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Clinical Trial Experience In Adult Patients
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most serious adverse reactions associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities.
The safety database in VIRAMUNE XR clinical trials contains data from 800 subjects treated with VIRAMUNE XR and 654 subjects treated with immediate release VIRAMUNE.
Trial 1100.1486 (VERxVE)
In Trial 1100.1486 (VERxVE) treatment-na´ve subjects received a lead-in dose of immediate-release VIRAMUNE 200 mg once daily for 14 days (n=1068) and then were randomized to receive either immediate-release VIRAMUNE 200 mg twice daily (n=506) or VIRAMUNE XR 400 mg once daily (n=505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4+ counts less than 250 cells/mm³ for women and less than 400 cells/mm³ for men [see INDICATIONS AND USAGE]. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subject's completion of the 96 week endpoint in the trial (mean observation period 98 weeks).
After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release VIRAMUNE group and 6% in the VIRAMUNE XR group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 8% in both the immediate-release VIRAMUNE group and VIRAMUNE XR group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.
Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release VIRAMUNE, and in 1% of subjects in either treatment group during the randomization phase. In addition, six cases of Stevens-Johnson syndrome were reported in the trial; all but one occurred within the first 30 days of nevirapine treatment.
No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release VIRAMUNE (200 mg once daily), with the exception of rash which occurred in 4% of subjects.
Adverse reactions of at least moderate intensity (Grades 2 or above) 2% or more of treatment-na´ve subjects receiving either immediate-release VIRAMUNE or VIRAMUNE XR after randomization in Trial 1100.1486 are shown in Table 2.
Table 2 : Selected Clinical Adverse Drug Reactions*
of at least Moderate Intensity (Grade 2 or above) Occurring in 2% or more
of Adult Subjects- Week 96 Analysis of Trial 1100.14861
|Adverse Drug Reaction||VIRAMUNE Immediate-Release
|* Excludes laboratory
abnormalities reported as ADRs
1Mean observation period 98 weeks.
2Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS).
3Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, jaundice.
Liver enzyme test abnormalities (AST, ALT) were observed in subjects receiving VIRAMUNE XR. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue therapy with nevirapine in the absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 3.
Table 3 : Grade 2 to Grade 4
Laboratory Abnormalities that Represent a Worsening from Baseline Observed in
at least 5% of Subjects in Either Treatment Group - Trial 1100.1486
|Laboratory Parameter (unit)||Limit||VIRAMUNE Immediate-Release (%) (N=506)||VIRAMUNE XR (%) (N=505)|
|Grade 2||2.6-5.0 x ULN||13||10|
|Grade 3||5.1-10.0 x ULN||3||4|
|Grade 4||> 10.0 x ULN||4||2|
|Grade 2||2.6-5.0 x ULN||9||7|
|Grade 3||5.1-10.0 x ULN||2||3|
|Grade 4||> 10.0 x ULN||2||2|
|Grade 2||1.6-2.0 x ULN||4||5|
|Grade 3||2.1-5.0 x ULN||4||2|
|Grade 4||> 5.0 x ULN||0||< 1|
|Grade 2||2.0-2.4 x ULN||38||33|
|Grade 3||1.0-1.9 x ULN||6||7|
|Grade 4||< 1.0 x ULN||< 1||0|
|Grade 2||1.6-2.0 x ULN||4||5|
|Grade 3||2.1-5.0 x ULN||4||2|
|Grade 4||> 5.0 x ULN||0||< 1|
|Grade 4||< 500/mm3||1||1|
|Grade 2||160-190 mg/dL||15||15|
|Grade 3||> 190 mg/dL||5||5|
|Grade 2||240-300 mg/dL||18||19|
|Grade 3||> 300 mg/dL||4||3|
Trial 1100.1526 (TRANxITION)
In Trial 1100.1526 (TRANxITION) subjects on immediate-release VIRAMUNE 200 mg twice daily for at least 18 weeks were randomized to either receive VIRAMUNE XR 400 mg once daily (n=295) or remain on their immediate-release VIRAMUNE treatment (n=148). Adverse reactions observed for VIRAMUNE XR subjects (48 week analysis) were similar to those observed in trial 1100.1486, as displayed in Table 2.
Clinical Trial Experience In Pediatric Patients
Adverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, non-randomized, cross-over trial to evaluate the safety and steady-state pharmacokinetic parameters of VIRAMUNE XR tablets in HIV-1-infected pediatric subjects 3 to less than 18 years of age. Safety was further examined in an optional extension phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were treated with VIRAMUNE XR once daily in combination with other antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse reactions related to VIRAMUNE XR in pediatric subjects were similar to those observed in adults. In pediatric subjects the incidence of Grade 2 or higher drug-related rash was 1%. There were no adverse reactions of Grade 2 or above which were considered to be related to treatment by the investigator that occurred in more than 1% of subjects [see Use In Specific Populations, CLINICAL PHARMACOLOGY, and Clinical Studies].
The following adverse reactions have been identified during post-approval use of immediate-release VIRAMUNE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
Investigations: decreased serum phosphorus
Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities [see WARNINGS AND PRECAUTIONS] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.
Read the Viramune XR (nevirapine extended-release tablets, for oral use) Side Effects Center for a complete guide to possible side effects
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine.
The results of drug interactions studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when coadministering these drugs.
The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently.
Table 4 : Established and Potential Drug Interactions:
Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug
Interaction Established Drug Interactions: See CLINICAL PHARMACOLOGY, Table 5
for Magnitude of Interaction.
|Drug Name||Effect on Concentration of Nevirapine or Concomitant Drug||Clinical Comment|
|HIV Antiviral Agents: Protease Inhibitors (PIs)|
|Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.|
|Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.|
|No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.|
|Indinavir*||↓ Indinavir||The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.|
|Lopinavir/Ritonavir*||↓Lopinavir||Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Dosing in pediatric patients:
Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
|Nelfinavir*||↓Nelfinavir M8 Metabolite
|The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.|
|Saquinavir/ritonavir||The interaction between nevirapine and saquinavir/ritonavir has not been evaluated||The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.|
|HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)|
|Efavirenz*||↓ Efavirenz||The appropriate doses of these combinations with respect to safety and efficacy have not been established.|
|Delavirdine Etravirine Rilpivirine||Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.|
|Hepatitis C Antiviral Agents|
|Boceprevir||Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.||Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.|
|Telaprevir||Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.||Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.|
|Analgesics: Methadone*||↓ Methadone||Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.|
|Antiarrhythmics: Amiodarone, disopyramide, lidocaine||Plasma concentrations may be decreased.||Appropriate doses for this combination have not been established.|
↑ 14-OH clarithromycin
|Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.|
|Rifabutin*||↑Rifabutin||Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.|
|Rifampin*||↓ Nevirapine||Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.|
Carbamazepine, clonazepam, ethosuximide
|Plasma concentrations of nevirapine and the anticonvulsant may be decreased.||Use with caution and monitor virologic response and levels of anticonvulsants.|
|Antifungals: Fluconazole*||↑Nevirapine||Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.|
|Ketoconazole*||↓ Ketoconazole||Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.|
|Itraconazole||↓ Itraconazole||Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.|
|Antithrombotics: Warfarin||Plasma concentrations may be increased.||Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.|
|Calcium channel blockers: Diltiazem, nifedipine, verapamil||Plasma concentrations may be decreased.||Appropriate doses for these combinations have not been established.|
|Cancer chemotherapy: Cyclophosphamide||Plasma concentrations may be decreased.||Appropriate doses for this combination have not been established.|
|Ergot alkaloids: Ergotamine||Plasma concentrations may be decreased.||Appropriate doses for this combination have not been established.|
|Immunosuppressants: Cyclosporine, tacrolimus, sirolimus||Plasma concentrations may be decreased.||Appropriate doses for these combinations have not been established.|
|Motility agents: Cisapride||Plasma concentrations may be decreased.||Appropriate doses for this combination have not been established.|
|Opiate agonists: Fentanyl||Plasma concentrations may be decreased.||Appropriate doses for this combination have not been established.|
|Oral contraceptives: Ethinyl estradiol and Norethindrone*||↓ Ethinyl estradiol
|Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.|
|* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.|
Read the Viramune XR Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/6/2014
Additional Viramune XR Information
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