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Darunavir 800 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatment-naïve subjects was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment duration of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.
During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea (28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Tabulated list of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated from the available data).
Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing
MedDRA system organ class Frequency category
Adverse reaction
Infections and infestations
uncommon
herpes simplex
Blood and lymphatic system disorders
uncommon
rare
thrombocytopenia, neutropenia, anaemia, leukopenia
increased eosinophil count
Immune system disorders
uncommon
immune reconstitution inflammatory syndrome, (drug) hypersensitivity
Endocrine disorders
uncommon
hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders
common
uncommon
diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia
gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase
Psychiatric disorders
common
uncommon
rare
insomnia
depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido
confusional state, altered mood, restlessness
Nervous system disorders
common
uncommon
rare
headache, peripheral neuropathy, dizziness
lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence
syncope, convulsion, ageusia, sleep phase rhythm disturbance
Eye disorders
uncommon
rare
conjunctival hyperaemia, dry eye
visual disturbance
Ear and labyrinth disorders
uncommon
vertigo
Cardiac disorders
uncommon
rare
myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia
acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders
uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon
rare
dyspnoea, cough, epistaxis, throat irritation
rhinorrhoea
Gastrointestinal disorders
very common
common
uncommon
rare
diarrhoea
vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence
pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia
stomatitis, haematemesis, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
common
uncommon
increased alanine aminotransferase
hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
common
uncommon
rare
Not known
rash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritus
angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation
DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma
toxic epidermal necrolysis, acute generalised exanthematous pustulosis
Musculoskeletal and connective tissue disorders
uncommon
rare
myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase
musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
Uncommon
rare
rare
acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria
decreased creatinine renal clearance
crystal nephropathy§
Reproductive system and breast disorders
Uncommon
erectile dysfunction, gynaecomastia
General disorders and administration site conditions
Common
Uncommon
rare
asthenia, fatigue
pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain
chills, abnormal feeling, xerosis
§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the "Rule of 3".
Adverse reactions observed with darunavir/cobicistat in adult patients
MedDRA system organ class Frequency category
Adverse reaction
Immune system disorders
common
uncommon
(drug) hypersensitivity
immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
common
anorexia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia
Psychiatric disorders
common
abnormal dreams
Nervous system disorders
very common
headache
Gastrointestinal disorders
very common
common
uncommon
diarrhoea, nausea
vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased
pancreatitis acute
Hepatobiliary disorders
common
uncommon
hepatic enzyme increased
hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
very common
common
rare
not known
rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis)
angioedema, pruritus, urticaria
drug reaction with eosinophilia and systemic symptoms*, Stevens-Johnson syndrome*
toxic epidermal necrolysis*, acute generalised exanthematous pustulosis*
Musculoskeletal and connective tissue disorders
common
uncommon
myalgia
osteonecrosis*
Renal and urinary disorders
rare
crystal nephropathy*§
Reproductive system and breast disorders
uncommon
Gynaecomastia*
General disorders and administration site conditions
common
uncommon
fatigue
asthenia
Investigations
common
increased blood creatinine
* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.
§
adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics (Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determined using the "Rule of 3".
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4. In a single arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to rash.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing darunavir/ritonavir + raltegravir compared to those containing darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).
Paediatric population
The safety assessment of darunavir with ritonavir in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see section 5.1):
• 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
• 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
• 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).
Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.
The safety assessment of Darunavir with cobicistat in paediatric patients was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced, virologically suppressed, N=7). Safety analyses of this study in adolescent subjects did not identify new safety concerns compared to the known safety profile of darunavir and cobicistat in adult subjects.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Darunavir 800 mg film-coated tablets | Clinical particulars - Overdose | Overdose
Human experience of acute overdose with darunavir co-administered with cobicistat or low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
5. Pharmacological properties
5.1 |
Darunavir 800 mg film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with cobicistat or ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of α1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Cobicistat and ritonavir inhibit CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product Characteristics.
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of cobicistat or low dose ritonavir is lower as compared to intake with food. Therefore, darunavir tablets should be taken with cobicistat or ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.
Biotransformation
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Elimination
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.
Special populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/L (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/L (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir 800 mg co-administered with cobicistat 150 mg in paediatric patients have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg in Study GS-US-216-0128. The geometric mean adolescent exposure (AUCtau) was similar for darunavir and increased 19% for cobicistat compared to exposures achieved in adults who received darunavir 800 mg co-administered with cobicistat 150 mg in Study GS-US-216-0130. The difference observed for cobicistat was not considered clinically relevant.
Adults in Study
GS-US-216-0130, week 24 (Reference)a Mean (%CV) GLSM
Adolescents in Study
GS-US-216-0128, day 10 (Test)b Mean (%CV) GLSM
GLSM Ratio
(90% CI)
(Test/Reference)
N
60c
7
DRV PK
Parameter
AUCtau (h.ng/mL)d
81,646 (32.2)
77,534
80,877 (29.5)
77,217
1.00 (0.79-1.26)
Cmax (ng/mL)
7,663 (25.1)
7,422
7,506 (21.7)
7,319
0.99 (0.83-1.17)
Ctau (ng/mLd
1,311 (74.0)
947
1,087 (91.6)
676
0.71 (0.34-1.48)
COBI PK
Parameter
AUCtau (h.ng/mL)d
7,596 (48.1)
7,022
8,741 (34.9)
8,330
1.19 (0.95-1.48)
Cmax (ng/mL)
991 (33.4)
945
1,116 (20.0)
1,095
1.16 (1.00-1.35)
Ctau (ng/mL)d
32.8 (289.4)
17.2e
28.3 (157.2)
22.0e
1.28 (0.51-3.22)
a Week 24 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.
b Day 10 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.
c N=59 for AUCtau and Ctau.
d Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating AUCtau and Ctau in Study GS-US-216-0128.
e N=57 and N=5 for GLSM of Ctau in Study GS-US-216-0130 and Study GS-US-216-0128, respectively.
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age ≥ 65) (see section 4.4). However, only limited data were available in patients above the age of 65 year.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.
Renal impairment
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects.
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, darunavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean ± SD)
Second trimester of pregnancy
(n=12)a
Third trimester of pregnancy
(n=12)
Postpartum (6-12 weeks)
(n=12)
Cmax, ng/ml
4,668 ± 1,097
5,328 ± 1,631
6,659 ± 2,364
AUC12h, ng.h/ml
39,370 ± 9,597
45,880 ± 17,360
56,890 ± 26,340
Cmin, ng/ml
1,922 ± 825
2,661 ± 1,269
2,851 ± 2,216
a n=11 for AUC12h
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir (mean ± SD)
Second trimester of pregnancy
(n=17)
Third Trimester of pregnancy
(n=15)
Postpartum (6-12 weeks)
(n=16)
Cmax, ng/ml
4,964 ± 1,505
5,132 ± 1,198
7,310 ± 1,704
AUC24h, ng.h/ml
62,289 ± 16,234
61,112 ± 13,790
92,116 ± 29,241
Cmin, ng/ml
1,248 ± 542
1,075 ± 594
1,473 ± 1,141
In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.
Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir exposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associated enzyme induction (see below).
Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of total darunavir
(mean ± SD)
Second trimester of pregnancy
(n=7)
Third trimester of pregnancy
(n=6)
Postpartum (6-12 weeks)
(n=6)
Cmax, ng/mL
4,340 ± 1,616
4,910 ± 970
7,918 ± 2,199
AUC24h, ng.h/mL
47,293 ± 19,058
47,991 ± 9,879
99,613 ± 34,862
Cmin, ng/mL
168 ± 149
184 ± 99
1,538 ± 1,344
The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as compared with postpartum.
5.3 |
Darunavir 800 mg film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir with low dose ritonavir should not be used in paediatric patients below 3 years of age.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
6. |
Darunavir 800 mg film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Silica, colloidal anhydrous
Silicified microcrystalline cellulose
Crospovidone
Magnesium stearate
Tablet film-coat
Polyvinyl alcohol – partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc
Iron oxide yellow (E172)
6.2 |
Darunavir 800 mg film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Darunavir 800 mg film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Darunavir 800 mg film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Darunavir 800 mg film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Blister pack:
OPA-Aluminium-PVC/Aluminium blister packs; pack sizes of 1x30, 1x60 and 1x90 film-coated tablets.
HDPE Bottle:
White opaque high-density polyethylene (HDPE) bottle closed with white opaque child-resistant polypropylene closure. Contains a cylindrical canister filled with silica gel as desiccant. Pack sizes of 30 and 90 (3x30) film-coated tablets.
Not all pack sizes may be marketed
6.6 |
Darunavir 800 mg film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Darunavir 800 mg film-coated tablets | Marketing authorisation holder | Amarox Limited
Congress House,
14 Lyon Road,
Harrow, Middlesex HA1 2EN,
United Kingdom
8. Marketing authorisation number(s)
PL 49445/0030
9. |
Darunavir 800 mg film-coated tablets | Date of first authorisation/renewal of the authorisation | 23/07/2020
10. |
Darunavir 800 mg film-coated tablets | Date of revision of the text | 13/01/2023 |
Darunavir 800mg Film-Coated Tablets | Name of the medicinal product | Darunavir 800 mg film-coated tablets
2. |
Darunavir 800mg Film-Coated Tablets | Qualitative and quantitative composition | Darunavir 800 mg film-coated tablets
Each film-coated tablet contains 800 mg of darunavir.
This medicine contains less than 1 mmol sodium (23 mg) per tablets, that is to say essentially 'sodium-free'.
For the full list of excipients, see section 6.1.
3. |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical form | Film-coated tablet.
Darunavir 800 mg film-coated tablets
Brown coloured, oval shaped, biconvex, tablet, debossed with “D” on one side and “800” on the other side.
4. |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Darunavir co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.
Darunavir co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients and adolescents (aged 12 years and older, weighing at least 40 kg) (see section 4.2).
Darunavir 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:
• antiretroviral therapy (ART)-naïve (see section 4.2).
• ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. In deciding to initiate treatment with Darunavir in such ART-experienced patients, genotypic testing should guide the use of Darunavir (see sections 4.2, 4.3, 4.4 and 5.1).
4.2 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Therapy should be initiated by a health care provider experienced in the management of HIV
infection. After therapy with darunavir has been initiated, patients should be advised not to alter the dosage, dose form or discontinue therapy without discussing with their health care provider.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different contraindications and recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).
Posology
Darunavir must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products. The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir. Cobicistat is not indicated for use in twice daily regimens or for use in the paediatric population less than 12 years of age weighing at least 40 kg).
Darunavir may also be available as an oral suspension for use in patients who are unable to swallow darunavir tablets.
ART-naïve adult patients
The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
ART-experienced adult patients
The recommended dose regimens are as follows:
• In ART-experienced patients with no darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once daily taken with food may be used. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.
• In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of Product Characteristics for Darunavir 600 mg tablets.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older). Darunavir 400mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. The dose of cobicistat to be used with darunavir in children less than 12 years of age has not been established.
ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The dose of cobicistat to be used with darunavir in children less than 12 years of age has not been established.
The recommended dose regimens are as follows:
• In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA< 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food or 800 mg once daily with cobicistat 150 mg once daily taken with food (in adolescent patients 12 years of age or older) may be used. Darunavir 400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen. The dose of cobicistat to be used with darunavir in children less than 12 years of age has not been established.
• In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose regimen is described in the Summary of Product Characteristics for darunavir 600 mg tablets.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
Advice on missed doses
If a once daily dose of darunavir and/or cobicistat or ritonavir is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of darunavir and cobicistat or ritonavir with food as soon as possible. If this is noticed later than 12 hours after the time it is usually taken, the missed dose should not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir and the recommended dosing interval of approximately 24 hours.
If a patient vomits within 4 hours of taking the medicine, another dose of darunavir with cobicistat or ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, the patient does not need to take another dose of darunavir with cobicistat or ritonavir until the next regularly scheduled time.
Special populations
Elderly
Limited information is available in this population, and therefore, darunavir should be used with caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, darunavir should be used with caution in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, darunavir must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections 4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients.
Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if any co-administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipovoxil. For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Paediatric population
Darunavir should not be used in children:
- below 3 years of age, because of safety concerns (see sections 4.4 and 5.3), or,
- less than 15 kg body weight, as the dose for this population has not been established in a sufficient number of patients (see section 5.1).
Darunavir taken with cobicistat should not be used in children aged 3 to 11 years of age weighing < 40 kg as the dose of cobicistat to be used in these children has not been established (see sections 4.4 and 5.3).
Darunavir 400 and 800 mg tablets are not suitable for this patient population. Other formulations are available, see the Summary of Product Characteristics for darunavir 600 mg tablets.
Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. darunavir/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see sections 4.4 and 5.2). Therefore, therapy with darunavir /cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir /cobicistat should be switched to an alternative regimen (see sections 4.4 and 4.6). darunavir /ritonavir may be considered as an alternative.
Method of administration
Patients should be instructed to take darunavir with cobicistat or low dose ritonavir within 30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).
4.3 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Concomitant treatment with any of the following medicinal products given the expected decrease in plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic effect (see sections 4.4 and 4.5).
Applicable to darunavir boosted with either ritonavir or cobicistat:
- The combination product lopinavir/ritonavir (see section 4.5).
- The strong CYP3A inducers rifampicin and herbal preparations containing St John's wort (Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible development of resistance (see sections 4.4 and 4.5).
Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated since these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect. Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 4.4 and 4.5).
Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that are highly dependent on CYP3A for clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These active substances include e.g.:
• alfuzosin
• amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
• astemizole, terfenadine
• colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
• ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
• elbasvir/grazoprevir
• cisapride
• dapoxetine
• domperidone
• naloxegol
• lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
• triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5)
• sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
• simvastatin, lovastatin and lomitapide (see section 4.5)
• dabigatran, ticagrelor (see section 4.5).
4.4 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance testing should be performed.
Darunavir 800 mg must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation of therapy with darunavir.
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir.
Darunavir binds predominantly to α1-acid glycoprotein. This protein binding is concentration-dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products highly bound to α1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients – once daily dosing
Darunavir used in combination with cobicistat or low dose ritonavir once daily in ART-experienced patients should not be used in patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA ≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 106/l (see section 4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see sections 4.2 and 5.3).
Pregnancy
Darunavir /ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections 4.5 and 5.2).
Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimester has been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in darunavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with darunavir /cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir /cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.6). Darunavir given with low dose ritonavir may be considered as an alternative.
Elderly
As limited information is available on the use of darunavir in patients aged 65 and over, caution should be exercised in the administration of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 and 5.2).
Severe skin reactions
During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Darunavir should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir (see section 4.8).
Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir used in combination with cobicistat or low dose ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir used in combination with cobicistat or low dose ritonavir treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using darunavir used in combination with cobicistat or low dose ritonavir, interruption or discontinuation of treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of darunavir have not been established in patients with severe underlying liver disorders and darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, darunavir should be used with caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these patients (see sections 4.2 and 5.2). Cobicistat has not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use of darunavir/cobicistat in these patients (see section 4.2).
Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This should be taken into consideration if darunavir with cobicistat is administered to patients in whom the estimated creatinine clearance is used to adjust doses of co-administered medicinal products (see section 4.2 and cobicistat SmPC).
There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that include tenofovir disoproxil without cobicistat.
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patient's additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated, and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical studies with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.8).
Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended doses. The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated. For full information on interactions with other medicinal products see section 4.5.
Pharmacokinetic enhancer and concomitant medications
Darunavir has different interaction profiles depending on whether the compound is boosted with ritonavir or cobicistat:
• Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3), and concomitant use with weak to moderate CYP3A inducers is not recommended (see section 4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with lopinavir/ritonavir, rifampicin and herbal products containing St John's wort, Hypericum perforatum, is contraindicated (see section 4.5).
• Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see section 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed in these cases.
Efavirenz in combination with boosted darunavir may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for darunavir 600 mg tablets (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).
4.5 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used as pharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinal products may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat (see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switching the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).
Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are contraindicated include rifampicin, St John's wort and lopinavir.
Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, azole antifungals like clotrimazole).
Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)
Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John's wort, rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3). Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, etravirine, nevirapine, fluticasone, and bosentan) is not recommended (see interaction table below).
For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independent of whether darunavir is boosted with ritonavir or with cobicistat (see section above).
Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
Co-administration of boosted darunavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (seethe Interaction table below).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).
Medicinal products that may be affected by darunavir boosted with cobicistat
The recommendations for darunavir boosted with ritonavir are adequate also for darunavir boosted with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a comparable way to ritonavir (see section 5.2).
Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Interaction table
Interaction studies have only been performed in adults.
Several of the interaction studies (indicated by # in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant medications depending on whether the compound is boosted with ritonavir or cobicistat. No interaction studies presented in the table have been performed with darunavir boosted with cobicistat. The same recommendations apply, unless specifically indicated. For further information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range (not determined as “ND”).
In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. When the recommendation is the same for darunavir when co-administered with a low dose ritonavir or cobicistat, the term “boosted darunavir” is used.
The below list of examples of drug-drug interactions is not comprehensive and therefore the label of each drug that is co-administered with darunavir should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by therapeutic areas
Interaction
Geometric mean change (%)
Recommendations concerning co-administration
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir
dolutegravir AUC ↓ 22%
dolutegravir C24h ↓ 38%
dolutegravir Cmax ↓ 11%
darunavir ↔*
* Using cross-study comparisons to historical pharmacokinetic data
Boosted darunavir and dolutegravir can be used without dose adjustment.
Raltegravir
Some clinical studies suggest raltegravir may cause a modest decrease in darunavir plasma concentrations.
At present the effect of raltegravir on darunavir plasma concentrations does not appear to be clinically relevant. Boosted darunavir and raltegravir can be used without dose adjustments.
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily
didanosine AUC ↓ 9%
didanosine Cmin ND
didanosine Cmax ↓ 16%
darunavir AUC ↔
darunavir Cmin ↔
darunavir Cmax ↔
Boosted darunavir and didanosine can be used without dose adjustments.
Didanosine is to be administered on an empty stomach, thus it should be administered 1 hour before or 2 hours after boosted darunavir given with food.
Tenofovir disoproxil
245 mg once daily‡
tenofovir AUC ↑ 22%
tenofovir Cmin ↑ 37%
tenofovir Cmax ↑ 24%
# darunavir AUC ↑ 21%
# darunavir Cmin ↑ 24%
# darunavir Cmax ↑ 16%
(↑ tenofovir from effect on MDR-1
transport in the renal tubules)
Monitoring of renal function may be indicated when boosted darunavir is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Darunavir co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.
Emtricitabine/tenofovir alafenamide
Tenofovir alafenamide ↔
Tenofovir ↑
The recommended dose of emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with boosted darunavir.
Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Not studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and boosted darunavir.
Boosted darunavir can be used with these NRTIs without dose adjustment.
Darunavir co-administered with cobicistat lowers the creatinine clearance. Refer to section 4.4 if creatinine clearance is used for dose adjustment of emtricitabine or lamivudine.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily
efavirenz AUC ↑ 21%
efavirenz Cmin ↑ 17%
efavirenz Cmax ↑ 15%
#darunavir AUC ↓ 13%
#darunavir Cmin ↓ 31%
#darunavir Cmax ↓ 15%
(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)
Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir co-administered with low dose ritonavir is given in combination with efavirenz.
Efavirenz in combination with
darunavir /ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Etravirine
100 mg twice daily
etravirine AUC ↓ 37%
etravirine Cmin ↓ 49%
etravirine Cmax ↓ 32%
darunavir AUC ↑ 15%
darunavir Cmin ↔
darunavir Cmax ↔
Darunavir co-administered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Nevirapine
200 mg twice daily
nevirapine AUC ↑ 27%
nevirapine Cmin ↑ 47%
nevirapine Cmax ↑ 18%
#darunavir: concentrations were consistent with historical data
(↑ nevirapine from CYP3A inhibition)
Darunavir co-administered with low dose ritonavir and nevirapine can be used without dose adjustments.
Co-administration with darunavir co-administered with cobicistat is not recommended (see section 4.4).
Rilpivirine
150 mg once daily
rilpivirine AUC ↑ 130%
rilpivirine Cmin ↑ 178%
rilpivirine Cmax ↑ 79%
darunavir AUC ↔
darunavir Cmin ↓ 11%
darunavir Cmax ↔
Boosted darunavir and rilpivirine can be used without dose adjustments.
HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir†
Atazanavir
300 mg once daily
atazanavir AUC ↔
atazanavir Cmin ↑ 52%
atazanavir Cmax ↓ 11%
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
Atazanavir: comparison of atazanavir/ritonavir 300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.
Darunavir co-administered with low dose ritonavir and atazanavir can be used without dose adjustments.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
Indinavir
800 mg twice daily
indinavir AUC ↑ 23%
indinavir Cmin ↑ 125%
indinavir Cmax ↔
#darunavir AUC ↑ 24%
#darunavir Cmin ↑ 44%
#darunavir Cmax ↑ 11%
Indinavir: comparison of indinavir/ritonavir 800/100 mg twice daily vs. indinavir/darunavir/ritonavir 800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.
When used in combination with darunavir co-administered with low dose ritonavir, dose adjustment of indinavir from 800 mg twice daily to 600 mg twice daily may be warranted in case of intolerance.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
Saquinavir
1,000 mg twice daily
#darunavir AUC ↓ 26%
#darunavir Cmin ↓ 42%
#darunavir Cmax ↓ 17%
saquinavir AUC ↓ 6%
saquinavir Cmin ↓ 18%
saquinavir Cmax ↓ 6%
Saquinavir: comparison of saquinavir/ritonavir 1,000/100 mg twice daily vs. saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily
Darunavir: comparison of darunavir/ritonavir 400/100 mg twice daily vs. darunavir/ritonavir 400/100 mg in combination with saquinavir 1,000 mg twice daily.
It is not recommended to combine darunavir co-administered with low dose ritonavir with saquinavir.
Darunavir co-administered with cobicistat should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 (see section 4.5).
HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir†
Lopinavir/ritonavir
400/100 mg twice daily
Lopinavir/ritonavir
533/133.3 mg twice daily
lopinavir AUC ↑ 9%
lopinavir Cmin ↑ 23%
lopinavir Cmax ↓ 2%
darunavir AUC ↓ 38%‡
darunavir Cmin ↓ 51%‡
darunavir Cmax ↓ 21%‡
lopinavir AUC ↔
lopinavir Cmin ↑ 13%
lopinavir Cmax ↑ 11%
darunavir AUC ↓ 41%
darunavir Cmin ↓ 55%
darunavir Cmax ↓ 21%
‡ based upon non dose normalised values
Due to a decrease in the exposure (AUC) of darunavir by 40%, appropriate doses of the combination have not been established. Hence, concomitant use of boosted darunavir and the combination product lopinavir/ritonavir is contraindicated (see section 4.3).
CCR5 ANTAGONIST
Maraviroc
150 mg twice daily
maraviroc AUC ↑ 305%
maraviroc Cmin ND
maraviroc Cmax ↑ 129%
darunavir, ritonavir concentrations were consistent with historical data
The maraviroc dose should be 150 mg twice daily when co-administered with boosted darunavir.
α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin
Based on theoretical considerations darunavir is expected to increase alfuzosin plasma concentrations.
(CYP3A inhibition)
Co-administration of boosted darunavir and alfuzosin is contraindicated (see section 4.3).
ANAESTHETIC
Alfentanil
Not studied. The metabolism of alfentanil is mediated via CYP3A, and may as such be inhibited by boosted darunavir.
The concomitant use with boosted darunavir may require to lower the dose of alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone
Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine
Not studied. Boosted darunavir is expected to increase these antiarrhythmic plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)
Caution is warranted and therapeutic concentration monitoring, if available, is recommended for these antiarrhythmics when co-administered with boosted darunavir.
Co-administration of boosted darunavir and amiodarone, bepridil, dronedarone, ivabradine, quinidine, or ranolazine is contraindicated (see section 4.3).
Digoxin
0.4 mg single dose
digoxin AUC ↑ 61%
digoxin Cmin ND
digoxin Cmax ↑ 29%
(↑ digoxin from probable inhibition of P-gp)
Given that digoxin has a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on boosted darunavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
ANTIBIOTIC
Clarithromycin
500 mg twice daily
clarithromycin AUC ↑ 57%
clarithromycin Cmin ↑ 174%
clarithromycin Cmax ↑ 26%
#darunavir AUC ↓ 13%
#darunavir Cmin ↑ 1%
#darunavir Cmax ↓17%
14-OH-clarithromycin concentrations were not detectable when combined with darunavir/ritonavir.
(↑ clarithromycin from CYP3A inhibition and possible P-gp inhibition)
Caution should be exercised when clarithromycin is combined with boosted darunavir.
For patients with renal impairment the Summary of Product Characteristics for clarithromycin should be consulted for the recommended dose.
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban
Not studied. Co-administration of boosted darunavir with these anticoagulants may increase concentrations of the anticoagulant, which may lead to an increased bleeding risk (CYP3A and/or P-gp inhibition)
The use of boosted darunavir and these anticoagulants is not recommended.
Dabigatran
Ticagrelor
Clopidogrel
Not studied. Co-administration with boosted darunavir may lead to a substantial increase in exposure to dabigatran or ticagrelor.
Not studied. Co-administration of clopidogrel with boosted darunavir is expected to decrease clopidogrel active metabolite plasma concentration, which may reduce the antiplatelet activity of clopidogrel.
Concomitant administration of boosted darunavir with dabigatran or ticagrelor is contraindicated (see section 4.3).
Co-administration of clopidogrel with boosted darunavir is not recommended.
Use of other antiplatelets not affected by CYP inhibition or induction (e.g. prasugrel) is recommended.
Warfarin
Not studied. Warfarin concentrations may be affected when co-administered with boosted darunavir.
It is recommended that the international normalised ratio (INR) be monitored when warfarin is combined with boosted darunavir.
ANTICONVULSANTS
Phenobarbital
Phenytoin
Not studied. Phenobarbital and phenytoin are expected to decrease plasma concentrations of darunavir and its pharmacoenhancer.
(induction of CYP450 enzymes)
Darunavir co-administered with low dose ritonavir should not be used in combination with these medicines.
The use of these medicines with darunavir/cobicistat is contraindicated (see section 4.3).
Carbamazepine
200 mg twice daily
carbamazepine AUC ↑ 45%
carbamazepine Cmin ↑ 54%
carbamazepine Cmax ↑ 43%
darunavir AUC ↔
darunavir Cmin ↓ 15%
darunavir Cmax ↔
No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine-related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
The use of carbamazepine with darunavir co-administered with cobicistat is contraindicated (see section 4.3).
Clonazepam
Not studied. Co-administration of boosted darunavir with clonazepam may increase concentrations of clonazepam. (CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir and clonazepam.
ANTIDEPRESSANTS
Paroxetine
20 mg once daily
Sertraline
50 mg once daily
Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone
paroxetine AUC ↓ 39%
paroxetine Cmin ↓ 37%
paroxetine Cmax ↓ 36%
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
sertraline AUC ↓ 49%
sertraline Cmin ↓ 49%
sertraline Cmax ↓ 44%
#darunavir AUC ↔
#darunavir Cmin ↓ 6%
#darunavir Cmax ↔
In contrast to these data with darunavir /ritonavir, darunavir/cobicistat may increase these antidepressant plasma concentrations (CYP2D6 and/or CYP3A inhibition).
Concomitant use of boosted darunavir and these antidepressants may increase concentrations of the antidepressant. (CYP2D6 and/or CYP3A inhibition)
If antidepressants are co-administered with boosted darunavir, the recommended approach is a dose titration of the antidepressant based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of these antidepressants who start treatment with boosted darunavir should be monitored for antidepressant response
Clinical monitoring is recommended when co-administering boosted darunavir with these antidepressants and a dose adjustment of the antidepressant may be needed.
ANTI-DIABETICS
Metformin
Not studied. Based on theoretical considerations darunavir co-administered with cobicistat is expected to increase metformin plasma concentrations.
(MATE1 inhibition)
Careful patient monitoring and dose adjustment of metformin is recommended in patients who are taking darunavir co-administered with cobicistat. (not applicable for darunavir co-administered with ritonavir)
ANTIEMETICS
Domperidone
Not studied
Co-administration of domperidone with boosted darunavir is contraindicated.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease plasma concentrations of voriconazole.
(induction of CYP450 enzymes)
Concentrations of voriconazole may increase or decrease when co-administered with darunavir co-administered with cobicistat.
(inhibition of CYP450 enzymes)
Voriconazole should not be combined with boosted darunavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Fluconazole
Isavuconazole
Itraconazole
Posaconazole
Clotrimazole
Not studied. Boosted darunavir may increase antifungal plasma concentrations and posaconazole, isavuconazole, itraconazole or fluconazole may increase darunavir concentrations.
(CYP3A and/or P-gp inhibition)
Not studied. Concomitant systemic use of clotrimazole and boosted darunavir may increase plasma concentrations of darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)
Caution is warranted and clinical monitoring is recommended.
When co-administration is required the daily dose of itraconazole should not exceed 200 mg.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine and boosted darunavir may increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with boosted darunavir is required. For patients with renal or hepatic impairment colchicine with boosted darunavir is contraindicated (see sections 4.3 and 4.4).
ANTIMALARIALS
Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours
artemether AUC ↓ 16%
artemether Cmin ↔
artemether Cmax ↓ 18%
dihydroartemisinin AUC ↓ 18%
dihydroartemisinin Cmin ↔
dihydroartemisinin Cmax ↓ 18%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%
darunavir AUC ↔
darunavir Cmin ↓ 13%
darunavir Cmax ↔
The combination of boosted darunavir and artemether/lumefantrine can be used without dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with caution.
ANTIMYCOBACTERIALS
Rifampicin
Rifapentine
Not studied. Rifapentine and rifampicin are strong CYP3A inducers and have been shown to cause profound decreases in concentrations of other protease inhibitors, which can result in virological failure and resistance development (CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.
The combination of rifapentine and boosted darunavir is not recommended.
The combination of rifampicin and boosted darunavir is contraindicated (see section 4.3).
Rifabutin
150 mg once every other day
rifabutin AUC** ↑ 55%
rifabutin Cmin ** ↑ ND
rifabutin Cmax ** ↔
darunavir AUC ↑ 53%
darunavir Cmin ↑ 68%
darunavir Cmax ↑ 39%
** sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite)
The interaction trial showed a comparable daily systemic exposure for rifabutin between treatment at 300 mg once daily alone and 150 mg once every other day in combination with darunavir/ritonavir (600/100 mg twice daily) with an about 10-fold increase in the daily exposure to the active metabolite 25-O-desacetylrifabutin. Furthermore, AUC of the sum of active moieties of rifabutin (parent drug + 25-O-desacetyl metabolite) was increased 1.6- fold, while Cmax remained comparable.
Data on comparison with a 150 mg once daily reference dose is lacking.
(Rifabutin is an inducer and substrate of CYP3A.) An increase of systemic exposure to darunavir was observed when darunavir co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
A dosage reduction of rifabutin by 75% of the usual dose of 300 mg/day (i.e. rifabutin 150 mg once every other day) and increased monitoring for rifabutin related adverse events is warranted in patients receiving the combination with darunavir co-administered with ritonavir. In case of safety issues, a further increase of the dosing interval for rifabutin and/or monitoring of rifabutin levels should be considered.
Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.
Based upon the safety profile of darunavir/ritonavir, the increase in darunavir exposure in the presence of rifabutin does not warrant a dose adjustment for darunavir/ritonavir.
Based on pharmacokinetic modeling, this dosage reduction of 75% is also applicable if patients receive rifabutin at doses other than 300 mg/day.
Co-administration of darunavir co-administered with cobicistat and rifabutin is not recommended.
ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine
Everolimus
Irinotecan
Not studied. Boosted darunavir is expected to increase these antineoplastic plasma concentrations.
(CYP3A inhibition)
Concentrations of these medicinal products may be increased when co-administered with boosted darunavir resulting in the potential for increased adverse events usually associated with these agents.
Caution should be exercised when combining one of these antineoplastic agents with boosted darunavir.
Concomitant use of everolimus or irinotecan and boosted darunavir is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A inhibition)
Concomitant administration of boosted darunavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine
Risperidone
Thioridazine
Lurasidone
Pimozide
Sertindole
Not studied. Boosted darunavir is expected to increase these antipsychotic plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp inhibition)
A dose decrease may be needed for these drugs when co-administered with boosted darunavir.
Concomitant administration of boosted darunavir and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).
β-BLOCKERS
Carvedilol
Metoprolol
Timolol
Not Studied. Boosted darunavir is expected to increase these β-blocker plasma concentrations.
(CYP2D6 inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with β-blockers. A lower dose of the β-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil
Not studied. Boosted darunavir can be expected to increase the plasma concentrations of calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)
Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with boosted darunavir.
CORTICOSTEROIDS
Corticosteroids primarily metabolised by CYP3A (including betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone)
Fluticasone: in a clinical study where ritonavir 100 mg capsules twice daily were co-administered with 50 μg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82-89%). Greater effects may be expected when fluticasone is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone. The effects of high fluticasone systemic exposure on ritonavir plasma levels are unknown.
Other corticosteroids: interaction not studied. Plasma concentrations of these medicinal products may be increased when co-administered with boosted darunavir, resulting in reduced serum cortisol concentrations.
Concomitant use of boosted darunavir and corticosteroids that are metabolised by CYP3A (e.g. fluticasone propionate or other inhaled or nasal corticosteroids) may increase the risk of development of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Co-administration with CYP3A-metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on CYP3A metabolism e.g. beclomethasone for intranasal or inhalational use should be considered, particularly for long term use.
Dexamethasone (systemic)
Not studied. Dexamethasone may decrease plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be used with caution when combined with boosted darunavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan and boosted darunavir may increase plasma concentrations of bosentan.
Bosentan is expected to decrease plasma concentrations of darunavir and/or its pharmacoenhancer.
(CYP3A induction)
When administered concomitantly with darunavir and low dose ritonavir, the patient's tolerability of bosentan should be monitored.
Co administration of darunavir co-administered with cobicistat and bosentan is not recommended.
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors
Elbasvir/grazoprevir
Boosted darunavir may increase the exposure to grazoprevir.
(CYP3A and OATP1B inhibition)
Concomitant use of boosted darunavir and elbasvir/grazoprevir is contraindicated (see section 4.3).
Glecaprevir/pibrentasvir
Based on theoretical considerations boosted darunavir may increase the exposure to glecaprevir and pibrentasvir. (P-gp, BCRP and /or OATP1B1/3 inhibition
It is not recommended to co-administer boosted darunavir with glecaprevir/lpibrentasvir.
HERBAL PRODUCTS
St John's wort (Hypericum perforatum)
Not studied. St John's wort is expected to decrease the plasma concentrations of darunavir or its pharmacoenhancers.
(CYP450 induction)
Boosted darunavir must not be used concomitantly with products containing St John's wort (Hypericum perforatum) (see section 4.3). If a patient is already taking St John's wort, stop St John's wort and if possible check viral levels. Darunavir exposure (and also ritonavir exposure) may increase on stopping St John's wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort.
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are expected to have markedly increased plasma concentrations when co-administered with boosted darunavir.
(CYP3A inhibition)
Increased plasma concentrations of lovastatin or simvastatin may cause myopathy, including rhabdomyolysis. Concomitant use of boosted darunavir with lovastatin and simvastatin is therefore contraindicated (see section 4.3).
Atorvastatin
10 mg once daily
atorvastatin AUC ↑ 3-4 fold
atorvastatin Cmin ↑ ≈5.5-10 fold
atorvastatin Cmax ↑ ≈2 fold
#darunavir/ritonavir
atorvastatin AUC ↑ 290% Ω
atorvastatin Cmax ↑ 319% Ω
atorvastatin Cmin ND Ω
Ω with darunavir/cobicistat 800/150 mg
When administration of atorvastatin and boosted darunavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Pravastatin
40 mg single dose
pravastatin AUC ↑ 81%¶
pravastatin Cmin ND
pravastatin Cmax ↑ 63%
¶ an up to five-fold increase was seen in a limited subset of subjects
When administration of pravastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Rosuvastatin
10 mg once daily
rosuvastatin AUC ↑ 48%║
rosuvastatin Cmax ↑ 144%║
║ based on published data with darunavir/ritonavir
rosuvastatin AUC ↑ 93%§
rosuvastatin Cmax ↑ 277%§
rosuvastatin Cmin ND§
§ with darunavir/cobicistat 800/150 mg
When administration of rosuvastatin and boosted darunavir is required, it is recommended to start with the lowest possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety.
OTHER LIPID MODIFYING AGENTS
Lomitapide
Based on theoretical considerations boosted darunavir is expected to increase the exposure of lomitapide when co-administered.
(CYP3A inhibition)
Co-administration is contraindicated (see section 4.3)
H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
Boosted darunavir can be co-administered with H2-receptor antagonists without dose adjustments.
IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus
Everolimus
Not studied. Exposure to these immunosuppressants will be increased when co-administered with boosted darunavir.
(CYP3A inhibition)
Therapeutic drug monitoring of the immunosuppressive agent must be done when co-administration occurs.
Concomitant use of everolimus and boosted darunavir is not recommended.
INHALED BETA AGONISTS
Salmeterol
Not studied. Concomitant use of salmeterol and boosted darunavir may increase plasma concentrations of salmeterol.
Concomitant use of salmeterol and boosted darunavir is not recommended. The combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone
individual dose ranging from 55 mg to 150 mg once daily
R(-) methadone AUC ↓ 16%
R(-) methadone Cmin ↓ 15%
R(-) methadone Cmax ↓ 24%
Darunavir /cobicistat may, in contrast, increase methadone plasma concentrations (see cobicistat SmPC).
No adjustment of methadone dosage is required when initiating co-administration with boosted darunavir. However, adjustment of the methadone dose may be necessary when concomitantly administered for a longer period of time. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.
Buprenorphine/naloxone
8/2 mg–16/4 mg once daily
buprenorphine AUC ↓ 11%
buprenorphine Cmin ↔
buprenorphine Cmax ↓ 8%
norbuprenorphine AUC ↑46%
norbuprenorphine Cmin ↑ 71%
norbuprenorphine Cmax ↑ 36%
naloxone AUC ↔
naloxone Cmin ND
naloxone Cmax ↔
The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when co-administered with boosted darunavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Fentanyl
Oxycodone
Tramadol
Based on theoretical considerations boosted darunavir may increase plasma concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)
Clinical monitoring is recommended when co-administering boosted darunavir with these analgesics.
OESTROGEN-BASED CONTRACEPTIVES
Drospirenone Ethinylestradiol (3 mg/0.02 mg once daily)
Ethinylestradiol
Norethindrone
35 μg/1 mg once daily
drospirenone AUC ↑ 58%€
drospirenone Cmin ND€
drospirenone Cmax ↑ 15%€
ethinylestradiol AUC ↓ 30%€
ethinylestradiol Cmin ND€
ethinylestradiol Cmax ↓ 14%€
€ with darunavir/cobicistat
ethinylestradiol AUC ↓ 44%β
ethinylestradiol Cmin ↓ 62%β
ethinylestradiol Cmax ↓ 32%β
norethindrone AUC ↓ 14%β
norethindrone Cmin ↓ 30%β
norethindrone Cmax ↔ β
β with darunavir/ritonavir
When darunavir is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia
Alternative or additional contraceptive measures are recommended when oestrogen-based contraceptives are co-administered with boosted darunavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
OPIOID ANTAGONIST
Naloxegol
Not studied.
Co-administration of boosted darunavir and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile dysfunction
Avanafil
Sildenafil
Tadalafil
Vardenafil
In an interaction study #, a comparable systemic exposure to sildenafil was observed for a single intake of 100 mg sildenafil alone and a single intake of 25 mg sildenafil co-administered with darunavir and low dose ritonavir.
The combination of avanafil and boosted darunavir is contraindicated (see section 4.3).
Concomitant use of other PDE-5 inhibitors for the treatment of erectile dysfunction with boosted darunavir should be done with caution. If concomitant use of boosted darunavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding 10 mg in 72 hours is recommended.
For the treatment of pulmonary arterial hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil or tadalafil for the treatment of pulmonary arterial hypertension and boosted darunavir may increase plasma concentrations of sildenafil or tadalafil.
(CYP3A inhibition)
A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension co-administered with boosted darunavir has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co-administration of boosted darunavir and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with boosted darunavir is not recommended.
PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily
#darunavir AUC ↔
#darunavir Cmin ↔
#darunavir Cmax ↔
Boosted darunavir can be co-administered with proton pump inhibitors without dose adjustments.
SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zoldipem
Midazolam (oral)
Triazolam
Not studied. Sedative/hypnotics are extensively metabolised by CYP3A. Co-administration with boosted darunavir may cause a large increase in the concentration of these medicines.
If parenteral midazolam is co-administered with boosted darunavir it may cause a large increase in the concentration of this benzodiazepine. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels.
Clinical monitoring is recommended when co-administering boosted darunavir with these sedatives/hypnotics and a lower dose of the sedatives/hypnotics should be considered.
If parenteral midazolam is co-administered with boosted darunavir, it should be done in an intensive care unit (ICU) or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Boosted darunavir with triazolam or oral midazolam is contraindicated (see section 4.3)
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine
Not studied.
Co-administration of boosted darunavir with dapoxetine is contraindicated.
UROLOGICAL DRUGS
Fesoterodine
Solifenacin
Not studied.
Use with caution. Monitor for fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
# Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology).
† The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir, nelfinavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
‡ Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.
4.6 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure (see section 5.2), which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therapy with darunavir/cobicistat should not be initiated during pregnancy, and women who become pregnant during therapy with darunavir/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.4).
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-feed under any circumstances if they are receiving darunavir.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with darunavir treatment in rats (see section 5.3).
4.7 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Darunavir in combination with cobicistat or ritonavir has no or negligible influence on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-administered with cobicistat or low dose ritonavir and should be borne in mind when considering a patient's ability to drive or operate machinery (see section 4.8)
4.8 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.
In the 96 week analysis, the safety profile of darunavir /ritonavir 800/100 mg once daily in treatment-naïve subjects was similar to that seen with darunavir /ritonavir 600/100 mg twice daily in treatment-experienced subjects except for nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea. No new safety findings were identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment duration of darunavir /ritonavir 800/100 mg once daily was 162.5 weeks.
During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea (28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.
Tabulated list of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated from the available data).
Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing
MedDRA system organ class
Frequency category
Adverse reaction
Infections and infestations
uncommon
herpes simplex
Blood and lymphatic system disorders
uncommon
thrombocytopenia, neutropenia, anaemia, leukopenia
rare
increased eosinophil count
Immune system disorders
uncommon
immune reconstitution inflammatory syndrome, (drug) hypersensitivity
Endocrine disorders
uncommon
hypothyroidism, increased blood thyroid stimulating hormone
Metabolism and nutrition disorders
common
diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, hyperlipidaemia
uncommon
gout, anorexia, decreased appetite, decreased weight, increased weight, hyperglycaemia, insulin resistance, decreased high density lipoprotein, increased appetite, polydipsia, increased blood lactate dehydrogenase
Psychiatric disorders
common
insomnia
uncommon
depression, disorientation, anxiety, sleep disorder, abnormal dreams, nightmare, decreased libido
rare
confusional state, altered mood, restlessness
Nervous system disorders
common
headache, peripheral neuropathy, dizziness
uncommon
lethargy, paraesthesia, hypoaesthesia, dysgeusia, disturbance in attention, memory impairment, somnolence
rare
syncope, convulsion, ageusia, sleep phase rhythm disturbance
Eye disorders
uncommon
conjunctival hyperaemia, dry eye
rare
visual disturbance
Ear and labyrinth disorders
uncommon
vertigo
Cardiac disorders
uncommon
myocardial infarction, angina pectoris, prolonged electrocardiogram QT, tachycardia
rare
acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders
uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon
dyspnoea, cough, epistaxis, throat irritation
rare
rhinorrhoea
Gastrointestinal disorders
Very common
diarrhoea
common
vomiting, nausea, abdominal pain, increased blood amylase, dyspepsia, abdominal distension, flatulence
uncommon
pancreatitis, gastritis, gastrooesophageal reflux disease, aphthous stomatitis, retching, dry mouth, abdominal discomfort, constipation, increased lipase, eructation, oral dysaesthesia
rare
stomatitis, haematemesis, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
common
increased alanine aminotransferase
uncommon
hepatitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, increased transaminase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
common
rash (including macular, maculopapular, papular, erythematous and pruritic rash), pruritus
uncommon
angioedema, generalised rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, nail pigmentation
rare
DRESS, Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrhoeic dermatitis, skin lesion, xeroderma
not known
toxic epidermal necrolysis, acute generalised exanthematous pustulosis
Musculoskeletal and connective tissue disorders
uncommon
myalgia, osteonecrosis, muscle spasms, muscular weakness, arthralgia, pain in extremity, osteoporosis, increased blood creatine phosphokinase
rare
musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
uncommon
acute renal failure, renal failure, nephrolithiasis, increased blood creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria
rare
decreased creatinine renal clearance
Reproductive system and breast disorders
uncommon
erectile dysfunction, gynaecomastia
General disorders and administration site conditions
common
asthenia, fatigue
uncommon
pyrexia, chest pain, peripheral oedema, malaise, feeling hot, irritability, pain
rare
chills, abnormal feeling, xerosis
Adverse reactions observed with darunavir/cobicistat in adult patients
MedDRA system organ class
Frequency category
Adverse reaction
Immune system disorders
common
(drug) hypersensitivity
uncommon
immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
common
anorexia, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia, hyperlipidaemia
Psychiatric disorders
common
abnormal dreams
Nervous system disorders
very common
headache
Gastrointestinal disorders
very common
diarrhoea, nausea
common
vomiting, abdominal pain, abdominal distension, dyspepsia, flatulence, pancreatic enzymes increased
uncommon
pancreatitis acute
Hepatobiliary disorders
common
hepatic enzyme increased
uncommon
hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
very common
rash (including macular, maculopapular, papular, erythematous, pruritic rash, generalised rash, and allergic dermatitis)
common
angioedema, pruritus, urticaria
rare
drug reaction with eosinophilia and systemic symptoms*, Stevens-Johnson syndrome*
not known
toxic epidermal necrolysis*, acute generalised exanthematous pustulosis*
Musculoskeletal and connective tissue disorders
common
myalgia
uncommon
osteonecrosis*
Reproductive system and breast disorders
uncommon
gynaecomastia*
General disorders and administration site conditions
common
fatigue
uncommon
asthenia
Investigations
common
increased blood creatinine
* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4. In a single arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to rash.
During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing darunavir /ritonavir + raltegravir compared to those containing darunavir/ ritonavir without raltegravir or raltegravir without darunavir /ritonavir. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4).
Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors, particularly in combination with NRTIs.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see section 4.4).
Paediatric population
The safety assessment of darunavir and ritonavir in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials. The following patient populations were evaluated (see section 5.1):
• 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who received darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.
• 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received darunavir oral suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.
• 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who received darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see section 5.1).
Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.
The safety assessment of darunavir with cobicistat in paediatric patients was evaluated in adolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced, virologically suppressed, N=7). Safety analyses of this study in adolescent subjects did not identify new safety concerns compared to the known safety profile of darunavir and cobicistat in adult subjects.
Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Darunavir 800mg Film-Coated Tablets | Clinical particulars - Overdose | Overdose
Human experience of acute overdose with darunavir co-administered with cobicistat or low dose ritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
5. Pharmacological properties
5.1 |
Darunavir 800mg Film-Coated Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with cobicistat or ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be explained by the higher concentrations of α1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Cobicistat and ritonavir inhibit CYP3A, thereby increasing the plasma concentrations of darunavir considerably.
For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product Characteristics.
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of cobicistat or low dose ritonavir is lower as compared to intake with food. Therefore, darunavir tablets should be taken with cobicistat or ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.
Biotransformation
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.
Elimination
After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9 l/h, respectively.
Special populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 600/100 mg twice daily (see section 4.2).
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily. Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.2).* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.2).* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
The pharmacokinetics of darunavir 800 mg co-administered with cobicistat 150 mg in paediatric patients have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg in Study GS-US-216-0128. The geometric mean adolescent exposure (AUCtau) was similar for darunavir and increased 19% for cobicistat compared to exposures achieved in adults who received darunavir 800 mg co-administered with cobicistat 150 mg in Study GS-US-216-0130. The difference observed for cobicistat was not considered clinically relevant.
Adults in Study GS-US-216-0130, week 24
(Reference)a
Mean (%CV)
GLSM
Adolescents in Study GS-US-216-0128, day 10
(Test)b
Mean (%CV)
GLSM
GLSM Ratio
(90% CI)
(Test/Reference)
N
60c
7
DRV PK Parameter
AUCtau (h.ng/mL)d
81,646 (32.2)
77,534
80,877 (29.5)
77,217
1.00 (0.79-1.26)
Cmax(ng/mL)
7,663 (25.1)
7,422
7,506 (21.7)
7,319
0.99 (0.83-1.17)
Ctau(ng/mL)d
1,311 (74.0)
947
1,087 (91.6)
676
0.71 (0.34-1.48)
COBI PK Parameter
AUCtau (h.ng/mL)d
7,596 (48.1)
7,022
8,741 (34.9)
8,330
1.19 (0.95-1.48)
Cmax(ng/mL)
991 (33.4)
945
1,116 (20.0)
1,095
1.16 (1.00-1.35)
Ctau(ng/mL)d
32.8 (289.4)
17.2e
28.3 (157.2)
22.e
1.28 (0.51-3.22)
a Week 24 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.
b Day 10 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.
c N=59 for AUCtau and Ctau.
d Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating AUCtau and Ctau in Study GS-US-216-0128.
e N=57 and N=5 for GLSM of Ctau in Study GS-US-216-0130 and Study GS-US-216-0128, respectively.
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age ≥ 65) (see section 4.4). However, only limited data were available in patients above the age of 65 year.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females compared to males. This difference is not clinically relevant.
Renal impairment
Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20) (see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown therefore, darunavir should be used with caution. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum.
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean ± SD)
Second trimester of pregnancy
(n=12)a
Third trimester of pregnancy
(n=12)
Postpartum
(6-12 weeks)
(n=12)
Cmax, ng/ml
4,668 ± 1,097
5,328 ± 1,631
6,659 ± 2,364
AUC12h, ng.h/ml
39,370 ± 9,597
45,880 ± 17,360
56,890 ± 26,340
Cmin, ng/ml
1,922 ± 825
2,661 ± 1,269
2,851 ± 2,216
a n=11 for AUC12h
Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of total darunavir
(mean ± SD)
Second trimester of pregnancy
(n=17)
Third trimester of pregnancy
(n=15)
Postpartum
(6-12 weeks)
(n=16)
Cmax, ng/ml
4,964 ± 1,505
5,132 ± 1,198
7,310 ± 1,704
AUC24h, ng.h/ml
62,289 ± 16,234
61,112 ± 13,790
92,116 ± 29,241
Cmin, ng/ml
1,248 ± 542
1,075 ± 594
1,473 ± 1,141
In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as compared with postpartum.
In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared with postpartum.
Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir exposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associated enzyme induction (see below).
Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of total darunavir
(mean ± SD)
Second trimester of pregnancy
(n=7)
Third trimester of pregnancy
(n=6)
Postpartum
(6-12 weeks)
(n=6)
Cmax, ng/ml
4,340 ± 1,616
4,910 ± 970
7,918 ± 2,199
AUC24h, ng.h/ml
47,293 ± 19,058
47,991 ± 9,879
99,613 ± 34,862
Cmin, ng/ml
168 ± 149
184 ± 99
1,538 ± 1,344
The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as compared with postpartum.
5.3 |
Darunavir 800mg Film-Coated Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment with darunavir. In rodents the target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity findings or target organs were identified up to exposures equivalent to clinical exposure at the recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation. These effects may be secondary to pup exposure to the active substance via the milk and/or maternal toxicity. No post weaning functions were affected with darunavir alone or in combination with ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir with low dose ritonavir should not be used in paediatric patients below 3 years of age.
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
6. |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Tablet core
Silicified Microcrystalline celluloseCrospovidoneHydroxypropyl CelluloseSodium chlorideSilica Colloidal AnhydrousMagnesium stearatePolacrilin potassium
Tablet film-coat
Polyvinyl alcohol-part. Hydrolyzed
Macrogol 4000Titanium dioxide (E171)TalcIron oxide red (E172)
6.2 |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical particulars - Shelf life | Shelf life
Unopened: 30 months
6.4 |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Darunavir 800 mg film-coated tablets
Opaque, white, high density polyethylene (HDPE) plastic bottle containing 30 tablets, fitted with polypropylene (PP) child resistant closure.
Pack sizes: 30 film-coated tablets or multipacks containing 90 (3 packs of 30) film-coated tablets
Not all pack sizes may be marketed.
6.6 |
Darunavir 800mg Film-Coated Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Darunavir 800mg Film-Coated Tablets | Marketing authorisation holder | Tillomed Laboratories Ltd
220 Butterfield
Great Marlings
Luton
LU2 8DL
United Kingdom
8. Marketing authorisation number(s)
PL 11311/0650
9. |
Darunavir 800mg Film-Coated Tablets | Date of first authorisation/renewal of the authorisation | 10/12/2019
10. |
Darunavir 800mg Film-Coated Tablets | Date of revision of the text | 15/07/2021 |
Denzapine 200mg Tablets | Name of the medicinal product | Denzapine® 200 mg Tablets
UK: Denzapine Official Recommendations
As a consequence of a recent European regulatory initiative, the Denzapine Summary of Product Characteristics (SmPC) has been harmonised across Europe. The SmPC states that blood monitoring should be carried out in accordance with national-specific official recommendations. These are reproduced below.
The Denzapine Monitoring Service (DMS) was developed in order to manage the risk of agranulocytosis associated with clozapine. It is available 24 hours a day. When a monitoring service is not used, evidence suggests a mortality rate from agranulocytosis of 0.3%[1]. This is compared to a mortality rate when clozapine is used in conjunction with a Monitoring Service, of 0.01%[2].
The Denzapine Monitoring Service provides centralised monitoring of leucocyte and neutrophil counts which is a mandatory requirement for all patients in the UK and Ireland who are treated with Denzapine. The use of Denzapine is restricted to patients who are registered with the Denzapine Monitoring Service. In addition to registering their patients, prescribing physicians must register themselves and a nominated pharmacist with the Denzapine Monitoring Service. All Denzapine-treated patients must be under the supervision of an appropriate specialist and supply of Denzapine is restricted to hospital and retail pharmacies registered with the Denzapine Monitoring Service. Denzapine is not sold to, or distributed through wholesalers.
The patient's white cell count with a differential count must be monitored:
• At least weekly for the first 18 weeks of treatment
• At least at 2 week intervals between weeks 18 and 52
• After 1 year of treatment with stable blood counts (green range), patients may be monitored at least at 4 week intervals
• Monitoring must continue throughout treatment and for at least 4 weeks after discontinuation
If the blood result of a patient taking Denzapine is below the normal range (See Section 4.4), Britannia will contact the physician and pharmacist registered to the patient on the Denzapine Monitoring Service to inform them.
The Denzapine Monitoring Service maintains a database which includes all patients who have developed abnormal leucocyte or neutrophil findings and who should not be re-exposed to Denzapine or any other brand of clozapine.
Prescribers and pharmacists should adhere to brand prescribing and dispensing of clozapine in order to prevent the disruption to effective monitoring that may be caused if patients switch brands.
Furthermore, in order to protect patient safety, at any one time patients should only be prescribed one brand of clozapine and only registered with the monitoring service connected to that brand.
Advice on Monitoring Clozapine Blood Levels
Blood clozapine level monitoring is advised in certain clinical situations such as when a patient ceases smoking or switches to e-cigarettes, when concomitant medicines may interact to increase clozapine blood levels, where poor clozapine metabolism is suspected, when a patient has pneumonia or other serious infection and in the event of onset of symptoms suggestive of toxicity (see section 4.4).
For further information regarding Denzapine and the Denzapine Monitoring Service please call 0333 200 4141 (UK).
[1] De la Chapelle A, et al. Clozapine-induced agranulocytosis: a genetic and epidemiologic study. Hum Genet, 1977. 37: p. 183-194.
[2] Denzapine Monitoring Service, data on file.
Denzapine can cause agranulocytosis. Its use should be limited to patients:
• with schizophrenia who are non-responsive to or intolerant of antipsychotic drug treatment, or with psychosis in Parkinson's disease when other treatment strategies have failed (see section 4.1)
• who have initially normal leucocyte findings (white blood cell count of ≥3500/mm3 (≥3.5 x 109 /L), and an absolute neutrophil count (ANC) of ≥2000/mm3 (≥2.0 x 109 /L)), and
• in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) can be performed as follows: weekly during the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine (see section 4.4).
Prescribing physicians should comply fully with the required safety measures. At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia (see section 4.4).
Denzapine must be dispensed under strict medical supervision in accordance with official recommendations (see section 4.4).
Myocarditis
Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. The increased risk of myocarditis is greatest in the first 2 months of treatment. Fatal cases of cardiomyopathy have also been reported rarely (see section 4.4).
Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first 2 months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction (see section 4.4).
If myocarditis or cardiomyopathy are suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist (see section 4.4).
Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine (see section 4.3 and 4.4).
2. |
Denzapine 200mg Tablets | Qualitative and quantitative composition | For Denzapine 200 mg Tablets: Each tablet contains 200 mg Clozapine.
Excipient(s) with known effect
One tablet contains 260 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. |
Denzapine 200mg Tablets | Pharmaceutical form | Tablet
For Denzapine 200 mg Tablets: Large, oval-shaped yellow tablets with '200' on one side and a breakline on the other side.
The breakline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. |
Denzapine 200mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment-resistant schizophrenia
Denzapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.
Psychosis during the course of Parkinson's disease
Denzapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed.
4.2 |
Denzapine 200mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage must be adjusted individually. For each patient the lowest effective dose should be used. For doses not realisable/practicable with this strength, other strengths of this medicinal product are available. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure, and sedation.
Initiation of Denzapine treatment must be restricted to those patients with a WBC count ≥3500/mm3 (3.5 x 109/L) and an absolute neutrophil count (ANC) ≥2000/mm3 (2.0 x 109/L) within standardised normal limits.
Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacodynamic and pharmacokinetic interactions with Denzapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5).
Switching from a previous antipsychotic therapy to Denzapine
It is generally recommended that Denzapine should not be used in combination with other antipsychotics, including depot preparations, which may have a myelosuppressive effect. When Denzapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards.
The following dosages are recommended:
Treatment-resistant schizophrenic patients
Starting therapy
12.5 mg (half a 25 mg tablet) once or twice on the first day, followed by one or two 25 mg tablets on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals.
Therapeutic dose range
In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. For maintenance dose, see below.
Maximum dose
To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e. not exceeding 100 mg) are permissible up to 900 mg/day. The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind.
Maintenance dose
After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may be appropriate.
Ending therapy
In the event of planned termination of Denzapine therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea (see section 4.4).
Re-starting therapy
In patients in whom the interval since the last dose of Denzapine exceeds 2 days, treatment should be re-initiated with 12.5 mg (half a 25 mg tablet) given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see section 4.4), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.
Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed
Starting therapy
The starting dose must not exceed 12.5 mg/day (half a 25 mg tablet), taken in the evening. Subsequent dose increases must be by 12.5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.
Therapeutic dose range
The mean effective dose is usually between 25 and 37.5 mg/day. In the event that treatment for at least one week with a dose of 50 mg fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week.
Maximum dose
The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of 100 mg/day must never be exceeded.
Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.
Maintenance dose
When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach results in the recurrence of psychotic symptoms, Denzapine dosage may be increased by increments of 12.5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see above).
Ending therapy
A gradual reduction in dose by steps of 12.5 mg over a period of at least one week (preferably two) is recommended.
Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis as indicated in section 4.4. In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
Special populations
Hepatic impairment
Patients with hepatic impairment should receive Denzapine with caution along with regular monitoring of liver function tests (see section 4.4).
Paediatric population
No paediatric studies have been performed. The safety and efficacy of Denzapine in children and adolescents under the age of 16 years have not yet been established. No data are available. It should not be used in this group until further data become available.
Patients 60 years of age and older
Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day.
Method of Administration
Oral
4.3 |
Denzapine 200mg Tablets | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• This product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Patients unable to undergo regular blood tests.
• History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
• History of clozapine-induced agranulocytosis.
• Denzapine treatment must not be started concurrently with drugs known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged.
• Impaired bone marrow function.
• Uncontrolled epilepsy.
• Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.
• Circulatory collapse and/or CNS depression of any cause.
• Severe renal or cardiac disorders (e.g. myocarditis).
• Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
• Paralytic ileus.
4.4 |
Denzapine 200mg Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Agranulocytosis
Denzapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring. The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations.
Because of the risks associated with Denzapine, its use is limited to patients in whom therapy is indicated as set out in section 4.1 and:
• who have initially normal leucocyte findings (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L), and
• in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least 4-week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine.
Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that might include an ECG, and the patient treated only if the expected benefits clearly outweigh the risks (see Section 4.3). The treating physician should consider performing a pre-treatment ECG.
Prescribing physicians must comply fully with the required safety measures.
Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts.
Immediate discontinuation of Denzapine is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109 /L) or the ANC is less than 1500/mm3 (1.5 x 109 /L) at any time during Denzapine treatment. Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Denzapine.
At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia. Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting Denzapine.
Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on Denzapine with the agreement of a haematologist.
White Blood Cell (WBC) Counts and Absolute Neutrophil Count (ANC) Monitoring
WBC and differential blood counts must be performed within 10 days prior to initiating Denzapine treatment to ensure that only patients with normal WBC counts (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L)) will receive the drug. After the start of Denzapine treatment the WBC count and ANC must be monitored weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least at four-week intervals thereafter.
Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine or until haematological recovery has occurred (see below Low WBC count/ANC). At each consultation, the patient must be reminded to contact the treating physician immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.
Low WBC count/ANC
If, during Denzapine therapy, either the WBC count falls to between 3500/mm3 (3.5 x 109/L) and 3000/mm3 (3.0 x 109/L) or the ANC falls to between 2000/mm3 (2.0 x 109/L) and 1500/mm3 (1.5 x 109/L), haematological evaluations must be performed at least twice weekly until the patient's WBC count and ANC stabilise within the range 3000-3500/mm3 (3.0 - 3.5 x 109/L) and 1500 - 2000/mm3 (1.5 - 2.0 x 109/L), respectively, or higher.
Immediate discontinuation of Denzapine treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109/L) or the ANC is less than 1500/mm3 (1.5 x 109/L) during Denzapine treatment. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Confirmation of the haematological values is recommended by performing two blood counts on two consecutive days; however, Denzapine should be discontinued after the first blood count.
Following discontinuation of Denzapine, haematological evaluation is required until haematological recovery has occurred.
Table 1
Blood cell count
Action required
WBC/mm3 (/L)
ANC/mm3 (/L)
≥3500 (≥3.5 x 109)
≥2000 (≥2.0 x 109)
Continue Denzapine treatment
≥3000 to <3500 (≥3.0 x 109 to <3.5 x 109)
≥1500 to <2000 (≥1.5 x 109 to <2.0 x 109)
Continue Denzapine treatment, sample blood twice weekly until counts stabilise or increase
<3000 (<3.0 x 109)
<1500 (<1.5 x 109)
Immediately stop Denzapine treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.
If Denzapine has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0 x 109/L) occurs or the ANC falls below 1000/mm3 (1.0 x 109/L), the management of this condition must be guided by an experienced haematologist.
Discontinuation of therapy for haematological reasons
Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies (see above) must not be re-exposed to Denzapine.
Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent the patient being accidentally rechallenged in the future.
Discontinuation of therapy for other reasons
Patients who have been on Denzapine for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If Denzapine treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment and the dose should be re-titrated (see section 4.2).
Other precautions
Eosinophilia
In the event of eosinophilia, discontinuation of Denzapine is recommended if the eosinophil count rises above 3000/mm3 (3.0 x 109/L); therapy should be restarted only after the eosinophil count has fallen below 1000/mm3 (1.0 x 109/L).
Thrombocytopenia
In the event of thrombocytopenia, discontinuation of Denzapine therapy is recommended if the platelet count falls below 50 000/mm3 (50 x 109/L).
Cardiovascular disorders
Orthostatic hypotension, with or without syncope, can occur during Denzapine treatment. Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur with concurrent use of benzodiazepines or any other psychotropic agent (see section 4.5) and during initial titration in association with rapid dose escalation; on very rare occasions they may occur even after the first dose. Therefore, patients commencing Denzapine treatment require close medical supervision. Monitoring of standing and supine blood pressure is necessary during the first weeks of treatment in patients with Parkinson's disease.
Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases of myocarditis have been fatal.
Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with clozapine use; these reports also include fatalities. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist.
In patients who are diagnosed with cardiomyopathy while on clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see section 4.8).
Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to Denzapine.
Myocardial infarction
In addition, there have been post marketing reports of myocardial infarction which may be fatal. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.
QT interval prolongation
As with other antipsychotics, caution should be exercised in patients with cardiovascular disease or a family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval.
Cerebrovascular Adverse Events
An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Denzapine should be used with caution in patients with risk factors for stroke.
Risk of thromboembolism
Since Denzapine may be associated with thromboembolism, immobilisation of patients should be avoided.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Denzapine and preventive measures undertaken.
Seizures
Patients with a history of epilepsy should be closely observed during Denzapine therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced (see section 4.2) and, if necessary, an anti-convulsant treatment should be initiated.
Anticholinergic effects
Denzapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction, paralytic ileus, megacolon and intestinal infarction ischaemia (see section 4.8). On rare occasions these cases have been fatal. Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that constipation is recognised and actively treated.
Fever
During Denzapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign. Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infection or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. If the diagnosis of NMS is confirmed, Denzapine must be discontinued immediately and appropriate medical measures should be administered.
Falls
Clozapine may cause seizures, somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions or medications that could exacerbate these effects, fall risk assessments must be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Metabolic changes
Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycaemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific profile.
Hyperglycaemia
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. A mechanism for this possible association has not yet been determined. Cases of severe hyperglycaemia with ketoacidosis or hyperosmolar coma have been reported very rarely in patients with no prior history of hyperglycaemia, some of which have been fatal. When follow-up data were available, discontinuation of clozapine resulted mostly in resolution of the impaired glucose tolerance, and reinstitution of clozapine resulted in its reoccurrence. Patients with an established diagnosis of diabetes mellitis who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. The discontinuation of clozapine should be considered in patients where active medical management of their hyperglycaemia has failed.
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.
Weight gain
Weight gain has been observed with atypical antipsychotic use, including Denzapine. Clinical monitoring of weight is recommended.
Rebound, withdrawal effects
Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea.
Special populations
Hepatic impairment
Patients with stable pre-existing liver disorders may receive Denzapine, but need regular liver function tests. Liver function tests should be performed in patients in whom symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, develop during Denzapine therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if symptoms of jaundice occur, treatment with Denzapine must be discontinued. It may be resumed (see “Re-starting therapy” under section 4.2) only when the results of liver function tests are normal. In such cases, liver function should be closely monitored after re-introduction of Denzapine.
Patients aged 60 years and older
Initiation of treatment in patients aged 60 years and older is recommended at a lower dose (see section 4.2).
Orthostatic hypotension can occur with Denzapine treatment and there have been reports of tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with compromised cardiovascular function, may be more susceptible to these effects.
Patients aged 60 years and older may also be particularly susceptible to the anticholinergic effects of Denzapine, such as urinary retention and constipation.
Increased mortality in older people with dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Denzapine is not approved for the treatment of dementia-related behavioural disturbances.
4.5 |
Denzapine 200mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Contraindication of concomitant use
Drugs known to have a substantial potential to depress bone marrow function must not be used concurrently with Denzapine (see section 4.3). These include co-trimoxazole, chloramphenicol, sulphonamides, pyrazolone analgesics e.g. phenylbutazone, penicillamine, carbamazepine or cytotoxic agents.
Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Denzapine because these cannot be rapidly removed from the body in situations where this may be required, e.g. neutropenia (see section 4.3).
Alcohol should not be used concomitantly with Denzapine due to possible potentiation of sedation.
Precautions including dose adjustment
Denzapine may enhance the central effects of CNS depressants such as narcotics, antihistamines, and benzodiazepines. Particular caution is advised when Denzapine therapy is initiated in patients who are receiving a benzodiazepine or any other psychotropic drug. These patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound and may lead to cardiac and/or respiratory arrest. It is not clear whether cardiac or respiratory collapse can be prevented by dose adjustment.
Because of the possibility of additive effects, caution is essential in the concomitant administration of drugs possessing anticholinergic, hypotensive, or respiratory depressant effects.
Owing to its anti-alpha-adrenergic properties, Denzapine may reduce the blood-pressure-increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor effect of epinephrine.
Concomitant administration of drugs known to inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for CYP 1A2 inhibitors such as caffeine (see below), perazine, and the selective serotonin reuptake inhibitor fluvoxamine. Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine and to a lesser degree sertraline are CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP 3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin, and protease inhibitors are unlikely, although some have been reported. Hormonal contraceptives (including combinations of estrogen and progesterone or progesterone only) are CYP 1A2, CYP 3A4 and CYP 2C19 inhibitors. Therefore initiation or discontinuation of hormonal contraceptives may require dose adjustment of clozapine according to the individual medical need. Because the plasma concentration of clozapine is increased by caffeine intake and decreased by nearly 50% following a 5-day caffeine-free period, dosage changes of clozapine may be necessary when there is a change in caffeine-drinking habit. In cases of sudden cessation of smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.
Cases have been reported of an interaction between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. The nature of this interaction has not been fully elucidated.
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine, leading to reduced efficacy. Drugs known to induce the activity of cytochrome P450 enzymes and with reported interactions with clozapine include, for instance, carbamazepine (not to be used concomitantly with clozapine, due to its myelosuppresive potential), phenytoin and rifampicin. Known inducers of CYP1A2 such as omeprazole, may lead to decreased clozapine levels. The potential for reduced efficacy of clozapine should be considered when it is used in combination with these drugs.
Others
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Denzapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
Caution is called for in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic antidepressants, phenothiazines and type IC anti-arrhythmics, which are known to bind to cytochrome P450 2D6, no clinically relevant interactions have been observed thus far.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QT interval, because they may increase the risk of ventricular arrhythmias, including Torsades de pointes. Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide, sertindole and haloperidol), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to cause electrolyte imbalance. Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.
An outline of drug interactions believed to be most important with Denzapine is given in Table 2 below (this is not an exhaustive list).
Table 2: Reference to the most common drug interactions with Denzapine
Drug
Interactions
Comments
Bone marrow suppressants (e.g. carbamazapine, chloramphenicol, sulphonamides (e.g. co-trimoxazole), pyrazolone analgesics (e.g. phenylbutazone), penicillamine, cytotoxic agents and long-acting depot injections of antipsychotics
Interact to increase the risk and/or severity of bone marrow suppression
Denzapine must not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see section 4.3)
Benzodiazepines
Concomitant use may increase risk of circulatory collapse, which may lead to cardiac and/or respiratory arrest
Whilst the occurrence is rare, caution is advised when using these drugs together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when Denzapine is added to an established benzodiazepine regimen.
Anticholinergics
Denzapine potentiates the action of these drugs through additive anticholinergic activity
Observe patients for anticholinergic side – effects, e.g. constipation, especially when using to help control hypersalivation
Antihypertensives
Denzapine can potentiate the hypotensive effects of these drugs due to its sympathomimetic antagonistic effects
Caution is advised if Denzapine is used concomitantly with antihypertensive agents. Patients should be advised of the risk of hypotension, especially during the period of initial dose titration
Alcohol, MAOIs, CNS depressants, including narcotics and benzodiazepines
Enhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these drugs
Caution is advised if Denzapine is used concomitantly with other CNS active agents. Advise patients of the possible additive sedative effects and caution them not to drive or operate machinery
Highly protein bound drugs
(e.g. warfarin and digoxin)
Denzapine may cause an increase in plasma concentration of these drugs due to displacement from plasma proteins
Patients should be monitored for the occurrence of side effects associated with these drugs, and doses of the protein bound drug adjusted, if necessary
Phenytoin
Addition of phenytoin to Denzapine drug regimen may cause a decrease in the clozapine plasma concentrations
If phenytoin must be used, the patient should be monitored closely for a worsening or recurrence of psychotic symptoms
Lithium
Concomitant use can increase the risk of development of neuroleptic malignant syndrome (NMS)
Observe for signs and symptoms of NMS
CYP1A2 inducing substances (e.g. omeprazole)
Concomitant use may decrease clozapine levels
Potential for reduced efficacy of clozapine should be considered.
CYP1A2 inhibiting substances (e.g. fluvoxamine, caffeine, ciprofloxacin) , perazine, or hormonal contraceptives (CYP1A2, CYP3A4, CYP2C19)
Concomitant use may increase clozapine levels
Potential for increase in adverse effects. Care is also required upon cessation of concomitant CYP1A2 or CYP3A4 inhibiting medications as there will be a decrease in clozapine levels. The effect of CYP2C19 inhibition will be minimal.
4.6 |
Denzapine 200mg Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
For clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.
Neonates exposed to antipsychotics (including Denzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast-feeding
Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving Denzapine should not breast-feed.
Fertility
Limited data available on the effects of clozapine on human fertility are inconclusive. In male and female rats, clozapine did not affect fertility when administered up to 40mg/kg, corresponding to a human equivalence dose of 6.4mg/kg, or approximately a third of the maximum permissible human dose.
Women of child-bearing potential
A return to normal menstruation may occur as a result of switching from other antipsychotics to Denzapine. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
4.7 |
Denzapine 200mg Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Denzapine has a major influence on the ability to drive and use machines.
Owing to the ability of Denzapine to cause sedation and lower the seizure threshold, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.
4.8 |
Denzapine 200mg Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. An important exception is its propensity to cause agranulocytosis (see section 4.4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson's disease in cases where standard treatment has failed. While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse events, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.
The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see section 4.4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation.
Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients (from 7.1 to 15.6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leucopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder.
Blood and lymphatic system
Development of granulocytopenia and agranulocytosis is a risk inherent to Denzapine treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see section 4.4). Table 3 below summarises the estimated incidence of agranulocytosis for each Denzapine treatment period.
Table 3: Estimated incidence of agranulocytosis1
Treatment period
Incidence of agranulocytosis per 100,000 person-weeks2 of observation
Weeks 0 - 18
32.0
Weeks 19 - 52
2.3
Weeks 53 and higher
1.8
1 From the UK Patient Monitoring Service lifetime registry experience between 1989 and 2001.
2 Person-time is the sum of individual units of time that the patients in the registry have been exposed to clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000 = 100,000), or in 200 patients who were in the registry for 500 weeks (200*500 = 100,000) before experiencing agranulocytosis.
The cumulative incidence of agranulocytosis in the UK since monitoring began is (0 - 11.6 years between 1989 and 2001) is 0.78%. The majority of cases (approximately 70%) occur within the first 18 weeks of treatment.
Metabolic and Nutritional Disorders
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. On very rare occasions, severe hyperglycaemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported in patients on clozapine treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of clozapine and in a few cases hyperglycaemia recurred when treatment was reinitiated. Although most patients had risk factors for non-insulin-dependent diabetes mellitus, hyperglycaemia has also been documented in patients with no known risk factors (see section 4.4).
Nervous System Disorders
The very common adverse events observed include drowsiness/sedation, and dizziness.
Denzapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures. These symptoms are more likely to occur with rapid dose increases and in patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant drugs the possibility of a pharmacokinetic interaction should be considered. In rare cases, patients treated with Denzapine may experience delirium.
Very rarely, tardive dyskinesia has been reported in patients on clozapine who had been treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other antipsychotics have improved on clozapine.
Cardiac Disorders
Tachycardia and postural hypotension with or without syncope may occur, especially in the initial weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and magnitude of dose titration. Circulatory collapse as a result of profound hypotension, in particular related to aggressive titration of the drug, with the possible serious consequences of cardiac or pulmonary arrest, has been reported with clozapine.
A minority of clozapine-treated patients experience ECG changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which normalise after discontinuation of clozapine. The clinical significance of these changes is unclear. However, such abnormalities have been observed in patients with myocarditis, which should therefore be considered.
Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion and myocarditis have been reported, some of which have been fatal. The majority of the cases of myocarditis occurred within the first 2 months of initiation of therapy with clozapine. Cardiomyopathy generally occurred later in the treatment.
Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known, however, whether eosinophilia is a reliable predictor of carditis.
Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest, palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms.
Very rare events of ventricular tachycardia and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine.
Sudden, unexplained deaths are known to occur among psychiatric patients who receive conventional antipsychotic medication but also among untreated psychiatric patients. Such deaths have been reported very rarely in patients receiving clozapine.
Vascular Disorders
Rare cases of thromboembolism have been reported.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs. The frequency is unknown.
Respiratory System
Respiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see sections 4.4 and 4.5).
Gastrointestinal System
Constipation and hypersalivation have been observed very frequently, and nausea and vomiting frequently. Very rarely ileus may occur (see section 4.4). Rarely Denzapine treatment may be associated with dysphagia. Aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.
Hepatobiliary Disorders
Transient, asymptomatic elevations of liver enzymes and rarely, hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, Denzapine should be discontinued (see section 4.4). In rare cases, acute pancreatitis has been reported.
Renal Disorders
Isolated cases of acute interstitial nephritis have been reported in association with Denzapine therapy.
Reproductive and Breast Disorders
Very rare reports of priapism have been received.
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6) has been reported. The frequency of this is not known.
General Disorders
Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving clozapine either alone or in combination with lithium or other CNS-active agents.
Acute withdrawal reactions have been reported (see section 4.4).
Tabulated list of adverse reactions
The table below (Table 4) summarises the adverse reactions accumulated from reports made spontaneously and during clinical studies.
Table 4: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical trial reports
Adverse reactions are ranked under headings of frequency, using the following convention: Very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Infections and infestations
Not known
Sepsis*
Blood and lymphatic system disorders
Common
Leucopenia/decreased WBC/neutropenia, eosinophilia, leucocytosis
Uncommon
Agranulocytosis
Rare
Anaemia
Very rare
ThrombocytopeniaThrombocythaemia
Immune system disorders
Not known
Angioedema*, leucocytoclastic vasculitis*
Endocrine disorders
Not known
Pseudophaeochromocytoma*
Metabolism and nutrition disorders
Common
Weight gain
Rare
Impaired glucose tolerance, diabetes mellitus, obesity*
Very rare
Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia
Psychiatric disorders
Common
Dysarthria
Uncommon
Dysphemia
Rare
Restlessness, agitation
Nervous system disorders
Very common
Drowsiness/sedation, dizziness
Common
Blurred vision, headache, tremor, rigidity, akathisia, extra pyramidal symptoms, seizures/convulsions/myoclonic jerks
Rare
Confusion, delirium
Very rare
Tardive dyskinesia, obsessive compulsive disorder
Not known
Cholinergic syndrome (after abrupt withdrawal)*, EEG changes*, pleurothotonus*, restless leg syndrome*
Cardiac disorders
Very common
Tachycardia
Common
ECG changes
Rare
Circulatory collapse, Ventricular arrhythmias (VF, VT), myocarditis, pericarditis/pericardial effusion
Very rare
Cardiomyopathy, cardiac arrest, QT prolongation, Torsades de pointes
Not known
Myocardial infarction which may be fatal*, chest pain/angina pectoris*, atrial fibrillation*, palpitations*, mitral valve incompetence associated with clozapine related cardiomyopathy*
Vascular disorders
Common
Hypertension, postural hypotension, syncope
Rare
Thromboembolism
Not known
Hypotension*, Venous thromboembolism
Respiratory, thoracic and mediastinal disorders
Rare
Aspiration of ingested food, pneumonia and lower respiratory tract infection which may be fatal, sleep apnoea syndrome*
Very rare
Respiratory depression/arrest
Not known
Pleural effusion*, nasal congestion*
Gastrointestinal disorders
Very common
Constipation, hypersalivation
Common
Nausea, vomiting, anorexia, dry mouth
Rare
Dysphagia
Very rare
Parotid gland enlargement, intestinal obstruction/paralytic ileus/faecal impaction
Not known
Megacolon*, intestinal infarction/ischaemia*, diarrhoea*, abdominal discomfort/heartburn/dyspepsia*, colitis*
Hepatobiliary disorders
Common
Elevated liver enzymes
Rare
Hepatitis, cholestatic jaundice, pancreatitis
Very rare
Fulminant hepatic necrosis
Not known
Hepatic steatosis*, hepatic necrosis*, hepatotoxicity*, hepatic fibrosis*, hepatic cirrhosis*, liver disorders including those hepatic events leading to life-threatening consequences such as liver injury (hepatic, cholestatic and mixed), liver failure which may be fatal, and liver transplant*.
Skin and subcutaneous tissue disorders
Very rare
Skin reactions
Not known
Pigmentation disorder*
Musculoskeletal and connective tissue disorders
Not known
Rhabdomyolysis*, muscle weakness*, muscle spasms*, muscle pain*, systemic lupus erythematous*
Renal and urinary disorders
Common
Urinary incontinence, urinary retention
Very rare
Interstitial nephritis
Not known
Renal failure*, Nocturnal enuresis*
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Very rare
Priapism
Not known
Retrograde ejaculation*
General disorders and administration site conditions
Common
Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation
Uncommon
Neuroleptic malignant syndrome
Very rare
Sudden unexplained death
Not known:
Polyserositis*
Investigations
Rare
Increased CPK
Injury, poisoning and procedural complications
Uncommon
Falls (associated with clozapine-induced seizures, somnolence, postural hypotension, motor and sensory instability)*
* Adverse drug reactions derived from post-marketing experience via spontaneous case reports and literature cases for the drug substance, Clozapine.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme: https://yellowcard.mhra.gov.uk/
Or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Denzapine 200mg Tablets | Clinical particulars - Overdose | Overdose
In cases of acute intentional or accidental clozapine overdosage for which information on the outcome is available, mortality to date is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000 mg. There have been reports of patients recovering from an overdose in excess of 10 000 mg. However, in a few adult individuals, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 to 200 mg resulted in strong sedation or coma without being lethal.
Signs and symptoms
Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extra pyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.
Treatment
There are no specific antidotes for Denzapine.
Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a 'reverse epinephrine' effect.
Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.
5. Pharmacological properties
5.1 |
Denzapine 200mg Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The absorption of orally administered Denzapine is 90 to 95%; neither the rate nor the extent of absorption is influenced by food.
Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.
Distribution
In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 L/kg. Clozapine is approximately 95% bound to plasma proteins.
Biotransformation/metabolism
Clozapine is almost completely metabolised before excretion by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Of the main metabolites only the desmethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of short duration.
Elimination
Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). After single doses of 75 mg the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days. Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.
Linearity/non-linearity
Dosage increases from 37.5 mg to 75 mg and 150 mg given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.
5.3 |
Denzapine 200mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see section 4.6).
6. |
Denzapine 200mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Micro-Crystalline Cellulose
Lactose monohydrate
Povidone
Sodium Starch Glycolate A
Magnesium Stearate
6.2 |
Denzapine 200mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Denzapine 200mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
Blister packs 4 years
HDPE bottles 4 years
6.4 |
Denzapine 200mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 30°C. Store in the original packaging. Keep in the outer carton to protect from light.
6.5 |
Denzapine 200mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Transparent PVC/PVDC/ Aluminium Foil Blister Strips in a cardboard carton containing 20 or 50 tablets.
Transparent PVC/PVDC/PE/ Aluminium Foil Blister Strips in a cardboard carton containing 20 or 50 tablets.
HDPE bottles with polypropylene child-resistant, tamper-evident cap containing 50 or 100 tablets.
Not all pack sizes may be marketed.
6.6 |
Denzapine 200mg Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Denzapine 200mg Tablets | Marketing authorisation holder | Britannia Pharmaceuticals Limited
200 Longwater Avenue
Green Park
Reading
Berkshire
RG2 6GP
UK
8. Marketing authorisation number(s)
PL 04483/0070
9. |
Denzapine 200mg Tablets | Date of first authorisation/renewal of the authorisation | 31 January 2012
10. |
Denzapine 25mg Tablets | Name of the medicinal product | Denzapine® 25 mg Tablets
UK: Denzapine Official Recommendations
As a consequence of a recent European regulatory initiative, the Denzapine Summary of Product Characteristics (SmPC) has been harmonised across Europe. The SmPC states that blood monitoring should be carried out in accordance with national-specific official recommendations. These are reproduced below.
The Denzapine Monitoring Service (DMS) was developed in order to manage the risk of agranulocytosis associated with clozapine. It is available 24 hours a day. When a monitoring service is not used, evidence suggests a mortality rate from agranulocytosis of 0.3%[1]. This is compared to a mortality rate when clozapine is used in conjunction with a Monitoring Service, of 0.01%[2].
The Denzapine Monitoring Service provides centralised monitoring of leucocyte and neutrophil counts which is a mandatory requirement for all patients in the UK and Ireland who are treated with Denzapine. The use of Denzapine is restricted to patients who are registered with the Denzapine Monitoring Service. In addition to registering their patients, prescribing physicians must register themselves and a nominated pharmacist with the Denzapine Monitoring Service. All Denzapine-treated patients must be under the supervision of an appropriate specialist and supply of Denzapine is restricted to hospital and retail pharmacies registered with the Denzapine Monitoring Service. Denzapine is not sold to, or distributed through wholesalers.
The patient's white cell count with a differential count must be monitored:
• At least weekly for the first 18 weeks of treatment
• At least at 2 week intervals between weeks 18 and 52
• After 1 year of treatment with stable blood counts (green range), patients may be monitored at least at 4 week intervals
• Monitoring must continue throughout treatment and for at least 4 weeks after discontinuation
If the blood result of a patient taking Denzapine is below the normal range (See Section 4.4), Britannia will contact the physician and pharmacist registered to the patient on the Denzapine Monitoring Service to inform them.
The Denzapine Monitoring Service maintains a database which includes all patients who have developed abnormal leucocyte or neutrophil findings and who should not be re-exposed to Denzapine or any other brand of clozapine.
Prescribers and pharmacists should adhere to brand prescribing and dispensing of clozapine in order to prevent the disruption to effective monitoring that may be caused if patients switch brands.
Furthermore, in order to protect patient safety, at any one time patients should only be prescribed one brand of clozapine and only registered with the monitoring service connected to that brand.
Advice on Monitoring Clozapine Blood Levels
Blood clozapine level monitoring is advised in certain clinical situations such as when a patient ceases smoking or switches to e-cigarettes, when concomitant medicines may interact to increase clozapine blood levels, where poor clozapine metabolism is suspected, when a patient has pneumonia or other serious infection and in the event of onset of symptoms suggestive of toxicity (see section 4.4).
For further information regarding Denzapine and the Denzapine Monitoring Service please call 0333 200 4141 (UK)
[1] De la Chapelle A, et al. Clozapine-induced agranulocytosis: a genetic and epidemiologic study. Hum Genet, 1977. 37: p. 183-194.
[2] Denzapine Monitoring Service, data on file.
Denzapine can cause agranulocytosis. Its use should be limited to patients:
• with schizophrenia who are non-responsive to or intolerant of antipsychotic drug treatment, or with psychosis in Parkinson's disease when other treatment strategies have failed (see section 4.1)
• who have initially normal leucocyte findings (white blood cell count of ≥3500/mm3 (≥3.5 x 109 /L), and an absolute neutrophil count (ANC) of ≥2000/mm3 (≥2.0 x 109 /L)), and
• in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) can be performed as follows: weekly during the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine (see section 4.4).
Prescribing physicians should comply fully with the required safety measures. At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia (see section 4.4).
Denzapine must be dispensed under strict medical supervision in accordance with official recommendations (see section 4.4).
Myocarditis
Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. The increased risk of myocarditis is greatest in the first 2 months of treatment. Fatal cases of cardiomyopathy have also been reported rarely (see section 4.4).
Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first 2 months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction (see section 4.4).
If myocarditis or cardiomyopathy are suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist (see section 4.4).
Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine (see section 4.3 and 4.4).
2. |
Denzapine 25mg Tablets | Qualitative and quantitative composition | For Denzapine 25 mg Tablets: Each tablet contains 25 mg Clozapine.
Excipient(s) with known effect
One tablet contains 32.44 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. |
Denzapine 25mg Tablets | Pharmaceutical form | Tablet
For Denzapine 25 mg Tablets: Round flat yellow bevel edged tablets embossed with “25” over a pressure sensitive breakline on one face, the other face plain. The tablet can be divided into equal halves.
4. |
Denzapine 25mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment-resistant schizophrenia
Denzapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.
Psychosis during the course of Parkinson's disease
Denzapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed.
4.2 |
Denzapine 25mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage must be adjusted individually. For each patient the lowest effective dose should be used. For doses not realisable/practicable with this strength, other strengths of this medicinal product are available. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure, and sedation.
Initiation of Denzapine treatment must be restricted to those patients with a WBC count ≥ 3500/mm3 (3.5 x 109/L) and an absolute neutrophil count (ANC) ≥2000/mm3 (2.0 x 109/L) within standardised normal limits.
Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacodynamic and pharmacokinetic interactions with Denzapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5).
Switching from a previous antipsychotic therapy to Denzapine
It is generally recommended that Denzapine should not be used in combination with other antipsychotics, including depot preparations, which may have a myelosuppressive effect. When Denzapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards.
The following dosages are recommended:
Treatment-resistant schizophrenic patients
Starting therapy
12.5 mg (half a 25 mg tablet) once or twice on the first day, followed by one or two 25 mg tablets on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals.
Therapeutic dose range
In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. For maintenance dose, see below.
Maximum dose
To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e. not exceeding 100 mg) are permissible up to 900 mg/day. The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind.
Maintenance dose
After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may be appropriate.
Ending therapy
In the event of planned termination of Denzapine therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation is necessary (e.g. because of leucopoenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea (see section 4.4).
Re-starting therapy
In patients in whom the interval since the last dose of Denzapine exceeds 2 days, treatment should be re-initiated with 12.5 mg (half a 25 mg tablet) given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see section 4.4), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.
Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed
Starting therapy
The starting dose must not exceed 12.5 mg/day (half a 25 mg tablet), taken in the evening. Subsequent dose increases must be by 12.5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.
Therapeutic dose range
The mean effective dose is usually between 25 and 37.5 mg/day. In the event that treatment for at least one week with a dose of 50 mg fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week.
Maximum dose
The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of 100 mg/day must never be exceeded.
Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.
Maintenance dose
When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach results in the recurrence of psychotic symptoms, Denzapine dosage may be increased by increments of 12.5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see above).
Ending therapy
A gradual reduction in dose by steps of 12.5 mg over a period of at least one week (preferably two) is recommended.
Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis as indicated in section 4.4. In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
Special populations
Hepatic impairment
Patients with hepatic impairment should receive Denzapine with caution along with regular monitoring of liver function tests (see section 4.4).
Paediatric population
No paediatric studies have been performed. The safety and efficacy of Denzapine in children and adolescents under the age of 16 years have not yet been established. No data are available. It should not be used in this group until further data become available.
Patients 60 years of age and older
Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day.
Method of Administration
Oral
4.3 |
Denzapine 25mg Tablets | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• This product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Patients unable to undergo regular blood tests.
• History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
• History of clozapine-induced agranulocytosis.
• Denzapine treatment must not be started concurrently with drugs known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged.
• Impaired bone marrow function.
• Uncontrolled epilepsy.
• Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.
• Circulatory collapse and/or CNS depression of any cause.
• Severe renal or cardiac disorders (e.g. myocarditis).
• Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
• Paralytic ileus.
4.4 |
Denzapine 25mg Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Agranulocytosis
Denzapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring. The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations.
Because of the risks associated with Denzapine, its use is limited to patients in whom therapy is indicated as set out in section 4.1 and:
• who have initially normal leucocyte findings (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L), and
• in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least 4-week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine.
Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that might include an ECG, and the patient treated only if the expected benefits clearly outweigh the risks (see section 4.3). The treating physician should consider performing a pre-treatment ECG.
Prescribing physicians must comply fully with the required safety measures.
Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts.
Immediate discontinuation of Denzapine is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109 /L) or the ANC is less than 1500/mm3 (1.5 x 109 /L) at any time during Denzapine treatment. Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Denzapine.
At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia. Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting Denzapine.
Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on Denzapine with the agreement of a haematologist.
White Blood Cell (WBC) Counts and Absolute Neutrophil Count (ANC) Monitoring
WBC and differential blood counts must be performed within 10 days prior to initiating Denzapine treatment to ensure that only patients with normal WBC counts (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L)) will receive the drug. After the start of Denzapine treatment the WBC count and ANC must be monitored weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least at four-week intervals thereafter.
Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine or until haematological recovery has occurred (see below Low WBC count/ANC). At each consultation, the patient must be reminded to contact the treating physician immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.
Low WBC count/ANC
If, during Denzapine therapy, either the WBC count falls to between 3500/mm3 (3.5 x 109/L) and 3000/mm3 (3.0 x 109/L) or the ANC falls to between 2000/mm3 (2.0 x 109/L) and 1500/mm3 (1.5 x 109/L), haematological evaluations must be performed at least twice weekly until the patient's WBC count and ANC stabilise within the range 3000-3500/mm3 (3.0 - 3.5 x 109/L) and 1500 - 2000/mm3 (1.5 - 2.0 x 109/L), respectively, or higher.
Immediate discontinuation of Denzapine treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109/L) or the ANC is less than 1500/mm3 (1.5 x 109/L) during Denzapine treatment. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Confirmation of the haematological values is recommended by performing two blood counts on two consecutive days; however, Denzapine should be discontinued after the first blood count.
Following discontinuation of Denzapine, haematological evaluation is required until haematological recovery has occurred.
Table 1
Blood cell count
Action required
WBC/mm3 (/L)
ANC/mm3 (/L)
≥3500 (≥3.5 x 109)
≥2000 (≥2.0 x 109)
Continue Denzapine treatment
≥3000 to <3500
(≥3.0 x 109 to <3.5 x 109)
≥1500 to <2000
(≥1.5 x 109 to <2.0 x 109)
Continue Denzapine treatment, sample blood twice weekly until counts stabilise or increase
<3000 (<3.0 x 109)
<1500 (<1.5 x 109)
Immediately stop Denzapine treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.
If Denzapine has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0 x 109/L) occurs or the ANC falls below 1000/mm3 (1.0 x 109/L), the management of this condition must be guided by an experienced haematologist.
Discontinuation of therapy for haematological reasons
Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies (see above) must not be re-exposed to Denzapine.
Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent the patient being accidentally rechallenged in the future.
Discontinuation of therapy for other reasons
Patients who have been on Denzapine for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If Denzapine treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment and the dose should be re-titrated (see section 4.2).
Other precautions
Eosinophilia
In the event of eosinophilia, discontinuation of Denzapine is recommended if the eosinophil count rises above 3000/mm3 (3.0 x 109/L); therapy should be restarted only after the eosinophil count has fallen below 1000/mm3 (1.0 x 109/L).
Thrombocytopenia
In the event of thrombocytopenia, discontinuation of Denzapine therapy is recommended if the platelet count falls below 50 000/mm3 (50 x 109/L).
Cardiovascular disorders
Orthostatic hypotension, with or without syncope, can occur during Denzapine treatment. Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur with concurrent use of benzodiazepines or any other psychotropic agent (see section 4.5) and during initial titration in association with rapid dose escalation; on very rare occasions they may occur even after the first dose. Therefore, patients commencing Denzapine treatment require close medical supervision. Monitoring of standing and supine blood pressure is necessary during the first weeks of treatment in patients with Parkinson's disease.
Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases of myocarditis have been fatal.
Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with clozapine use; these reports also include fatalities. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist.
In patients who are diagnosed with cardiomyopathy while on clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see section 4.8).
Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to Denzapine.
Myocardial infarction
In addition, there have been post marketing reports of myocardial infarction which may be fatal. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.
QT interval prolongation
As with other antipsychotics, caution should be exercised in patients with cardiovascular disease or a family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval.
Cerebrovascular Adverse Events
An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Denzapine should be used with caution in patients with risk factors for stroke.
Risk of thromboembolism
Since Denzapine may be associated with thromboembolism, immobilisation of patients should be avoided.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Denzapine and preventive measures undertaken.
Seizures
Patients with a history of epilepsy should be closely observed during Denzapine therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced (see section 4.2) and, if necessary, anti-convulsant treatment should be initiated.
Anticholinergic effects
Denzapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction, paralytic ileus, megacolon and intestinal infarction ischaemia (see section 4.8). On rare occasions these cases have been fatal. Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that constipation is recognised and actively treated.
Fever
During Denzapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign. Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infection or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. If the diagnosis of NMS is confirmed, Denzapine must be discontinued immediately and appropriate medical measures should be administered.
Falls
Clozapine may cause seizures, somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions or medications that could exacerbate these effects, fall risk assessments must be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Metabolic changes
Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycaemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific profile.
Hyperglycaemia
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. A mechanism for this possible association has not yet been determined. Cases of severe hyperglycaemia with ketoacidosis or hyperosmolar coma have been reported very rarely in patients with no prior history of hyperglycaemia, some of which have been fatal. When follow-up data were available, discontinuation of clozapine resulted mostly in resolution of the impaired glucose tolerance, and reinstitution of clozapine resulted in its reoccurrence. Patients with an established diagnosis of diabetes mellitis who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. The discontinuation of clozapine should be considered in patients where active medical management of their hyperglycaemia has failed.
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.
Weight gain
Weight gain has been observed with atypical antipsychotic use, including Denzapine. Clinical monitoring of weight is recommended.
Rebound, withdrawal effects
Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea.
Special populations
Hepatic impairment
Patients with stable pre-existing liver disorders may receive Denzapine, but need regular liver function tests. Liver function tests should be performed in patients in whom symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, develop during Denzapine therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if symptoms of jaundice occur, treatment with Denzapine must be discontinued. It may be resumed (see “Re-starting therapy” under section 4.2) only when the results of liver function tests are normal. In such cases, liver function should be closely monitored after re-introduction of Denzapine.
Patients aged 60 years and older
Initiation of treatment in patients aged 60 years and older is recommended at a lower dose (see section 4.2).
Orthostatic hypotension can occur with Denzapine treatment and there have been reports of tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with compromised cardiovascular function, may be more susceptible to these effects.
Patients aged 60 years and older may also be particularly susceptible to the anticholinergic effects of Denzapine, such as urinary retention and constipation.
Increased mortality in older people with dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Denzapine is not approved for the treatment of dementia-related behavioural disturbances.
4.5 |
Denzapine 25mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Contraindication of concomitant use
Drugs known to have a substantial potential to depress bone marrow function must not be used concurrently with Denzapine (see section 4.3). These include co-trimoxazole, chloramphenicol, sulphonamides, pyrazolone analgesics e.g. phenylbutazone, penicillamine, carbamazepine or cytotoxic agents.
Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Denzapine because these cannot be rapidly removed from the body in situations where this may be required, e.g. neutropenia (see section 4.3).
Alcohol should not be used concomitantly with Denzapine due to possible potentiation of sedation.
Precautions including dose adjustment
Denzapine may enhance the central effects of CNS depressants such as narcotics, antihistamines, and benzodiazepines. Particular caution is advised when Denzapine therapy is initiated in patients who are receiving a benzodiazepine or any other psychotropic drug. These patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound and may lead to cardiac and/or respiratory arrest. It is not clear whether cardiac or respiratory collapse can be prevented by dose adjustment.
Because of the possibility of additive effects, caution is essential in the concomitant administration of drugs possessing anticholinergic, hypotensive, or respiratory depressant effects.
Owing to its anti-alpha-adrenergic properties, Denzapine may reduce the blood-pressure-increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor effect of epinephrine.
Concomitant administration of drugs known to inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for CYP 1A2 inhibitors such as caffeine (see below), perazine, and the selective serotonin reuptake inhibitor fluvoxamine. Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine and to a lesser degree sertraline are CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP 3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin, and protease inhibitors are unlikely, although some have been reported. Hormonal contraceptives (including combinations of estrogen and progesterone or progesterone only) are CYP 1A2, CYP 3A4 and CYP 2C19 inhibitors. Therefore initiation or discontinuation of hormonal contraceptives may require dose adjustment of clozapine according to the individual medical need. Because the plasma concentration of clozapine is increased by caffeine intake and decreased by nearly 50% following a 5-day caffeine-free period, dosage changes of clozapine may be necessary when there is a change in caffeine-drinking habit. In cases of sudden cessation of smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.
Cases have been reported of an interaction between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. The nature of this interaction has not been fully elucidated.
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine, leading to reduced efficacy. Drugs known to induce the activity of cytochrome P450 enzymes and with reported interactions with clozapine include, for instance, carbamazepine (not to be used concomitantly with clozapine, due to its myelosuppresive potential), phenytoin and rifampicin. Known inducers of CYP1A2 such as omeprazole, may lead to decreased clozapine levels. The potential for reduced efficacy of clozapine should be considered when it is used in combination with these drugs.
Others
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Denzapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
Caution is called for in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic antidepressants, phenothiazines and type IC anti-arrhythmics, which are known to bind to cytochrome P450 2D6, no clinically relevant interactions have been observed thus far.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QT interval, because they may increase the risk of ventricular arrhythmias, including Torsades de pointes. Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide, sertindole and haloperidol), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to cause electrolyte imbalance. Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.
An outline of drug interactions believed to be most important with Denzapine is given in Table 2 below (this is not an exhaustive list).
Table 2: Reference to the most common drug interactions with Denzapine
Drug
Interactions
Comments
Bone marrow suppressants (e.g. carbamazapine, chloramphenicol, sulphonamides (e.g. co-trimoxazole), pyrazolone analgesics (e.g. phenylbutazone), penicillamine, cytotoxic agents and long-acting depot injections of antipsychotics
Interact to increase the risk and/or severity of bone marrow suppression.
Denzapine must not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see section 4.3)
Benzodiazepines
Concomitant use may increase risk of circulatory collapse, which may lead to cardiac and/or respiratory arrest.
Whilst the occurrence is rare, caution is advised when using these drugs together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when Denzapine is added to an established benzodiazepine regimen.
Anticholinergics
Denzapine potentiates the action of these drugs through additive anticholinergic activity.
Observe patients for anticholinergic side-effects, e.g. constipation, especially when using to help control hypersalivation.
Antihypertensives
Denzapine can potentiate the hypotensive effects of these drugs due to its sympathomimetic antagonistic effects.
Caution is advised if Denzapine is used concomitantly with antihypertensive agents. Patients should be advised of the risk of hypotension, especially during the period of initial dose titration
Alcohol, MAOIs, CNS depressants, including narcotics and benzodiazepines
Enhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these drugs.
Caution is advised if Denzapine is used concomitantly with other CNS active agents. Advise patients of the possible additive sedative effects and caution them not to drive or operate machinery.
Highly protein bound drugs
(e.g. warfarin and digoxin)
Denzapine may cause an increase in plasma concentration of these drugs due to displacement from plasma proteins.
Patients should be monitored for the occurrence of side effects associated with these drugs, and doses of the protein bound drug adjusted, if necessary.
Phenytoin
Addition of phenytoin to Denzapine drug regimen may cause a decrease in the clozapine plasma concentrations.
If phenytoin must be used, the patient should be monitored closely for a worsening or recurrence of psychotic symptoms.
Lithium
Concomitant use can increase the risk of development of neuroleptic malignant syndrome (NMS).
Observe for signs and symptoms of NMS.
CYP1A2 inducing substances (e.g. omeprazole)
Concomitant use may decrease clozapine levels.
Potential for reduced efficacy of clozapine should be considered.
CYP1A2 inhibiting substances e.g. fluvoxamine, caffeine, ciprofloxacin, perazine, or hormonal contraceptives (CYP1A2, CYP3A4, CYP2C19)
Concomitant use may increase clozapine levels.
Potential for increase in adverse effects. Care is also required upon cessation of concomitant CYP1A2 or CYP3A4 inhibiting medications as there may be a decrease in clozapine levels. The effect of CYP2C19 inhibition will be minimal.
4.6 |
Denzapine 25mg Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
For clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.
Neonates exposed to antipsychotics (including Denzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast-feeding
Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving Denzapine should not breast-feed.
Fertility
Limited data available on the effects of clozapine on human fertility are inconclusive. In male and female rats, clozapine did not affect fertility when administered up to 40mg/kg, corresponding to a human equivalence dose of 6.4mg/kg, or approximately a third of the maximum permissible human dose.
Women of child-bearing potential
A return to normal menstruation may occur as a result of switching from other antipsychotics to Denzapine. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
4.7 |
Denzapine 25mg Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Denzapine has a major influence on the ability to drive and use machines.
Owing to the ability of Denzapine to cause sedation and lower the seizure threshold, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.
4.8 |
Denzapine 25mg Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. An important exception is its propensity to cause agranulocytosis (see section 4.4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson's disease in cases where standard treatment has failed. While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse events, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.
The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see section 4.4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation.
Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients (from 7.1 to 15.6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leucopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder.
Blood and lymphatic system
Development of granulocytopenia and agranulocytosis is a risk inherent to Denzapine treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see section 4.4). Table 3 below summarises the estimated incidence of agranulocytosis for each Denzapine treatment period.
Table 3: Estimated incidence of agranulocytosis1
Treatment period
Incidence of agranulocytosis per 100,000 person-weeks2 of observation
Weeks 0 - 18
32.0
Weeks 19 - 52
2.3
Weeks 53 and higher
1.8
1 From the UK Patient Monitoring Service lifetime registry experience between 1989 and 2001.
2 Person-time is the sum of individual units of time that the patients in the registry have been exposed to clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000 = 100,000), or in 200 patients who were in the registry for 500 weeks (200*500 = 100,000) before experiencing agranulocytosis.
The cumulative incidence of agranulocytosis in the UK since monitoring began is (0 - 11.6 years between 1989 and 2001) is 0.78 %. The majority of cases (approximately 70 %) occur within the first 18 weeks of treatment.
Metabolic and Nutritional Disorders
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. On very rare occasions, severe hyperglycaemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported in patients on clozapine treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of clozapine and in a few cases hyperglycaemia recurred when treatment was reinitiated. Although most patients had risk factors for non-insulin-dependent diabetes mellitus, hyperglycaemia has also been documented in patients with no known risk factors (see section 4.4.).
Nervous System Disorders
The very common adverse events observed include drowsiness/sedation, and dizziness.
Denzapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures. These symptoms are more likely to occur with rapid dose increases and in patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant drugs the possibility of a pharmacokinetic interaction should be considered. In rare cases, patients treated with Denzapine may experience delirium.
Very rarely, tardive dyskinesia has been reported in patients on clozapine who had been treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other antipsychotics have improved on clozapine.
Cardiac Disorders
Tachycardia and postural hypotension with or without syncope may occur, especially in the initial weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and magnitude of dose titration. Circulatory collapse as a result of profound hypotension, in particular related to aggressive titration of the drug, with the possible serious consequences of cardiac or pulmonary arrest, has been reported with clozapine.
A minority of clozapine-treated patients experience ECG changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which normalise after discontinuation of clozapine. The clinical significance of these changes is unclear. However, such abnormalities have been observed in patients with myocarditis, which should therefore be considered.
Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion and myocarditis have been reported, some of which have been fatal. The majority of the cases of myocarditis occurred within the first 2 months of initiation of therapy with clozapine. Cardiomyopathy generally occurred later in the treatment.
Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known, however, whether eosinophilia is a reliable predictor of carditis.
Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest, palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms.
Very rare events of ventricular tachycardia and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine
Sudden, unexplained deaths are known to occur among psychiatric patients who receive conventional antipsychotic medication but also among untreated psychiatric patients. Such deaths have been reported very rarely in patients receiving clozapine.
Vascular Disorders
Rare cases of thromboembolism have been reported.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs. The frequency is unknown.
Respiratory System
Respiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see sections 4.4 and 4.5).
Gastrointestinal System
Constipation and hypersalivation have been observed very frequently, and nausea and vomiting frequently. Very rarely ileus may occur (see section 4.4). Rarely Denzapine treatment may be associated with dysphagia. Aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.
Hepatobiliary Disorders
Transient, asymptomatic elevations of liver enzymes and rarely, hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, Denzapine should be discontinued (see section 4.4). In rare cases, acute pancreatitis has been reported.
Renal Disorders
Isolated cases of acute interstitial nephritis have been reported in association with Denzapine therapy.
Reproductive and Breast Disorders
Very rare reports of priapism have been received.
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6) has been reported. The frequency of this is not known.
General Disorders
Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving clozapine either alone or in combination with lithium or other CNS-active agents.
Acute withdrawal reactions have been reported (see section 4.4).
Tabulated list of adverse reactions
The table below (Table 4) summarises the adverse reactions accumulated from reports made spontaneously and during clinical studies.
Table 4: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical trial reports
Adverse reactions are ranked under headings of frequency, using the following convention: Very common (≥1/10), common (≥ 1/100, to < 1/10), uncommon (≥ 1/1,000, to < 1/100), rare (≥ 1/10,000, to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)
Infections and infestations
Not known
Sepsis*
Blood and lymphatic system disorders
Common
Leucopoenia/decreased WBC/neutropenia, eosinophilia, leucocytosis
Uncommon
Agranulocytosis
Rare
Anaemia
Very rare
ThrombocytopeniaThrombocythaemia
Immune system disorders
Not known
Angioedema*, leucocytoclastic vasculitis*
Endocrine disorders
Not known
Pseudophaeochromocytoma*
Metabolism and nutrition disorders
Common
Weight gain
Rare
Impaired glucose tolerance, diabetes mellitus, obesity*
Very rare
Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia
Psychiatric disorders
Common
Dysarthria
Uncommon
Dysphemia
Rare
Restlessness, agitation
Nervous system disorders
Very common
Drowsiness/sedation, dizziness
Common
Blurred vision, headache, tremor, rigidity, akathisia, extra pyramidal symptoms, seizures/convulsions/myoclonic jerks
Rare
Confusion, delirium
Very rare
Tardive dyskinesia, obsessive compulsive disorder
Not known
Cholinergic syndrome (after abrupt withdrawal)*, EEG changes*, pleurothotonus*, restless leg syndrome*
Cardiac disorders
Very common
Tachycardia
Common
ECG changes
Rare
Circulatory collapse, ventricular arrhythmias (VF, VT), myocarditis, pericarditis/pericardial effusion
Very rare
Cardiomyopathy, cardiac arrest, QT prolongation, Torsades de pointes
Not known
Myocardial infarction which may be fatal*, chest pain/angina pectoris*, atrial fibrillation*, palpitations*, mitral valve incompetence associated with clozapine related cardiomyopathy*
Vascular disorders
Common
Hypertension, postural hypotension, syncope
Rare
Thromboembolism
Not known
Hypotension*, Venous thromboembolism
Respiratory, thoracic and mediastinal disorders
Rare
Aspiration of ingested food, pneumonia and lower respiratory tract infection which may be fatal, sleep apnoea syndrome*
Very rare
Respiratory depression/arrest
Not known
Pleural effusion*, nasal congestion*
Gastrointestinal disorders
Very common
Constipation, hypersalivation
Common
Nausea, vomiting, anorexia, dry mouth
Rare
Dysphagia
Very rare
Parotid gland enlargement, intestinal obstruction/paralytic ileus/faecal impaction
Not known
Megacolon*, intestinal infarction/ischaemia*, diarrhoea*, abdominal discomfort/heartburn/dyspepsia*, colitis*
Hepatobiliary disorders
Common
Elevated liver enzymes
Rare
Hepatitis, cholestatic jaundice, pancreatitis
Very rare
Fulminant hepatic necrosis
Not known
Hepatic steatosis*, hepatic necrosis*, hepatotoxicity*, hepatic fibrosis*, hepatic cirrhosis*, liver disorders including those hepatic events leading to life-threatening consequences such as liver injury (hepatic, cholestatic and mixed), liver failure which may be fatal and liver transplant*.
Skin and subcutaneous tissue disorders
Very rare
Skin reactions
Not known
Pigmentation disorder*
Musculoskeletal and connective tissue disorders
Not known
Rhabdomyolysis*, muscle weakness*, muscle spasms*, muscle pain*, systemic lupus erythematous*
Renal and urinary disorders
Common
Urinary incontinence, urinary retention
Very rare
Interstitial nephritis
Not known
Renal failure*, Nocturnal enuresis*
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Very rare
Priapism
Not known
Retrograde ejaculation*
General disorders and administration site conditions
Common
Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation
Uncommon
Neuroleptic malignant syndrome
Very rare
Sudden unexplained death
Not known:
Polyserositis*
Investigations
Rare
Increased CPK
Injury, poisoning and procedural complications
Uncommon
Falls (associated with clozapine-induced seizures, somnolence, postural hypotension, motor and sensory instability)*
* Adverse drug reactions derived from post-marketing experience via spontaneous case reports and literature cases for the drug substance, Clozapine.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 |
Denzapine 25mg Tablets | Clinical particulars - Overdose | Overdose
In cases of acute intentional or accidental clozapine overdosage for which information on the outcome is available, mortality to date is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000 mg. There have been reports of patients recovering from an overdose in excess of 10 000 mg. However, in a few adult individuals, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 to 200 mg resulted in strong sedation or coma without being lethal.
Signs and symptoms
Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extra pyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.
Treatment
There are no specific antidotes for Denzapine.
Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a 'reverse epinephrine' effect.
Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.
5. Pharmacological properties
5.1 |
Denzapine 25mg Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The absorption of orally administered Denzapine is 90 to 95%; neither the rate nor the extent of absorption is influenced by food.
Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.
Distribution
In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 L/kg. Clozapine is approximately 95% bound to plasma proteins.
Biotransformation/metabolism
Clozapine is almost completely metabolised before excretion by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Of the main metabolites only the desmethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of short duration.
Elimination
Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). After single doses of 75 mg the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days. Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.
Linearity/non-linearity
Dosage increases from 37.5 mg to 75 mg and 150 mg given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.
5.3 |
Denzapine 25mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see section 4.6).
6. |
Denzapine 25mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Micro-Crystalline Cellulose
Lactose monohydrate
Povidone
Sodium Starch Glycolate A
Magnesium Stearate
6.2 |
Denzapine 25mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Denzapine 25mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Denzapine 25mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 30°C. Store in the original packaging. Keep in the outer carton to protect from light.
6.5 |
Denzapine 25mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Transparent PVC/PVDC/ Aluminium Foil Blister Strips in a cardboard carton containing 28 or 84 tablets.
Transparent PVC/PVDC/PE/ Aluminium Foil Blister Strips in a cardboard carton containing 28 or 84 tablets.
HDPE bottles with polypropylene child-resistant, tamper-evident cap containing 100 tablets.
Not all pack sizes may be marketed.
6.6 |
Denzapine 25mg Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements
7. |
Denzapine 25mg Tablets | Marketing authorisation holder | Britannia Pharmaceuticals Limited
200 Longwater Avenue
Green Park
Reading
Berkshire
RG2 6GP
UK
8. Marketing authorisation number(s)
PL 04483/0067
9. |
Denzapine 25mg Tablets | Date of first authorisation/renewal of the authorisation | 31 January 2012
10. |
Denzapine 50mg Tablets | Name of the medicinal product | Denzapine® 50 mg Tablets
UK: Denzapine Official Recommendations
As a consequence of a recent European regulatory initiative, the Denzapine Summary of Product Characteristics (SmPC) has been harmonised across Europe. The SmPC states that blood monitoring should be carried out in accordance with national-specific official recommendations. These are reproduced below.
The Denzapine Monitoring Service (DMS) was developed in order to manage the risk of agranulocytosis associated with clozapine. It is available 24 hours a day. When a monitoring service is not used, evidence suggests a mortality rate from agranulocytosis of 0.3%[1]. This is compared to a mortality rate when clozapine is used in conjunction with a Monitoring Service, of 0.01%[2].
The Denzapine Monitoring Service provides centralised monitoring of leucocyte and neutrophil counts which is a mandatory requirement for all patients in the UK and Ireland who are treated with Denzapine. The use of Denzapine is restricted to patients who are registered with the Denzapine Monitoring Service. In addition to registering their patients, prescribing physicians must register themselves and a nominated pharmacist with the Denzapine Monitoring Service. All Denzapine-treated patients must be under the supervision of an appropriate specialist and supply of Denzapine is restricted to hospital and retail pharmacies registered with the Denzapine Monitoring Service. Denzapine is not sold to, or distributed through wholesalers.
The patient's white cell count with a differential count must be monitored:
• At least weekly for the first 18 weeks of treatment
• At least at 2 week intervals between weeks 18 and 52
• After 1 year of treatment with stable blood counts (green range), patients may be monitored at least at 4 week intervals
• Monitoring must continue throughout treatment and for at least 4 weeks after discontinuation
If the blood result of a patient taking Denzapine is below the normal range (See Section 4.4), Britannia will contact the physician and pharmacist registered to the patient on the Denzapine Monitoring Service to inform them.
The Denzapine Monitoring Service maintains a database which includes all patients who have developed abnormal leucocyte or neutrophil findings and who should not be re-exposed to Denzapine or any other brand of clozapine.
Prescribers and pharmacists should adhere to brand prescribing and dispensing of clozapine in order to prevent the disruption to effective monitoring that may be caused if patients switch brands.
Furthermore, in order to protect patient safety, at any one time patients should only be prescribed one brand of clozapine and only registered with the monitoring service connected to that brand.
Advice on Monitoring Clozapine Blood Levels
Blood clozapine level monitoring is advised in certain clinical situations such as when a patient ceases smoking or switches to e-cigarettes, when concomitant medicines may interact to increase clozapine blood levels, where poor clozapine metabolism is suspected, when a patient has pneumonia or other serious infection and in the event of onset of symptoms suggestive of toxicity (see section 4.4).
For further information regarding Denzapine and the Denzapine Monitoring Service please call 0333 200 4141 (UK).
[1] De la Chapelle A, et al. Clozapine-induced agranulocytosis: a genetic and epidemiologic study. Hum Genet, 1977. 37: p. 183-194.
[2] Denzapine Monitoring Service, data on file.
Denzapine can cause agranulocytosis. Its use should be limited to patients:
• with schizophrenia who are non-responsive to or intolerant of antipsychotic drug treatment, or with psychosis in Parkinson's disease when other treatment strategies have failed (see section 4.1)
• who have initially normal leucocyte findings (white blood cell count of ≥3500/mm3 (3.5 x 109 /L), and an absolute neutrophil count (ANC) of ≥2000/mm3 (2.0 x 109 /L)), and
• in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) can be performed as follows: weekly during the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least every 4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine (see section 4.4).
Prescribing physicians should comply fully with the required safety measures. At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia (see section 4.4).
Denzapine must be dispensed under strict medical supervision in accordance with official recommendations (see section 4.4).
Myocarditis
Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. The increased risk of myocarditis is greatest in the first 2 months of treatment. Fatal cases of cardiomyopathy have also been reported rarely (see section 4.4).
Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first 2 months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction (see section 4.4).
If myocarditis or cardiomyopathy are suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist (see section 4.4).
Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine (see section 4.3 and 4.4).
2. |
Denzapine 50mg Tablets | Qualitative and quantitative composition | For Denzapine 50 mg Tablets: Each tablet contains 50mg Clozapine.
Excipient(s) with known effect
One tablet contains 65mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
3. |
Denzapine 50mg Tablets | Pharmaceutical form | Tablet
For Denzapine 50mg Tablets: Round, flat yellow, bevel edged tablets embossed with “50” over a pressure sensitive breakline on one face, the other face plain.
The breakline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4. |
Denzapine 50mg Tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Treatment-resistant schizophrenia
Denzapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.
Psychosis during the course of Parkinson's disease
Denzapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed.
4.2 |
Denzapine 50mg Tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The dosage must be adjusted individually. For each patient the lowest effective dose should be used. For doses not realisable/practicable with this strength, other strengths of this medicinal product are available. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure, and sedation.
Initiation of Denzapine treatment must be restricted to those patients with a WBC count ≥3500/mm3 (3.5 x 109/L) and an absolute neutrophil count (ANC) ≥2000/mm3 (2.0 x 109/L) within standardised normal limits.
Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacodynamic and pharmacokinetic interactions with Denzapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5).
Switching from a previous antipsychotic therapy to Denzapine
It is generally recommended that Denzapine should not be used in combination with other antipsychotics, including depot preparations, which may have a myelosuppressive effect. When Denzapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards.
The following dosages are recommended:
Treatment-resistant schizophrenic patients
Starting therapy
12.5 mg (half a 25 mg tablet) once or twice on the first day, followed by one or two 25 mg tablets on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals.
Therapeutic dose range
In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. For maintenance dose, see below.
Maximum dose
To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e. not exceeding 100 mg) are permissible up to 900 mg/day. The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind.
Maintenance dose
After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may be appropriate.
Ending therapy
In the event of planned termination of Denzapine therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea (see section 4.4).
Re-starting therapy
In patients in whom the interval since the last dose of Denzapine exceeds 2 days, treatment should be re-initiated with 12.5 mg (half a 25 mg tablet) given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see section 4.4), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.
Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed
Starting therapy
The starting dose must not exceed 12.5 mg/day (half a 25 mg tablet), taken in the evening. Subsequent dose increases must be by 12.5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.
Therapeutic dose range
The mean effective dose is usually between 25 and 37.5 mg/day. In the event that treatment for at least one week with a dose of 50 mg fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week.
Maximum dose
The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of 100 mg/day must never be exceeded.
Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.
Maintenance dose
When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach results in the recurrence of psychotic symptoms, Denzapine dosage may be increased by increments of 12.5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see above).
Ending therapy
A gradual reduction in dose by steps of 12.5 mg over a period of at least one week (preferably two) is recommended.
Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis as indicated in section 4.4. In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
Special populations
Hepatic impairment
Patients with hepatic impairment should receive Denzapine with caution along with regular monitoring of liver function tests (see section 4.4).
Paediatric population
No paediatric studies have been performed. The safety and efficacy of Denzapine in children and adolescents under the age of 16 years have not yet been established. No data are available. It should not be used in this group until further data become available
Patients 60 years of age and older
Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day.
Method of Administration
Oral
4.3 |
Denzapine 50mg Tablets | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• This product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Patients unable to undergo regular blood tests.
• History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy).
• History of clozapine-induced agranulocytosis.
• Denzapine treatment must not be started concurrently with drugs known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged.
• Impaired bone marrow function.
• Uncontrolled epilepsy.
• Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.
• Circulatory collapse and/or CNS depression of any cause.
• Severe renal or cardiac disorders (e.g. myocarditis).
• Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
• Paralytic ileus.
4.4 |
Denzapine 50mg Tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Agranulocytosis
Denzapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring. The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations.
Because of the risks associated with Denzapine, its use is limited to patients in whom therapy is indicated as set out in section 4.1 and:
• who have initially normal leucocyte findings (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L), and
• in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks of therapy, at least every 2 weeks between weeks 18 and 52, and at least 4-week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine.
Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that might include an ECG, and the patient treated only if the expected benefits clearly outweigh the risks (see section 4.3). The treating physician should consider performing a pre-treatment ECG.
Prescribing physicians must comply fully with the required safety measures.
Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Prescriptions should not be issued for periods longer than the interval between two blood counts.
Immediate discontinuation of Denzapine is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109 /L) or the ANC is less than 1500/mm3 (1.5 x 109 /L) at any time during Denzapine treatment. Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to Denzapine.
At each consultation, a patient receiving Denzapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia. Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting Denzapine.
Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may be started on Denzapine with the agreement of a haematologist.
White Blood Cell (WBC) Counts and Absolute Neutrophil Count (ANC) Monitoring
WBC and differential blood counts must be performed within 10 days prior to initiating Denzapine treatment to ensure that only patients with normal WBC counts (WBC count ≥3500/mm3 (3.5 x 109/L) and ANC ≥2000/mm3 (2.0 x 109/L)) will receive the drug. After the start of Denzapine treatment the WBC count and ANC must be monitored weekly for the first 18 weeks, at least every 2 weeks between weeks 18 and 52, and at least at four-week intervals thereafter.
Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of Denzapine or until haematological recovery has occurred (see below Low WBC count/ANC). At each consultation, the patient must be reminded to contact the treating physician immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.
Low WBC count/ANC
If, during Denzapine therapy, either the WBC count falls to between 3500/mm3 (3.5 x 109/L) and 3000/mm3 (3.0 x 109/L) or the ANC falls to between 2000/mm3 (2.0 x 109/L) and 1500/mm3 (1.5 x 109/L), haematological evaluations must be performed at least twice weekly until the patient's WBC count and ANC stabilise within the range 3000-3500/mm3 (3.0 - 3.5 x 109/L) and 1500 - 2000/mm3 (1.5 - 2.0 x 109/L), respectively, or higher.
Immediate discontinuation of Denzapine treatment is mandatory if either the WBC count is less than 3000/mm3 (3.0 x 109/L) or the ANC is less than 1500/mm3 (1.5 x 109/L) during Denzapine treatment. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection. Confirmation of the haematological values is recommended by performing two blood counts on two consecutive days; however, Denzapine should be discontinued after the first blood count.
Following discontinuation of Denzapine, haematological evaluation is required until haematological recovery has occurred.
Table 1
Blood cell count
Action required
WBC/mm3 (/L)
ANC/mm3 (/L)
≥3500 (≥3.5 x 109)
≥2000 (≥2.0 x 109)
Continue Denzapine treatment
≥3000 to <3500
(≥3.0 x 109 to <3.5 x 109)
≥1500to <2000
(≥1.5 x 109 to <2.0 x 109)
Continue Denzapine treatment, sample blood twice weekly until counts stabilise or increase
<3000 (<3.0 x 109)
< 1500 (<1.5 x 109)
Immediately stop Denzapine treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient.
If Denzapine has been withdrawn and either a further drop in the WBC count below 2000/mm3 (2.0 x 109/L) occurs or the ANC falls below 1000/mm3 (1.0 x 109/L), the management of this condition must be guided by an experienced haematologist.
Discontinuation of therapy for haematological reasons
Patients in whom Denzapine has been discontinued as a result of either WBC or ANC deficiencies (see above) must not be re-exposed to Denzapine.
Prescribers are encouraged to keep a record of all patients' blood results and to take any steps necessary to prevent the patient being accidentally rechallenged in the future.
Discontinuation of therapy for other reasons
Patients who have been on Denzapine for more than 18 weeks and have had their treatment interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If Denzapine treatment has been interrupted for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment and the dose should be re-titrated (see section 4.2).
Other precautions
Eosinophilia
In the event of eosinophilia, discontinuation of Denzapine is recommended if the eosinophil count rises above 3000/mm3 (3.0 x 109/L); therapy should be restarted only after the eosinophil count has fallen below 1000/mm3 (1.0 x 109/L).
Thrombocytopenia
In the event of thrombocytopenia, discontinuation of Denzapine therapy is recommended if the platelet count falls below 50 000/mm3 (50 x 109/L).
Cardiovascular disorders
Orthostatic hypotension, with or without syncope, can occur during Denzapine treatment. Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such events are more likely to occur with concurrent use of benzodiazepines or any other psychotropic agent (see section 4.5) and during initial titration in association with rapid dose escalation; on very rare occasions they may occur even after the first dose. Therefore, patients commencing Denzapine treatment require close medical supervision. Monitoring of standing and supine blood pressure is necessary during the first weeks of treatment in patients with Parkinson's disease.
Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases of myocarditis have been fatal.
Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with clozapine use; these reports also include fatalities. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, Denzapine treatment should be promptly stopped and the patient immediately referred to a cardiologist.
In patients who are diagnosed with cardiomyopathy while on clozapine treatment, there is potential to develop mitral valve incompetence. Mitral valve incompetence has been reported in cases of cardiomyopathy related to clozapine treatment. These cases of mitral valve incompetence reported either mild or moderate mitral regurgitation on two-dimensional echocardiography (2DEcho) (see section 4.8).
Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to Denzapine.
Myocardial infarction
In addition, there have been post marketing reports of myocardial infarction which may be fatal. Causality assessment was difficult in the majority of these cases because of serious pre-existing cardiac disease and plausible alternative causes.
QT interval prolongation
As with other antipsychotics, caution should be exercised in patients with cardiovascular disease or a family history of QT prolongation.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase QTc interval.
Cerebrovascular Adverse Events
An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Denzapine should be used with caution in patients with risk factors for stroke.
Risk of thromboembolism
Since Denzapine may be associated with thromboembolism, immobilisation of patients should be avoided.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Denzapineand preventive measures undertaken.
Seizures
Patients with a history of epilepsy should be closely observed during Denzapine therapy since dose-related convulsions have been reported. In such cases, the dose should be reduced (see section 4.2) and, if necessary, an anti-convulsant treatment should be initiated.
Anticholinergic effects
Denzapine exerts anticholinergic activity, which may produce undesirable effects throughout the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle glaucoma. Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction, paralytic ileus, megacolon and intestinal infarction ischaemia (see section 4.8). On rare occasions these cases have been fatal. Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that constipation is recognised and actively treated.
Fever
During Denzapine therapy, patients may experience transient temperature elevations above 38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign. Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever should be carefully evaluated to rule out the possibility of an underlying infection or the development of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. If the diagnosis of NMS is confirmed, Denzapine must be discontinued immediately and appropriate medical measures should be administered.
Falls
Clozapine may cause seizures, somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions or medications that could exacerbate these effects, fall risk assessments must be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Metabolic changes
Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycaemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific profile.
Hyperglycaemia
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. A mechanism for this possible association has not yet been determined. Cases of severe hyperglycaemia with ketoacidosis or hyperosmolar coma have been reported very rarely in patients with no prior history of hyperglycaemia, some of which have been fatal. When follow-up data were available, discontinuation of clozapine resulted mostly in resolution of the impaired glucose tolerance, and reinstitution of clozapine resulted in its reoccurrence. Patients with an established diagnosis of diabetes mellitis who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. The discontinuation of clozapine should be considered in patients where active medical management of their hyperglycaemia has failed.
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine, is recommended.
Weight gain
Weight gain has been observed with atypical antipsychotic use, including Denzapine. Clinical monitoring of weight is recommended.
Rebound, withdrawal effects
Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and diarrhoea.
Special populations
Hepatic impairment
Patients with stable pre-existing liver disorders may receive Denzapine, but need regular liver function tests. Liver function tests should be performed in patients in whom symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, develop during Denzapine therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if symptoms of jaundice occur, treatment with Denzapine must be discontinued. It may be resumed (see “Re-starting therapy” under section 4.2) only when the results of liver function tests are normal. In such cases, liver function should be closely monitored after re-introduction of Denzapine.
Patients aged 60 years and older
Initiation of treatment in the patients aged 60 years and older is recommended at a lower dose (see section 4.2).
Orthostatic hypotension can occur with Denzapine treatment and there have been reports of tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with compromised cardiovascular function, may be more susceptible to these effects.
Patients aged 60 years and older may also be particularly susceptible to the anticholinergic effects of Denzapine, such as urinary retention and constipation.
Increased mortality in older people with dementia
Data from two large observational studies showed that older people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Denzapine is not approved for the treatment of dementia-related behavioural disturbances.
4.5 |
Denzapine 50mg Tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Contraindication of concomitant use
Drugs known to have a substantial potential to depress bone marrow function must not be used concurrently with Denzapine (see section 4.3). These include co-trimoxazole, chloramphenicol, sulphonamides, pyrazolone analgesics e.g. phenylbutazone, penicillamine, carbamazepine or cytotoxic agents.
Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used concurrently with Denzapine because these cannot be rapidly removed from the body in situations where this may be required, e.g. neutropenia (see section 4.3).
Alcohol should not be used concomitantly with Denzapine due to possible potentiation of sedation.
Precautions including dose adjustment
Denzapine may enhance the central effects of CNS depressants such as narcotics, antihistamines, and benzodiazepines. Particular caution is advised when Denzapine therapy is initiated in patients who are receiving a benzodiazepine or any other psychotropic drug. These patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound and may lead to cardiac and/or respiratory arrest. It is not clear whether cardiac or respiratory collapse can be prevented by dose adjustment.
Because of the possibility of additive effects, caution is essential in the concomitant administration of drugs possessing anticholinergic, hypotensive, or respiratory depressant effects.
Owing to its anti-alpha-adrenergic properties, Denzapine may reduce the blood-pressure-increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor effect of epinephrine.
Concomitant administration of drugs known to inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to be reduced to prevent undesirable effects. This is more important for CYP 1A2 inhibitors such as caffeine (see below), perazine, and the selective serotonin reuptake inhibitor fluvoxamine. Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine and to a lesser degree sertraline are CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less likely. Similarly, pharmacokinetic interactions with CYP 3A4 inhibitors such as azole antimycotics, cimetidine, erythromycin, and protease inhibitors are unlikely, although some have been reported. Hormonal contraceptives (including combinations of estrogen and progesterone or progesterone only) are CYP 1A2, CYP 3A4 and CYP 2C19 inhibitors. Therefore initiation or discontinuation of hormonal contraceptives may require dose adjustment of clozapine according to the individual medical need. Because the plasma concentration of clozapine is increased by caffeine intake and decreased by nearly 50% following a 5-day caffeine-free period, dosage changes of clozapine may be necessary when there is a change in caffeine-drinking habit. In cases of sudden cessation of smoking, the plasma clozapine concentration may be increased, thus leading to an increase in adverse effects.
Cases have been reported of an interaction between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. The nature of this interaction has not been fully elucidated.
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine, leading to reduced efficacy. Drugs known to induce the activity of cytochrome P450 enzymes and with reported interactions with clozapine include, for instance, carbamazepine (not to be used concomitantly with clozapine, due to its myelosuppresive potential), phenytoin and rifampicin. Known inducers of CYP1A2 such as omeprazole, may lead to decreased clozapine levels. The potential for reduced efficacy of clozapine should be considered when it is used in combination with these drugs.
Others
Concomitant use of lithium or other CNS-active agents may increase the risk of development of neuroleptic malignant syndrome (NMS).
Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Denzapine was co-administered with valproic acid have been reported. These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not been determined.
Caution is called for in patients receiving concomitant treatment with other drugs which are either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic antidepressants, phenothiazines and type IC anti-arrhythmics, which are known to bind to cytochrome P450 2D6, no clinically relevant interactions have been observed thus far.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to increase the QT interval, because they may increase the risk of ventricular arrhythmias, including Torsades de pointes. Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide, sertindole and haloperidol), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.
As with other antipsychotics, caution should be exercised when clozapine is prescribed with medicines known to cause electrolyte imbalance. Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.
An outline of drug interactions believed to be most important with Denzapine is given in Table 2 below (this is not an exhaustive list).
Table 2: Reference to the most common drug interactions with Denzapine
Drug
Interactions
Comments
Bone marrow suppressants (e.g. carbamazapine, chloramphenicol, sulphonamides (e.g. co-trimoxazole), pyrazolone analgesics (e.g. phenylbutazone), penicillamine, cytotoxic agents and long-acting depot injections of antipsychotics
Interact to increase the risk and/or severity of bone marrow suppression
Denzapine must not be used concomitantly with other agents having a well known potential to suppress bone marrow function (see Section 4.3)
Benzodiazepines
Concomitant use may increase risk of circulatory collapse, which may lead to cardiac and/or respiratory arrest
Whilst the occurrence is rare, caution is advised when using these drugs together. Reports suggest that respiratory depression and collapse are more likely to occur at the start of this combination or when Denzapine is added to an established benzodiazepine regimen.
Anticholinergics
Denzapine potentiates the action of these drugs through additive anticholinergic activity
Observe patients for anticholinergic side – effects, e.g. constipation, especially when using to help control hypersalivation
Antihypertensives
Denzapine can potentiate the hypotensive effects of these drugs due to its sympathomimetic antagonistic effects
Caution is advised if Denzapine is used concomitantly with antihypertensive agents. Patients should be advised of the risk of hypotension, especially during the period of initial dose titration
Alcohol, MAOIs, CNS depressants, including narcotics and benzodiazepines
Enhanced central effects. Additive CNS depression and cognitive and motor performance interference when used in combination with these drugs
Caution is advised if Denzapine is used concomitantly with other CNS active agents. Advise patients of the possible additive sedative effects and caution them not to drive or operate machinery
Highly protein bound drugs
(e.g. warfarin and digoxin)
Denzapine may cause an increase in plasma concentration of these drugs due to displacement from plasma proteins
Patients should be monitored for the occurrence of side effects associated with these drugs, and doses of the protein bound drug adjusted, if necessary
Phenytoin
Addition of phenytoin to Denzapine drug regimen may cause a decrease in the clozapine plasma concentrations
If phenytoin must be used, the patient should be monitored closely for a worsening or recurrence of psychotic symptoms
Lithium
Concomitant use can increase the risk of development of neuroleptic malignant syndrome (NMS)
Observe for signs and symptoms of NMS
CYP1A2 inducing substances (e.g. omeprazole)
Concomitant use may decrease clozapine levels
Potential for reduced efficacy of clozapine should be considered.
CYP1A2 inhibiting substances (e.g. fluvoxamine, caffeine, ciprofloxacin) , perazine, or hormonal contraceptives (CYP1A2, CYP3A4, CYP2C19)
Concomitant use may increase clozapine levels
Potential for increase in adverse effects. Care is also required upon cessation of concomitant CYP1A2 or CYP3A4 inhibiting medications as there will be a decrease in clozapine levels. The effect of CYP2C19 inhibition will be minimal.
4.6 |
Denzapine 50mg Tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
For clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.
Neonates exposed to antipsychotics (including Denzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast-feeding
Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant; therefore, mothers receiving Denzapine should not breast-feed.
Fertility
Limited data available on the effects of clozapine on human fertility are inconclusive. In male and female rats, clozapine did not affect fertility when administered up to 40mg/kg, corresponding to a human equivalence dose of 6.4mg/kg, or approximately a third of the maximum permissible human dose.
Women of child-bearing potential
A return to normal menstruation may occur as a result of switching from other antipsychotics to Denzapine. Adequate contraceptive measures must therefore be ensured in women of childbearing potential.
4.7 |
Denzapine 50mg Tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Denzapine has a major influence on the ability to drive and use machines.
Owing to the ability of Denzapine to cause sedation and lower the seizure threshold, activities such as driving or operating machinery should be avoided, especially during the initial weeks of treatment.
4.8 |
Denzapine 50mg Tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. An important exception is its propensity to cause agranulocytosis (see section 4.4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson's disease in cases where standard treatment has failed. While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse events, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.
The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see section 4.4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation.
Data from the clinical trials experience showed that a varying proportion of clozapine-treated patients (from 7.1 to 15.6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine. The more common events considered to be causes of discontinuation were leucopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder.
Blood and lymphatic system
Development of granulocytopenia and agranulocytosis is a risk inherent to Denzapine treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. Because immediate withdrawal of the drug is required to prevent the development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see section 4.4). Table 3 below summarises the estimated incidence of agranulocytosis for each Denzapine treatment period.
Table 3: Estimated incidence of agranulocytosis1
Treatment period
Incidence of agranulocytosis per 100,000 person-weeks2 of observation
Weeks 0 - 18
32.0
Weeks 19 - 52
2.3
Weeks 53 and higher
1.8
1 From the UK Patient Monitoring Service lifetime registry experience between 1989 and 2001.
2 Person-time is the sum of individual units of time that the patients in the registry have been exposed to clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000 = 100,000), or in 200 patients who were in the registry for 500 weeks (200*500 = 100,000) before experiencing agranulocytosis.
The cumulative incidence of agranulocytosis in the UK since monitoring began is (0 - 11.6 years between 1989 and 2001) is 0.78%. The majority of cases (approximately 70%) occur within the first 18 weeks of treatment.
Metabolic and Nutritional Disorders
Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine. On very rare occasions, severe hyperglycaemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported in patients on clozapine treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of clozapine and in a few cases hyperglycaemia recurred when treatment was reinitiated. Although most patients had risk factors for non-insulin-dependent diabetes mellitus, hyperglycaemia has also been documented in patients with no known risk factors (see section 4.4).
Nervous System Disorders
The very common adverse events observed include drowsiness/sedation, and dizziness.
Denzapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures. These symptoms are more likely to occur with rapid dose increases and in patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant drugs the possibility of a pharmacokinetic interaction should be considered. In rare cases, patients treated with Denzapine may experience delirium.
Very rarely, tardive dyskinesia has been reported in patients on clozapine who had been treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other antipsychotics have improved on clozapine.
Cardiac Disorders
Tachycardia and postural hypotension with or without syncope may occur, especially in the initial weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and magnitude of dose titration. Circulatory collapse as a result of profound hypotension, in particular related to aggressive titration of the drug, with the possible serious consequences of cardiac or pulmonary arrest, has been reported with clozapine.
A minority of clozapine-treated patients experience ECG changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which normalise after discontinuation of clozapine. The clinical significance of these changes is unclear. However, such abnormalities have been observed in patients with myocarditis, which should therefore be considered.
Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion and myocarditis have been reported, some of which have been fatal. The majority of the cases of myocarditis occurred within the first 2 months of initiation of therapy with clozapine. Cardiomyopathy generally occurred later in the treatment.
Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known, however, whether eosinophilia is a reliable predictor of carditis.
Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest, palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms which may be present in addition to the above include flu-like symptoms.
Very rare events of ventricular tachycardia and QT prolongation which may be associated with Torsades De Pointes have been observed although there is no conclusive causal relationship to the use of this medicine.
Sudden, unexplained deaths are known to occur among psychiatric patients who receive conventional antipsychotic medication but also among untreated psychiatric patients. Such deaths have been reported very rarely in patients receiving clozapine.
Vascular Disorders
Rare cases of thromboembolism have been reported.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs. The frequency is unknown.
Respiratory System
Respiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see sections 4.4).
Gastrointestinal System
Constipation and hypersalivation have been observed very frequently, and nausea and vomiting frequently. Very rarely ileus may occur (see section 4.4). Rarely Denzapine treatment may be associated with dysphagia. Aspiration of ingested food may occur in patients presenting with dysphagia or as a consequence of acute overdosage.
Hepatobiliary Disorders
Transient, asymptomatic elevations of liver enzymes and rarely, hepatitis and cholestatic jaundice may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, Denzapine should be discontinued (see section 4.4). In rare cases, acute pancreatitis has been reported.
Renal Disorders
Isolated cases of acute interstitial nephritis have been reported in association with Denzapine therapy.
Reproductive and Breast Disorders
Very rare reports of priapism have been received.
Pregnancy, puerperium and perinatal conditions
Drug withdrawal syndrome neonatal (see section 4.6) has been reported. The frequency of this is not known.
General Disorders
Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving clozapine either alone or in combination with lithium or other CNS-active agents.
Acute withdrawal reactions have been reported (see section 4.4).
Tabulated list of adverse reactions
The table below (Table 4) summarises the adverse reactions accumulated from reports made spontaneously and during clinical studies.
Table 4: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical trial reports
Adverse reactions are ranked under headings of frequency, using the following convention: Very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare ( < 1/10,000), not known (cannot be estimated from the available data).
Infections and infestations
Not known
Sepsis*
Blood and lymphatic system disorders
Common
Leucopenia/decreased WBC/neutropenia, eosinophilia, leucocytosis
Uncommon
Agranulocytosis
Rare
Anaemia
Very rare
ThrombocytopeniaThrombocythaemia
Immune system disorders
Not known
Angioedema*, leucocytoclastic vasculitis*
Endocrine disorders
Not known
Pseudophaeochromocytoma*
Metabolism and nutrition disorders
Common
Weight gain
Rare
Impaired glucose tolerance, diabetes mellitus, obesity*
Very rare
Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridaemia, hypercholesterolaemia
Psychiatric disorders
Common
Dysarthria
Uncommon
Dysphemia
Rare
Restlessness, agitation
Nervous system disorders
Very common
Drowsiness/sedation, dizziness
Common
Blurred vision, headache, tremor, rigidity, akathisia, extra pyramidal symptoms, seizures/convulsions/myoclonic jerks
Rare
Confusion, delirium
Very rare
Tardive dyskinesia, obsessive compulsive disorder
Not known
Cholinergic syndrome (after abrupt withdrawal)*, EEG changes*, pleurothotonus*, restless leg syndrome*
Cardiac disorders
Very common
Tachycardia
Common
ECG changes
Rare
Circulatory collapse, Ventricular arrhythmias (VF, VT), myocarditis, pericarditis/pericardial effusion
Very rare
Cardiomyopathy, cardiac arrest, QT prolongation, Torsades de pointes
Not known
Myocardial infarction which may be fatal*, chest pain/angina pectoris*, atrial fibrillation*, palpitations*, mitral valve incompetence associated with clozapine related cardiomyopathy*
Vascular disorders
Common
Hypertension, postural hypotension, syncope
Rare
Thromboembolism
Not known
Hypotension*, Venous thromboembolism
Respiratory, thoracic and mediastinal disorders
Rare
Aspiration of ingested food, pneumonia and lower respiratory tract infection which may be fatal, sleep apnoea syndrome*
Very rare
Respiratory depression/arrest
Not known
Pleural effusion*, nasal congestion*
Gastrointestinal disorders
Very common
Constipation, hypersalivation
Common
Nausea, vomiting, anorexia, dry mouth
Rare
Dysphagia
Very rare
Parotid gland enlargement, intestinal obstruction/paralytic ileus/faecal impaction
Not known
Megacolon*, intestinal infarction/ischaemia*, diarrhoea*, abdominal discomfort/heartburn/dyspepsia*, colitis*
Hepatobiliary disorders
Common
Elevated liver enzymes
Rare
Hepatitis, cholestatic jaundice, pancreatitis
Very rare
Fulminant hepatic necrosis
Not known
Hepatic steatosis*, hepatic necrosis*, hepatotoxicity*, hepatic fibrosis*, hepatic cirrhosis*, liver disorders including those hepatic events leading to life-threatening consequences such as liver injury (hepatic, cholestatic and mixed), liver failure which may be fatal and liver transplant*.
Skin and subcutaneous tissue disorders
Very rare
Skin reactions
Not known
Pigmentation disorder*
Musculoskeletal and connective tissue disorders
Not known
Rhabdomyolysis*, muscle weakness*, muscle spasms*, muscle pain*, systemic lupus erythematous*
Renal and urinary disorders
Common
Urinary incontinence, urinary retention
Very rare
Interstitial nephritis
Not known
Renal failure*, Nocturnal enuresis*
Pregnancy, puerperium and perinatal conditions
Not known
Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Very rare
Priapism
Not known
Retrograde ejaculation*
General disorders and administration site conditions
Common
Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature regulation
Uncommon
Neuroleptic malignant syndrome
Very rare
Sudden unexplained death
Not known:
Polyserositis*
Investigations
Rare
Increased CPK
Injury, poisoning and procedural complications
Uncommon
Falls (associated with clozapine-induced seizures, somnolence, postural hypotension, motor and sensory instability)*
* Adverse drug reactions derived from post-marketing experience via spontaneous case reports and literature cases for the drug substance, Clozapine.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme: https://yellowcard.mhra.gov.uk/ Or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Denzapine 50mg Tablets | Clinical particulars - Overdose | Overdose
In cases of acute intentional or accidental clozapine overdosage for which information on the outcome is available, mortality to date is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000 mg. There have been reports of patients recovering from an overdose in excess of 10 000 mg. However, in a few adult individuals, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 to 200 mg resulted in strong sedation or coma without being lethal.
Signs and symptoms
Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extra pyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.
Treatment
There are no specific antidotes for Denzapine.
Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a 'reverse epinephrine' effect.
Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.
5. Pharmacological properties
5.1 |
Denzapine 50mg Tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The absorption of orally administered Denzapine is 90 to 95%; neither the rate nor the extent of absorption is influenced by food.
Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50 to 60%.
Distribution
In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range: 0.4 to 4.2 hours), and the volume of distribution is 1.6 L/kg. Clozapine is approximately 95% bound to plasma proteins.
Biotransformation/metabolism
Clozapine is almost completely metabolised before excretion by CYP1A2 and CYP3A4, and to some extent by CYP2C19 and CYP2D6. Of the main metabolites only the desmethyl metabolite was found to be active. Its pharmacological actions resemble those of clozapine, but are considerably weaker and of short duration.
Elimination
Its elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6 to 26 hours). After single doses of 75 mg the mean terminal half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days. Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.
Linearity/non-linearity
Dosage increases from 37.5 mg to 75 mg and 150 mg given twice daily were found to result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC), and in the peak and minimum plasma concentrations.
5.3 |
Denzapine 50mg Tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive toxicity, see section 4.6).
6. |
Denzapine 50mg Tablets | Pharmaceutical particulars - List of excipients | List of excipients
Micro-Crystalline cellulose
Lactose monohydrate
Povidone
Sodium Starch Glycolate A
Magnesium Stearate
6.2 |
Denzapine 50mg Tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Denzapine 50mg Tablets | Pharmaceutical particulars - Shelf life | Shelf life
Blister packs 4 years
HDPE bottles 4 years
6.4 |
Denzapine 50mg Tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 30°C. Store in the original packaging. Keep in the outer carton to protect from light.
6.5 |
Denzapine 50mg Tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Transparent PVC/PVDC/ Aluminium Foil Blister Strips in a cardboard carton containing 20, 50 or 100 tablets.
Transparent PVC/PVDC/PE/ Aluminium Foil Blister Strips in a cardboard carton containing 20, 50 or 100 tablets.
HDPE bottles with polypropylene child-resistant, tamper-evident cap containing 50 or 100 tablets.
Not all pack sizes may be marketed.
6.6 |
Denzapine 50mg Tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
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