Apo-Nevirapine Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

APO-NEVIRAPINE or APO-NEVIRAPINE XR (nevirapine) is indicated as an alternative for:

• treatment of HIV-1 infection in combination with other antiretroviral agents.

The decision to use APO-NEVIRAPINE or APO-NEVIRAPINE XR should take into account liver and skin toxicity, potentially fatal, especially in patients with higher CD4 counts and in women (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and Skin). Clinical trials have not established equivalence of nevirapine to protease inhibitors or to other NNRTIs.

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm³ or in adult males with CD4+ cell counts greater than 400 cells/mm³ unless the benefit outweighs the risk.

Geriatrics (> 65 years of age):

Clinical studies of nevirapine immediate release or nevirapine extended release tablets 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.

Paediatrics (<15 years of age):

Safety and effectiveness of APO-NEVIRAPINE or APO-NEVIRAPINE XR in HIV-1 infected pediatric patients younger than 15 years of age has not been established. Nevirapine is metabolized more rapidly in pediatric patients than in adults.

CONTRAINDICATIONS

• APO-NEVIRAPINE or APO-NEVIRAPINE XR (Nevirapine) is contraindicated in patients with clinically significant hypersensitivity to any of its components. For a complete listing see the DOSAGE FORMS, COMPOSITION AND PACKAGING sections of the Product Monograph.
• APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be administered to patients with severe hepatic dysfunction or pre-treatment AST or ALT > 5X Upper Limit of Normality (ULN).
• APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be readministered to patients who have been discontinued for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to nevirapine.
• APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be readministered in patients who previously had AST or ALT > 5X Upper Limit of Normality (ULN) during nevirapine therapy (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and Skin).
• APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be administered to patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption.
• Herbal preparations containing St John’s wort (Hypericum perforatum) must not be used while taking APO-NEVIRAPINE or APO-NEVIRAPINE XR due to the risk of potentially significant decreases of plasma concentrations and reduced clinical effects of nevirapine (see DRUG INTERACTIONS).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Nevirapine immediate release or nevirapine extended release tablets should not be initiated in adult females, including pregnant women, with CD4+ cell counts > 250 cell/mm³ and in adult males with CD4 cell counts> 400 cells/mm³ unless the benefit outweighs the risk. Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine. An increased risk of hepatic adverse events is associated with female gender and higher CD4 counts (see, General and Hepatic/Biliary/Pancreatic sections below).

Severe, life-threatening skin reactions, including fatal cases, have been reported with nevirapine treatment, occurring almost exclusively during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome characterized by rash, constitutional findings, and organ dysfunction (see ADVERSE REACTIONS, Adverse Drug Reaction Overview). Patients should be carefully monitored during the first 18 weeks of treatment. 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 immediate release or nevirapine extended release tablets and seek medical evaluation immediately (see Guidelines for the MANAGEMENT OF RASH EVENTS, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

General

Women and patients with higher CD4 counts are at increased risk of hepatic adverse events. The first 18 weeks of therapy with APO-NEVIRAPINE or APO-NEVIRAPINE XR are a critical period during which intensive 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, however it may be prudent to conduct clinical and laboratory monitoring more often than once per month; for example, liver function tests at baseline, prior to dose escalation and at two weeks post dose escalation. After the initial 18 week period, frequent clinical and laboratory monitoring should continue throughout treatment. The greatest risk of hepatic events and skin reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past this period and monitoring should continue at frequent intervals.

Resistant virus emerges rapidly and uniformly when APO-NEVIRAPINE or APO-NEVIRAPINE XR are administered as monotherapy. Therefore, APO-NEVIRAPINE or APO-NEVIRAPINE XR should always be administered in combination with other antiretroviral agents for the treatment of HIV-1 infection.

When discontinuing an antiretroviral regimen containing APO-NEVIRAPINE or APO-NEVIRAPINE XR, the longer half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than APO-NEVIRAPINE or APO-NEVIRAPINE XR are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.

When administering APO-NEVIRAPINE or APO-NEVIRAPINE XR as part of a multi-drug antiretroviral treatment regimen, the complete product information for each therapeutic component should be consulted before initiation of treatment.

Patients receiving APO-NEVIRAPINE or APO-NEVIRAPINE XR or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. Nevirapine immediate release or nevirapine extended release tablets therapy has not been shown to reduce the risk of horizontal transmission of HIV-1 to others.

Inform patients that they may occasionally see soft remnants of APO-NEVIRAPINE XR in their stool, which sometimes resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

Hepatic/Biliary/Pancreatic

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. 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 counts at the initiation of therapy place patients at greater risk of hepatic adverse events. Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm³, including pregnant women receiving chronic treatment for HIV infection, or in adult males with CD4+ cell counts greater than 400 cells/mm³ unless the benefit outweighs the risk. In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions must discontinue APO-NEVIRAPINE or APO-NEVIRAPINE XR and seek medical evaluation immediately. APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be restarted following severe hepatic, skin or hypersensitivity reactions.

In clinical trials, the risk of hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls 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. Some of these events have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia. Rash and fever accompanied some of these hepatic events. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver function tests.

In rare instances rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with nevirapine use.

Increased AST or ALT levels and/or co-infection with hepatitis B and C at the start of antiretroviral therapy are associated with a greater risk of hepatic adverse events.

In a retrospective analysis of pooled clinical studies with nevirapine immediate-release tablets, women had a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 counts at initiation of nevirapine therapy were at higher risk for symptomatic hepatic events with nevirapine. Women with CD4 counts > 250 cells/mm³ had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts < 250 cells/mm³ (11.0% versus 0.9%). An increased risk was also observed in men with CD4 counts > 400 cells/mm³ (6.3% versus 2.3% for men with CD4 counts < 400 cells/mm³).

APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be administered to patients with severe hepatic dysfunction (see CONTRAINDICATIONS). Single dose pharmacokinetic results suggest caution should be exercised when APO-NEVIRAPINE or APO-NEVIRAPINE XR is administered to patients with moderate hepatic dysfunction. APO-NEVIRAPINE or APO-NEVIRAPINE XR is extensively metabolised by the liver and nevirapine metabolites are eliminated largely by the kidney. Increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease.

Risk Factors for Symptomatic Hepatic Events

• Elevated pretreatment ALT or AST
• HBV and/or HCV coinfection ^‡

• Higher CD4+ cell count at initiation of nevirapine immediate release or

  nevirapine extended release therapy

• Female gender

• Women with CD4+ cell counts >250 cells/mm³, including pregnant

  women receiving chronic treatment for HIV infection, are at considerably higher risk of hepatotoxicity, including fatal events

Patient Management

• Counsel patients that if signs or symptoms of hepatitis,^§ severe skin

  reactions, or hypersensitivity occur, then discontinue nevirapine immediate release or nevirapine extended release tablets and seek medical evaluation immediately

• Frequent clinical and laboratory monitoring is essential, especially during

  the first 18 weeks of treatment - extra vigilance is warranted during the first 6 weeks

• Baseline assessments should include LFTs and HBV/HCV status

• If hepatic symptoms occur:

  Permanently discontinue nevirapine immediate release or nevirapine extended release tablets

  Consider stopping all potential hepatotoxins, including concomitant antiretrovirals

  Evaluate patient for other causes, including HBV/HCV coinfection, alcohol use, and coadministered medications

  Continue to monitor patient until symptoms resolve

• In some cases, hepatic injury has progressed despite discontinuation of

  treatment

* Hepatic events include symptomatic hepatitis and/or ALT/AST >5X ULN. ‡ Risk factors associated with regimens with and without nevirapine immediate release or nevirapine extended release .

§ Signs and symptoms of hepatitis may include anorexia, malaise, jaundice, nausea/vomiting, bilirubinemia, acholic stools, hepatomegaly, and hepatic tenderness. Other constitutional symptoms may include fever, arthralgia, fatigue, and other findings of generalized organ dysfunction. The presence of one or more of these findings does not necessarily indicate hepatitis. Diagnosis should be based on sound clinical judgment.

|| If nevirapine immediate release or nevirapine extended release tablets has been interrupted for >7 days, reintroduce with 200-mg once -daily lead-in dose. MANAGEMENT OF HEPATIC EVENTS WITH NEVIRAPINE IMMEDIATE RELEASE or NEVIRAPINE EXTENDED RELEASE

TABLETS*

Other Important Information

• The 14-day lead-in period with nevirapine tablets 200 mg daily must be strictly followed^||

• Nevirapine immediate release or nevirapine extended release tablets should not be used for multiple-dose postexposure prophylaxis. Serious hepatotoxicity, including hepatic failure, has occurred in this

  Severe, life-threatening, and in some cases fatal, hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. Patients with signs and symptoms of hepatitis must seek medical evaluation immediately and should be advised to discontinue nevirapine immediate release or nevirapine extended release tablets.

Skin

Severe, life-threatening skin reactions, including fatal cases, have been reported with nevirapine treatment, occurring almost exclusively during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity syndrome characterized by rash, constitutional findings, and organ dysfunction (see ADVERSE REACTIONS, Adverse Drug Reaction Overview). Patients should be carefully monitored during the first 18 weeks of treatment. 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 APO-NEVIRAPINE or APO-NEVIRAPINE XR and seek medical evaluation immediately (see Guidelines for the MANAGEMENT OF RASH EVENTS, WARNINGS AND PRECAUTIONS; Skin and ADVERSE REACTIONS, Skin and Subcutaneous Tissues).

APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be restarted following severe skin rash or hypersensitivity reaction (see Guideline for the MANAGEMENT OF RASH EVENTS). Some of the risk factors for developing serious cutaneous reactions include failure to follow the initial dosing of 200 mg daily during the 14-day lead-in period and delay in stopping the nevirapine treatment after the onset of the initial symptoms.

Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg/day which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period of 200 mg immediate-release tablet, dose escalation to 200 mg immediate-release tablet twice-daily or 400 mg extended-release tablet once daily should not occur until the rash has resolved. (see Guideline for the MANAGEMENT OF RASH EVENTS, and DOSAGE AND ADMINISTRATION, Monitoring of Patients) Patients should be monitored closely if an isolated rash of any severity occurs. The risk of development of resistance to nevirapine is unknown when the 200 mg once daily dosing regimen is continued beyond 14 days.

If patients present with a suspected APO-NEVIRAPINE or APO-NEVIRAPINE XR -associated rash, liver function tests should be performed. Patients with rash-associated AST or ALT elevations should be permanently discontinued from APO-NEVIRAPINE or APO-NEVIRAPINE XR.

In rare instances rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with nevirapine use.

Women appear to be at higher risk than men of developing rash with APO-NEVIRAPINE or APO-NEVIRAPINE XR.

In a clinical trial, the concomitant use of prednisone (40 mg/day for the first 14 days of nevirapine immediate-release administration) was associated with an increase in the incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, the use of prednisone to prevent nevirapine immediate release or nevirapine extended release tablets -associated rash is not recommended.

MANAGEMENT OF RASH EVENTS WITH NEVIRAPINE IMMEDIATE RELEASE or NEVIRAPINE EXTENDED RELEASE

TABLETS*

Patient Management

The recommended 14-day, 200-mg once-daily lead-in dose, prior to escalation to 200 mg immediate-release tablet twice daily or 400 mg extended-release tablet once daily, has been shown to reduce the frequency of rash and must be strictly followed

Do not increase the dose of nevirapine immediate release or nevirapine extended release tablets in the presence of rash

If nevirapine immediate release or nevirapine extended release tablets is interrupted for >7 days, reintroduce with the 14-day, 200-mg once-daily lead-in dose

It is suggested that nevirapine immediate release or nevirapine extended release tablets and other medications that often cause rash should not be started simultaneously

Prednisone should not be used to prevent rash. Prednisone administration during the first 2 weeks of therapy with nevirapine appears to increase the incidence of rash

Antihistamines do not appear to be effective in preventing rash with nevirapine immediate release or nevirapine extended release tablets

Definitions (cont’d)

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis (TEN)

• Urticaria: pruritic raised rash with welts

  (may be mild, moderate, or severe)

• Constitutional symptoms include fever,

  blistering, oral erosive lesions, conjunctivitis, facial edema, and myalgia/arthralgia

  *Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included severe cases of SJS, TEN, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs and symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine immediate release or nevirapine extended release tablets as soon as possible.

Definitions

• Mild or moderate rash may include:

  • Erythema

  • Diffuse erythematous or

    maculopapular rash

• Severe rash may include:

  • Extensive erythematous or

    maculopapular rash

  • Rash with moist desquamation
  • Rash with angioedema

  • Serum sickness-like reaction

    Access rash and evaluate ALT/AST

    Risk Management Algorithm

    • Mild or moderate rash with

      no constitutional symptoms

    • Rash + no increase in ALT

      or AST

      • Severe rash or
      • Rash + constitutional symptoms + organ dysfunction or
      • Rash + increased ALT or AST

If urticarial rash (mild or moderate), the patient may continue nevirapine, but DO NOT reintroduce nevirapine if it is stopped. If rash or prodromal symptoms occur during lead-in, the dose should not be escalated until rash resolves. The risk of development of resistance to nevirapine is unknown when the 200 mg once daily dosing regimen is continued beyond 14 days

Can continue Permanently discontinue Post-Exposure Prophylaxis

APO-NEVIRAPINE or APO-NEVIRAPINE XR is not recommended for post-exposure prophylaxis. In the setting of post-exposure prophylaxis, an unapproved use, serious hepatotoxicity, including one instance of liver failure requiring transplantation, and serious skin rash including Stevens-Johnson syndrome, have been reported in HIV-uninfected individuals receiving multiple doses of nevirapine in combination with other antiretroviral agents.

Carcinogenesis and Mutagenesis

In long-term carcinogenicity studies, the incidence of hepatocellular adenomas and carcinomas in mice increased at all doses in males and at the two high doses in females. In rats an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies were lower than that measured in humans at the recommended daily dose.

In genetic toxicology assays, nevirapine showed no evidence of mutagenic activity in a battery of in vitro and in vivo assays including microbial assays for gene mutation (Ames test in Salmonella strains and E. coli), mammalian cell gene mutation (HGRPT) assays in Chinese hamster ovary (CHO) cell line, cytogenetic assays using a CHO cell line and mouse bone marrow micronucleus assay following oral administration. In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that observed following a human clinical dosage of 400 mg/day.

Renal

APO-NEVIRAPINE or APO-NEVIRAPINE XR is extensively metabolised by the liver and nevirapine metabolites are eliminated largely by the kidney. In renal dysfunction, a single dose study suggested that patients with a creatinine clearance ≥ 20 mL/min do not require an adjustment in APO-NEVIRAPINE or APO-NEVIRAPINE XR dosing (see DETAILED PHARMACOLOGY, Special Populations).

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.

Immune Reactivation Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy, 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 few weeks or months of initiation of combination antiretroviral therapy. Relevant examples are cytomegalovirus retinitis, generalised and /or focal mycobacterial infections, and Pneumocytis pneumonia. Autoimmune disorders (such as Graves’ disease) 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. Any inflammatory symptoms should be evaluated and treatment intstituted when necessary.

Concomitant Use with Other Drugs

APO-NEVIRAPINE or APO-NEVIRAPINE XR can alter plasma exposure of other drugs, and other drugs can alter plasma exposure of APO-NEVIRAPINE or APO-NEVIRAPINE XR. Combining the following compounds with APO-NEVIRAPINE or APO-NEVIRAPINE XR is not recommended: efavirenz, rifampicin (rifampin), ketoconazole; delavirdine, etravirine, rilpivirine, elvitegravir (in combination with cobicistat), boceprevir; if not co-administered with low dose ritonavir: fosamprenavir and saquinavir (see DRUG INTERACTIONS).

Birth Control Methods

Depo Medroxyprogesterone Acetate (DMPA)

Hormonal methods of birth control other than DMPA should not be used as the sole method of contraception in women taking APO-NEVIRAPINE or APO-NEVIRAPINE XR. Nevirapine may lower the plasma concentrations of these medications (see DRUG INTERACTIONS). Therefore, when postmenopausal hormone therapy is used during administration of APO-NEVIRAPINE or APO-NEVIRAPINE XR, its therapeutic effect should be monitored.

Special Populations

Pregnant Women:

APO-NEVIRAPINE or APO-NEVIRAPINE XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There have been no adequate and well-controlled studies of nevirapine in pregnant women, nor are there reports of infants born to women who conceived while receiving nevirapine chronic dosing in clinical trials. 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 for HIV infection. Regardless of pregnancy status, women with CD4 counts >250 cells/mm³ should not initiate APO-NEVIRAPINE or APO-NEVIRAPINE XR unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women. (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of nevirapine

No human data on fertility are available.

Antiretroviral Pregnancy Registry:

To monitor maternal-fetal outcomes of pregnant women exposed to nevirapine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Women:

It is currently recommended that HIV-1 infected women should not breast feed infants regardless of the use of antiretroviral agents, to avoid post-natal transmission of HIV-1.

Preliminary results from a pharmacokinetic study (ACTG 250) of 10 HIV-1-infected pregnant women who were administered a single oral dose of 100 or 200 mg nevirapine at a median of 5.8 hours before delivery, indicated that nevirapine readily crosses the placenta and is found in breast milk (breast milk samples taken from 3 out of 10 mothers).

Pediatrics (< 15 years of age):

Safety and effectiveness of APO-NEVIRAPINE or APO-NEVIRAPINE XR in HIV-1-infected pediatric patients younger than 15 years of age have not been established. Nevirapine is metabolized more rapidly in pediatric patients than in adults.

Geriatrics (> 65 years of age):

Clinical studies of APO-NEVIRAPINE or APO-NEVIRAPINE 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.

Ethnic Origin:

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median C_minss= 4.7 μg/mL Black, 3.8 μg/mL Hispanic, 4.3 μg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Monitoring and Laboratory Tests

Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment (see WARNINGS AND PRECAUTIONS, General). The optimal frequency of monitoring during this period has not been established, however it may be prudent to conduct clinical and laboratory monitoring more often than once per month; for example, liver function tests at baseline, prior to dose escalation and at two weeks post-dose escalation. Monitoring should continue at frequent intervals thereafter, depending on the patient's clinical status. Liver function tests should be performed immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Liver function tests should also be obtained 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 hepatic injury should be considered in this setting, even if liver function tests are initially normal or alternative diagnoses are possible (see WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION). Nevirapine immediate release or nevirapine extended release tablets administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities (> 5X ULN) (excluding GGT), until the liver function test elevations have returned to baseline. Nevirapine may then be restarted at the lead-in dose of one immediate-release 200 mg tablet daily for 14 days followed by one 200 mg nevirapine immediate-release tablet twice daily or one 400 mg nevirapine extended-release tablet once daily. Increasing the daily dose to 200 mg twice daily (400 mg/day) should be done with caution, after extended observation. If rash is observed during the lead-in period of 200 mg immediate-release tablet, dose escalation to 200 mg immediate-release tablet twice-daily or 400 mg extended-release tablet once daily should not occur until the rash has resolved (see Guideline for the MANAGEMENT OF RASH EVENTS, and DOSAGE AND ADMINISTRATION). Patients should be aware that this may not prevent serious adverse reactions. APO-NEVIRAPINE or APO-NEVIRAPINE XR should be permanently discontinued if moderate or severe liver function test abnormalities recur (see WARNINGS AND PRECAUTIONS).

If clinical hepatitis occurs, APO-NEVIRAPINE or APO-NEVIRAPINE XR should be permanently discontinued and not restarted after recovery. If either AST or ALT increase to > 5X ULN, APO-NEVIRAPINE or APO-NEVIRAPINE XR should be immediately stopped. APO-NEVIRAPINE or APO-NEVIRAPINE XR should not be readministered to patients who have been discontinued for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to APO-NEVIRAPINE or APO-NEVIRAPINE XR (see Guideline for the MANAGEMENT OF HEPATIC EVENTS). In some cases hepatic injury progresses despite the discontinuation of treatment.

For patients already on a regimen of nevirapine immediate-release tablets twice daily who switch to nevirapine extended-release tablets once daily there is no need for a change in their monitoring schedule.

With AST or ALT values > 2X ULN, liver tests should be monitored more frequently.

Asymptomatic elevation of liver enzymes occurs frequently in patients infected with HIV and is not necessarily a contraindication to initiating therapy with APO-NEVIRAPINE or APO-NEVIRAPINE XR. Asymptomatic GGT elevations are not a contraindication to continuing therapy.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most serious adverse reactions associated with nevirapine immediate-release or extended-release tablets are clinical hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Clinical 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, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and renal dysfunction. Severe and life-threatening hepatic injury, and fatal fulminant hepatitis, have been reported in patients treated with nevirapine. The first 18 weeks of treatment is a critical period, but such events may also occur later. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk continues past this period and monitoring should continue at frequent intervals throughout treatment. (see WARNINGS AND PRECAUTIONS Hepatic/Biliary/Pancreatic and Skin).

Hepato-Biliary

In controlled clinical trials, clinical hepatic events regardless of severity occurred in 4.0% (range 2.5% to 11.0%) of patients who received nevirapine immediate-release tablets and 1.2% of patients in control groups. Transaminase elevations (ALT or AST > 5X ULN) were observed in 8.8% of patients receiving nevirapine immediate-release tablets and 6.2% of patients in control groups in clinical trials. In a retrospective analysis of controlled and uncontrolled clinical trials, patients with higher CD4 counts at initiation of nevirapine immediate-release tablets therapy, particularly women, were at greater risk for acute symptomatic hepatic events, including death, especially in the first six weeks of therapy.

Patients with chronic hepatitis B or C infection were at higher risk for later hepatic events (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

In the Phase 3 trial comparing nevirapine extended release formulation to nevirapine immediate release formulation in treatment naïve subjects (see CLINICAL TRIALS, Trial 1100.1486, VERxVE) safety data included all patient visits up to the time of the last patient’s completion of study week 144. The incidence of symptomatic hepatic events during the nevirapine immediate-release lead-in phase was 0.5%. After the lead-in period the incidence of symptomatic hepatic events was 2.4% in the nevirapine immediate-release group and 1.6% in the nevirapine extended-release group.

In the Phase 3 trial comparing nevirapine extended release formulation to nevirapine immediate release formulation in treatment experienced subjects (see CLINICAL TRIALS, Trial 1100.1526, TRANxITION) no Grade 3 or 4 clinical hepatic events were observed in either treatment group.

Skin and Subcutaneous Tissues

The most common clinical toxicity of nevirapine is rash. In placebo-controlled trials involving 1374 patients treated with nevirapine immediate-release tablets (Table 1), rash, of all grades and causality occurred in 14-20% of patients treated with nevirapine. Severe or life-threatening rash occurred in approximately 2% of nevirapine immediate-release tablets treated patients, almost exclusively within the first 6 weeks of therapy.

Rashes were usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Allergic reactions (anaphylaxis, angio-oedema and urticaria) have been reported. Severe and life-threatening skin reactions have occurred in patients treated with nevirapine, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Fatal cases of SJS, TEN and hypersensitivity reactions have been reported. Based on a denominator of 2861 nevirapine-treated clinical trial patients treated with nevirapine immediate-release tablets, the overall incidence of SJS was 0.3% (9/2861).

Rashes occur alone or in the context of a hypersensitivity syndrome characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia and renal dysfunction.

TABLE 1: RISK OF RASH (%) IN ADULT PLACEBO CONTROLLED TRIALS ¹ – REGARDLESS OF CAUSALITY

1 Trials 1037, 1038, 1046 and 1090

2 % based on Kaplan-Meier probability estimates

3 NCI grading system

In the Phase 3 trial comparing nevirapine extended release formulation to nevirapine immediate release formulation in treatment naïve subjects (see CLINICAL TRIALS, Trial 1100.1486, VERxVE) safety data included all patient visits up to the point in time of when the last patient completed 144 weeks in the trial. This also includes safety data for patient visits in the post-week 144 open label extension (which patients in either treatment group who completed the 144 week blinded phase could enter). Severe or life-threatening rash considered related to nevirapine treatment occurred in 1.1% of patients during the lead-in phase with nevirapine immediate-release. Severe rash occurred in 1.4% and 0.2% of the of the nevirapine immediate-release and nevirapine extended-release groups respectively during the randomization phase. No life-threatening (Grade 4) rash events considered related to nevirapine were reported during the randomised phase of this study. Six cases of Stevens-Johnson Syndrome were reported in the trial, all but one occurred within the first 30 days of nevirapine immediate-release treatment.

In the Phase 3 trial comparing nevirapine extended-release formulation to nevirapine immediate-release formulation in treatment experienced subjects (see CLINICAL TRIALS, Trial 1100.1526, TRANxITION) no Grade 3 or 4 rash was observed in either treatment group.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse Reactions in Controlled Clinical Trials

No new adverse drug reactions from those previously known to be associated with nevirapine immediate release tablets have been observed in clinical studies comparing the immediate-release and extended-release formulations.

Treatment related, adverse experiences of moderate or severe intensity observed in >2% of patients receiving nevirapine immediate-release tablets in placebo-controlled trials are shown in Table 2.

TABLE 2: PERCENTAGE OF PATIENTS WITH MODERATE OR SEVERE DRUG RELATED REACTIONS IN ADULT PLACEBO-CONTROLLED TRIALS

¹ Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4+ counts <200 cells/mm³.

² Background therapy included ZDV and ZDV+ddI; nevirapine monotherapy was administered in some patients. Patients had CD4+ >200 cells/mm³.

Abnormal Hematologic and Clinical Chemistry Findings

The most frequently observed laboratory test abnormalities are elevations in liver function tests (LFTs), including ALT, AST, GGT, total bilirubin and alkaline phosphatase. Asymptomatic elevations of GGT levels are the most frequent. Cases of jaundice have been reported. Cases of hepatitis, severe and life-threatening hepatotoxicity, and fatal fulminant hepatitis, have been reported in patients treated with nevirapine.

Liver function test abnormalities (AST, ALT) were observed more frequently in patients receiving nevirapine immediate-release tablets than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue nevirapine immediate-release tablets therapy in the absence of elevations in other liver function tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing nevirapine immediate-release tablets and control regimens (Table 3).

TABLE 3: PERCENTAGE OF ADULT PATIENTS WITH MARKED LABORATORY ABNORMALITIES

¹ Background therapy included 3TC for all patients and combinations of NRTIs and PIs. Patients had CD4+ counts <200 cells/mm³.

² Background therapy included ZDV and ZDV+ddI; nevirapine monotherapy was administered in some patients. Patients had CD4+ ≥200 cells/mm³.

Because clinical hepatitis has been reported in nevirapine immediate-release tablets treated patients, intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment. Monitoring should continue at frequent intervals thereafter, depending on the patient’s clinical status (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Post-Market Adverse Drug Reactions

In addition to the adverse events identified during clinical trials, the following events have been reported with the use of nevirapine in clinical practice:

Body as a Whole: fever, somnolence, drug withdrawal (see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS), redistribution/accumulation of body fat (see WARNINGS AND PRECAUTIONS, Fat Redistribution).

Gastrointestinal: vomiting

Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure

Hematology: anemia (more commonly observed in children), eosinophilia, neutropenia

Musculoskeletal: arthralgia

Neurologic: paraesthesia

Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise or significant hepatic abnormalities (see WARNINGS AND PRECAUTIONS, Skin) plus one or more of the following: hepatitis, eosinophilia, granulocytopenia and/or renal dysfunction have been reported with the use of nevirapine.

Apart from rash and abnormal LFTs, the most frequently reported adverse events related to nevirapine therapy across all clinical trials were nausea, fatigue, fever, headache, vomiting, diarrhea, abdominal pain and myalgia. In very rare instances, cases of anaemia and neutropenia may be associated with nevirapine immediate release or extended release tablets therapy. Arthralgia has been reported as a stand-alone event in rare instances in patients receiving nevirapine containing regimens.

The following events have also been reported when nevirapine has been used in combination with other anti-retroviral agents: pancreatitis, peripheral neuropathy and thrombocytopenia. These events are commonly associated with other anti-retroviral agents and may be expected to occur when nevirapine immediate release or extended release tablets is used in combination with other agents.

In summary the list of side effects, which can be expected with nevirapine immediate release or extended release tablets treatment, includes:

Blood and lymphatic system disorders

Granulocytopenia, anaemia

Immune system disorders

Drug reaction with eosinophilia and systemic symptoms, anaphylactic reaction, hypersensitivity (characterised by rash associated with constitutional symptoms such as fever, arthalgia, myalgia and lymphadenopathy plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, renal dysfunction or other visceral involvement has also been reported. Also including anaphylactic reaction, angioedema, urticaria)

Nervous system disorders

Headache

Gastrointestinal disorders

Diarrhoea, abdominal pain, nausea, vomiting

Hepatobiliary disorders

Hepatitis (including severe and life threatening hepatotoxicity), hepatitis fulminant (which may be fatal), jaundice

Skin and subcutaneous tissue disorders

Rash, Stevens-Johnson Syndrome/toxic epidermal necrolysis (which may be fatal), angioedema, urticaria

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia

General disorders and administration site conditions

Pyrexia, fatigue

Investigations

Liver function test abnormal (alanine aminotransferase increased; transaminases increased; aspartate aminotransferase increased; gamma-glutamyltransferase increased; hepatic enzyme increased; hypertransaminasaemia; total bilirubin, alkaline phosphatase), blood phosphorus decreased, blood pressure increased

DRUG INTERACTIONS

Serious Drug Interactions

• St. John’s Wort is contraindicated
• Efavirenz is not recommended
• Fosamprenavir is not recommended
• Rifampicin is not recommended
• Ketoconazole is not recommended
• See Table 4 for drugs that may need a dose adjustment

Overview

Cytochrome P450

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A4 and 2B6. Co-administration of APO-NEVIRAPINE or APO-NEVIRAPINE XR and drugs primarily metabolized by CYP3A4 or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects.

Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9 or 2C19.

Table 4 contains the results of drug interaction studies performed with nevirapine and other drugs likely to be co-administered. Alterations in dose or regimen may also be recommended based on these drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated.

The following data were generated using the nevirapine immediate-release tablets but are expected to apply to all dosage forms.

Drug-Drug Interactions

TABLE 4: ESTABLISHED AND OTHER POTENTIAL SIGNIFICANT DRUG INTERACTIONS; ALTERATION IN DOSE OR REGIMEN MAY BE RECOMMENDED BASED ON DRUG INTERACTION STUDIES OR PREDICTED INTERACTIONS.

§ = C_min below detectable level of the assay

↑ = Increase, ↓ = Decrease, ↔ = No Effect

^a Pediatric subjects ranging in age from 6 months to 12 years

^b Parallel group design; n for nevirapine+lopinavir/ritonavir, n for lopinavir/ritonavir alone ^c Discontinued in Canada

^d Nevirapine is not approved in Canada for use in paediatric patient population

The effects of Nevirapine on the pharmacokinetics of co-administered drugs and the co-administered drugs on Nevirapine are summarized in Tables 5and 6, respectively. This data is based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated.

TABLE 5: DRUG INTERACTIONS: PHARMACOKINETIC PARAMETERS FOR NEVIRAPINE IN THE PRESENCE OF CO-ADMINISTERED DRUG (SEE TABLE 4 FOR RECOMMENDED ALTERATIONS IN DOSE OR REGIMEN)

↑ = Increase, ↓ = Decrease

^† = Mean ratio measured at 95% Confidence Interval

^a For information regarding clinical recommendations see Table 4

^b Studies reported from healthy subjects

TABLE 6: DRUG INTERACTIONS: PHARMACOKINETIC PARAMETERS FOR CO-ADMINISTERED DRUG IN THE PRESENCE OF NEVIRAPINE (SEE TABLE 4 FOR RECOMMENDED ALTERATIONS IN DOSE OR REGIMEN)

§ = C_min below detectable level of the assay

↑ = Increase, ↓ = Decrease, ↔ = No Effect

^† = Mean ratio measured at 95% Confidence Interval

^a For information regarding clinical recommendations see Table 4

^b Pediatric subjects ranging in age from 6 months to 12 years

^c Parallel group design; n for nevirapine +lopinavir/ritonavir, n for lopinavir/ritonavir alone ^d Studies reported from healthy subjects

^e Discontinued in Canada

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 listed in Table 7. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for the classes of drugs listed in Table 7, additional clinical monitoring may be warranted when co-administering these drugs.

TABLE 7: POTENTIAL DRUG INTERACTIONS: USE WITH CAUTION, DOSE ADJUSTMENT OF CO-ADMINISTERED DRUG MAY BE NEEDED DUE TO POSSIBLE DECREASE IN CLINICAL EFFECT

* Cisapride is no longer marketed in Canada

Other Drugs Metabolized By CYP3A

Biotransformation of nevirapine involves extensive cytochrome P450 metabolism (CYP3A>CYP2B6) and glucuronidation with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy. Available data on the potential interaction between nevirapine and other drugs that are extensively metabolized by CYP3A are limited and preliminary; therefore, careful monitoring of the therapeutic effectiveness of CYP3A-metabolized drugs is recommended when taken in combination with nevirapine.

In Vitro Studies

Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin, rifampin and trimethoprim/sulphamethoxazole. Ketoconazole and erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites.

Drug-Lifestyle Interactions

Effects on ability to drive and use machines

There are no specific studies about the ability to drive vehicles and use machinery. However, patients should be advised that they may experience undesirable effects such as drowsiness during treatment with APO-NEVIRAPINE or APO-NEVIRAPINE XR. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience drowsiness they should avoid potentially hazardous tasks such as driving or operating machinery.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• APO-NEVIRAPINE or APO-NEVIRAPINE XR should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box).”
• Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment with APO-NEVIRAPINE or APO-NEVIRAPINE XR (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
• APO-NEVIRAPINE or APO-NEVIRAPINE XR administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities (> 5x ULN) (excluding GGT), until the liver function test elevations have returned to baseline (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Recommended Dose and Dosage Adjustment

Immediate-Release Tablets

The recommended dose for APO-NEVIRAPINE (nevirapine) is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, as part of a multi-drug antiretroviral treatment regimen. APO-NEVIRAPINE or APO-NEVIRAPINE XR can be taken with or without food. The manufacturer’s recommended dosage and monitoring for the concomitantly administered antiretroviral therapy should be used.

Extended-Release Tablets

Patients should initiate therapy with one 200 mg tablet of nevirapine immediate-release once daily for the first 14 days (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 nevirapine extended-release once daily.

The nevirapine extended-release tablets should not be broken or chewed. Nevirapine extended-release tablets can be taken with or without food. Nevirapine immediate-release tablets and nevirapine extended-release tablets should be combined with at least two additional antiretroviral agents. For concomitantly administered therapy, the manufacturers recommended dosage should be followed.

Patients currently on a nevirapine immediate-release twice daily regimen

Patients already on a regimen of nevirapine immediate-release 200 mg twice daily in combination with other antiretroviral agents can be switched to nevirapine extended-release 400 mg once daily in combination with other antiretroviral agents without a lead-in period of nevirapine immediate-release.

Monitoring of Patients

APO-NEVIRAPINE or APO-NEVIRAPINE XR should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (see WARNINGS AND PRECAUTIONS, Skin). Patients experiencing rash during the 14-day lead-in period of 200 mg/day of immediate-release tablets should not have their nevirapine dose increased to 400 mg/day until the rash has resolved (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and Skin). The risk of development of resistance to nevirapine is unknown when the 200 mg once daily dosing regimen is continued beyond 14 days.

Patients with Renal Impairment

In End Stage Renal Disease (ESRD) appropriate doses of nevirapine immediate release or nevirapine extended release tablets with respect to safety and efficacy have not been established. Subjects with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC over a one week exposure period with an accumulation of nevirapine hydroxy-metabolites in plasma. An additional 200 mg dose of nevirapine immediate-release tablets following each dialysis treatment is recommended in patients requiring dialysis. In renal dysfunction, a single dose study suggested that patients with a creatinine clearance ≥ 20 mL/min do not require an adjustment in nevirapine dosing. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require an adjustment in nevirapine dosing; however, caution should be exercised when nevirapine immediate release or nevirapine extended release tablets is administered to patients with moderate hepatic impairment. Nevirapine immediate release or nevirapine extended release tablets should not be administered to patients with severe hepatic dysfunction.

Patients with Lactose Intolerance

Nevirapine immediate-release tablets contain 482 mg of lactose per maximum recommended daily dose.

Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Missed Dose

Patients who miss a dose should take it as soon as they remember and then continue as before. Do not double the next dosage.

Patients who interrupt APO-NEVIRAPINE or APO-NEVIRAPINE XR dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily for the first 14 days (lead-in) followed by one 200 mg tablet twice daily or one 400 mg tablet once daily.

OVERDOSAGE

For management of a suspected overdose, contact your regional Poison Control Centre immediately.

There is no known antidote for APO-NEVIRAPINE or APO-NEVIRAPINE XR overdosage. The use of activated charcoal may be helpful.

Cases of nevirapine overdose with nevirapine immediate-release at doses ranging from 800 to 6000 mg per day for up to 15 days have been reported. Patients have experienced edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, increase in transaminases, and weight decrease. All subsided following discontinuation of nevirapine.

In one case, a patient accidentally ingested nevirapine 1200 mg daily for three days, and then 1800 mg for a fourth day. The patient suffered fever, generalized rash, nausea, vomiting, headache, chills, and facial swelling, and was admitted to hospital for 5 days. The event resolved without sequelae.

In another case, a patient ingested 9 tablets of nevirapine (1800 mg) per day for 10 days. The patient presented with rash (erythema nodosum), pulmonary infiltrate, and bilateral edema of hands and feet. He was hospitalized for 2 weeks during which time he was aggressively diuresed. The events resolved over 3 weeks.

No acute toxicities or sequelae were reported for one patient who ingested 800 mg of nevirapine for one day.

ACTION AND CLINICAL PHARMACOLOGY

Absorption

Nevirapine is readily absorbed (>90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for the 50 mg tablet and 91.8% for the oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 μg/mL are attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady state trough nevirapine concentrations of 4.5 ± 1.9 μg/mL (17 ± 7 μM), (n=242) were attained at 400 mg/day.

When nevirapine (200 mg) was administered to 24 healthy adults (12 male, 12 female), with either a high fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate study in HIV-1-infected patients (n=6), nevirapine steady-state systemic exposure (AUC_τ) was not significantly altered by ddI, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or ddI.

Distribution

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier. Following intravenous administration in healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine also is widely distributed in humans. Nevirapine is approximately 57-61% bound to plasma proteins in the plasma concentration range of 1-10 μg/mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P-450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P-450 isozymes from the CYP3A4 and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg b.i.d. followed by a single dose of 50 mg ¹⁴C-nevirapine, approximately 91.4% ± 10.5% of the radiolabeled dose was recovered, with urine (81.3% ± 11.1%) representing the primary route of excretion compared to feces (10.1% ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P-450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total dose) was made up of parent compound; therefore, renal excretion of nevirapine plays a minor role in elimination of the parent compound.

Excretion

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A4 and 2B6. Nevirapine induces CYP3A4 and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A4 and CYP2B6 mediated metabolism leads to an approximately 1.5 to 2 fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg/day.

Special Populations and Conditions

Pediatrics:

Safety and effectiveness of APO-NEVIRAPINE or APO-NEVIRAPINE XR in HIV-1 infected pediatric patients younger than 15 years of age has not been established.

Age:

Nevirapine pharmacokinetics in HIV-1-infected adult males and females do not appear to change with age (range 18-68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years. Nevirapine is metabolized more rapidly in pediatric patients than in adults.

Gender:

In one Phase I study in healthy volunteers (15 females, 15 males), the weight-adjusted apparent volume of distribution (Vdss/F) of nevirapine was higher in the female subjects (1.54 L/kg) compared to the males (1.38 L/kg), suggesting that nevirapine was distributed more extensively in the female subjects. However, this difference was offset by a slightly shorter terminal-phase half-life in the females resulting in no significant gender difference in nevirapine oral clearance (24.6±7.7 mL/kg/hr in females vs. 19.9±3.9 mL/kg/hr in males after single dose) or plasma concentrations following either single- or multiple-dose administration(s).

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (37 females, 205 males) revealed no clinically significant difference in nevirapine steady-state trough concentrations (median C_minss = 4.6 μg/mL females, 4.2 μg/mL males) with long-term nevirapine treatment at 400 mg/day.

Race:

The pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity. However, an evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median C_minss = 4.7 μg/mL Black, 3.8 μg/mL Hispanic, 4.3 μg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day.

Hepatic Insufficiency:

The single-dose pharmacokinetics of nevirapine have been compared in 10 subjects with hepatic impairment and 8 subjects with normal hepatic function. Overall, the results suggest that mild to moderate hepatic impairment had no significant effect on the pharmacokinetics of nevirapine. However, the pharmacokinetics of nevirapine in one subject with a Child-Pugh score of 8 and moderate to severe ascites suggests that patients with worsening hepatic function may be at risk of accumulating nevirapine in the systemic circulation (see DOSAGE AND ADMINISTRATION, Patients with Hepatic Impairment).

In a 200 mg nevirapine single dose pharmacokinetic study of HIV-negative patients with mild and moderate hepatic impairment, a significant increase in the AUC of nevirapine was observed in one patient with moderate hepatic impairment and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation.

Renal Insufficiency:

The single dose pharmacokinetics of nevirapine have been compared in 23 subjects with either mild (50 ≤ Cl_cr < 80 mL/min), moderate (30 ≤ Cl_cr < 50 mL/min) or severe (Cl_cr < 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring dialysis and 8 subjects with normal renal function (CL_cr > 80 mL/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine. Subjects with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC over a one week exposure period with an accumulation of nevirapine hydroxy-metabolites in plasma (see DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

STORAGE AND STABILITY

Solid substance stability studies have shown nevirapine bulk drug to be extremely stable. APO-NEVIRAPINE 200 mg immediate-release tablets are packaged in bottles of 100 tablets and APO-NEVIRAPINE XR 400 mg extended-release tablets are packaged in bottles of 30, 60, 100 tablets and blisters of 10 tablets (100 tablets) and should be stored at 15^ºC - 30^ºC (59ºF – 86ºF).

DOSAGE FORMS, COMPOSITION AND PACKAGING

Immediate-Release Tablets

APO-NEVIRAPINE (nevirapine) 200 mg immediate-release tablets are white colored, oval-shaped scored biconvex tablets with engraved “APO” and bisect on one side and “NAV” bisect “200” on the other side.

Each tablet contains 200 mg of nevirapine and the non-medicinal ingredients: anhydrous lactose, microcrystalline cellulose, copovidone, crospovidone and magnesium stearate.

Tablets are packaged in bottles of 100 tablets.

Extended-Release Tablets

APO-NEVIRAPINE XR (nevirapine) 400 mg extended-release tablets are yellow colored, oval-shaped, biconvex tablets engraved with “APO” on one side and “NV400” on the other side. Each tablet contains 400 mg of nevirapine and the non-medicinal ingredients: hypromellose, methylcellulose, magnesium stearate, yellow iron oxide.

Tablets are packaged in bottles of 30, 60, 100 tablets and blisters of 10 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

DRUG SUBSTANCE

I.N.N. /U.S.A.N. Name : Nevirapine USP

Chemical Name : 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3' e][1,4]diazepin-6-one

Structural Formula :

M.W. : 266.30g/mol

Molecular Formula : C₁₅H₁₄N₄O

Physical Form : White to off-white crystalline powder

Solubility : Practically insoluble in water, sparingly soluble or slightly soluble in dichloromethane, slightly soluble in methyl alcohol.

pKa : pKa¹ = 2.8

Polymorphism statement : Nevirapine exhibits polymorphism. The crystalline form II is considered for the purpose of development.

Log P² / Hydrophobicity : 1.725

Hygroscopicity : Nevirapine is Non-hygroscopic in nature. Initial water content:

0.10% w/w. After exposed to 75% RH at 25°C for 3 days, Water content: 0.17% w/w

CLINICAL TRIALS

Comparative Bioavailability Studies (Immediate-release tablets)

A comparative, single dose, double blinded, randomized 2-way crossover bioavailability study, conducted under fasting conditions was performed on healthy male volunteers. The results obtained from 18 healthy male volunteers who completed the study are summarized in the following table. The rate and extent of absorption of nevirapine were measured and compared following a single oral dose (1X 200 mg tablet) of Apo-Nevirapine (nevirapine) 200 mg tablets (Apotex Inc.) and Viramune® (nevirapine) 200 mg tablets (Boehringer Ingelheim (Canada) Ltd./ Ltée).

TABLE 8: SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

(IMMEDIATE-RELEASE TABLETS: FASTING CONDITIONS)

Comparative Bioavailability Study (Extended-release tablets)

Two randomized, single dose, double-blinded, 2-way crossover comparative bioavailability studies, conducted under fasting and fed conditions, were performed on healthy male volunteers. The results obtained from 36 and 21 volunteers who completed the fasting and fed studies respectively are summarized in the following tables. The rate and extent of absorption of nevirapine were measured and compared following a single oral dose (1 x 400 mg tablet) of Apo-Nevirapine XR (nevirapine) 400 mg extended-release tablets (Apotex Inc.) and Viramune® XR (nevirapine) 400 mg extended-release tablets (Boehringer Ingelheim (Canada) Ltd./ Ltée).

TABLE 9: SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

(EXTENDED-RELEASE TABLETS: FASTING CONDITIONS)

TABLE 9a: SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

(EXTENDED-RELEASE TABLETS: FED CONDITIONS)

Study Demographics and trial design

Table 10: SUMMARY OF PATIENT DEMOGRAPHICS FOR NEVIRAPINE IMMEDIATE-RELEASE FORMULATION (1100.1090)

Table 11: SUMMARY OF PATIENT DEMOGRAPHICS FOR NEVIRAPINE IMMEDIATE-RELEASE FORMULATION (1100.1046)

TABLE 12: SUMMARY OF PATIENT DEMOGRAPHICS FOR NEVIRAPINE EXTENDED-RELEASE FORMULATION (1100.1486)

TABLE 13: SUMMARY OF PATIENT DEMOGRAPHICS FOR NEVIRAPINE EXTENDED-RELEASE FORMULATION (1100.1526)

^a For study 1100.1526, although 149 and 296 patients were randomized to the nevirapine IR and ER groups, respectively, demographic data were available for the 148 and 295 patients who received study treatment in the nevirapine IR and ER groups, respectively.

Trial BI 1090 (Patients With Advanced HIV Disease, with or without Prior Antiretroviral Treatment)

Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 adult patients with <200 CD4+ cells at screening. More than 75% of patients had extensive prior treatment with monotherapy or dual therapy prior to entering the trial. Treatment in this trial reflected the pre-HAART era of standard of care. BI 1090 compared treatment with nevirapine + lamivudine versus placebo + lamivudine in NNRTI naive patients, who were also taking other background antiretroviral agents. Treatment doses were nevirapine, 200 mg daily for two weeks followed by 200 mg twice daily, or placebo; lamivudine 150 mg twice daily; other antiretroviral agents were given at standard doses. The patients (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV infection, with a median baseline CD4+ cell count of 96 cells/mm³ and a baseline HIV RNA of 4.58 log₁₀ copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. There was no maximum limit to the duration of prior antiretroviral treatment. The 24% of patients who were permanently lost to follow-up during the study are included in the intent to treat (ITT) evaluations of virologic outcome. Patients were classified as responders at 48 weeks if their viral load decreased and remained below the limit of quantification (LOQ=50 copies/mL) by 48 weeks. Patients were categorized as non-responders if they did not complete 48 weeks, changed or added additional antiretroviral therapy, or experienced an AIDS defining event prior to 48 weeks. The virologic responder rate at 48 weeks was significantly higher for nevirapine patients (19%) than for placebo patients (3%).

Of the 2249 patients, 527 (23.4%) entered the trial as treatment naive or having received only ZDV prior to entering the trial. The patients had advanced HIV-infection with a median CD4+ cell count of 91 cells/mm³ and baseline HIV RNA of 5.02 log₁₀ copies/mL (105,213 copies/mL). The virologic responder rates at 48 weeks were significantly higher for the nevirapine patients (40%) than the placebo patients (3%).

The change from baseline in CD4+ count through one year of therapy was significantly greater for the nevirapine group compared to the placebo group for the overall study population (64 cells/mm³ vs 22 cells/mm³, respectively). This was also evident for patients who entered the trial as first HAART (treatment naϊve or having received only ZVD); the change from baseline in CD4+ count was significantly greater for the nevirapine group over placebo (85 cells/mm³ vs 25 cells/mm³, respectively).

Using an endpoint of the time to first new AIDS disease event or death in an intent to treat analysis in the overall study population, there was a 28% improvement in event-free survival in the nevirapine group compared to the placebo group (Risk ratio: 1.28; 95% confidence interval: 1.03 to 1.58).

INCAS (BI Trial 1046 – Adult Antiretroviral Naive Patients)

INCAS (BI Trial 1046) compared treatment with nevirapine+ZDV+ddI versus ZDV+ddI versus nevirapine+ZDV in 151 HIV-1-infected patients (median age 36 years, 94% Caucasian, 93% male) with CD4+ cell counts of 200–600 cells/mm³ (median 370 cells/mm³) and a mean baseline plasma HIV-1 RNA concentration of 4.41 log₁₀ copies/mL (25,704 copies/mL). Treatment doses were nevirapine, 200 mg daily for two weeks followed by 200 mg twice daily, or placebo; ZDV, 200 mg three times daily; ddI, 125 or 200 mg twice daily.

Using an intent to treat evaluation of virologic outcome, patients were classified as responders at 48 weeks if their viral load decreased and remained below LOQ (400 copies/mL) by 48 weeks. Patients were categorized as non-responders if they did not complete 48 weeks, changed or added additional antiretroviral therapy, or experienced an AIDS defining event prior to 48 weeks. The virologic responder rates at 48 weeks were significantly higher for nevirapine+ZDV+ddI patients (45%) compared to either the ZDV+ddI (19%) or nevirapine+ZDV patients (0%).

CD4+ cell counts in the nevirapine+ZDV+ddI group increased above baseline by a mean of 139 cells/mm³ at one year, significantly greater than the increase of 87 cells/mm³ in the ZDV+ddI patients. The nevirapine+ZDV group mean decreased by 6 cells/mm³ below baseline.

The clinical efficacy of nevirapine extended-release is based on 48-week data from an ongoing, randomised, double-blind, double-dummy Phase 3 trial (VERxVE - Study 1100.1486) in treatment-naïve patients and on 24-week data from an ongoing, randomised, open-label trial in patients who transitioned from nevirapine immediate-release tablets administered twice daily to nevirapine extended-release tablets administered once daily (TRANxITION – Study 1100.1526).

Treatment-naïve patients

VERxVE (Study 1100.1486) is a Phase 3 study in which treatment-naïve patients received nevirapine immediate-release 200 mg once daily for 14 days and then were randomised to receive either nevirapine immediate-release 200 mg twice daily or nevirapine extended-release 400 mg once daily. All patients received tenofovir + emtricitabine as background therapy. Randomisation was stratified by screening HIV-1 RNA level (≤100,000 copies/mL and >100,000 copies/mL). Selected demographic and baseline disease characteristics are displayed in Table

14.

TABLE 14: DEMOGRAPHIC AND BASELINE DISEASE CHARACTERISTICS IN STUDY 1100.1486

^a Includes 2 patients who were randomised but never received blinded medication. ^b Includes American Indians/Alaska native and Hawaiian/Pacific islander.

Table 15 describes week 48 outcomes in the VERxVE study (1100.1486). These outcomes include all patients who were randomised after the 14 day lead-in with nevirapine immediate- release and received at least one dose of blinded study medication.

TABLE 15: OUTCOMES AT WEEK 48 IN STUDY 1100.1486^a

a Includes patients who received at least one dose of blinded study medication after randomisation. Patients who discontinued treatment during the lead-in period are excluded. b Includes lost to follow-up, consent withdrawn, noncompliance, lack of efficacy, pregnancy, and other.

At week 48, mean change from baseline in CD4+ cell count was 184 cells/mm³ and 197 cells/mm³ for the groups receiving nevirapine immediate-release and nevirapine extended- release respectively. Non-inferiority of the extended-release formulation to the immediate-release formulation was observed. The lower bound of the 95% CI of the difference in virologic response proportions was greater than -10% (Table 16).

Table 16 shows outcomes at 48 weeks in Trial 1100.1486 based on baseline viral load.

TABLE 16: STUDY 1100.1486 – SUSTAINED VIROLOGIC RESPONSE AT WEEK 48 (LLOQ = 50 COPIES/ML, AMPLICOR-CORRECTED, TLOVR ALGORITHM, FAS)

^a Based on Cochran’s statistic with continuity correction for the variance calculation.

Patients switching from nevirapine immediate-release to nevirapine extended-release TRANxITION (Study 1100.1526) is a Phase 3 study to evaluate safety and antiviral activity in patients switching from nevirapine immediate-release to nevirapine extended-release. In this open-label study, 443 patients already on an antiviral regimen containing nevirapine immediate-release 200 mg twice daily with HIV-1 RNA <50 copies/mL were randomised in a 2:1 ratio to nevirapine extended-release 400 mg once daily or nevirapine immediate-release 200 mg twice daily. Approximately half of the patients had tenofovir + emtricitabine as their background therapy, with the remaining patients receiving abacavir sulfate + lamivudine or zidovudine + lamivudine. Approximately half of the patients had at least 3 years of prior exposure to nevirapine immediate-release prior to entering Trial 1100.1526.

At 24 weeks after randomisation in the TRANxITION study, 92.6% and 93.6% of patients receiving nevirapine immediate-release 200 mg twice daily or nevirapine extended-release 400 mg once daily, respectively, continued to have HIV-1 RNA <50 copies/mL. Non-inferiority of the extended-release formulation to the immediate-release formulation was observed. The lower bound of the 95% CI of the difference in virologic response proportions was greater than - 10% (Table 17).

TABLE 17: STUDY 1100.1526 – SUSTAINED VIROLOGIC RESPONSE AT WEEK 24 (LLOQ = 50 COPIES/ML, AMPLICOR-CORRECTED, TLOVR ALGORITHM, FAS)

^a Based on Cochran’s statistic with continuity correction for the variance calculation.

DETAILED PHARMACOLOGY

Mechanism of Action

APO-NEVIRAPINE or APO-NEVIRAPINE XR is a highly selective, non-nucleoside reverse transcriptase inhibitor (NNRTI) of Human Immunodeficiency Virus Type 1 (HIV-1). The enzymatic activity of reverse transcriptase (RT) is required for replication of HIV. Nevirapine binds directly to RT and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme’s catalytic site. The inhibitory activity of nevirapine is not competitive with respect to template or nucleoside triphosphates. Reverse transcriptase from HIV-2 and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) are not inhibited by nevirapine.

Pharmacodynamics

Nevirapine is a non-nucleoside RT inhibitor which exhibits selective antiviral activity against HIV-1. Nevirapine inhibits the replication of a wide variety of HIV-1 strains in a number of cellular assays. HIV-1 isolates exhibiting reduced susceptibility to nevirapine were selected in cell culture experiments and during in vivo clinical studies.

The in vitro antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte derived macrophages, and lymphoblastoid cell lines. In recent studies using human cord blood lymphocytes and human embryonic kidney 293 cells, EC50 values (50% inhibitory concentration) ranged from 14->400 nM against laboratory and clinical isolates of HIV-1. Some isolates of HIV-1 group M clade A demonstrated reduced susceptibility to nevirapine in vitro. The antiviral activity of nevirapine against HIV-1, group M, clade E is unknown.

Nevirapine exhibited antiviral activity in vitro against group M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF), CRF01_AE, CRF02_AG and CRF12_BF (median EC50 value of 63 nM). Nevirapine had no antiviral activity in vitro against isolates from group O HIV-1 and HIV-2. Some isolates of HIV-1 group M clade A demonstrated reduced susceptibility to nevirapine in vitro. The antiviral activity of nevirapine against HIV-1, group M, clade E is unknown.

Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity in vitro and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in vitro.

Pharmacokinetics

The pharmacokinetics of nevirapine have been studied in nine Phase I studies and two Phase IIA studies in both HIV-1 infected adults (n=380) and healthy adult volunteers (n=119) given single doses of up to 400 mg and multiple doses of up to 600 mg/day (given q.d. or b.i.d.).

The pharmacokinetics of nevirapine are characterized by rapid and nearly complete oral absorption, an apparent volume of distribution that exceeds total body water, and a prolonged disposition phase in humans. Nevirapine is approximately 60% bound to plasma proteins in the plasma concentration range of 1-10 μg/mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% of the concentration in plasma; this ratio is approximately equal to the fraction not bound to plasma protein. Nevirapine is extensively biotransformed by cytochrome P450 to several hydroxylated metabolites; in vitro studies suggest that this metabolism is mediated primarily by CYP3A, although other CYP isozymes may have a secondary role. The multiple dose pharmacokinetics are characterized by metabolic autoinduction of cytochrome P450 isozymes resulting in a 1.5 to 2 fold increase in nevirapine systemic clearance as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from 45 hours (single dose) to approximately 25 to 30 hours with multiple dosing. The pharmacokinetics of nevirapine remain approximately linear in the dose range of 200-400 mg/day following induction.

The pharmacokinetics of nevirapine has been studied in a single dose study (Trial 1100.1485) of nevirapine extended-release in 17 healthy volunteers. The relative bioavailability of nevirapine when dosed as one 400 mg nevirapine extended-release tablet, relative to two 200 mg nevirapine immediate-release tablets, was approximately 75%. The study demonstrated that the nevirapine extended-release formulation exhibited very slow absorption with a mean T_max of approximately 24 hours compared to a mean T_max of approximately 4 to 6 hours for nevirapine IR 200 mg and 400 mg, respectively. The mean peak plasma concentration of nevirapine was 2060 ng/mL measured at a mean of 24.5 hours after administration of a single dose 400 mg nevirapine extended-release tablet. This is in comparison to a mean peak plasma concentration of 3150 ng/mL measured at a mean 6.35 hours after administration of a single dose of 400 mg immediate release tablets.

The pharmacokinetics of nevirapine extended-release has also been studied in a multiple dose pharmacokinetics study (Trial 1100.1489) in 24 HIV-1 infected patients who switched from chronic nevirapine immediate-release therapy to nevirapine extended-release. The nevirapine AUC_0-24,ss and C_min,_ss measured after 19 days of fasted dosing of nevirapine extended-release 400 mg once daily were approximately 80% and 90%, respectively, of the AUC_0-24,ss and C_min,_ss measured when patients were dosed with nevirapine immediate release 200 mg twice daily. The mean nevirapine C_min,_ss was 2920 ng/mL for the extended release formulation compared to 3240 ng/mL for the immediate release formulation.

When nevirapine extended-release was dosed with a high fat meal, the nevirapine AUC_{0-24, ss} and C_min,_ss were approximately 94% and 98%, respectively, of the AUC_0-24,ss and C_min,_ss measured when patients were dosed with nevirapine immediate-release tablets. The difference in nevirapine pharmacokinetics observed when nevirapine extended-release tablets are dosed under fasted or fed conditions is not considered clinically relevant, as long term virological efficacy depends on maintaining the C_min above 3000 ± 500 ng/mL threshold. Both the fed and fasted conditions met this criterion. Nevirapine extended-release tablets can be taken with or without food.

The effects of gender on the pharmacokinetics of nevirapine extended-release have been investigated in Trial 1100.1486. Female patients tend to have higher (approximately 20 - 30%) trough concentrations in both nevirapine extended-release and nevirapine immediate-release treatment groups.

Nevirapine pharmacokinetics in HIV-1 infected adults does not appear to change with age (range 18 - 68 years). Black patients (n=80/group) in Trial 1100.1486 showed approximately 30% higher trough concentrations than Caucasian patients (250-325 patients/group) in both the nevirapine immediate-release and nevirapine extended-release treatment groups over 48 weeks of treatment at 400 mg/day.

Nevirapine extended-release has not been evaluated in subjects with hepatic impairment or renal dysfunction.

Special Populations

Renal Impairment

The single-dose pharmacokinetics of nevirapine immediate-release has been compared in 23 subjects with either mild (50 creatinine clearance < 80 ml/min), moderate (30 creatinine clearance < 50 ml/min) or severe renal dysfunction (creatinine clearance < 30 ml/min), renal impairment or end-stage renal disease (ESRD) requiring dialysis, and 8 subjects with normal renal function (creatinine clearance > 80 ml/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine. However, subjects with ESRD requiring dialysis exhibited a 43.5 % reduction in nevirapine AUC over a one-week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in plasma. In renal dysfunction, a single-dose study suggested that patients with creatinine clearance 20 ml/min do not require an adjustment in nevirapine dosing. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

Hepatic Impairment

The single-dose pharmacokinetics of nevirapine have been compared in 10 subjects with hepatic dysfunction and 8 subjects with normal hepatic function. Overall, the results suggest that patients with mild to moderate hepatic dysfunction, defined as Child-Pugh Classification Score ≤ 7, do not require an adjustment in nevirapine dosing. However, the pharmacokinetics of nevirapine in one subject with a Child-Pugh score of 8 and moderate to severe ascites suggests that patients with worsening hepatic function may be at risk of accumulating nevirapine in the systemic circulation.

In a single dose pharmacokinetic study of 200 mg nevirapine immediate-release tablets in HIV-negative patients with mild and moderate hepatic impairment, a significant increase in the AUC of nevirapine was observed in one patient with moderate hepatic impairment and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation.

Therefore caution should be exercised when nevirapine immediate release tablets or nevirapine extended release tablets are administered to patients with moderate hepatic dysfunction. Nevirapine immediate release tablets or nevirapine extended release tablets should not be administered to patients with severe hepatic dysfunction.

Special Analysis

Gender

In one Phase I study in healthy volunteers (15 females, 15 males), the weight-adjusted apparent volume of distribution (Vdss/F) of nevirapine was higher in the female subjects (1.54 L/kg) compared to the males (1.38 L/kg), (p=0.001, Wilcoxon rank sum test) suggesting that nevirapine was distributed more extensively in the female subjects. However, this difference was offset by a slightly shorter terminal-phase half-life in the females resulting in no significant gender difference in nevirapine oral clearance or plasma concentrations following either single- or multiple-dose administration(s). Furthermore, an evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (37 females, 205 males) revealed no clinically significant difference in nevirapine steady-state trough concentrations (median C_minss = 4.6 μg/mL females, 4.2 μg/mL males) with long-term nevirapine treatment at 400 mg/day.

Age

Nevirapine pharmacokinetics in HIV-1-infected adult males and females do not appear to change with age (range 18-68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years. Nevirapine is metabolized more rapidly in pediatric patients than in adults.

Ethnic Origin

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected patients (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median C_minss= 4.7 μg/mL Black, 3.8 μg/mL Hispanic, 4.3 μg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

VIROLOGY

Resistance

HIV isolates with reduced susceptibility (100-250 fold) to nevirapine emerge in vitro. Genotypic analysis showed mutations in the HIV-1 RT gene Y181C and/or V106A depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in vitro was not altered when selection included nevirapine in combination with several other NRTI’s.

Phenotypic or genotypic changes in HIV-1 isolates from treatment-naïve patients treated with either nevirapine immediate-release (n=24) or nevirapine immediate-release and ZDV (n=14) were monitored in Phase I/II trials over 1 to ≥ 12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients had decreased susceptibility to nevirapine in vitro; one or more of the RT mutations at amino acid positions 103, 106, 108, 181, 188, and 190 were detected in some patients as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the patients tested (n=24) had HIV isolates with a > 100 fold decrease in susceptibility to nevirapine in vitro compared to baseline, and had one or more of the nevirapine-associated RT resistance mutations; 19 of 24 patients (80%) had isolates with a position 181 mutation regardless of dose.

The prevalence of phenotypic drug resistance was assessed in 60 patients with a viral rebound after they received a protease inhibitor (PI) or nevirapine containing regimen. Resistance testing was done within 36 weeks of viral rebound classified as a subsequent increase to >500 copies/mL following an initial viral load decrease to <500 copies/mL or a viral rebound of ≥ 0.5 log₁₀ following an initial drop of ≥ 1.0 log₁₀. In total, 88.9% given nevirapine had strains with reduced susceptibility to the drug. Overall, 46 patients (76.7%) harboured a strain resistant to ≥ 1 drug of their initial PI or nevirapine containing regimen. Of 53 patients who remained on treatment at the time of the study (40 had switched to a different combination from that at baseline), 6 harboured isolates susceptible to all drugs they had ever received.

Genotypic analysis of isolates from antiretroviral naïve patients with virologic rebound (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (study 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 patients, respectively, contained one or more of the following NNRTI resistance-associated mutations: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L and M230L.

Genotypic analysis was performed on isolates from 86 antiretroviral naïve patients who discontinued the VERxVE study (1100.1486) after experiencing virologic failure (rebound, partial response) or due to an adverse event or who had transient increase in viral load during the course of the study. The analysis of these samples of patients receiving nevirapine immediate-release twice daily or nevirapine extended-release once daily in combination with tenofovir and emtricitabine showed that isolates from 50 patients contained resistance mutations expected with a nevirapine-based regimen. Of these 50 patients, 28 developed resistance to efavirenz and 39 developed resistance to etravirine (the most frequently emergent resistance mutation being Y181C). There were no differences based on the formulation taken (immediate-release twice daily or extended-release once daily).

The observed mutations at failure were those expected with a nevirapine-based regimen. Two new substitution on codons previously associated with nevirapine resistance were observed: one patient with Y1811 in the nevirapine extended-release group and one patient with Y188N in the nevirapine immediate-release group; resistance to nevirapine was confirmed by phenotype.

Cross-Resistance

Rapid emergence of HIV strains which are cross-resistant to NNRTI’s has been observed in vitro. Data on cross-resistance between the NNRTI nevirapine and nucleoside analogue RT inhibitors are very limited. In four patients, ZDV-resistant isolates tested in vitro retained susceptibility to nevirapine and in six patients, nevirapine-resistant isolates were susceptible to ZDV and ddI. One case of double resistance to ZDV and nevirapine including transmission has been reported.

Cross-resistance between nevirapine and HIV protease inhibitors is unlikely because the enzyme targets involved are different.

Cross-resistance among the currently registered NNRTIs is broad. Some genotypic resistance data indicate that in most patients failing NNRTIs, viral strains express cross-resistance to the other NNRTIs.

Nevirapine must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, 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 nevirapine, 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.

TOXICOLOGY

Acute, Subchronic and Chronic Toxicity in Laboratory Animals

Acute oral toxicity studies conducted in the mouse, rat, dog, and monkey revealed that the NOEL was 200 mg/kg, and lethality did not occur in any of these species with single PO doses ranging from 50 to 400 mg/kg. These studies indicated that the species sensitivity was (in order of decreasing sensitivity): rat > dog > mouse > monkey. Subchronic non-clinical NOELs ranged from 5 to <650 mg/kg/day, in mice, rats, and dogs. Maximum tolerated dose (MTD) ranged from 25 to 1500 mg/kg/day in the same species. Chronic studies in the rat and dog indicated that the liver and haematopoietic system are amongst the target organs, with NOELs of 5.50 mg/kg/day and MTDs of 50-200 mg/kg/day.

There was no evidence of teratogenicity in reproductive studies performed in rats and rabbits treated with oral doses up to 50 and 300 mg/kg/day nevirapine. In rats a significant decrease in fetal body weight occurred at doses providing systemic exposure approximately 50% higher, based on AUC, than that seen at the recommended clinical dose. Maternal toxicity and observable effects on fetal development were not observed in the rat with a systemic exposure equivalent to that seen at the recommended human dose or in the rabbit with a systemic exposure approximately 50% higher than that seen at the recommended human dose. REFERENCES

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