nevirapine 400 MG 24 HR Extended Release Oral Tablet
DRUG INTERACTIONS
7 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 co-administering 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 (12.3), Table 5 for Magnitude of Interaction.
* 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.
Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment HIV Antiviral Agents: Protease Inhibitors (PIs) Atazanavir/Ritonavir* ↓ Atazanavir ↑ Nevirapine 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.
Fosamprenavir* ↓Amprenavir ↑Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir* ↓Amprenavir ↑Nevirapine 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 ↓Nelfinavir C min 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.
Other Agents 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.
Antibiotics: Clarithromycin* ↓ Clarithromycin ↑ 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 avium-intracellulare 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.
Anticonvulsants: 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 decreased.
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 increased.
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 ↓ Norethindrone 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.
Co-administration of VIRAMUNE XR can alter the concentrations of other drugs, and other drugs may alter the concentration of nevirapine.
The potential for drug interactions must be considered prior to and during therapy.
(5.4 , 7 , 12.3)
OVERDOSAGE
10 There is no known antidote for nevirapine overdosage.
Cases of immediate-release VIRAMUNE overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported.
Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease.
All events subsided following discontinuation of immediate-release VIRAMUNE.
DESCRIPTION
11 VIRAMUNE XR is the brand name for nevirapine extended-release tablets.
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1).
Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds.
The chemical name of nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2′,3′-e][1,4] diazepin-6-one.
Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C 15 H 14 N 4 O.
Nevirapine has the following structural formula: VIRAMUNE XR Tablets are for oral administration.
Each tablet contains 100 mg or 400 mg of nevirapine and the inactive ingredients lactose monohydrate, hypromellose, iron oxide, and magnesium stearate.
Chemical Structure – Viramune
CLINICAL STUDIES
14 14.1 Adult Patients The clinical efficacy of VIRAMUNE XR is based on 96-week data from an ongoing, randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486, VERxVE) in treatment-naïve subjects and on 48-week data in an ongoing, randomized, open-label trial in subjects who switched from immediate-release VIRAMUNE tablets administered twice daily to VIRAMUNE XR tablets administered once daily (Trial 1100.1526, TRANxITION).
Treatment-naïve Subjects Trial 1100.1486 (VERxVE) is a Phase 3 trial in which treatment-naïve subjects received immediate-release VIRAMUNE 200 mg once daily for 14 days and then were randomized to receive either immediate-release VIRAMUNE 200 mg twice daily or VIRAMUNE XR 400 mg once daily.
All subjects received tenofovir + emtricitabine as background therapy.
Randomization was stratified by screening HIV-1 RNA level (less than or equal to 100,000 copies per mL and greater than 100,000 copies per mL).
Subject demographic and baseline disease characteristics were balanced between the two treatment groups.
With respect to demographics: 85% of the subjects were male, 75% were white, 20% were black, and approximately 29% were from North America.
With respect to baseline disease characteristics: mean viral load was 4.7 log 10 copies per mL, mean CD4 + cell count was 228 cells/mm 3 and 73% of subjects had clade B HIV-1 subtype.
Approximately two-thirds of the subjects had a baseline HIV-RNA level of less than or equal to 100,000 copies per mL.
Table 6 describes week 96 outcomes in the Trial 1100.1486 (VERxVE).
These outcomes include all subjects who were randomized after the 14 day lead-in with immediate-release VIRAMUNE and received at least one dose of blinded study medication.
Table 6 Outcomes at Week 96 in Trial 1100.1486 #Includes subjects who changed optimized background therapy (OBT) to new class or changed OBT not permitted per protocol or due to lack of efficacy prior to Week 96, subjects who discontinued prior to Week 96 for lack or loss of efficacy and subjects with HIV RNA greater than or equal to 50 copies/mL in the Week 96 window.
*Includes subjects who discontinued due to adverse events or death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the specified window.
**Other includes: withdrew consent, lost to follow-up, moved away, etc.
Week 96 VIRAMUNE Immediate-Release N=506 VIRAMUNE XR N=505 Virologic Success – HIV RNA < 50 copies/mL 67% 69% Virologic Failure # 18% 17% No Virologic Data at Week 96 Window Reasons Discontinued trial/study drug due to adverse event or death* Discontinued trial/study drug for other reasons** Missing data during window but on trial 10% 5% <1% 8% 5% 1% At 96 weeks, mean change from baseline in CD4 + cell count adjusting for baseline HIV-1 viral load stratum was 222 cells/mm 3 and 244 cells/mm 3 for the groups receiving immediate-release VIRAMUNE and VIRAMUNE XR, respectively.
Subjects Switching from Immediate-release VIRAMUNE to VIRAMUNE XR Trial 1100.1526 (TRANxITION) is a Phase 3 trial to evaluate safety and antiviral activity of switching from immediate-release VIRAMUNE to VIRAMUNE XR.
In this open-label trial, 443 subjects already on an antiviral regimen containing immediate-release VIRAMUNE 200 mg twice daily with HIV-1 RNA less than 50 copies per mL were randomized in a 2:1 ratio to VIRAMUNE XR 400 mg once daily or immediate-release VIRAMUNE 200 mg twice daily.
Approximately half of the subjects had tenofovir+emtricitabine as their background therapy, with the remaining subjects receiving abacavir sulfate+lamivudine or zidovudine+lamivudine.
Approximately half of the subjects had at least 3 years of exposure to immediate-release VIRAMUNE prior to entering the trial.
At 48 weeks after randomization in Trial 1100.1526, 91% of subjects receiving immediate-release VIRAMUNE 200 mg twice daily and 93% of subjects receiving VIRAMUNE XR 400 mg once daily continued to have HIV-1 RNA less than 50 copies per mL.
14.2 Pediatric Patients Trial 1100.1518 was an open-label, multiple-dose, non-randomized, crossover trial performed in 85 HIV-1 infected pediatric subjects 3 to less than 18 years of age who had received at least 18 weeks of immediate-release VIRAMUNE and had plasma HIV-1 RNA less than 50 copies per mL prior to trial enrollment.
Subjects were stratified according to age (3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years).
Following a 10-day period with immediate-release VIRAMUNE, subjects were treated with VIRAMUNE XR tablets once daily in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined.
Forty of the 80 subjects who completed the initial part of the study were enrolled in an optional extension phase of the trial which evaluated the safety and antiviral activity of VIRAMUNE XR through a minimum of 24 weeks of treatment.
Zidovudine or stavudine plus lamivudine were the most commonly used background therapies in subjects who entered the optional extension phase.
Baseline demographics included: 55% of the subjects were female, 93% were black, 7% were white, and approximately 84% were from Africa.
Subjects had a median baseline CD4 + cell count of 925 cells/mm 3 (range 207 to 2057 cells/mm 3 ).
Of the 40 subjects who entered the treatment extension phase, 39 completed at least 24 weeks of treatment and one subject discontinued prematurely due to an adverse reaction.
After 24 weeks or more of treatment with VIRAMUNE XR, all 39 subjects continued to have plasma HIV-1 RNA less than 50 copies per mL.
Median CD4 + cell counts for the 3 to less than 6 year, 6 to less than 12 year, and 12 to less than 18 year age groups were 1113 cells/mm 3 , 853 cells/mm 3 , and 682 cells/mm 3 , respectively.
These CD4 + cell counts were similar to those observed at baseline.
HOW SUPPLIED
16 /STORAGE AND HANDLING VIRAMUNE XR tablets, 400 mg, are yellow, oval, biconvex tablets, debossed with “V04” on one side and the Boehringer Ingelheim logo on the other side.
VIRAMUNE XR 400 mg tablets are supplied in bottles of 30 (NDC 54868-6370-0).
Storage Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].
Store in a safe place out of the reach of children.
RECENT MAJOR CHANGES
Indications and Usage (1) 11/2012 Dosage and Administration General Dosing Considerations (2.1) 11/2012 Pediatric Patients (2.3) 11/2012 Dosage Adjustment (2.5) 11/2012 Warnings and Precautions Immune Reconstitution Syndrome (5.5) 11/2012
GERIATRIC USE
8.5 Geriatric Use Clinical studies of VIRAMUNE XR did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
DOSAGE FORMS AND STRENGTHS
3 VIRAMUNE XR Tablets 100 mg, yellow, round, biconvex extended-release tablets, debossed with “V01” on one side and the Boehringer Ingelheim logo on the other side.
400 mg, yellow, oval, biconvex extended-release tablets, debossed with “V04” on one side and the Boehringer Ingelheim logo on the other side.
100 mg and 400 mg tablets (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Nevirapine is an antiviral drug [ see Microbiology (12.4) ].
INDICATIONS AND USAGE
1 VIRAMUNE XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in children 6 to less than 18 years of age [ see Clinical Studies (14.1 , 14.2) ].
Additional important information regarding the use of VIRAMUNE XR for the treatment of HIV-1 infection: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine should not be initiated in adult females with CD4 + cell counts greater than 250 cells/mm 3 or in adult males with CD4 + cell counts greater than 400 cells/mm 3 unless the benefit outweighs the risk [ see Boxed Warning and Warnings and Precautions (5.1) ].
The 14-day lead-in period with immediate-release VIRAMUNE dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash [ see Dosage and Administration (2.5) and Warnings and Precautions (5.2) ].
If rash persists beyond the 14-day lead-in period with immediate-release VIRAMUNE, do not begin dosing with VIRAMUNE XR.
The lead-in dosing with 200 mg once-daily immediate-release VIRAMUNE should not be continued beyond 28 days, at which point an alternative regimen should be sought.
VIRAMUNE XR is an NNRTI indicated for combination antiretroviral treatment of HIV-1 infection in adults and in children 6 to less than 18 years of age.
(1) Important Considerations: Initiation of treatment is not recommended in the following populations unless the benefits outweigh the risks.
(1 , 5.1) adult females with CD4 + cell counts greater than 250 cells/mm 3 adult males with CD4 + cell counts greater than 400 cells/mm 3 The 14-day lead-in period with immediate-release VIRAMUNE (200 mg once daily) must be strictly followed; it has been demonstrated to reduce the frequency of rash.
(2.5 , 5.2)
PEDIATRIC USE
8.4 Pediatric Use VIRAMUNE XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in children 6 to less than 18 years of age [ see Indications and Usage (1) , Dosage and Administration (2.3) ].
The use of VIRAMUNE XR for the treatment of HIV-1 infection in pediatric patients 6 to less than 18 years of age is based on pharmacokinetic, safety, and antiviral activity data from an open-label trial with VIRAMUNE XR.
The results of this trial were supported by previous demonstration of efficacy in adult patients [ see Adverse Reactions (6.2) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ].
VIRAMUNE XR is not recommended for children less than 6 years of age.
Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than 6 years of age to support the use of VIRAMUNE XR in this age group.
Furthermore, VIRAMUNE XR is not recommended for children less than 3 years of age because they are not able to swallow tablets.
PREGNANCY
8.1 Pregnancy Pregnancy Category B.
There are no adequate and well-controlled trials of nevirapine in pregnant women.
The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine.
The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.
Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection.
Regardless of pregnancy status, women with CD4 + cell counts greater than 250 cells/mm 3 should not initiate nevirapine unless the benefit outweighs the risk.
It is unclear if pregnancy augments the risk observed in non-pregnant women [ see Boxed Warning ].
VIRAMUNE XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to immediate-release VIRAMUNE and VIRAMUNE XR, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling (800) 258-4263.
Animal Data No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits.
The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC).
In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
NUSRING MOTHERS
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.
Nevirapine is excreted in breast milk.
Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving VIRAMUNE XR.
BOXED WARNING
WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine.
In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure.
These events are often associated with rash.
Female gender and higher CD4 + cell counts at initiation of therapy place patients at increased risk; women with CD4 + cell counts greater than 250 cells/mm 3 , including pregnant women receiving nevirapine in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk.
However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4 + cell counts and at any time during treatment.
Hepatic failure has also been reported in patients without HIV taking nevirapine for post-exposure prophylaxis (PEP).
Use of nevirapine for occupational and non-occupational PEP is contraindicated [ see Contraindications (4.2) ].
Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately [ see Warnings and Precautions (5.1) ].
SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine.
These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately.
Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment.
The 14-day lead-in period with immediate-release VIRAMUNE 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed [ see Warnings and Precautions (5.2) ].
MONITORING: Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions.
Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events.
Do not restart nevirapine following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions.
In some cases, hepatic injury has progressed despite discontinuation of treatment.
WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS See full prescribing information for complete boxed warning.
Fatal and non-fatal hepatotoxicity (5.1) Fatal and non-fatal skin reactions (5.2) Discontinue immediately if experiencing: Signs or symptoms of hepatitis (5.1) Increased transaminases combined with rash or other systemic symptoms (5.1) Severe skin or hypersensitivity reactions (5.2) Any rash with systemic symptoms (5.2) Monitoring during the first 18 weeks of therapy is essential.
Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events (5) .
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS 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 associated with signs of hypersensitivity which can 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.
The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions.
The optimal frequency of monitoring during this time period has not been established.
Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release VIRAMUNE, prior to initiation of VIRAMUNE XR (during the lead-in period), and at two weeks after initiation of VIRAMUNE XR therapy.
After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE XR treatment.
In addition, the 14-day lead-in period with immediate-release VIRAMUNE has been demonstrated to reduce the frequency of rash [ see Dosage and Administration (2.2 , 2.5) ].
Patients already on a regimen of immediate-release VIRAMUNE twice daily who switch to VIRAMUNE XR therapy should continue with their ongoing clinical and laboratory monitoring.
Hepatotoxicity: Fatal and non-fatal hepatotoxicity has been reported.
Monitor liver function tests before and during therapy.
Permanently discontinue nevirapine if clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur.
Do not restart nevirapine after recovery.
(5.1) Rash: Fatal and non-fatal skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions, have been reported.
Permanently discontinue nevirapine if severe skin reactions or hypersensitivity reactions occur.
Check transaminase levels immediately for all patients who develop a rash in the first 18 weeks of treatment.
(5.2) Monitor patients for immune reconstitution syndrome and fat redistribution.
(5.5 , 5.6) 5.1 Hepatotoxicity and Hepatic Impairment Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine.
The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy.
The risk continued to be greater in the nevirapine groups in controlled clinical trials through 18 weeks of treatment.
However, hepatic events may occur at any time during treatment.
In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels.
Rash was observed in approximately half of the patients with symptomatic hepatic adverse events.
Fever and flu-like symptoms accompanied some of these hepatic events.
Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia.
Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use.
Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.
Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction.
Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment.
Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly.
The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [ see Boxed Warning , Dosage and Administration (2.4) , and Patient Counseling Information (17.1) ].
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine.
Do not restart nevirapine after recovery.
In some cases, hepatic injury progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 + cell counts.
In a retrospective analysis of pooled clinical trials with immediate-release VIRAMUNE, during the first 6 weeks of treatment women had a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%).
Patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events.
Women with CD4 + cell counts greater than 250 cells/mm 3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4 + cell counts less than 250 cells/mm 3 (11% versus 1%).
An increased risk was observed in men with CD4 + cell counts greater than 400 cells/mm 3 (6% versus 1% for men with CD4 + cell counts less than 400 cells/mm 3 ).
However, all patients, regardless of gender, CD4 + cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 + cell counts.
Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of immediate-release VIRAMUNE in the setting of post-exposure prophylaxis (PEP), an unapproved use.
Use of VIRAMUNE XR for occupational and non-occupational PEP is contraindicated [ see Contraindications (4.2) ].
Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis.
Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity.
Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Contraindications (4.1) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ].
VIRAMUNE XR has not been evaluated in subjects with hepatic impairment.
5.2 Skin Reactions Severe and life-threatening skin reactions, including fatal cases, have been reported in patients taking nevirapine.
These have occurred most frequently during the first 6 weeks of therapy.
These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure.
Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately [ see Boxed Warning and Patient Counseling Information (17.1) ].
Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.
If patients present with a suspected nevirapine-associated rash, measure transaminases immediately.
Permanently discontinue nevirapine in patients with rash-associated transaminase elevations [ see Warnings and Precautions (5.1) ].
Patients must initiate therapy with immediate-release VIRAMUNE daily for the first 14 days.
This lead-in period has been shown to reduce the frequency of rash.
Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings.
Do not initiate VIRAMUNE XR if a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day immediate-release VIRAMUNE lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) until the rash has resolved.
The total duration of the immediate-release VIRAMUNE lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [ see Dosage and Administration (2.5) ].
Patients must be monitored closely if isolated rash of any severity occurs.
Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with nevirapine.
In a clinical trial of immediate-release VIRAMUNE, concomitant prednisone use (40 mg per day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy.
Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.
5.3 Resistance VIRAMUNE XR must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen.
Resistant virus emerges rapidly when nevirapine is administered as monotherapy.
The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance.
When discontinuing an antiretroviral regimen containing VIRAMUNE XR, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [ see Microbiology (12.4) ].
5.4 Drug Interactions See Table 4 for listings of established and potential drug interactions [ see Drug Interactions (7) ].
Concomitant use of St.
John’s wort ( Hypericum perforatum ) or St.
John’s wort-containing products and nevirapine is not recommended.
Co-administration of St.
John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs.
Co-administration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.
5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine.
During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).
17.1 Hepatotoxicity and Skin Reactions Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death.
Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring.
Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly.
Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity and skin reactions.
However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment.
Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions.
Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately.
If nevirapine is discontinued due to hepatotoxicity, do not restart it.
Patients, particularly women, with increased CD4 + cell count at initiation of nevirapine therapy (greater than 250 cells/mm 3 in women and greater than 400 cells/mm 3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash.
Advise patients that co-infection with hepatitis B or C and/or increased transaminases at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT [ see Boxed Warning and Warnings and Precautions (5.1) ].
The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy.
Instruct patients that if any rash occurs during the two-week lead-in period with immediate-release VIRAMUNE, do not initiate VIRAMUNE XR until the rash resolves.
The total duration of the lead-in dosing period with immediate-release VIRAMUNE should not exceed 28 days, at which point an alternative regimen may need to be started.
Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately.
Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult a physician.
Nevirapine should not be restarted following severe skin rash or hypersensitivity reaction.
Women tend to be at higher risk for development of nevirapine-associated rash.
For patients who interrupt VIRAMUNE XR dosing for more than 7 days and for whom restarting nevirapine therapy is not contraindicated, restart the recommended lead-in dosing with immediate-release VIRAMUNE using one 200 mg tablet daily (150 mg/m 2 /day in pediatric patients) for the first 14 days [ see Boxed Warning, Dosage and Administration (2.5) , and Warnings and Precautions (5.2) ].
17.2 Administration Inform patients to take VIRAMUNE XR every day as prescribed.
Patients should not alter the dose without consulting their doctor.
If a dose is missed, patients should take the next dose as soon as possible.
However, if a dose is skipped, the patient should not double the next dose.
Advise patients to report to their doctor the use of any other medications.
Instruct patients to swallow VIRAMUNE XR tablets whole.
They must not be chewed, crushed, or divided.
VIRAMUNE XR is not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections.
Advise patients to remain under the care of a physician when using VIRAMUNE XR.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others: Do not share needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection.
Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not breastfeed.
We do not know if VIRAMUNE XR can be passed to your baby in your breast milk and whether it could harm your baby.
Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Inform patients that they may occasionally see soft remnants of VIRAMUNE XR in their stool.
These occurrences have not been shown to affect drug levels or response.
17.3 Drug Interactions VIRAMUNE XR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St.
John’s wort [ see Warnings and Precautions (5.4) and Drug Interactions (7) ].
17.4 Contraceptives Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), should not be used as the sole method of contraception in women taking VIRAMUNE XR, since VIRAMUNE XR may lower the plasma levels of these medications.
Additionally, when oral contraceptives are used for hormonal regulation during VIRAMUNE XR therapy, the therapeutic effect of the hormonal therapy should be monitored [ see Drug Interactions (7) ].
17.5 Methadone VIRAMUNE XR may decrease plasma concentrations of methadone by increasing its hepatic metabolism.
Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly.
Monitor methadone-maintained patients beginning nevirapine therapy for evidence of withdrawal and adjust methadone dose accordingly [ see Drug Interactions (7) ].
17.6 Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [ see Warnings and Precautions (5.6) ].
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA Copyright 2012 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED IT5243GK142012 10006580/04 Distributed by: Physicians Total Care, Inc.
Tulsa, OK 74146
DOSAGE AND ADMINISTRATION
2 The VIRAMUNE XR tablets must be swallowed whole and must not be chewed, crushed, or divided (2.1) Adult patients must initiate therapy with one 200 mg tablet of immediate-release VIRAMUNE once daily for the first 14 days, followed by one 400 mg tablet of VIRAMUNE XR once daily.
(2.2) Adult patients already on a regimen of immediate-release VIRAMUNE twice daily can be switched to VIRAMUNE XR 400 mg once daily without the 14-day lead-in period of immediate-release VIRAMUNE.
(2.2) Pediatric patients (ages 6 to less than18 years) must initiate therapy with immediate-release VIRAMUNE (as 150 mg/m 2 of VIRAMUNE Oral Suspension or as VIRAMUNE tablet) at a dose not to exceed 200 mg per day administered once daily for the first 14 days, followed by VIRAMUNE XR once daily as shown in the following table.
(2.3) Recommended Dosing for Pediatric Patients 6 to less than 18 years of age by BSA after the Lead-in Period BSA range (m 2 ) VIRAMUNE XR tablets dose (mg) 0.58 – 0.83 200 mg once daily (2 x 100 mg) 0.84 – 1.16 300 mg once daily (3 x 100 mg) Greater than or equal to 1.17 400 mg once daily (1 x 400 mg) Pediatric patients already on a regimen of twice-daily VIRAMUNE Oral Suspension or immediate-release VIRAMUNE can be switched to VIRAMUNE XR once daily without the 14-day lead-in period of VIRAMUNE Oral Suspension or immediate-release VIRAMUNE.
(2.3) If any patient experiences rash during the 14-day lead-in period with immediate-release VIRAMUNE do not initiate VIRAMUNE XR until the rash has resolved.
Do not continue the immediate-release VIRAMUNE lead-in dosing regimen beyond 28 days.
(2.5) If dosing is interrupted for greater than 7 days, restart 14-day lead-in dosing.
(2.5) 2.1 General Dosing Considerations VIRAMUNE XR tablets must be swallowed whole and must not be chewed, crushed, or divided.
Children should be assessed for their ability to swallow tablets before prescribing VIRAMUNE XR tablets.
VIRAMUNE XR can be taken with or without food.
No recommendations can be made regarding substitution of four VIRAMUNE XR 100 mg tablets for one VIRAMUNE XR 400 mg tablet.
2.2 Adult Patients Patients not currently taking immediate-release VIRAMUNE Patients must initiate therapy with one 200 mg tablet of immediate-release VIRAMUNE daily for the first 14 days in combination with other antiretroviral agents (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg tablet of VIRAMUNE XR once daily.
Switching Patients from immediate-release VIRAMUNE to VIRAMUNE XR Patients already on a regimen of immediate-release VIRAMUNE twice daily in combination with other antiretroviral agents can be switched to VIRAMUNE XR 400 mg once daily in combination with other antiretroviral agents without the 14-day lead-in period of immediate-release VIRAMUNE.
2.3 Pediatric Patients Pediatric patients may be dosed using VIRAMUNE XR 400 mg or 100 mg tablets.
VIRAMUNE XR is dosed based on a patient’s body surface area (BSA) calculated using the Mosteller formula.
All pediatric patients must initiate therapy with immediate-release VIRAMUNE (as 150 mg/m 2 of VIRAMUNE Oral Suspension or as VIRAMUNE tablets), at a dose not to exceed 200 mg per day, administered once daily for the first 14 days.
This lead-in period should be used because it has been demonstrated to reduce the frequency of rash.
This lead-in period is not required if the patient is already on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents.
The recommended oral doses of VIRAMUNE XR for pediatric patients 6 to less than 18 years of age based upon their BSA are described in the table below.
The total daily dose should not exceed 400 mg for any patient.
Table 1 Recommended VIRAMUNE XR Dosing for Pediatric Patients 6 to less than 18 years of age by BSA after the Lead-in Period with Immediate-Release VIRAMUNE BSA range (m 2 ) VIRAMUNE XR tablets dose (mg) 0.58 – 0.83 200 mg once daily (2 x 100 mg) 0.84 – 1.16 300 mg once daily (3 x 100 mg) Greater than or equal to 1.17 400 mg once daily (1 x 400 mg) Mosteller Formula: BSA (m 2 ) = formula 2.4 Monitoring of Patients Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine.
The optimal frequency of monitoring during this period has not been established.
Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release VIRAMUNE, prior to initiation of VIRAMUNE XR, and at two weeks after initiation of VIRAMUNE XR therapy.
After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout VIRAMUNE XR treatment [ see Warnings and Precautions (5) ].
In some cases, hepatic injury has progressed despite discontinuation of treatment.
Patients already on a regimen of immediate-release VIRAMUNE twice daily who switch to VIRAMUNE XR once daily should continue with their ongoing clinical and laboratory monitoring.
2.5 Dosage Adjustment Patients with Rash Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings [ see Boxed Warning, Warnings and Precautions (5.2) , and Patient Counseling Information (17.1) ].
Do not initiate therapy with VIRAMUNE XR if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of immediate-release VIRAMUNE until the rash has resolved [ see Warnings and Precautions (5.2) and Patient Counseling Information (17.1) ].
The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.
Patients with Hepatic Events If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine.
Do not restart nevirapine after recovery [ see Warnings and Precautions (5.1) ].
Patients with Dose Interruption For patients who interrupt VIRAMUNE XR dosing for more than 7 days, restart the recommended lead-in dosing with immediate-release VIRAMUNE, using one 200 mg tablet daily for the first 14 days.
Patients with Renal Impairment Patients with CrCL greater than or equal to 20 mL per min and not requiring dialysis do not require an adjustment in dosing.
The pharmacokinetics of nevirapine have not been evaluated in patients with CrCL less than 20 mL per min.
An additional 200 mg dose of immediate-release VIRAMUNE following each dialysis treatment is indicated in patients requiring dialysis.
Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [ see Clinical Pharmacology (12.3) ].
VIRAMUNE XR has not been studied in patients with renal dysfunction.