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Product
Antiretroviral products (Nevirapine)
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Antiretroviral products (Nevirapine)
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Nevirapine Tablets
Nevirapine Oral Suspension
COMPOSITION
NEVIMUNE Tablets
Each tablet contains
Nevirapine 200 mg
NEVIMUNE Oral Suspension
Each 5 ml contains
Nevirapine 50 mg
PHARMACOLOGY
Pharmacodynamics
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme`s catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases [such as human DNA polymerases (alpha), (beta), (gamma), or (delta)] are not inhibited by nevirapine. |
Pharmacokinetics
Absorption and Bioavailability: 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 a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 µg/mL (7.5 µM) were 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. NEVIMUNE may be administered with or without food, antacid or didanosine.
Distribution: Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk (see WARNINGS AND PRECAUTIONS : Lactation ). Nevirapine is about 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% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.
Metabolism/Elimination: In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A4 and CYP2B6 families, although other isozymes may have a secondary role. Cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans.
Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A4 and 2B6. 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.
INDICATIONS
NEVIMUNE is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Additional important information regarding the use of nevirapine for the treatment of HIV-1 infection:
• Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, NEVIMUNE should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm 3 or in adult males with CD4+ cell counts greater than 400 cells/mm 3 unless the benefit outweighs the risk (see WARNINGS ).
• The 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash (see WARNINGS; DOSAGE AND ADMINISTRATION ).
DOSAGE AND ADMINISTRATION
Adults
The recommended dose for nevirapine is 200 mg 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 200 mg twice daily, in combination with other antiretroviral agents. For concomitantly administered antiretroviral therapy, the full prescribing information for those drugs should be consulted.
Pediatric patients
The recommended oral dose of nevirapine for pediatric patients 2 months to 8 years of age is 4 mg/kg once daily for the first 14 days followed by 7 mg/kg twice daily thereafter. For patients 8 years and older the recommended dose is 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.
NEVIMUNE suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 ml or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient.
Monitoring of patients
Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver 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 nevirapine treatment (see Warnings and Precautions ). In some cases, hepatic injury has progressed despite discontinuation of treatment.
Dosage Adjustment
Nevirapine should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (see Warnings and Precautions ). Patients experiencing rash during the 14-day lead-in period of 200 mg/day (4 mg/kg/day in pediatric patients) should not have their nevirapine dose increased until the rash has resolved (see Warnings and Precautions ) .
If a clinical (symptomatic) hepatic event occurs, nevirapine should be permanently discontinued. Do not restart nevirapine after recovery (see Warnings and Precautions ).
Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing, using one 200 mg tablet daily (4 mg/kg/day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (4 or 7 mg/kg twice daily, according to age, for pediatric patients).
An additional 200 mg dose of nevirapine following each dialysis treatment is indicated in patients receiving dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. Patients with CrCL ≥ 20 mL/min do not require an adjustment in nevirapine dosing.
CONTRAINDICATIONS
Nevirapine is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the tablet or the oral suspension.
WARNINGS AND PRECAUTIONS
General
The most serious adverse reactions associated with nevirapine are hepatitis/ hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/ hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy or renal dysfunction.
The first 18 weeks of therapy with nevirapine are a critical period during which intensive monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of 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 nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash.
The duration of clinical benefit from antiretroviral therapy may be limited. Patients receiving nevirapine 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.
When administering nevirapine as part of an antiretroviral regimen, the complete product information for each therapeutic component should be consulted before initiation of treatment.
Hepatic Events
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 controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11.0%) of patients who received nevirapine and 1.2% of patients in control groups.
The risk of symptomatic 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. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver function tests.
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 immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if liver function tests are initially normal or alternative diagnoses are possible.
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, NEVIMUNE should be permanently discontinued. Do not restart NEVIMUNE after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 counts. In general, during the first 6 weeks of treatment, women have 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 are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review, women with CD4 counts > 250 cells/mm 3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts < 250 cells/mm 3 (11.0% versus 0.9%). An increased risk was observed in men with CD4 counts > 400 cells/mm 3 (6.3% versus 1.2% for men with CD4 counts < 400 cells/mm 3 ). However, all patients, regardless of gender, CD4 count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 counts. Co-infection with hepatitis B or C and/or increased liver function tests at the start of therapy with nevirapine is associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in ALT or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-unifected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis, an unapproved use.
Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, NEVIMUNE should not be administered to patients with severe hepatic impairment.
Skin Reactions
Severe, life-threatening skin reactions, including fatal cases, have been reported with nevirapine treatment, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterized by rash, constitutional findings and organ dysfunction including hepatic failure. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 1.5% of nevirapine recipients compared to 0.1% of placebo subjects.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Nevirapine should not be restarted following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.
If patients present with a suspected nevirapine-associated rash, liver function tests should be performed. Patients with rash-associated AST or ALT elevations should be permanently discontinued from nevirapine.
Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg/day (4 mg/kg/day in pediatric patients), which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation should not occur until the rash has resolved (see Dosage and Administration ). Patients should be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with nevirapine.
In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash, is not recommended.
Drug Interactions
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A4 and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when coadministered with nevirapine.
Clinical comments about possible dosage modifications based on observed pharmacokinetic changes are listed in Table 1. This data is based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated.
In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are listed in Table 2. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for the classes of drugs listed in Table 2, additional clinical monitoring may be warranted when co-administering these drugs.
Resistance
NEVIMUNE 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 NEVIMUNE , 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.
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 Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.
St. John`s wort
Concomitant use of St. John`s wort (hypericum perforatum) or St. John`s wort- containing products and nevirapine is not recommended. Co-administration of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), including nevirapine, with St. John`s wort is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs.
Renal Impairment
Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. No adjustment in nevirapine dosing is required in patients with CrCL ≥ 20 mL/min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known.
Hepatic Impairment
It is not clear whether a dosing adjustment is needed for patients with mild to moderate hepatic impairment, because multiple dose pharmacokinetic data are not available for this population. However, patients with moderate hepatic impairment and ascites may be at risk of accumulating nevirapine in the systemic circulation. Caution should be exercised when nevirapine is administered to patients with moderate hepatic impairment. Nevirapine should not be administered to patients with severe hepatic impairment.
Pregnancy
Pregnancy Category B.
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
There are no adequate and well-controlled studies of nevirapine in pregnant women.
Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV infection. Regardless of pregnancy status, women with CD4 counts >250 cells/mm3 should not initiate NEVIMUNE unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women (see Boxed WARNING ).
NEVIMUNE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation
It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Nevirapine is excreted in breast milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving nevirapine.
Pediatric use
The pharmacokinetics of nevirapine have been studied in two studies in children with HIV-1 infection. For dose recommendations for pediatric patients see Dosage and Administration . The most frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine. The evaluation of the antiviral activity of nevirapine in pediatric patients is ongoing.
UNDESIRABLE EFFECTS
The most serious adverse reactions associated with nevirapine are clinical hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction (see Warnings and Precautions ).
Adults
The most common clinically toxicity of nevirapine is rash, which can be severe or life threatening (see Warnings and Precautions ). Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials, Grade 1 and 2 rashes were reported in 13.3% of patients receiving nevirapine compared to 5.8% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 1.5% of nevirapine recipients compared to 0.1% of subjects receiving placebo. Women tend to be at higher risk for development of nevirapine associated rash.
In controlled clinical trials, symptomatic hepatic events regardless or severity occurred in 4.0% (range 0% to 11.0%) of patients who received nevirapine and 1.2% of patients in control groups. Female gender and higher CD4 counts (>250 cells/mm 3 in women and > 400 cells/mm 3 in men) place patients at increased risk of these events (see Warnings and Precautions ).
Asymptomatic transaminase elevations (AST or ALT>5X ULN) were observed in 5.8% (range 0% to 9.2%) of patients who received nevirapine and 5.5% of patients in control groups. Co-infection with hepatitis B or C and/or increased liver function tests at the start of therapy with nevirapine is associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.
Post marketing Surveillance
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, 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, 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 syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities (see WARNINGS AND PRECAUTIONS) plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of nevirapine.
Pediatric Patients
Safety was assessed in trial B1 882 in which patients were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these patients in trial B1 892). The most frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and nevirapine. Serious adverse events were assessed in ACTG 245, a double-blind, placebo-controlled trial of nevirapine (n=305) in which pediatric patients received combination treatment with nevirapine. In this trial, two patients were reported to experience Stevens-Johnson syndrome or Steven-Johnson/toxic epidermal necrolysis transition syndrome. Cases of allergic reaction, including one case of anaphylaxis, were also reported. In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.
OVERDOSAGE
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of nevirapine.
PACKAGING INFORMATION
NEVIMUNE Tablets : Container of 30 tablets
NEVIMUNE Suspension : Bottle of 100 ml
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