious adverse reactions
2 (0.4%)a
3 (0.6%)
Adverse reactions leading to treatment
discontinuation
11 (2%)b
15 (3%)
a. Seizure (n=1), infusion-related reaction (n=1).
b. Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST increased
(n=1), GFR decreased (n=2), acute kidney injury (n=3).
Study GS-US-540-5773 was a randomized, open-label clinical trial in hospitalized subjects with
severe COVID-19 treated with VEKLURY 200 mg on Day 1 and 100 mg once daily for 5 (n=200) or
10 days (n=197). Adverse reactions were reported in 33 (17%) subjects in the 5-day group and 40
(20%) subjects in the 10-day group [see Clinical Studies (14.2)]. The most common adverse reactions
occurring in at least 5% of subjects in either the VEKLURY 5-day or 10-day group, respectively, were
nausea (5% vs 3%), AST increased (3% vs 6%), and ALT increased (2% vs 7%). Rates of any
adverse reactions, serious adverse reactions, and adverse reactions leading to treatment
discontinuation are presented in Table 7.
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Table 7
Summary of Adverse Reaction Rates in Hospitalized Subjects with Severe COVID
19 in Study 5773
Types of Adverse Reactions
VEKLURY
5 Days
N=200
n (%)
VEKLURY
10 Days
N=197
n (%)
Any adverse reaction, all Grades
33 (17%)
40 (20%)
Serious adverse reactions
3 (2%)a
4 (2%)a
Adverse reactions leading to treatment discontinuation
5 (3%)b
9 (5%)b
a. Transaminases increased (n=5), hepatic enzyme increased (n=1), hypertransaminasaemia (n=1).
b. Transaminases increased (n=4), hepatic enzyme increased (n=2), LFT increased (n=2), hypertransaminasaemia
(n=1), ALT increased (n=1), ALT increased and AST increased (n=2), injection site erythema (n=1), rash (n=1).
Study GS-US-540-5774 was a randomized, open-label clinical trial in hospitalized subjects with
moderate COVID-19 treated with VEKLURY 200 mg on Day 1 and 100 mg daily for 5 (n=191) or 10
days (n=193), or standard of care (SOC) only (n=200) [see Clinical Studies (14.3)]. Adverse reactions
were reported in 36 (19%) subjects in the 5-day group and 25 (13%) subjects in the 10-day group.
The most common adverse reaction occurring in at least 5% of subjects in the VEKLURY groups was
nausea (7% in the 5-day group, 4% in the 10-day group). Rates of any adverse reactions, serious
adverse reactions, and adverse reactions leading to treatment discontinuation are presented in
Table 8.
Table 8
Summary of Adverse Reactiona Rates in Hospitalized Subjects with Moderate
COVID-19 in Study 5774
Types of Adverse Reactions
VEKLURY
5 Days
N=191
n (%)
VEKLURY
10 Days
N=193
n (%)
Any adverse reaction, all Grades
36 (19%)
25 (13%)
Serious adverse reactions
1 (<1%)b
0
Adverse reactions leading to treatment discontinuation
4 (2%)c
4 (2%)c
a. Attribution of events to study drug was not performed for the SOC group.
b. Heart rate decreased.
c. ALT increased (n=2), ALT increased and AST increased (n=1), hypertransaminasaemia (n=1), blood alkaline
phosphatase increased (n=1), rash (n=2), heart rate decreased (n=1).
Study GS-US-540-9012 was a randomized, double-blind, placebo-controlled clinical trial in subjects
who were non-hospitalized, were symptomatic for COVID-19 for ≤7 days, had confirmed SARS-CoV
2 infection, and had at least one risk factor for progression to hospitalization treated with VEKLURY
(n=279; 276 adults and 3 pediatric subjects 12 years of age and older weighing at least 40 kg) or
placebo (n=283; 278 adults and 5 pediatric subjects 12 years of age and older weighing at least
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40 kg) for 3 days. Of the 279 subjects treated with VEKLURY, 227 subjects received at least one
dose of VEKLURY at an outpatient facility, 44 subjects received at least one dose of VEKLURY in a
home healthcare setting, and 8 subjects received at least one dose of VEKLURY at a skilled nursing
facility. Subjects treated with VEKLURY received 200 mg on Day 1 and 100 mg once daily on
subsequent days [see Clinical Studies (14.4)]. Adverse reactions (all grades) were reported in 34
(12%) subjects in the VEKLURY group and 25 (9%) subjects in the placebo group. The most common
adverse reaction occurring in at least 5% of subjects in the VEKLURY group was nausea (6%). There
were no serious adverse reactions or adverse reactions leading to treatment discontinuation in either
treatment group. Safety in subjects who received VEKLURY in a home healthcare setting was
comparable to that observed in the overall GS-US-540-9012 study population, but these findings are
based on limited data.
Less Common Adverse Reactions in Adults from Clinical Trials
Clinically significant adverse reactions that were reported in <2% of subjects exposed to VEKLURY in
clinical trials are listed below:
• Hypersensitivity reactions [see Warnings and Precautions (5.1)].
• Generalized seizure
• Rash
Laboratory Abnormalities
Study GS-US-399-5505 was a Phase 1, randomized, blinded, placebo-controlled clinical trial in
healthy volunteers administered VEKLURY 200 mg on Day 1 and 100 mg for either 4 days or 9 days.
Mild (Grade 1, n=8) to moderate (Grade 2, n=1) elevations in ALT were observed in 9 of 20 subjects
receiving 10 days of VEKLURY; the elevations in ALT resolved upon discontinuation of VEKLURY.
No subjects (0 of 9) who received 5 days of VEKLURY had graded increases in ALT.
The frequencies of laboratory abnormalities (Grades 3-4) occurring in at least 3% of subjects with
COVID-19 receiving VEKLURY in Trials NIAID ACTT-1, 5773, and 5774 are presented in Table 9,
Table 10, and Table 11, respectively.
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Table 9
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
with Mild, Moderate, or Severe COVID-19 in NIAID ACTT-1
Laboratory Parameter Abnormalitya
VEKLURY 10 Days
N=532
Placebo
N=516
ALT increased
3%
6%
AST increased
6%
8%
Bilirubin increased
2%
5%
Creatinine clearance decreasedb
18%
20%
Creatinine increased
15%
16%
eGFR decreased
18%
24%
Glucose increased
12%
13%
Hemoglobin decreased
15%
22%
Lymphocytes decreased
11%
18%
Prothrombin time increased
9%
4%
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
Table 10
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
with Severe COVID-19 in Trial 5773
Laboratory Parameter Abnormalitya
VEKLURY
5 Days
N=200
VEKLURY
10 Days
N=197
ALT increased
6%
8%
AST increased
7%
6%
Creatinine clearance decreasedb
10%
19%
Creatinine increased
5%
15%
Glucose increased
11%
8%
Hemoglobin decreased
6%
8%
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
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Table 11
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
with Moderate COVID-19 in Trial 5774
Laboratory Parameter Abnormalitya
VEKLURY
5 Days
N=191
VEKLURY 10
Days
N=193
SOC
N=200
ALT increased
2%
3%
8%
Creatinine clearance decreasedb
2%
5%
8%
Glucose increased
4%
3%
2%
Hemoglobin decreased
3%
1%
6%
SOC=Standard of care.
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
The frequencies of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects with
COVID-19 receiving VEKLURY in Trial GS-US-540-9012 are presented in Table 12.
Table 12
Laboratory Abnormalities (Grades 3-4) Reported in ≥2% of Non-Hospitalized
Subjects in Trial 9012
Laboratory Parameter Abnormalitya
VEKLURY 3 Days
N=279
Placebo
N=283
Creatinine clearance decreasedb
6%
2%
Creatinine increased
3%
1%
Glucose increased
6%
6%
Lymphocytes decreased
2%
1%
Prothrombin time increased
1%
2%
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
b. Based on the Cockcroft-Gault formula.
Clinical Trials Experience in Adults with COVID-19 and Renal Impairment
Study GS-US-540-5912 was a randomized, double-blind, placebo-controlled clinical trial in which 163
hospitalized subjects with confirmed COVID-19 and acute kidney injury (AKI; N=60), chronic kidney
disease (CKD; eGFR <30 mL/minute/1.73m2; N=44), or end-stage renal disease (ESRD; eGFR <15
mL/minute/1.73m2; N=59) on hemodialysis received VEKLURY for up to 5 days [see Use in Specific
Populations (8.6)]. The adverse reactions observed were consistent with those observed in clinical
trials of VEKLURY in adults. Adverse reactions (all grades) were reported in 13 (8%) subjects in the
VEKLURY group and 3 (4%) subjects in the placebo group. The most common adverse reactions
were nausea (1%), abdominal pain (1%), and diarrhea (1%). No subjects experienced serious
adverse reactions. One subject permanently discontinued treatment due to an adverse reaction:
lipase increased.
The frequencies of laboratory abnormalities (Grades 3-4) occurring in at least 3% of subjects with
COVID-19 receiving VEKLURY in Trial GS-US-540-5912 are presented in Table 13.
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Table 13
Laboratory Abnormalities (Grades 3-4) Reported in ≥3% of Hospitalized Subjects
in Trial 5912
Laboratory Parameter Abnormalitya
VEKLURY 5 Days
N=163
Placebo
N=80
Lymphocytes decreased
27%
27%
Hemoglobin decreased
25%
25%
Glucose increased
15%
19%
Uric acid increased
11%
4%
Creatinine increased
12%
14%
Albumin decreased
12%
10%
Lipase increased
12%
7%
Prothrombin time increased
11%
4%
Prothrombin INR increased
7%
4%
AST increased
6%
4%
Thromboplastin time increased
5%
4%
ALT increased
5%
6%
Sodium increased
3%
3%
Calcium increased
3%
0
a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Division of AIDS (DAIDS) Table
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017.
Clinical Trials in Pediatric Subjects
Study GS-US-540-5823 was a Phase 2/3, single-arm, open-label clinical trial in hospitalized subjects
from birth to <18 years of age and weighing at least 1.5 kg with mild, moderate, and severe COVID
19 treated with weight-based VEKLURY (n=58) for up to 10 days [see Clinical Studies (14.6)]:
• Cohorts 1, 8: Subjects ≥12 years and weighing ≥40 kg (n=12) and subjects <12 years and
weighing ≥40 kg (n=5): Received 200 mg on Day 1 and 100 mg once daily on subsequent days.
• Cohorts 2-4: Subjects ≥28 days and weighing ≥20 to <40 kg (n=12); subjects ≥28 days and
weighing ≥12 to <20 kg (n=12); and subjects ≥28 days and weighing ≥3 to <12 kg (n=12):
Received 5 mg/kg on Day 1 and 2.5 mg/kg once daily on subsequent days.
• Cohort 5: Subjects 14 to <28 days old, gestational age (GA) >37 weeks, and weighing ≥2.5 kg
(n=3): Received 5 mg/kg on Day 1 and 2.5 mg/kg once daily on subsequent days.
• Cohorts 6-7: Subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and
subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1): Received 2.5 mg/kg on
Day 1 and 1.25 mg/kg once daily on subsequent days.
The adverse reactions observed were consistent with those observed in clinical trials of VEKLURY in
adults.
Infants, children, and adolescents; Cohorts 1-4, 8: Adverse reactions (all grades) were reported in 8
(15%) subjects. The most common adverse reaction occurring in at least 5% of subjects was ALT
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7
increased (6%). No subjects experienced serious adverse reactions. Two (4%) subjects permanently
discontinued treatment due to adverse reactions (ALT increased [n=1], ALT increased and AST
increased and hyperbilirubinemia [n=1]). Laboratory abnormalities (Grades 3-4) occurring in at least
3% of subjects with COVID-19 receiving VEKLURY in Trial 5823 and who had at least one post-
baseline value for the specified test were hemoglobin decreased (18%, 9/51), eGFR decreased (18%,
7/40), creatinine increased (10%, 5/52), direct bilirubin increased (9%, 2/23), prothrombin time
increased (7%, 3/46), APTT increased (7%, 3/45), lymphocytes decreased (6% 2/33), proteinuria
(6%, 2/36), WBC decreased (4%, 2/51), ALT increased (4%, 2/51), glucose increased (4%, 2/52),
glycosuria (4%, 2/46), potassium decreased (4%, 2/52).
Neonates and infants; Cohorts 5-7: Laboratory abnormalities (Grades 3-4) were reported in 3/5
subjects: APTT increased (2/5); direct bilirubin increased (1/5); creatinine increased (1/5);
prothrombin time increased (1/5); prothrombin/INR increased (1/5); and potassium increased (1/5).
Emergency Use Authorization Experience in Subjects with COVID-19
The following adverse reactions have been identified during use of VEKLURY under Emergency Use
Authorization:
• General disorders and administration site conditions: Administration site extravasation
• Skin and subcutaneous tissue disorders: Rash
• Immune system disorders: Anaphylaxis, angioedema, infusion-related reactions, hypersensitivity
• Investigations: Transaminase elevations
DRUG INTERACTIONS
7.1 Effects of Other Drugs on VEKLURY
Due to potential antagonism based on data from cell culture experiments, concomitant use of
VEKLURY with chloroquine phosphate or hydroxychloroquine sulfate is not recommended [see
Warnings and Precautions (5.3) and Microbiology (12.4)]. Based on drug interaction studies
conducted with VEKLURY, no clinically significant drug interactions are expected with inducers of
cytochrome P450 (CYP) 3A4 or inhibitors of Organic Anion Transporting Polypeptides (OATP)
1B1/1B3 and, P-glycoprotein (P-gp) [see Clinical Pharmacology (12.3)].
7.2 Effects of VEKLURY on Other Drugs
Based on drug interaction studies conducted with VEKLURY, it is a weak inhibitor of CYP3A and
does not inhibit OATP1B1/1B3 [see Clinical Pharmacology (12.3)].
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8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data from a clinical trial (IMPAACT 2032), published reports, the COVID-PR pregnancy
exposure registry, and compassionate use of remdesivir in pregnant individuals have not identified a
drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
following exposure in the second and third trimester. However, there are insufficient pregnancy data
available to evaluate the risk of remdesivir exposure during the first trimester. A study evaluating the
pharmacokinetics of remdesivir during pregnancy demonstrated no clinically relevant differences
between pregnant and non-pregnant individuals. No dose adjustments are recommended in patients
who receive VEKLURY during pregnancy (see Data) and [see Clinical Pharmacology (12.3)]. In
nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryo-fetal
development when administered to pregnant animals at systemic exposures (AUC) of the
predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the
exposure in humans at the recommended human dose (RHD) (see Data). There are maternal and
fetal risks associated with untreated COVID-19 in pregnancy (see Clinical Considerations).
The background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo-fetal risk
COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including
preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic
disease, and fetal death.
Data
Human Data
A non-randomized, open-label clinical study (IMPAACT 2032) evaluated pharmacokinetics and safety
of up to 10 days of treatment with VEKLURY in 25 hospitalized pregnant and 28 hospitalized non-
pregnant individuals of childbearing potential. Subjects received VEKLURY 200 mg once daily for 1
day followed by VEKLURY 100 mg once daily on subsequent days via intravenous infusion. Subjects
were enrolled prior to their fourth VEKLURY infusion. Assessments occurred at the following
intervals: Screening; Pre-infusion (defined as 48 hours prior to start of first infusion); each infusion
day; 48 hours after the last infusion; 7 days after the last infusion; 4 weeks after the last infusion.
Assessments also occurred 24 hours post-delivery in subjects who delivered. Treatment with
VEKLURY was stopped in subjects who were discharged from the hospital prior to the completion of
10 days of treatment.
Of the 25 pregnant subjects, median age was 33 years (Q1, Q3: 27 years, 37 years); 40% were
White, 24% were Black, and 48% were Hispanic or Latino. A total of 9 subjects (36%) were on high-
flow oxygen; 12 subjects (48%) were on low-flow oxygen; and 1 subject (4%) was on room air, at
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baseline. Three subjects (12%) did not have data available on baseline oxygen status. The overall
median (Q1, Q3) duration of symptoms prior to hospitalization was 7 (6, 9) days. The overall median
(Q1, Q3) duration of symptoms prior to first dose of VEKLURY was 8 (6, 9) days.
Of the 25 pregnant subjects, median gestational age was 28 weeks at baseline (range 22 to 33
weeks) and about half of subjects were in each of the second and third trimester of pregnancy. No
clinically relevant differences in the pharmacokinetics of remdesivir or its metabolites (GS-704277
and GS-441524) were observed between pregnant (n=21) and non-pregnant (n=22) individuals [see
Clinical Pharmacology (12.3)]. No difference in pharmacokinetics of remdesivir or its metabolites is
expected between the first and second/third trimesters. The adverse reactions observed were
consistent with those observed in clinical trials of VEKLURY in adults [see Adverse Reactions (6.1)].
There were no adverse reactions in infants born during the study (n=16).
Animal Data
Remdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20
mg/kg/day) on Gestation Days 6 through 17, and 7 through 20, respectively, and also to rats from
Gestation Day 6 to Lactation/Post-partum Day 20. No adverse effects on embryo-fetal (rats and
rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in
pregnant animals. During organogenesis, exposures to the predominant circulating metabolite (GS
441524) were 4 times higher (rats and rabbits) than the exposure in humans at the RHD. In a
pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir
(GS-441524) were similar to the human exposures at the RHD.
8.2 Lactation
Risk Summary
A published case report describes the presence of remdesivir and active metabolite GS-441524 in
human milk. Available data (n=11) from pharmacovigilance reports do not indicate adverse effects on
breastfed infants from exposure to remdesivir and its metabolite through breastmilk. There are no
available data on the effects of remdesivir on milk production. In animal studies, remdesivir and
metabolites have been detected in the nursing pups of mothers given remdesivir, likely due to the
presence of remdesivir in milk (see Data). The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for VEKLURY and any potential adverse
effects on the breastfed child from VEKLURY or from the underlying maternal condition.
Breastfeeding individuals with COVID-19 should follow practices according to clinical guidelines to
avoid exposing the infant to COVID-19.
Data
Remdesivir and its metabolites were detected in the plasma of nursing rat pups, likely due to the
presence of remdesivir and/or its metabolites in milk, following daily intravenous administration of
remdesivir to pregnant rats from Gestation Day 6 to Lactation Day 20. Exposures in nursing pups
were approximately 1% that of maternal exposure on Lactation Day 10. The concentration of
remdesivir in animal milk does not necessarily predict the concentration of drug in human milk.
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8.4 Pediatric Use
The safety and effectiveness of VEKLURY for the treatment of COVID-19 have been established in
pediatric patients from birth to less than 18 years of age and weighing at least 1.5 kg, who are:
• Hospitalized, or
• Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to
severe COVID-19, including hospitalization or death.
Use in this age group is supported by the following:
• Trials in adults [see Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5)]
• An open-label trial (Study 5823) in 58 hospitalized pediatric subjects [see Adverse Reactions
(6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)].
Use of VEKLURY in pediatric patients from birth to less than 18 years of age and weighing at least
1.5 kg is supported by Study 5823 where 58 hospitalized pediatric subjects were treated with weight-
based VEKLURY for up to 10 days in the following cohorts:
• Cohorts 1-4, 8; infants, children, and adolescents: Subjects ≥12 years and weighing ≥40 kg
(n=12); subjects <12 years and weighing ≥40 kg (n=5); subjects ≥28 days and weighing ≥20 to
<40 kg (n=12); subjects ≥28 days and weighing ≥12 to <20 kg (n=12); and subjects ≥28 days
and weighing ≥3 to <12 kg (n=12);
• Cohorts 5-7; neonates and infants: Subjects 14 to <28 days old, GA >37 weeks, and weighing
≥2.5 kg (n=3); subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and
subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1).
The safety and pharmacokinetic results in pediatric subjects were similar to those in adults [see
Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)].
Use of VEKLURY in pediatric patients weighing at least 40 kg is further supported by a clinical trial of
VEKLURY in non-hospitalized subjects that included 3 pediatric subjects 12 years and older, and by
clinical trials in hospitalized subjects that included 30 adult subjects weighing 40 to 50 kg. The safety
in this weight group was comparable to adult subjects weighing greater than 50 kg. Thirty-nine
pediatric patients 12 years and older and weighing at least 40 kg received VEKLURY in a
compassionate use program in hospitalized subjects; the available clinical data from these patients
are limited [see Adverse Reactions (6.1) and Clinical Studies (14)].
Use of VEKLURY in pediatric patients with renal impairment is supported by safety data in adults [see
Adverse Reactions (6.1), Use in Specific Populations (8.6)]. Limited data are available regarding the
safety of VEKLURY in pediatric patients with mild or moderate renal impairment. No data are
available regarding the safety of VEKLURY in pediatric patients with severe renal impairment. In
adults with severe renal impairment, including those requiring dialysis, exposures of GS-441524 and
GS-704277, the metabolites of remdesivir, and betadex sulfobutyl ether sodium (SBECD) are
increased [see Clinical Pharmacology (12.3)]. VEKLURY contains SBECD which, when administered
intravenously, is eliminated through glomerular filtration and therefore when administered to pediatric
patients with renal immaturity or renal impairment, may result in higher exposure to SBECD.
The safety and effectiveness of VEKLURY have not been established in pediatric patients weighing
less than 1.5 kg.
22
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8.5 Geriatric Use
Of the 1,062 hospitalized subjects with SARS-CoV-2 infection randomized in ACTT-1, 36% were 65
years or older. Of the 397 hospitalized subjects with SARS-CoV-2 infection randomized in Study GS
US-540-5773, 42% were 65 years or older. Of the 584 hospitalized subjects with SARS-CoV-2
infection randomized in Study GS-US-540-5774, 27% were 65 years or older. Of the 562 non-
hospitalized subjects with SARS-CoV-2 infection randomized in Study GS-US-540-9012, 17% were
65 years or older. Reported clinical experience has not identified differences in responses between
the elderly and younger patients [see Clinical Studies (14)]. No dosage adjustment is required in
patients over the age of 65 years. In general, appropriate caution should be exercised in the
administration of VEKLURY and monitoring of elderly patients, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Renal Impairment
Use of VEKLURY in patients with COVID-19 and renal impairment, including those on dialysis, is
supported by safety and pharmacokinetic data from the following:
• a randomized, double-blind, placebo-controlled trial (Study 5912) in adults [see Adverse
Reactions (6.1) and Clinical Pharmacology (12.3)].
• an open-label, parallel-group, single-dose trial in subjects with normal renal function and renal
impairment (Study 9015) [see Clinical Pharmacology (12.3)].
The pharmacokinetics and safety of VEKLURY in patients with COVID-19 and renal impairment,
including those on dialysis, were evaluated in 163 subjects in a randomized, double-blind, placebo-
controlled trial, Study GS-US-540-5912 [see Adverse Reactions (6.1) and Clinical Pharmacology
(12.3)].
Study GS-US-540-5912 evaluated VEKLURY 200 mg once daily for 1 day followed by VEKLURY 100
mg once daily for 4 days (for a total of up to 5 days of intravenously administered therapy) in 243
hospitalized adult subjects with confirmed COVID-19 and renal impairment. The trial included 90
subjects (37%) with AKI (defined as a 50% increase in serum creatinine within a 48-hour period that
was sustained for ≥6 hours despite supportive care), 64 subjects (26%) with CKD (eGFR <30
mL/minute/1.73m2), and 89 subjects (37%) with ESRD (eGFR <15 mL/minute/1.73m2) requiring
hemodialysis. Subjects were randomized in a 2:1 manner, stratified by ESRD, high-flow oxygen
requirement, and region (US vs ex-US) to receive VEKLURY (n=163) or placebo (n=80), plus
standard of care.
At baseline, mean age was 69 years (with 62% of subjects aged 65 or older); 57% of subjects were
male, 67% were White, 26% were Black, and 3% were Asian. The most common baseline risk factors
were hypertension (89%), diabetes mellitus (79%), and cardiovascular or cerebrovascular disease
(51%); the distribution of risk factors was similar between the two treatment groups. A total of 45
subjects (19%) were on high-flow oxygen, 144 (59%) were on low-flow oxygen, and 54 (22%) were
on room air at baseline; no subjects were on invasive mechanical ventilation (IMV). A total of 182
subjects (75%) were not on renal replacement therapy, and 31 subjects (13%) had received a
COVID-19 vaccine.
The safety results in subjects with COVID-19 and renal impairment, including those on dialysis, were
consistent with those observed in clinical trials of VEKLURY in adults [see Adverse Reactions (6.1)].
23
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Study GS-US-540-5912 closed prematurely due to feasibility issues and was underpowered to
assess for efficacy because of lower than expected enrollment.
The pharmacokinetics and safety of VEKLURY in subjects with normal renal function and renal
impairment, including those on dialysis, were evaluated in 75 subjects (43 subjects with renal
impairment plus 32 matched control subjects with normal renal function) in an open-label, parallel-
group, single-dose trial, Study GS-US-540-9015 [see Clinical Pharmacology (12.3)].
In studies GS-US-540-5912 and GS-US-540-9015, exposures of GS-441524 and GS-704277, the
metabolites of remdesivir, and SBECD are increased in subjects with mild to severe renal impairment,
including those requiring dialysis, relative to subjects with normal renal function [see Clinical
Pharmacology (12.3)].
No dosage adjustment of VEKLURY is recommended for patients with any degree of renal
impairment, including those on dialysis [see Dosage and Administration (2.2, 2.4), Use in Specific
Populations (8.4)].
8.7 Hepatic Impairment
No dosage adjustment of VEKLURY is recommended for patients with mild, moderate, or severe
hepatic impairment (Child-Pugh Class A, B, or C) [see Clinical Pharmacology (12.3)].
Perform hepatic laboratory testing in all patients before starting VEKLURY and while receiving
VEKLURY as clinically appropriate [see Dosage and Administration (2.2) and Warnings and
Precautions (5.2)].
10 OVERDOSAGE
There is no human experience of acute overdosage with VEKLURY. Treatment of overdose with
VEKLURY should consist of general supportive measures including monitoring of vital signs and
observation of the clinical status of the patient. There is no specific antidote for overdose with
VEKLURY.
11 DESCRIPTION
VEKLURY contains remdesivir, a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. The
chemical name for remdesivir is 2-ethylbutyl N-{(S)-[2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5
anhydro-d-altrononitril-6-O-yl]phenoxyphosphoryl}-L-alaninate. It has a molecular formula of
C27H35N6O8P and a molecular weight of 602.6 g/mol. Remdesivir has the following structural formula:
24
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0
f:'
\__...
0
.II
\
II
0
HN1 .. p-Q.,.........._,.O
i
0-0
VEKLURY for injection contains 100 mg of remdesivir as a sterile, preservative-free lyophilized white
to off-white to yellow powder in a single-dose clear glass vial. It requires reconstitution and then
further dilution prior to administration by intravenous infusion [see Dosage and Administration (2.5,
2.6)]. The inactive ingredients are 3 g betadex sulfobutyl ether sodium and may include hydrochloric
acid and/or sodium hydroxide for pH adjustment.
VEKLURY injection contains 100 mg/20 mL (5 mg/mL) of remdesivir as a sterile, preservative-free,
clear, colorless to yellow solution in a single-dose clear glass vial. It requires dilution prior to
administration by intravenous infusion [see Dosage and Administration (2.5, 2.6)]. The inactive
ingredients are 6 g betadex sulfobutyl ether sodium, Water for Injection, USP, and may include
hydrochloric acid and/or sodium hydroxide for pH adjustment.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Remdesivir is an antiviral drug with activity against severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) [see Microbiology (12.4)].
12.2 Pharmacodynamics
Exposure-Response
Remdesivir and metabolites exposure-response relationships and the time course of
pharmacodynamics response are unknown.
Cardiac Electrophysiology
At 3 times the maximum recommended dose, clinically significant QTc interval prolongation was not
observed.
12.3 Pharmacokinetics
The pharmacokinetic (PK) properties of remdesivir and metabolites are provided in Table 14. The
multiple dose PK parameters of remdesivir and metabolites in adults with COVID-19 are provided in
Table 15.
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Table 14
Pharmacokinetic Properties of Remdesivir and Metabolites (GS-441524 and GS
704277)
Remdesivir
GS-441524
GS-704277
Absorption
Tmax (h)a
0.67-0.68
1.51-2.00
0.75-0.75
Distribution
% bound to human plasma
proteins
88-93.6b
2
1
Blood-to-plasma ratio
0.68-1.0
1.19
0.56
Elimination
t1/2 (h)c
1
27
1.3
Metabolism
Metabolic pathway(s)
CES1 (80%)
Cathepsin A (10%)
CYP3A (10%)
Not significantly
metabolized
HINT1
Excretion
Major route of elimination
Metabolism
Glomerular filtration
and active tubular
secretion
Metabolism
% of dose excreted in
urined
10
49
2.9
% of dose excreted in
fecesd
ND
0.5
ND
ND=not detected
a. Remdesivir administered as a 30-minute IV infusion (Study GS-US-399-5505); range of median observed on Day 1
and Day 5 or 10.
b. Range of protein binding for remdesivir from 2 independent experiments show no evidence of concentration-
dependent protein binding for remdesivir.
c. Median (Study GS-US-399-4231).
d. Mean (Study GS-US-399-4231).
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Table 15
Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS
704277) Following IV Administration of VEKLURY 100 mg to Adults with COVID-19
Parameter
Meanb (95% CI)
Remdesivir
GS-441524
GS-704277
Cmax
(nanogram per mL)
2700 (2440,
2990)
143 (135, 152)
198 (180, 218)
AUCtau
(nanogram•h per mL)
1710 (1480,
1980)
2410 (2250, 2580)
392 (348, 442)
Ctrough
(nanogram per mL)
ND
61.5 (56.5, 66.8)
ND
CI=Confidence Interval; ND=Not detectable (at 24 hours post-dose)
a. Population PK estimates for 30-minute IV infusion of remdesivir for 3 days (Study GS-US-540-9012, n=147).
b. Geometric mean estimates.
Specific Populations
Pharmacokinetic differences based on sex, race, age, and renal function on the exposures of
remdesivir were evaluated using population pharmacokinetic analysis. Sex and race did not affect the
pharmacokinetics of remdesivir and its metabolites (GS-441524 and GS-704277).
Pregnant Individuals
The pharmacokinetics of remdesivir and its circulating metabolites (GS-441524 and GS-704277)
were evaluated in pregnant individuals with COVID-19. Exposures (AUCtau, Cmax, and Ctau) of
remdesivir and its circulating metabolites during pregnancy were similar to those in non-pregnant
individuals (see Table 16).
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Table 16
Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS
704277) Following Intravenous Administration of VEKLURY to Pregnant and Non-
Pregnant Individuals with COVID-19
Parameter
Meanb (90% CI)
Pregnant Individuals
(N=21)
Non-Pregnant Individuals
(N=22)
Remdesivir
Cmax (nanogram per mL)
1360 (978, 1890)
1240 (891, 1720)
AUCtau (nanogram•h per mL)
1250 (916, 1700)c
1300 (1070, 1590)d
GS-441524
Cmax (nanogram per mL)
113 (102, 126)
121 (108, 136)
AUCtau (nanogram•h per mL)
1840 (1630, 2070)e
2050 (1780, 2350)f
Ctau (nanogram per mL)
51.6 (44.7, 59.6)e
57.1 (48.7, 66.9)f
GS-704277
Cmax (nanogram per mL)
217 (187, 252)
213 (188, 240)
AUCtau (nanogram•h per mL)
454 (406, 508)e
437 (384, 497)
CI=Confidence Interval
a. Study CO-US-590-5961 (IMPAACT).
b. Geometric mean estimates.
c. N=18
d. N=17
e. N=20
f.
N=21
Patients with Renal Impairment
The pharmacokinetics of remdesivir and its metabolites (GS-441524 and GS-704277) and excipient
SBECD were evaluated in healthy subjects, those with mild (eGFR 60-89 mL/minute/1.73m2),
moderate (eGFR 30-59 mL/minute/1.73m2), severe (eGFR 15-29 mL/minute/1.73m2) renal
impairment, or kidney failure (eGFR <15 mL/minute/1.73m2) on dialysis or not on dialysis following a
single dose of up to 100 mg of VEKLURY (see Table 16); and in COVID-19 patients with severely
reduced kidney function (AKI [defined as a 50% increase in serum creatinine within a 48-hour period
that was sustained for ≥6 hours despite supportive care]; CKD [eGFR <30 mL/minute/1.73m2]; or
ESRD [eGFR <15 mL/minute/1.73m2] requiring hemodialysis) receiving VEKLURY 200 mg loading
dose on Day 1 followed by 100 mg from Day 2 to Day 5 (see Table 17). Pharmacokinetic exposures
of remdesivir were not affected by renal function or timing of VEKLURY administration around
dialysis.
Exposures of GS-441524, GS-704277, and SBECD were up to 7.9-fold, 2.8-fold, and 21-fold higher,
respectively, in those with renal impairment compared to those with normal renal function (see Table
17 and Table 18). These changes are not considered to be clinically significant [see Adverse
Reactions (6.1) and Use in Specific Populations (8.6)].
Remdesivir was not efficiently removed through hemodialysis. Average hemodialysis clearance of
GS-441524 and GS-704277 was 149 mL/minute and 92.6 mL/minute, respectively.
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Table 17
Comparison of PK Parametersa of Remdesivir and Metabolites (GS-441524 and
GS-704277) Following IV Administration of Single Dose VEKLURY to Adults with
Renal Impairmentb as Compared to Adults with Normal Renal Function
Mean Ratio
(90% CI)c
60-89 mL
per
minuteb
N=10
30-59 mL
per
minuteb
N=10
15-29 mL
per minuteb
N=10
<15 mL per minuteb
Pre
hemodialysis
N=6
Post
hemodialysis
N=6
No
dialysis
N=3
Remdesivir
Cmax
0.96
(0.71, 1.31)
1.20
(1.01, 1.42)
0.97
(0.83, 1.13)
0.89
(0.67, 1.18)
1.13
(0.79, 1.60)
0.94
(0.65, 1.35)
AUCinf
1.00
(0.75, 1.32)
1.22
(0.98, 1.52)
0.94
(0.83, 1.07)
0.80
(0.59, 1.08)
1.08
(0.72, 1.63)
0.89
(0.55, 1.43)
GS-441524
Cmax
1.07
(0.90, 1.26)
1.44
(1.13, 1.85)
1.68
(1.28, 2.20)
2.27
(1.72, 2.99)
3.07
(2.21, 4.26)
3.00
(2.63, 3.42)
AUCinf
1.19
(0.97, 1.47)
2.02
(1.57, 2.62)
3.26
(2.39, 4.46)
4.97
(3.65, 6.77)
6.22
(4.44, 8.71)
7.87
(6.49, 9.53)
GS-704277
Cmax
2.25
(1.20, 4.20)
1.83
(1.34, 2.49)
1.27
(0.96, 1.68)
1.43
(1.00, 2.05)
1.23
(0.84, 1.80)
1.76
(1.19, 2.61)
AUCinf
1.39
(1.13, 1.71)
2.01
(1.48, 2.73)
1.78
(1.27, 2.49)
2.18
(1.61, 2.95)
2.06
(1.42, 2.97)
2.81
(1.79, 4.43)
CI=Confidence Interval
a. Exposures were estimated using noncompartmental analysis from a dedicated Phase 1 renal impairment Study GS
US-540-9015; single doses up to 100 mg were administered; each subject with renal impairment had a matched
control participant enrolled with normal renal function (eGFR ≥90 mL/minute/1.73m2), same sex, and similar BMI (±
20%) and age (± 10 years).
b. eGFR was calculated using Modification of Diet in Renal Disease equation and values represent mL/minute/1.73m2.
c. No effect=1.0 (0.5-2.0)
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Table 18
Comparison of PK Parameters of Remdesivir and Metabolites (GS-441524 and
GS-704277) Following IV Administration of VEKLURY (200 mg on Day 1 Followed
by 100 mg Daily on Days 2-5) in Adults with COVID-19 witha or withoutb Severely
Reduced Kidney Functionc
Mean Ratio (90% CI)d
Remdesivir
GS-441524
GS-704277
Cmax
1.39 (1.25, 1.54)
4.98 (4.61, 5.38)
1.84 (1.63, 2.08)
AUCtau
1.79 (1.59, 2.01)
6.59 (6.05, 7.18)
3.94 (3.50, 4.43)
Ctau
ND
5.82 (5.25, 6.45)
ND
CI=Confidence Interval; ND=Not detectable (at 24 hours post-dose)
a. Population PK estimates for 30-minute IV infusion of remdesivir for 5 days (Study GS-US-540-5912, n=90).
b. Population PK estimates for 30-minute IV infusion of remdesivir for 3 days (Study GS-US-540-9012, n=148).
c. AKI (defined as a 50% increase in serum creatinine within a 48-hour period that was sustained for ≥6 hours despite
supportive care); CKD (eGFR <30 mL/minute/1.73m2); or ESRD (eGFR <15 mL/minute/1.73m2) requiring
hemodialysis.
d. No effect=1.0 (0.5-2.0)
Patients with Hepatic Impairment
The pharmacokinetics of remdesivir and GS-441524 were evaluated in healthy subjects and those
with moderate or severe hepatic impairment (Child-Pugh Class B or C) following a single dose of 100
mg of VEKLURY (see Table 19). Relative to subjects with normal hepatic function, mean exposures
(AUCinf, Cmax) of remdesivir and GS-441524 were similar in subjects with moderate hepatic
impairment and higher in subjects with severe hepatic impairment. The exposure differences in
subjects with severe hepatic impairment are not considered to be clinically significant [see Use in
Specific Populations (8.7)].
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Table 19
Comparison of PK Parameters of Remdesivir and GS-441524 Following IV
Administration of Single Dose VEKLURY to Adults with Hepatic Impairment as
Compared to Adults with Normal Hepatic Function
Mean Ratio (90% CI)a
Moderate Hepatic Impairment
N=10
Severe Hepatic Impairment
N=6
Remdesivir
AUCinf
1.21 (0.87, 1.67)
1.56 (1.20, 2.03)
Cmax
1.10 (0.75, 1.60)
1.03 (0.70, 1.51)
Unbound AUCinf
1.15 (0.86, 1.54)
2.44 (1.93, 3.08)
Unbound Cmax
1.04 (0.73, 1.48)
1.57 (1.08, 2.29)
GS-441524
AUCinf
0.90 (0.69, 1.17)
1.31 (0.93, 1.84)
Cmax
1.09 (0.86, 1.38)
1.48 (1.17, 1.86)
C24
0.93 (0.69, 1.24)
1.16 (0.76, 1.77)
CI=Confidence Interval
a. No effect=1.0 (0.5-2.0)
Pediatric Patients
Population pharmacokinetic models for remdesivir and its circulating metabolites (GS-441524 and
GS-704277), developed using pooled data from studies in healthy subjects and in adult and pediatric
patients with COVID-19, were used to estimate pharmacokinetic exposures in pediatric patients aged
from birth to <18 years and weighing ≥1.5 kg (Study 5823). Geometric mean estimated exposures
(AUCtau, Cmax, and Ctau) for patients ≥28 days to <18 years old and weighing ≥3 kg (Cohorts 1-4 and
8, n=50) at the doses administered were 33% to 130% higher for remdesivir, 3% lower to 60% higher
for GS-441524, and 32% to 124% higher for GS-704277 as compared to those in adult patients with
COVID-19; however, the increases were not considered clinically significant. Individual estimated
exposures (AUCtau, Cmax, and Ctau) for patients 14 to <28 days old, GA >37 weeks, and weighing ≥2.5
kg (Cohort 5, n=3); patients <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (Cohort 6,
n=1); and patients <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (Cohort 7, n=1) at the
doses administered were higher for remdesivir, GS-441524, and GS-704277 as compared to median
exposures in adult patients with COVID-19; however, the increases were not considered clinically
significant. As limited PK data were available in Cohorts 5-7, additional analyses were conducted
using a simulated population.
Using age and weight distributions from pediatric growth charts, simulated population datasets were
created for Cohorts 5-6. Modeling and simulation incorporating maturation functions that account for
renal function and drug metabolizing enzyme ontogeny with age were used to predict exposures for
subjects <28 days old, GA >37 weeks, and weighing ≥1.5 kg and subjects ≥28 days old and weighing
≥1.5 to <3 kg. Predicted geometric mean exposures (AUCtau, Cmax, and Ctau) at the recommended
doses were 10% to 96% higher for remdesivir, 15% lower to 3% higher for GS-441524, and 14%
lower to 132% higher for GS-704277 as compared to those in adult patients with COVID-19; however,
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changes in exposure were not considered clinically significant. Results of simulated population led to
the recommended dosing regimen as they more closely align with adult exposures compared to the
doses studied.
Plasma exposures of excipient SBECD were generally similar for all pediatric patients at the doses
administered in Study GS-US-540-5823 and were similar compared to adults with normal renal
function, although data are very limited [see Use in Specific Populations (8.4)].
The multiple dose PK parameters of remdesivir and metabolites in pediatric patients with COVID-19
in Cohorts 1-4 and 8 are provided in Table 20.
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Table 20
Multiple Dose PK Parametersa of Remdesivir and Metabolites (GS-441524 and GS
704277) Following Intravenous Administration of VEKLURY 100 mg (Cohorts 1
and 8) or 2.5 mg/kg (Cohorts 2-4) to Pediatric Patients with COVID-19
Parameter
Meanb (95% CI)
Cohort 1
Cohort 8
Cohort 2
Cohort 3
Cohort 4
12 to
<18 Years
and
Weighing
≥40 kg
(N=12)
<12 Years
and
Weighing
≥40 kg
(N=5)
28 Days to
<18 Years
and
Weighing
20 to <40 kg
(N=12)
28 Days to
<18 Years
and
Weighing
12 to <20 kg
(N=11)
28 Days to
<18 Years
and
Weighing
3 to <12 kg
(N=10)
Remdesivir
Cmax (nanogram
per mL)
3890 (3110,
4870)
3920 (2260,
6820)
5730 (4660,
7050)
5570 (4250,
7300)
4870 (3750,
6340)
AUCtau
(nanogram•h per
mL)
2470 (1920,
3160)
2270 (1200,
4310)
3510 (2560,
4820)
3930 (2140,
7210)
2910 (1880,
4510)
GS-441524
Cmax (nanogram
per mL)
196 (122,
315)
163 (57.6,
461)
183 (129,
260)
171 (130,
223)
205 (174,
241)
AUCtau
(nanogram•h per
mL)
3430 (1980,
5920)
2640 (767,
9100)
2370 (1500,
3740)
2410 (1740,
3340)
2850 (2290,
3540)
Ctau (nanogram
per mL)
98.5 (59.1,
164)
76.2 (23.9,
243)
59.9 (34.2,
105)
68.9 (47.4,
100)
79.7 (59.5,
107)
GS-704277
Cmax (nanogram
per mL)
308 (211,
450)
266 (137,
514)
419 (306,
575)
444 (335,
587)
385 (294,
504)
AUCtau
(nanogram•h per
mL)
819 (474,
1420)
518 (192,
1400)
753 (542,
1050)
733 (504,
1060)
687 (484,
973)
CI=Confidence Interval
a. Population PK estimates for 30-minutes IV infusion of remdesivir for up to 10 days (Study GS-US-540-5823).
b. Geometric mean estimates.
Drug Interaction Studies
In vitro, remdesivir is a substrate for enzymes CYP3A, carboxylesterase 1 (CES1), and cathepsin A
(CatA) and OATP1B1 and P-gp transporters; GS-704277 is a substrate for OATP1B1 and OATP1B3.
In vitro, remdesivir is an inhibitor of CYP3A, UGT1A1, OATP1B1, OATP1B3, and MATE1; however,
no clinically significant effects on substrates of UGT1A1 or MATE1 are expected. No inhibitory
interactions were identified for GS-704277 or GS-441524 in vitro.
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Remdesivir is not a substrate for CYP1A1, 1A2, 2B6, 2C9, 2C19, or OATP1B3. GS-704277 and GS
441524 are not substrates for CYP1A1, 1A2, 2B6, 2C8, 2C9, 2D6, or 3A5. GS-441524 is also not a
substrate for CYP2C19 or 3A4. GS-704277 and GS-441524 are not substrates for OAT1, OAT3,
OCT1, OCT2, MATE1, or MATE2k. GS-441524 is also not a substrate for OATP1B1 or OATP1B3.
Drug-drug interaction studies were conducted with VEKLURY. Table 21 summarizes the
pharmacokinetic effects of other drugs on remdesivir and metabolites GS-704277 and GS-441524.
Table 22 summarizes the effects of remdesivir on the pharmacokinetics of other drugs.
Table 21
Effect of Other Drugs on Remdesivir and Metabolites GS-704277 and GS-441524
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Remdesivir
Dose
(mg)
N
Mean Ratio (90% CI) of Remdesivir, GS
704277, and GS-441524 PK With/Without
Coadministered Drug
No Effect = 1.00 (0.70-1.43)
Cmax
AUCinf
C24
Cyclosporin Aa
400 single dose
100 single
dose
9
remdesivir
1.49
(1.38
1.60)
1.89
(1.77
2.02)
-
GS-704277
2.51
(2.26
2.78)
2.97
(2.75
3.20)
-
GS-441524
1.17
(1.12
1.22)
1.03
(0.99
1.08)
1.02
(0.95
1.10)
Carbamazepinea
300 twice daily
100 single
dose
8
remdesivir
0.87
(0.78
0.97)
0.92
(0.83
1.02)
-
GS-704277
0.96
(0.84
1.10)
0.98
(0.92
1.05)
-
GS-441524
0.97
(0.88
1.07)
0.83
(0.78
0.89)
0.71
(0.64
0.78)
CI=confidence interval
a. Interaction study conducted in healthy volunteers.
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Table 22
Effect of Remdesivir on the Pharmacokinetics of Other Drugs
Coadministered
Drug
Dose of
Coadministered
Drug (mg)
Remdesivir
Dose
(mg)
N
Mean Ratio (90% CI) of Coadministered
Drug PK With/Without Remdesivir
No Effect = 1.00 (0.80-1.25)
Cmax
AUCinf
Midazolama
2.5 single dose
200 single
dose
19
1.29 (1.19-1.41)
1.20 (1.14-1.26)
Midazolama
2.5 single dose
200 single
dose
followed by
100 once
daily (10
doses)b
14
1.45 (1.23- 1.70)
1.30 (1.16- 1.45)
Pitavastatina
2 single dose
200 single
dose
20
1.05 (0.92-1.20)
1.17 (1.09-1.24)
CI=confidence interval
a. Interaction study conducted in healthy volunteers.
b. Midazolam administered with last dose of remdesivir.
12.4 Microbiology
Mechanism of Action
Remdesivir is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is
essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that distributes into cells
where it is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or
cathepsin A, depending upon the cell type. The nucleoside monophosphate is subsequently
phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate
metabolite (GS-443902). Remdesivir triphosphate (RDV-TP) acts as an analog of adenosine
triphosphate (ATP) and competes with high selectivity (3.65-fold) over the natural ATP substrate for
incorporation into nascent RNA chains by the SARS-CoV-2 RdRp, which results in delayed chain
termination (position i+3) during replication of the viral RNA. In a biochemical assay assessing RDV
TP incorporation by the MERS-CoV RdRp complex, RDV-TP inhibited RNA synthesis with an IC50
value of 0.032 µM. RDV-TP can also inhibit viral RNA synthesis following its incorporation into the
template viral RNA as a result of read-through by the viral polymerase that may occur at higher
nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the
efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting
viral RNA synthesis. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA
polymerases, including human mitochondrial RNA polymerase.
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Antiviral Activity
In Cell Culture
Remdesivir exhibited cell culture antiviral activity against a clinical isolate of SARS-CoV-2 in primary
human airway epithelial (HAE) cells with a 50% effective concentration (EC50) of 9.9 nM after 48
hours of treatment. Remdesivir inhibited the replication of SARS-CoV-2 in the continuous human lung
epithelial cell lines Calu-3 and A549-hACE2 with EC50 values of 280 nM after 72 hours of treatment
and 115 nM after 48 hours of treatment, respectively.
Remdesivir EC50 values for SARS-CoV-2 in A549-hACE2 cells were not different when combined with
chloroquine phosphate or hydroxychloroquine sulfate at concentrations up to 2.5 μM. In a separate
study, the antiviral activity of remdesivir was antagonized by chloroquine phosphate in a dose-
dependent manner when the two drugs were co-incubated at clinically relevant concentrations in
HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC50 values were
observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of
chloroquine phosphate or hydroxychloroquine sulfate reduced formation of remdesivir triphosphate in
A549-hACE2, HEp-2, and normal human bronchial epithelial cells.
Based on cell culture susceptibility testing by virus yield reduction assay and/or N protein ELISA
assay, remdesivir retained similar antiviral activity against clinical isolates of SARS-CoV-2 variants
compared to an earlier lineage SARS-CoV-2 (lineage A) isolate, including Alpha (B.1.1.7), Beta
(B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.429), Zeta (P.2), Iota (B.1.526), Kappa
(B.1.617.1), Lambda (C.37), and Omicron variants (including B.1.1.529/BA.1, BA.2, BA.2.12.1,
BA.2.75, BA.4, BA.4.6, BA.5, BF.5, BF.7, BQ.1, BQ.1.1, CH.1.1, EG.1.2, EG.5.1, FL.22, XBB,
XBB.1.5, XBB.1.16, XBB.2.3.2, and XBF). For these variants, the EC50 fold change values ranged
between 0.2 and 2.3 compared to an earlier lineage SARS-CoV-2 (lineage A) isolate. Using the
SARS-CoV-2 replicon system, remdesivir retained similar antiviral activity against Omicron
subvariants BA.2.86 and XBB.1.9.2 compared to the wildtype reference replicon (lineage B).
In Clinical Trials
SARS-CoV-2 RNA shedding results from GS-US-540-5776 (ACTT-1) indicate that remdesivir does
not significantly reduce the amount of detectable SARS-CoV-2 RNA in oropharyngeal or
nasopharyngeal swabs or plasma samples in hospitalized patients compared to placebo, and SARS
CoV-2 RNA shedding results from GS-US-540-9012 indicate that remdesivir does not significantly
reduce the amount of detectable SARS-CoV-2 RNA in nasopharyngeal swabs in non-hospitalized
patients compared to placebo.
Resistance
In Cell Culture
SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. In a
selection with GS-441524, the parent nucleoside of remdesivir, virus pools emerged expressing
amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in the viral RdRp
(nsp12). When these substitutions were individually introduced into a wild-type recombinant virus by
site-directed mutagenesis, 1.7- to 3.5-fold reductions in susceptibility to remdesivir were observed. In
a cell culture resistance selection experiment with remdesivir, nsp12 amino acid substitution E802D
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Reference ID: 5508433
emerged, resulting in a 1.4- to 2.5-fold reduction in susceptibility to remdesivir. In another selection
with remdesivir using a SARS-CoV-2 isolate containing the P323L substitution in the viral
polymerase, a single amino acid substitution at V166L emerged. Recombinant SARS-CoV-2 with
substitutions at P323L alone or P323L+V166L in combination exhibited 1.3- and 1.5-fold reductions in
remdesivir susceptibility, respectively.
Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified
two substitutions (F476L and V553L) in the viral RdRp (nsp12) at residues conserved across CoVs.
Introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold
reduction in susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a
mouse model. When individually introduced into a SARS-CoV-2 recombinant virus, the corresponding
substitutions at F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir.
In Clinical Studies
In a literature publication, the SARS-CoV-2 nsp12 E802D substitution previously identified in a
resistance selection experiment emerged in one individual treated with remdesivir. The E802D
substitution resulted in a 1.4- to 2.5-fold increase in the remdesivir EC50 value.
In Study CO-US-540-5776 (ACTT-1), among 61 subjects with baseline and post-baseline sequencing
data available, the rate of emerging substitutions in the viral RdRp (nsp12) was similar in subjects
treated with VEKLURY compared to placebo. Two subjects treated with VEKLURY had an emergent
substitution previously identified in resistance selection experiments (nsp12 V792I in one and C799F
in the other). These substitutions are associated with 2.2- and 2.5-fold decreases in remdesivir
susceptibility, respectively, based on assessments of clinical isolates. In one subject treated with
VEKLURY, nsp12 V792F emerged at low frequency and was associated with a 1.8-fold decrease in
remdesivir susceptibility.
In Study GS-US-540-5773, among 19 subjects treated with VEKLURY with baseline and post-
baseline sequencing data available, the V792F substitution in viral RdRp (nsp12) emerged at low
frequency in one subject.
In Study GS-US-540-9012, among 244 subjects with baseline and post-baseline sequencing data
available, the rate of emerging substitutions in the viral RdRp (nsp12) was similar in subjects treated
with VEKLURY compared to placebo. In one subject treated with VEKLURY, one substitution in the
RdRp (nsp12 A376V) emerged and was associated with a 12.6-fold decrease in remdesivir
susceptibility in a subgenomic replicon assay. This subject was not hospitalized and showed
alleviation of all baseline symptoms, except loss of taste and smell, prior to or on Day 14.
In Study GS-US-540-5912, among 60 subjects with baseline and post-baseline sequencing data
available, substitutions in the viral RdRp (nsp12) emerged in 8 subjects treated with VEKLURY. In 4
subjects treated with VEKLURY, three substitutions in the RdRp (nsp12 E136V, M794I, or C799F)
emerged and were associated with 2.9-, 2.9-, and 3.4-fold reduced susceptibility to remdesivir in a
subgenomic replicon assay.
In Study GS-US-540-5823, among pediatric subjects with baseline and post-baseline sequencing
data available, treatment-emergent substitutions in the viral RdRp (nsp12) were observed in 3 of 27
subjects treated with VEKLURY and were evaluated for susceptibility to remdesivir. In one subject,
two substitutions (nsp12 substitutions V166L and V792I) emerged and were associated with
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Reference ID: 5508433
1.85- and 3.6-fold decreases in remdesivir susceptibility relative to reference, respectively. This
subject was hospitalized at baseline, recovered from COVID-19, and was released from the hospital
on Day 13. None of the substitutions observed in any of the other genes (nsp9-10, nsp13-14)
encoding for proteins of the viral replication-transcription complex have been associated with reduced
susceptibility to remdesivir.
The relationship between the level of reduced susceptibility to remdesivir observed in subgenomic
replicon assays and the inhibition of SARS-CoV-2 replication by remdesivir in humans has not been
fully established.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Given the short-term administration of VEKLURY for the treatment of COVID-19, long-term animal
studies to evaluate the carcinogenic potential of remdesivir were not conducted.
Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome
aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.
Impairment of Fertility
Nonclinical toxicity studies in rats demonstrated no adverse effect on male fertility at exposures of the
predominant circulating metabolite (GS-441524) approximately 2 times the exposure in humans at
the RHD.
Reproductive toxicity, including decreases in corpora lutea, numbers of implantation sites, and viable
embryos, was seen when remdesivir was administered by daily intravenous administration at a
systemically toxic dose (10 mg/kg) in female rats 14 days prior to mating and during conception;
exposures of the predominant circulating metabolite (GS-441524) were 1.3 times the exposure in
humans at the RHD.
13.2 Animal Toxicology and/or Pharmacology
Intravenous administration (slow bolus) of remdesivir to male rhesus monkeys at dosage levels of 5,
10, and 20 mg/kg/day for 7 days resulted, at all dose levels, in increased mean urea nitrogen and
increased mean creatinine, renal tubular atrophy, and basophilia and casts.
Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of ≥3 mg/kg/day for up
to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction.
Kidney-related effects in rats and monkeys were observed at exposures of the predominant
circulating metabolite (GS-441524) that are lower than the exposure in humans at the RHD.
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14 CLINICAL STUDIES
14.1 Description of Clinical Trials
The efficacy and safety of VEKLURY were evaluated in the trials summarized in Table 23.
Table 23
Trials Conducted with VEKLURY in Subjects with COVID-19
Trial
Population
Trial Arms (N)
Timepoint
NIAID ACTT-1a
(NCT04280705)
Hospitalized with
mild/moderate and severe
COVID-19
VEKLURY 10 Days (532)
Placebo (516)
29 Days after
Randomization
GS-US-540-5773b
(NCT04292899)
Hospitalized with severe
COVID-19
VEKLURY 5 Days (200)
VEKLURY 10 Days (197)
Day 14
GS-US-540-5774b
(NCT04292730)
Hospitalized with moderate
COVID-19
VEKLURY 5 Days (191)
VEKLURY 10 Days (193)
Standard of care (200)
Day 11
GS-US-540-9012a
(NCT04501952)
Non-hospitalized with mild
to-moderate COVID-19 and
at high risk for progression
to severe disease
VEKLURY 3 Days (279)
Placebo (283)
Day 28
GS-US-540-5823
(Cohorts 1-8)c
(NCT04431453)
Hospitalized pediatric
subjects from birth to <18
years of age and weighing
at least 1.5 kg with COVID
19
VEKLURY up to 10 Days
(58)
Day 10
COVID-19: coronavirus disease 2019
a. Randomized, double-blind, placebo-controlled trial.
b. Randomized, open-label trial.
c. Open-label trial, descriptive outcome analyses.
14.2 NIAID ACTT-1 Study in Hospitalized Subjects with Mild/Moderate and Severe COVID-19
A randomized, double-blind, placebo-controlled clinical trial (ACTT-1) of hospitalized adult subjects
with confirmed SARS-CoV-2 infection and mild, moderate, or severe COVID-19 compared treatment
with VEKLURY for 10 days (n=541) with placebo (n=521). Mild/moderate disease was defined as
SpO2 >94% and respiratory rate <24 breaths/minute without supplemental oxygen; severe disease
was defined as an SpO2 ≤94% on room air, a respiratory rate ≥24 breaths/minute, an oxygen
requirement, or a requirement for mechanical ventilation. Subjects had to have at least one of the
following to be enrolled in the trial: radiographic infiltrates by imaging, SpO2 ≤94% on room air, a
requirement for supplemental oxygen, or a requirement for mechanical ventilation. Subjects treated
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with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days, for 10 days of
treatment via intravenous infusion. Treatment with VEKLURY was stopped in subjects who were
discharged from the hospital prior to the completion of 10 days of treatment.
At baseline, mean age was 59 years (with 36% of subjects aged 65 or older); 64% of subjects were
male, 53% were White, 21% were Black, and 13% were Asian; 24% were Hispanic or Latino; 105
subjects had mild/moderate disease (10% in both treatment groups); 957 subjects had severe
disease (90% in both treatment groups). Subjects in this trial were unvaccinated. A total of 285
subjects (27%) (n=131 received VEKLURY) were on invasive mechanical ventilation or ECMO. The
most common comorbidities were hypertension (51%), obesity (45%), and type 2 diabetes mellitus
(31%); the distribution of comorbidities was similar between the two treatment groups.
The primary clinical endpoint was time to recovery within 29 days after randomization. Recovery was
defined as discharged from the hospital without limitations on activities, discharged from the hospital
with limitations on activities and/or requiring home oxygen, or hospitalized but not requiring
supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery
was 10 days in the VEKLURY group compared to 15 days in the placebo group (recovery rate ratio
1.29 [95% CI 1.12 to 1.49], p<0.001). Among subjects with mild/moderate disease at enrollment
(n=105), the median time to recovery was 5 days in both the VEKLURY and placebo groups
(recovery rate ratio 1.22 [95% CI 0.82 to 1.81]). Among subjects with severe disease at enrollment
(n=957), the median time to recovery was 11 days in the VEKLURY group compared to 18 days in
the placebo group (recovery rate ratio 1.31 [95% CI 1.12 to 1.52]).
A key secondary endpoint was clinical status on Day 15 assessed on an 8-point ordinal scale
consisting of the following categories:
1. not hospitalized, no limitations on activities;
2. not hospitalized, limitation on activities and/or requiring home oxygen;
3. hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care;
4. hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19
related or otherwise);
5. hospitalized, requiring supplemental oxygen;
6. hospitalized, on noninvasive ventilation or high-flow oxygen devices;
7. hospitalized, on invasive mechanical ventilation or ECMO; and
8. death.
Overall, the odds of improvement in the ordinal scale were higher in the VEKLURY group at Day 15
when compared to the placebo group (odds ratio 1.54 [95% CI 1.25 to 1.91]).
Overall, 29-day mortality was 11% for the VEKLURY group vs 15% for the placebo group (hazard
ratio 0.73 [95% CI 0.52 to 1.03]).
14.3 Study GS-US-540-5773 in Hospitalized Subjects with Severe COVID-19
A randomized, open-label multi-center clinical trial (Study 5773) in adult subjects with confirmed
SARS-CoV-2 infection, an SpO2 of ≤94% on room air, and radiological evidence of pneumonia
compared 200 subjects who received VEKLURY for 5 days with 197 subjects who received
VEKLURY for 10 days. Treatment with VEKLURY was stopped in subjects who were discharged from
the hospital prior to completion of their protocol-defined duration of treatment. Subjects on
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mechanical ventilation at screening were excluded. All subjects received 200 mg of VEKLURY on
Day 1 and 100 mg once daily on subsequent days via intravenous infusion, plus standard of care.
At baseline, the median age of subjects was 61 years (range, 20 to 98 years); 64% were male, 75%
were White, 12% were Black, and 12% were Asian; 22% were Hispanic or Latino. More subjects in
the 10-day group than the 5-day group required invasive mechanical ventilation or ECMO (5% vs
2%), or high-flow oxygen support (30% vs 25%), at baseline. Subjects in this trial were unvaccinated.
Median duration of symptoms and hospitalization prior to first dose of VEKLURY were similar across
treatment groups.
The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale consisting of
the following categories:
1. death;
2. hospitalized, receiving invasive mechanical ventilation or ECMO;
3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices;
4. hospitalized, requiring low-flow supplemental oxygen;
5. hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or
not related to COVID-19);
6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that
specified in the protocol for remdesivir administration); and
7. not hospitalized.
Overall, after adjusting for between-group differences at baseline, subjects receiving a 5-day course
of VEKLURY had similar clinical status at Day 14 as those receiving a 10-day course (odds ratio for
improvement 0.75 [95% CI 0.51 to 1.12]). There were no statistically significant differences in
recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between-group
differences at baseline. All-cause mortality at Day 28 was 12% vs 14% in the 5- and 10-day treatment
groups, respectively.
14.4 Study GS-US-540-5774 in Hospitalized Subjects with Moderate COVID-19
A randomized, open-label multi-center clinical trial (Study 5774) of hospitalized adult subjects with
confirmed SARS-CoV-2 infection, SpO2 >94% and radiological evidence of pneumonia compared
treatment with VEKLURY for 5 days (n=191) and treatment with VEKLURY for 10 days (n=193) with
standard of care (n=200). Treatment with VEKLURY was stopped in subjects who were discharged
from the hospital prior to completion of their protocol-defined duration of treatment. Subjects treated
with VEKLURY received 200 mg on Day 1 and 100 mg once daily on subsequent days via
intravenous infusion.
At baseline, the median age of subjects was 57 years (range, 12 to 95 years); 61% were male, 61%
were White, 19% were Black, and 19% were Asian; 18% were Hispanic or Latino. Subjects in this trial
were unvaccinated. Baseline clinical status, oxygen support status, and median duration of symptoms
and hospitalization prior to first dose of VEKLURY were similar across treatment groups.
The primary endpoint was clinical status on Day 11 assessed on a 7-point ordinal scale consisting of
the following categories:
1. death;
2. hospitalized, receiving invasive mechanical ventilation or ECMO;
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3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices;
4. hospitalized, requiring low-flow supplemental oxygen;
5. hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or
not related to COVID-19);
6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that
specified in the protocol for remdesivir administration); and
7. not hospitalized.
Overall, the odds of improvement in the ordinal scale were higher in the 5-day VEKLURY group at
Day 11 when compared to those receiving only standard of care (odds ratio 1.65 [95% CI 1.09 to
2.48], p=0.017). The odds of improvement in clinical status with the 10-day treatment group when
compared to those receiving only standard of care were not statistically significant (odds ratio 1.31
[95% CI 0.88 to 1.95]). All-cause mortality at Day 28 was ≤2% in all treatment groups.
14.5 Study GS-US-540-9012 in Non-Hospitalized Subjects with Mild-to-Moderate COVID-19 and
at High Risk for Progression to Severe Disease
A randomized, double-blind, placebo-controlled, clinical trial (Study 9012) evaluated VEKLURY 200
mg once daily for 1 day followed by VEKLURY 100 mg once daily for 2 days (for a total of 3 days of
intravenously administered therapy) in 554 adult and 8 pediatric subjects (12 years of age and older
and weighing at least 40 kg) who were non-hospitalized, had mild-to-moderate COVID-19, were
symptomatic for COVID-19 for ≤7 days, had confirmed SARS-CoV-2 infection, and had at least one
risk factor for progression to hospitalization. Risk factors for progression to hospitalization included
age ≥60 years, obesity (BMI ≥30), chronic lung disease, hypertension, cardiovascular or
cerebrovascular disease, diabetes mellitus, immunocompromised state, chronic mild or moderate
kidney disease, chronic liver disease, current cancer, and sickle cell disease. Subjects who received,
required, or were expected to require supplemental oxygen were excluded from the trial. Subjects
were randomized in a 1:1 manner, stratified by residence in a skilled nursing facility (yes/no), age
(<60 vs ≥60 years), and region (US vs ex-US) to receive VEKLURY (n=279) or placebo (n=283), plus
standard of care.
At baseline, mean age was 50 years (with 30% of subjects aged 60 or older); 52% were male, 80%
were White, 8% were Black, and 2% were Asian; 44% were Hispanic or Latino; median body mass
index was 30.7 kg/m2. Subjects in this trial were unvaccinated. VEKLURY or placebo was first
administered to subjects in outpatient facilities (84%), home healthcare settings (13%), or skilled
nursing facilities (3%). The most common comorbidities were diabetes mellitus (62%), obesity (56%),
and hypertension (48%). Median (Q1, Q3) duration of symptoms prior to treatment was 5 (3, 6) days;
median viral load was 6.3 log10 copies/mL at baseline. The baseline demographics and disease
characteristics were well balanced across the VEKLURY and placebo treatment groups.
The primary endpoint was the proportion of subjects with COVID-19 related hospitalization (defined
as at least 24 hours of acute care) or all-cause mortality through Day 28. Events occurred in 2 (0.7%)
subjects treated with VEKLURY compared to 15 (5.3%) subjects concurrently randomized to placebo
(hazard ratio 0.134 [95% CI 0.031 to 0.586]; p=0.0076). No deaths were observed through Day 28.
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14.6 Study GS-US-540-5823 in Hospitalized Pediatric Subjects with COVID-19
The primary objectives of this Phase 2/3 single-arm, open-label clinical trial (Study GS-US-540-5823)
were to evaluate pharmacokinetics and safety of up to 10 days of treatment with VEKLURY in
pediatric subjects. A total of 58 pediatric subjects from birth (including preterm to term infants) to
<18 years of age and weighing at least 1.5 kg with confirmed SARS-CoV-2 infection and mild,
moderate, or severe COVID-19 was evaluated in eight cohorts:
• Cohorts 1-4, 8; infants, children, and adolescents: Subjects ≥12 years and weighing ≥40 kg
(n=12); subjects <12 years and weighing ≥40 kg (n=5); subjects ≥28 days and weighing ≥20 to
<40 kg (n=12); subjects ≥28 days and weighing ≥12 to <20 kg (n=12); and subjects ≥28 days
and weighing ≥3 to <12 kg (n=12). Subjects weighing ≥40 kg received 200 mg of VEKLURY on
Day 1 followed by VEKLURY 100 mg once daily on subsequent days; subjects weighing ≥3 kg
to <40 kg received VEKLURY 5 mg/kg on Day 1 followed by VEKLURY 2.5 mg/kg once daily
on subsequent days;
• Cohorts 5-7; neonates and infants: Subjects 14 to <28 days old, GA >37 weeks, and weighing
≥2.5 kg (n=3); subjects <14 days old, GA >37 weeks, and weighing ≥2.5 kg at birth (n=1); and
subjects <56 days old, GA ≤37 weeks, and weighing ≥1.5 kg at birth (n=1). Subjects 14 to <28
days old, GA >37 weeks, and weighing ≥2.5 kg received VEKLURY 5 mg/kg on Day 1 followed
by VEKLURY 2.5 mg/kg once daily on subsequent days. Subjects <14 days old, GA >37
weeks, and weighing at least 2.5 kg at birth, and subjects <56 days old, GA ≤37 weeks, and
weighing ≥1.5 kg at birth, received VEKLURY 2.5 mg/kg on Day 1 followed by VEKLURY 1.25
mg/kg once daily on subsequent days.
Assessments occurred at the following intervals: Screening; Day 1 (Baseline); Days 2-10, or until
discharge, whichever came earlier; Follow-Up on Day 30 (±5). Treatment with VEKLURY was
stopped in subjects who were discharged from the hospital prior to the completion of 10 days of
treatment.
Infants, children, and adolescents: At baseline, median age was 7 years (Q1, Q3: 2 years, 12 years);
57% were female, 70% were White, 30% were Black, and 44% were Hispanic or Latino; median
weight was 25 kg (range: 4 to 192 kg). Subjects in this trial were unvaccinated. A total of 12 subjects
(23%) were on invasive mechanical ventilation, 18 (34%) were on non-invasive ventilation or high-
flow oxygen; 10 (19%) were on low-flow oxygen; and 13 (25%) were on room air, at baseline. The
overall median (Q1, Q3) duration of symptoms and hospitalization prior to first dose of VEKLURY was
5 (3, 7) days and 1 (1, 3) day, respectively.
The descriptive outcome analyses showed treatment with VEKLURY for up to 10 days resulted in an
overall median (Q1, Q3) change from baseline in clinical status (assessed on a 7-point ordinal scale
ranging from death [score of 1] to ventilatory support and decreasing levels of oxygen to hospital
discharge [score of 7]) of +2.0 (1.0, 4.0) points on Day 10.
Recovery (defined as an improvement from a baseline clinical status score of 2 through 5 to a score
of 6 or 7, or an improvement from a baseline score of 6 to a score of 7) was reported for 62% of
subjects on Day 10; median (Q1, Q3) time to recovery was 7 (5, 16) days.
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Overall, 60% of subjects were discharged by Day 10, and 83% of subjects were discharged by Day
30. Three subjects (6%) from Cohorts 1-4 and Cohort 8 died during the study.
Neonates and infants: At baseline, subjects ranged in age from 12 to 30 days; 3/5 were female, 4/5
were White, 1/5 was Black; weight ranged from 2.2 to 3.5 kg. Three subjects were on invasive
mechanical ventilation and 2 were on high-flow oxygen. The duration of symptoms and hospitalization
prior to first dose of VEKLURY ranged from 2 to 9 days and 1 to 9 days, respectively.
The descriptive outcome analyses showed treatment with VEKLURY for up to 10 days resulted in
recovery (defined as an improvement from a baseline clinical status score of 2 through 5 to a score of
6 or 7, or an improvement from a baseline score of 6 to a score of 7) for 3 subjects, including for one
subject by Day 10. Time to recovery ranged from 9 to 19 days.
Overall, a total of 3 subjects were discharged by Day 30, of which one subject was discharged by Day
10. No subjects from Cohorts 5-7 died during the study.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
VEKLURY for injection: 100 mg (NDC 61958-2901-2), is supplied as a single-dose vial containing a
sterile, preservative-free white to off-white to yellow lyophilized powder. It requires reconstitution and
further dilution prior to administration by intravenous infusion [see Dosage and Administration (2.4)].
Discard unused portion. The container closure is not made with natural rubber latex.
VEKLURY injection: 100 mg/20 mL (5 mg/mL) (NDC 61958-2902-2), is supplied as a single-dose vial
containing a sterile, preservative-free, clear, colorless to yellow aqueous-based solution. It requires
dilution prior to administration by intravenous infusion [see Dosage and Administration (2.4)]. Discard
unused portion. The container closure is not made with natural rubber latex.
Storage and Handling
Do not reuse or save reconstituted or diluted VEKLURY for future use. These products contain no
preservative; therefore, partially used vials should be discarded [see Dosage and Administration
(2.5)].
VEKLURY for Injection
Store VEKLURY for injection, 100 mg vials below 30°C (below 86°F) until required for use.
After reconstitution, use vials immediately to prepare diluted solution. Dilute the reconstituted solution
in 0.9% sodium chloride injection, USP within the same day as administration. The diluted VEKLURY
solution in the infusion bags can be stored up to 24 hours at room temperature (20°C to 25°C [68°F to
77°F]) prior to administration or 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
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VEKLURY Injection
Store VEKLURY injection vials at refrigerated temperature (2°C to 8°C [36°F to 46°F]) until required
for use.
Dilute within the same day as administration. Prior to dilution, equilibrate VEKLURY injection to room
temperature (20°C to 25°C [68°F to 77°F]). Sealed vials can be stored up to 12 hours at room
temperature prior to dilution. Store VEKLURY injection after dilution in the infusion bags for no more
than 24 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 48 hours at refrigerated
temperature (2°C to 8°C [36°F to 46°F]).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions have been seen in patients receiving VEKLURY during
and after infusion. Advise patients to inform their healthcare provider if they experience any of the
following: changes in heart rate; fever; shortness of breath, wheezing; swelling of the lips, face, or
throat; rash; nausea; sweating; or shivering [see Warnings and Precautions (5.1)].
Increased Risk of Transaminase Elevations
Inform patients that VEKLURY may increase the risk of hepatic laboratory abnormalities. Advise
patients to alert their healthcare provider immediately if they experience any symptoms of liver
inflammation [see Warnings and Precaution (5.2)].
Drug Interactions
Inform patients that VEKLURY may interact with other drugs. Advise patients to report to their
healthcare provider the use of any other prescription or nonprescription medication or herbal
products, including chloroquine phosphate or hydroxychloroquine sulfate [see Warnings and
Precautions (5.3), Drug Interactions (7), and Microbiology (12.4)].
Pregnancy
Inform patients to notify their healthcare provider in the event of a pregnancy [see Use in Specific
Populations (8.1)].
VEKLURY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks
referenced herein are the property of their respective owners.
© 2025 Gilead Sciences, Inc. All rights reserved
45
Reference ID: 5508433
PATIENT INFORMATION
VEKLURY® (VEK-lur-ee)
VEKLURY® (VEK-lur-ee)
(remdesivir)
(remdesivir)
for injection
injection
What is VEKLURY?
VEKLURY is a prescription medicine used for the treatment of coronavirus disease 2019 (COVID-19) in adults and children
weighing at least 3 pounds (1.5 kg) who are:
•
Hospitalized, or
•
Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19,
including hospitalization or death.
It is not known if VEKLURY is safe and effective in children weighing less than 3 pounds (1.5 kg).
Do not take VEKLURY if you are allergic to remdesivir or any of the ingredients in VEKLURY. See the end of this
leaflet for a complete list of ingredients in VEKLURY.
Before receiving VEKLURY, tell your healthcare provider about all of your medical conditions, including if you:
•
have liver problems
•
are pregnant or plan to become pregnant. It is not known if VEKLURY may harm your unborn baby if taken during the
first trimester of pregnancy. Tell your healthcare provider right away if you are or if you become pregnant.
•
are breastfeeding or plan to breastfeed. VEKLURY can pass into your breast milk. Talk to your healthcare provider
about the best way to feed your baby.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements. VEKLURY may interact with other medicines.
Especially tell your healthcare provider if you are taking the medicines chloroquine phosphate or
hydroxychloroquine sulfate.
How will I receive VEKLURY?
•
Hospitalized: VEKLURY is given to you through a vein by intravenous (IV) infusion one time each day for up to 10
days. Your healthcare provider will decide how many doses you need.
•
Not hospitalized: VEKLURY is given to you through a vein by intravenous (IV) infusion one time each day for 3 days.
•
Your healthcare provider will do certain blood tests before starting and during treatment with VEKLURY.
What are the possible side effects of VEKLURY?
VEKLURY may cause serious side effects, including:
•
Allergic reactions. Allergic reactions can happen during or after infusion with VEKLURY. Your healthcare provider will
monitor you for signs and symptoms of allergic reactions during your infusion and for at least 1 hour after your infusion.
Tell your healthcare provider right away if you get any of the following signs and symptoms of an allergic reaction:
o
changes in your heart rate
o
rash
o
fever
o
nausea
o
shortness of breath, wheezing
o
sweating
o
swelling of the lips, face, or throat
o
shivering
•
Increase in liver enzymes. Increases in liver enzymes are common in people who have received VEKLURY and may
be a sign of liver injury. Your healthcare provider will do blood tests to check your liver enzymes before and during
treatment with VEKLURY as needed. Your healthcare provider may stop treatment with VEKLURY if you develop liver
problems.
The most common side effect of VEKLURY is nausea.
These are not all of the possible side effects of VEKLURY.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
1
Reference ID: 5508433
General information about the safe and effective use of VEKLURY.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your
pharmacist or healthcare provider for information about VEKLURY that is written for healthcare professionals.
What are the ingredients in VEKLURY?
Active ingredient: remdesivir
Inactive ingredients:
VEKLURY for injection: betadex sulfobutyl ether sodium and may include hydrochloric acid and/or sodium hydroxide for
pH adjustment.
VEKLURY injection: betadex sulfobutyl ether sodium, Water for Injection, USP, and may include hydrochloric acid and/or
sodium hydroxide for pH adjustment.
Manufactured and distributed by: Gilead Sciences, Inc., Foster City, CA 94404
VEKLURY is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.
© 2025 Gilead Sciences, Inc. All rights reserved.
214787-GS-020
For more information, call 1-800-445-3235 or go to www.VEKLURY.com.
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 12/2024
2
Reference ID: 5508433
| custom-source | 2025-02-12T15:48:26.621851 | {'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214787s030lbl.pdf', 'application_number': 214787, 'submission_type': 'SUPPL ', 'submission_number': 30} |
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