NEVIRAPINE ER

General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Never administer more than one form of nevirapine (e.g., immediate-release and extended-release) at the same time.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.

Route-Specific Administration

Oral Administration
-Administer with or without food.
Oral Solid Formulations
-Extended-release tablet: Swallow whole. Do not chew, crush, or divide.

Oral Liquid Formulations
-Oral suspension: Shake gently prior to administration. Use of an oral dosing syringe is recommended for administration, 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.

Rash was the most common adverse event experienced by nevirapine recipients during clinical trials (21%). Cases of allergic reaction, including 1 case of anaphylactoid reactions, were also reported. Two cases of Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome were reported during pediatric clinical trials (n = 305). Most rashes occurred within the first 6 weeks of treatment and were mild to moderate, erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face, and/or extremities. Specific types of rash observed in patients treated with nevirapine during clinical trials included maculopapular rash, bullous rash, erythema nodosum, erythematous rash, papular rash, allergic dermatitis, and drug reaction with eosinophilia and systemic symptoms (DRESS). Severe, life-threatening skin reactions, including fatalities, have also occurred. Severe cutaneous reactions include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. The majority of severe rashes occurred within the first 6 to 8 weeks of therapy and hospitalization was required in 25% of the patients with severe rash. If a severe rash or a hypersensitivity reaction accompanied by a rash and other symptoms [e.g., angioedema, arthralgia, blisters or oral ulceration, conjunctivitis, eosinophilia, facial edema, fatigue, fever, granulocytopenia, lymphadenopathy, malaise, myalgia, ulcerative stomatitis, urticaria, or renal dysfunction] occurs, nevirapine should be discontinued immediately; nevirapine therapy should not be restarted in these patients. Additionally, liver damage may accompany a skin rash; therefore, all patients developing a rash, at any time during treatment (but especially during the first 18 weeks), should have liver function tests performed. Nevirapine must be initiated with a 14-day dose escalation or lead-in period, which has been shown to reduce the frequency of rash. Severe cutaneous reactions have been associated with improper dose escalation and/or delays in seeking medical attention when the cutaneous symptoms appeared.

Nevirapine, in combination with other antiretroviral medications, has been associated with both asymptomatic and clinically symptomatic hepatotoxicity. Hepatotoxicity has been reported in 2% of pediatric patients. Asymptomatic hepatotoxicity, defined as an increase in hepatic enzymes without any associated clinical signs or symptoms, occurs at a rate similar to that seen with other antiretroviral drugs. In adult clinical trials, elevated hepatic enzymes (greater than 5-times upper limit of normal (ULN)) were observed in 6% of nevirapine-treated patients. Additionally, hyperbilirubinemia (greater than 2.5 mg/dL) occurred in 2% of adult patients. Symptomatic hepatotoxicity is more common with nevirapine compared to other antiretroviral drugs and consists of elevated hepatic enzymes plus at least one symptom, which is typically rash but may include flu-like symptoms or fever. During adult clinical trials, symptomatic hepatotoxicity developed in 4% of nevirapine recipients. Severe, and in some cases fatal, hepatotoxicities, including fulminant cholestatic hepatitis, hepatic necrosis, and hepatic failure, have occurred. The risk of hepatic events, regardless of severity, is increased during the initial 18 weeks of treatment, with the greatest risk occurring during the first 6 weeks of therapy; however, health care providers are advised that hepatic events may occur at any time during treatment. Extensive monitoring of patients is required during the first 18 weeks of therapy and then frequently throughout nevirapine treatment. In some cases, patients present with non-specific, prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, vomiting, jaundice , liver tenderness or hepatomegaly, with or without initially abnormal liver enzyme levels. The diagnosis of hepatotoxicity should be considered in this setting, even if liver enzymes are initially normal or alternative diagnosis are possible. Some events have progressed to hepatic failure with elevated liver enzymes, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged aPTT, or eosinophilia. Rash accompanied approximately half, and fever accompanied some, of these events. Serious hepatotoxicity, including hepatic failure requiring liver transplantation in one case, has been reported in HIV-uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP). Other serious adverse reactions related to nevirapine taken for PEP include hepatotoxicity, fulminant hepatitis, skin reactions, and rhabdomyolysis; use of nevirapine for PEP is contraindicated. If clinical hepatotoxicity occurs, nevirapine should be discontinued and not restarted after recovery.

Frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults. Gastrointestinal adverse drug reactions experienced by <= 2% of adult nevirapine recipients during clinical trials included abdominal pain and diarrhea.

Antimicrobial resistance can occur during therapy with nevirapine. In vitro studies from the manufacturer show that monotherapy with nevirapine resulted in the emergence of HIV-1 isolates resistant to nevirapine. In one study, antimicrobial resistance was seen in all 21 subjects at 12 weeks of therapy despite the fact that the mean trough nevirapine concentration exceeded the IC50 of the virus. In another study, the development of resistance was rapid (i.e., within 1 week) and uniform, occurring in all isolates from patients regardless of whether they received nevirapine as monotherapy or in combination with zidovudine (ZDV).

Hematologic nevirapine-associated adverse events in pediatric patients are similar to those observed in adults, with the exception of granulocytopenia and possibly anemia being more common in children. Anemia was reported in 7% of patients, while neutropenia was noted in 9% of patients during a trial in South African children (n = 123, patients received combination therapy with lamivudine and zidovudine). Anemia has been reported more commonly in children receiving nevirapine in post-marketing surveillance; however, development of anemia due to concomitant medication use cannot be ruled out. Other hematologic adverse events experienced by adult nevirapine recipients included thrombocytopenia (<= 1%) and eosinophilia.

Metabolic adverse events have been associated with nevirapine therapy. Frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults. During adult clinical trials, hypercholesterolemia (>= 240 mg/dL) and elevated low-density lipoproteins (>= 160 mg/dL) were observed in approximately 20% of nevirapine recipients, respectively; the impact of nevirapine on cholesterol in pediatric patients has not been clearly defined. Cases of hypophosphatemia have been noted in post-marketing reports.

Cases of drug withdrawal, drowsiness, and paresthesias have occurred during post-marketing use of nevirapine.

While more commonly associated with protease inhibitor therapy, a lipodystrophy syndrome consisting of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and other cushingoid features has been reported in patients receiving long-term highly active antiretroviral therapy (HAART), including nevirapine. The mechanism that causes body fat changes is not known. The incidence and causal relationship with nevirapine has not been established.

Frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults. During adult clinical trials, headache was more frequently reported by nevirapine-treated patients (1-4%) than by patients receiving placebo (<= 1%).

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1-2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Nevirapine has been associated with severe or life-threatening hepatotoxicity, including fatal cases. The first 18 weeks of therapy are the critical period during which it is essential to intensively monitor patients to detect potentially life-threatening hepatotoxicity. The greatest risk of severe hepatic events associated with skin reactions occurs in the first 6 weeks of therapy; however, the risk of any hepatic event, with or without rash, continues past this period and monitoring should continue at frequent intervals. Obtain liver function tests at baseline, at treatment week 2 (prior to dose escalation), 2 weeks post-dose escalation, and then monthly for the first 18 weeks of therapy. In addition, the 14-day lead-in period must be strictly followed. Patients with hepatic disease associated with elevated hepatic enzymes and/or a history of chronic hepatitis B or C are at increased risk of developing hepatic toxicity. Adult women appear to have a three-fold higher risk than adult men for rash associated hepatic events; women with CD4 counts greater than 250/mm3 at the initiation of therapy are at considerably higher risk (12-fold) for drug-induced hepatotoxicity, which may be life-threatening. Based on this higher observed risk of serious liver toxicity in female patients with higher CD4 counts prior to initiation of therapy, postpubertal adolescent girls with CD4 counts greater than 250/mm3 should not be started on nevirapine therapy unless benefits clearly outweigh risks. Adult males with CD4 counts greater than 400/mm3 may also be at higher risk for rash-associated hepatic events. Although certain patient populations are at increased risk, nevirapine-associated hepatotoxicity may occur in both genders, all CD4 counts, and at anytime during treatment including in non-HIV infected individuals taking nevirapine for post-exposure prophylaxis. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. Some events occurred after short-term exposure including individuals receiving nevirapine for post-exposure prophylaxis; as a result, use for post-exposure prophylaxis is contraindicated. Patients with signs or symptoms of hepatitis must seek medical attention immediately and should be advised to discontinue nevirapine therapy. Do not restart nevirapine following severe hepatic reactions; in some cases hepatic injury progresses despite discontinuation of treatment. Do not administer nevirapine to patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic disease as increased nevirapine concentrations and nevirapine accumulation may be observed. Carefully monitor patients with any degree hepatic impairment for evidence of drug-induced toxicity. Additionally, all patients should be screened for hepatitis B and HIV coinfection to assure appropriate treatment. Patients who are co-infected with HIV and hepatitis B (HBV) and require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Nevirapine has been associated with severe or life-threatening cutaneous toxicity and nevirapine hypersensitivity reactions, including fatal cases. Patients developing signs or symptoms of serious rash or nevirapine hypersensitivity reactions must discontinue therapy immediately. The first 18 weeks of therapy are the critical period during which it is essential to intensively monitor patients to detect potentially life-threatening skin reactions. The greatest risk of severe rash occurs in the first 6 weeks of therapy; however, the risk of any cutaneous reaction continues past this period and monitoring should continue at frequent intervals. The optimal frequency of monitoring is not established. Some experts recommend clinical monitoring more frequently than once per month during the first 18 weeks of therapy. Monitoring should continue at frequent intervals thereafter. In addition, the 14-day lead-in period must be strictly followed. Risk factors for developing severe cutaneous or hypersensitivity reactions include failure to follow the initial dosing and lead-in period and delay in stopping nevirapine treatment after the onset of initial symptoms (e.g., severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction). If rash is observed during the initial lead-in period, nevirapine dosage should not be escalated until the rash has resolved. Patients should be monitored closely if a rash of any severity develops. In a clinical trial, concomitant use of prednisone (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, the use of prednisone to prevent nevirapine-associated rash is not recommended. Adult women appear to be at higher risk than men of developing skin reactions and rash-associated hepatic events; it is not clear whether this increased risk also applies to pediatric females. Nevirapine should not be restarted following severe skin or other nevirapine hypersensitivity reactions.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when nevirapine is used either alone or in combination with other agents. In patients whom a discontinuation or interruption of nevirapine therapy is planned, there is an increased risk of NNRTI-resistant mutations. Pharmacokinetic data demonstrate the persistence of detectable drug concentrations for at least 21 days after discontinuation of nevirapine; simultaneously stopping all drugs in a regimen containing nevirapine may result in functional nevirapine monotherapy due to its long half-life. This is further complicated by evidence that certain genetic polymorphisms, more common among some ethnic groups (such as in Black patients and in Hispanic patients), may result in a slower rate of clearance. Some experts recommend stopping nevirapine before the other antiretroviral drugs, although the optimal interval between stopping nevirapine and other antiretroviral drugs is not known. An alternative strategy is to substitute the nevirapine with a protease inhibitor (PI) prior to interruption of all antiretroviral drugs; if this strategy is used, the goal is to ensure that the PI used also achieves complete viral suppression during this interval. Further research to determine the best approach to temporarily discontinuing nevirapine is needed. Additionally, nevirapine should be reintroduced using the dose escalation guidelines for initiation of therapy if a patient has interrupted treatment with nevirapine. Although the FDA-approved labeling recommends reinitiation of lead-in dosing for patients who have interrupted therapy for more than 7 days, the HIV guidelines recommend that children who interrupt therapy for 14 days or less should be restarted on full-dose nevirapine. If dosing is interrupted for more than 14 days, dosing should be restarted with the lead-in dosing for 14 days, followed by full-dose escalation.

In one small pharmacokinetic study, no significant changes in nevirapine pharmacokinetics were found in HIV seronegative adults with mild (CrCl 50-79 ml/min), moderate (CrCl 30-49 ml/min), or severe (CrCl < 30 ml/min) renal impairment not requiring hemodialysis. However, individuals with renal failure requiring hemodialysis (dialysis) exhibited a 44% reduction in AUC over a one-week exposure period and there was also evidence of accumulation of the nevirapine hydroxy-metabolites in plasma these subjects.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop in the setting of immune reconstitution; the time to onset is variable and may occur months after treatment initiation.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children < 3 years is not usually recommended; however, treatment should be considered for all children >= 3 years and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Description: Nevirapine is a first-generation oral non-nucleoside reverse transcriptase inhibitor (NNRTI). Unlike nucleoside reverse transcriptase inhibitors (NRTIs), nevirapine does not require phosphorylation for activity. Nevirapine is approved for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents. It is also used for perinatal HIV prophylaxis in combination with zidovudine or as part of a 3-drug combination antiretroviral regimen with zidovudine and lamivudine at treatment doses for neonates with presumed HIV exposure or those at high risk for perinatal HIV transmission. Like other antiretrovirals, nevirapine is not recommended as monotherapy because of rapid emergence of resistant HIV isolates. Serious and life-threatening hepatotoxicity and skin rashes have been reported with nevirapine use. Females and patients with higher CD4 cell counts prior to initiation of therapy are at increased risk of liver toxicity. Nevirapine is FDA-approved for use in pediatric patients as young as 15 days old for treatment; the extended-release tablets are approved in children and adolescents 6 years and older with a BSA of 1.17 m2 or more.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Nevirapine (3-dose regimen) is used in combination with zidovudine or as part of a 3-drug combination antiretroviral regimen with zidovudine and lamivudine at treatment doses for the prevention of perinatal HIV transmission in neonates with presumed HIV exposure or those at high risk for perinatal HIV transmission (i.e., mother has not received antepartum antiretroviral therapy). Nevirapine, administered with 2 nucleoside reverse transcriptase inhibitors (NRTIs), is also a preferred regimen if HIV treatment initiation is planned prior to 14 days of age. A change to lopinavir/ritonavir should be considered when the infant is 14 days of age and 42 weeks postmenstrual age or older, due to better outcomes associated with lopinavir/ritonavir.
-Nevirapine plus a 2-NRTI backbone option is an alternative NNRTI-based regimen for initial therapy in treatment-naive infants and children 14 days to younger than 3 years.
-Nevirapine is NOT recommended as part of an initial treatment regimen for treatment-naive adolescents due to its higher toxicity.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
NOTE: Although the FDA-approved labeling recommends re-initiation of lead-in dosing for patients who have interrupted therapy for more than 7 days, guidelines recommend that children who interrupt therapy for 14 days or less should be restarted on full-dose nevirapine. If dosing is interrupted for more than 14 days, dosing should be restarted with the lead-in dosing for 14 days, followed by full-dose escalation.
Oral dosage (immediate-release):
Neonates 32 to 33 weeks gestation and 0 to 13 days postnatal age*: 2 mg/kg/dose PO twice daily. This is an investigational dose based on PK modeling and simulation data from IMPAACT P1106 and P1115 trials.
Neonates 32 to 33 weeks gestation and 14 to 27 days postnatal age*: 4 mg/kg/dose PO twice daily. This is an investigational dose based on PK modeling and simulation data from IMPAACT P1106 and P1115 trials.
Neonates 32 to 33 weeks gestation and 4 to 6 weeks postnatal age*: 6 mg/kg/dose PO twice daily. This is an investigational dose based on PK modeling and simulation data from IMPAACT P1106 and P1115 trials.
Neonates 32 to 33 weeks gestation and older than 6 weeks postnatal age*: 200 mg/m2/dose PO twice daily.
Neonates 34 to 36 weeks gestation and 0 to 6 days postnatal age*: 4 mg/kg/dose PO twice daily. This is an investigational dose that was studied as part of the IMPAACT 1115 protocol. This study demonstrated that nevirapine dosed at 4 mg/kg/dose twice daily for 1 week followed by 6 mg/kg/dose twice daily achieved concentrations appropriate for treatment.
Neonates 34 to 36 weeks gestation and 1 to 4 weeks postnatal age*: 6 mg/kg/dose PO twice daily. This is an investigational dose that was studied as part of the IMPAACT 1115 protocol. This study demonstrated that nevirapine dosed at 4 mg/kg/dose twice daily for 1 week followed by 6 mg/kg/dose twice daily achieved concentrations appropriate for treatment.
Neonates 34 to 36 weeks gestation and older than 4 weeks postnatal age*: 200 mg/m2/dose PO twice daily.
Neonates 37 weeks gestation and older and 0 to 14 days postnatal age*: 6 mg/kg/dose PO twice daily. This is an investigational dose that was studied as part of the IMPAACT 1115 protocol. This study demonstrated that nevirapine dosed at 6 mg/kg/dose twice daily achieved concentrations appropriate for treatment.
Neonates 37 weeks gestation and older and 15 to 29 days postnatal age: 6 mg/kg/dose PO twice daily. This is an investigational dose that was studied as part of the IMPAACT 1115 protocol. This study demonstrated that nevirapine dosed at 6 mg/kg/dose twice daily achieved concentrations appropriate for treatment. The FDA-approved dose is 150 mg/m2/dose PO once daily for 14 days, then 150 mg/m2/dose PO twice daily.
Infants and Children 1 to 7 years: 200 mg/m2/dose (Max: 200 mg/dose) PO once daily for 14 days, then 200 mg/m2/dose (Max: 200 mg/dose) PO twice daily. The FDA-approved dose is 150 mg/m2/dose (Max: 200 mg/dose) PO once daily for 14 days, then 150 mg/m2/dose (Max: 200 mg/dose) PO twice daily. Some clinicians initiate nevirapine without a lead-in dose for children younger than 2 years to decrease the risk of suboptimal dosing and the potential for virologic failure. In addition, no rash events occurred in this age group in patients who received full dose vs. half dose nevirapine in a clinical trial.
Children 8 to 12 years: 120 to 150 mg/m2/dose (Max: 200 mg/dose) PO once daily for 14 days, then 120 to 150 mg/m2/dose (Max: 200 mg/dose) PO twice daily. The FDA-approved dose is 150 mg/m2/dose (Max: 200 mg/dose) PO once daily for 14 days, then 150 mg/m2/dose (Max: 200 mg/dose) PO twice daily.
Adolescents: 200 mg PO once daily for 14 days, then 200 mg PO twice daily. The FDA-approved dose is 150 mg/m2/dose (Max: 200 mg/dose) PO once daily for 14 days, then 150 mg/m2/dose (Max: 200 mg/dose) PO twice daily.
Oral dosage (extended-release):
Children and Adolescents 6 to 17 years with BSA 1.17 m2 or more: 400 mg PO once daily for persons switching from twice daily immediate-release nevirapine or once daily nevirapine after lead-in dosing for 14 days.

For perinatal human immunodeficiency virus (HIV) prophylaxis* in neonates at high risk for HIV acquisition:
NOTE: Presumptive therapy with a 3-drug combination antiretroviral (ARV) regimen, consisting of zidovudine, lamivudine, and either nevirapine or raltegravir at treatment doses, is recommended for neonates with presumed HIV exposure (mothers with unknown HIV status who test HIV positive at delivery or postpartum or whose newborns have a positive HIV antibody test) and neonates born to HIV-infected mothers who have not received antepartum ARV treatment, who have received only intrapartum ARV treatment, who have suboptimal viral suppression (defined as at least 2 consecutive tests with HIV RNA less than 50 copies/mL obtained at least 4 weeks apart within 4 weeks of delivery), or who have acute or primary HIV infection during pregnancy or breastfeeding. Consider raltegravir use in the 3-drug combination ARV prophylaxis regimen if the mother has HIV-1 and HIV-2 infection, since HIV-2 is not susceptible to nevirapine. A 2-drug ARV prophylaxis regimen with 3 doses of nevirapine (prophylaxis dosage) and 6 weeks of zidovudine may also be considered based on clinical scenario.
NOTE: The ARV regimen for newborns born to mothers with known or suspected drug resistance should be determined in consultation with a pediatric HIV specialist before delivery or through consultation via the National Perinatal HIV hotline (1-888-448-8765). Additionally, no evidence exists that shows that neonatal prophylaxis regimens customized based on presence of maternal drug resistance are more effective than standard neonatal prophylaxis regimens.
Oral dosage (3-Drug Combination Antiretroviral Prophylaxis Regimen):
Neonates 32 to 33 weeks gestation and 0 to 13 days: 2 mg/kg/dose PO twice daily in combination with zidovudine and lamivudine. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For nevirapine and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Neonates 32 to 33 weeks gestation and 14 to 27 days: 4 mg/kg/dose PO twice daily in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For nevirapine and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Neonates 32 to 33 weeks gestation and 4 to 6 weeks: 6 mg/kg/dose PO twice daily in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For nevirapine and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Neonates 34 to 36 weeks gestation and 0 to 6 days: 4 mg/kg/dose PO twice daily in combination with zidovudine and lamivudine. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For nevirapine and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Neonates 34 to 36 weeks gestation and 1 to 4 weeks: 6 mg/kg/dose PO twice daily in combination with zidovudine and lamivudine. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For nevirapine and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Neonates 37 weeks gestation and older and 0 to 4 weeks: 6 mg/kg/dose PO twice daily in combination with zidovudine and lamivudine. Initiate treatment as close to the time of birth as possible, preferably within 6 hours of delivery. The optimal duration of presumptive HIV therapy in high-risk infants is unknown. A 6-week course of zidovudine is recommended. For nevirapine and lamivudine, a treatment duration of 2 to 6 weeks is recommended. The recommended duration for these drugs varies based on HIV nucleic acid test (NAT) results, maternal viral load at the time of delivery, and additional risk factors for HIV transmission, including breastfeeding. Consultation with an expert in pediatric HIV is recommended when selecting a therapy duration, as this decision should be based on patient-specific risk factors and interim HIV NAT results.
Oral dosage (2-Drug Combination Antiretroviral Prophylaxis Regimen):
Neonates 32 weeks gestation and older weighing 1.5 to 2 kg: 8 mg PO for a total of 3 doses given with zidovudine for 6 weeks. Give the first nevirapine dose as soon as possible after birth (within 48 hours). Give the second nevirapine dose 48 hours after the first dose. Give the third nevirapine dose 96 hours after the second dose. The NICHD-HPTN 040/PACTG 1043 study showed an approximately 50% reduction in transmission rate in neonates receiving zidovudine plus nevirapine compared to zidovudine alone.
Neonates 32 weeks gestation and older weighing more than 2 kg: 12 mg PO for a total of 3 doses given with zidovudine for 6 weeks. Give the first nevirapine dose as soon as possible after birth (within 48 hours). Give the second nevirapine dose 48 hours after the first dose. Give the third nevirapine dose 96 hours after the second dose. The NICHD-HPTN 040/PACTG 1043 study showed an approximately 50% reduction in transmission rate in neonates receiving zidovudine plus nevirapine compared to zidovudine alone.

For human immunodeficiency virus (HIV) prophylaxis* to prevent mother-to-child transmission (MTCT) during breastfeeding:
-for human immunodeficiency virus (HIV) prophylaxis* in infants at low risk of HIV acquisition during breastfeeding:
NOTE: Nevirapine is recommended as an optional postnatal prophylaxis regimen for infants at low risk of HIV acquisition during breastfeeding. If prescribed, these simplified doses can be given from birth after confirmation of a negative infant NAT test. Optimal treatment duration has not been established. Some recommend only 6 weeks of nevirapine treatment while others recommend continuing nevirapine treatment throughout breastfeeding. Treatment can be given for 1 to 4 weeks after weaning.
Oral dosage (suspension):
Neonates: 15 mg PO once daily.
Infants younger than 6 weeks: 15 mg PO once daily.
Infants 6 weeks to 6 months: 20 mg PO once daily.
Infants 6 to 9 months: 30 mg PO once daily.
Infants and Children 9 to 24 months: 40 mg PO once daily.
-for human immunodeficiency virus (HIV) prophylaxis* in infants at high risk of HIV acquisition during breastfeeding:
NOTE: Extended postnatal prophylaxis with nevirapine is recommended for infants of women with unsuppressed viral load who choose to breastfeed. If prescribed, these simplified doses should start after confirmation of a negative infant NAT test and after completion of 6 weeks of presumptive HIV therapy. Treatment should continue during breastfeeding and for 1 to 4 weeks after weaning to minimize the risk of transmission.
Oral dosage (suspension):
Infants 6 weeks to 6 months: 20 mg PO once daily.
Infants 6 to 9 months: 30 mg PO once daily.
Infants and Children 9 to 24 months: 40 mg PO once daily.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 4,500 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs


Dosage adjustment in patients with rash
-If a mild to moderate rash without constitutional symptoms is observed during the first 14 days of therapy with the immediate-release formulation, do not increase the immediate-release formulation dose to twice daily and do not start treatment with the extended-release tablet until the rash has resolved.
-The total duration of the lead-in dosing period should not exceed 28 days. If the rash does not resolve by treatment day 28, discontinue nevirapine and use an alternative treatment regimen.
-Although the FDA-approved labeling recommends reinitiation of lead-in dosing for patients who have interrupted therapy for more than 7 days, the HIV guidelines recommend that pediatric patients who interrupt therapy for less than 14 days should be restarted on full-dose nevirapine. If dosing is interrupted for more than 14 days, dosing should be restarted with the lead-in dosing for 14 days, followed by full-dose escalation.

Maximum Dosage Limits:
-Neonates
0 to 6 days: Safety and efficacy have not been established; however, doses of 4 mg/kg/day PO for neonates 32 to 33 weeks gestation, 8 mg/kg/day PO for neonates 34 to 36 weeks gestation, and 12 mg/kg/day PO for neonates 37 weeks gestation and older are recommended off-label for perinatal prophylaxis and treatment. Three doses of 8 mg PO (weight 1.5 to 2 kg) or 12 mg PO (weight more than 2 kg) given within first week of life (birth, 48 hours later, and 96 hours after second dose) also recommended off-label for perinatal prophylaxis.
7 to 14 days: Safety and efficacy have not been established; however, doses of 4 mg/kg/day PO for neonates 32 to 33 weeks gestation and 12 mg/kg/day PO for neonates 34 weeks gestation and older are recommended off-label for perinatal prophylaxis and treatment.
15 days and older: Doses of 8 mg/kg/day PO for neonates 32 to 33 weeks gestation and 12 mg/kg/day PO for neonates 34 weeks gestation and older are recommended off-label for perinatal prophylaxis and treatment, although 300 mg/m2/day PO is the FDA-approved dose for treatment.
-Infants
12 mg/kg/day PO is recommended off-label for perinatal prophylaxis and treatment, although 300 mg/m2/day PO is the FDA-approved dose for treatment.
-Children
1 to 5 years: doses up to 400 mg/m2/day PO for immediate release formulations are recommended off-label, although 300 mg/m2/day PO is the FDA-approved maximum; safety and efficacy have not been established for extended-release tablet.
6 to 7 years and BSA less than 1.17 m2: doses up to 400 mg/m2/day PO for immediate release formulations are recommended off-label, although 300 mg/m2/day PO is the FDA-approved maximum; safety and efficacy have not been established for extended-release tablet.
6 to 7 years and BSA 1.17 m2 or more: doses up to 400 mg/m2/day PO for immediate release formulations are recommended off-label, although 300 mg/m2/day PO is the FDA-approved maximum; 400 mg/day PO for extended-release tablet.
8 to 12 years and BSA less than 1.17 m2: 300 mg/m2/day (Max: 400 mg/day) PO for immediate release formulations; safety and efficacy have not been established for extended-release tablet.
8 to 12 years and BSA 1.17 m2 or more: 300 mg/m2/day (Max: 400 mg/day) PO for immediate release formulations; 400 mg/day PO for extended-release tablets.
-Adolescents
BSA less than 1.17 m2: 300 mg/m2/day PO for immediate release formulations; safety and efficacy have not been established for extended-release tablet.
BSA 1.17 m2 or more: 300 mg/m2/day (Max: 400 mg/day) PO for immediate release formulations; 400 mg/day PO for extended-release tablets.

Patients with Hepatic Impairment Dosing
There are no recommendations for dosage adjustments in patients with mild (Child-Pugh Class A) hepatic impairment. Do not administer nevirapine to patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. Use of the extended-release formulation has not been studied in patients with hepatic impairment.

Patients with Renal Impairment Dosing
No nevirapine dosage adjustments are required for patients with any degree of renal impairment that does not require hemodialysis. Use of the extended-release formulation has not been studied in patients with renal impairment.

Intermittent hemodialysis:
Patients who have renal failure requiring hemodialysis should receive an additional dose of the immediate-release formulation after each dialysis treatment.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Nevirapine is a non-nucleoside reverse transcriptase inhibitor of HIV. It binds directly to reverse transcriptase which causes disruption of the enzyme's catalytic site, thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Nevirapine does not compete with template or nucleoside triphosphates. Combination therapy with nevirapine and zidovudine has been shown to be synergistic against HIV replication.

Pharmacokinetics: Nevirapine is administered orally. It is highly lipophilic and is widely distributed throughout the body. Protein binding is approximately 60%. The cerebrospinal fluid concentration is about 45% of the corresponding plasma concentration which is approximately equal to the fraction of nevirapine not bound to plasma protein. Metabolism to hydroxylated metabolites occurs primarily via cytochrome P450 (CYP) 3A and 2B6. These metabolites are then further metabolized by glucuronide conjugation. Elimination of nevirapine and its metabolites is mainly in the urine. In radiolabeled pharmacokinetic studies, approximately 91% of a radiolabeled dose was detected in the urine and over 80% of the radioactivity in the urine consisted of glucuronide conjugates of the hydroxylated metabolites. About 10% was recovered in the feces. Less than 3% of the total dose is excreted unchanged in the urine. After a single dose, the terminal elimination half-life in adults is about 45 hours. After multiple dosing with 200 to 400 mg/day, the elimination half-life is decreased to approximately 25 to 30 hours due to induction of hepatic CYP isoenzymes 3A and 2B6. Clearance is also increased 1.5- to 2-fold because of auto-induction. Pharmacokinetic data demonstrate the persistence of detectable drug concentrations for at least 21 days after discontinuation of nevirapine.

Affected cytochrome P450 isoenzymes: CYP3A4, CYP2B6
Nevirapine induces the hepatic enzymes CYP3A4 and CYP2B6 by approximately 20% to 25%. While primarily an inducer of these enzymes, in vitro data suggests nevirapine may also have mild inhibitory effects on CYP3A4.


-Route-Specific Pharmacokinetics
Oral Route
In studies of healthy adults, the bioavailability was approximately 93% for the immediate-release tablet, 91% for the oral solution, and 75% for the extended-release tablets. After multiple doses, peak plasma concentrations increase linearly in the dose range of 200 to 400 mg/day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and are interchangeable at doses up to 200 mg. Food does not significantly affect the extent of absorption.


-Special Populations
Pediatrics
Neonates
In neonates who received the 3-dose nevirapine regimen to prevent perinatal HIV transmission, serum concentrations were more than 100 mg/mL in all newborns through 10 days of life (n = 23). The elimination half-life in these neonates was 17.8 to 50.3 hours (median 30.2 hours).
In the IMPAACT 1115 study, nevirapine dosed at 6 mg/kg/dose twice daily for infants 37 weeks gestation and older and 4 mg/kg/dose twice daily for 1 week and 6 mg/kg/dose twice daily thereafter for infants 34 to 36 weeks gestation achieved concentrations appropriate for treatment. Among 438 infants (389 infants 37 weeks gestation and older), measured nevirapine concentrations were above the minimum HIV treatment target (3 mcg/mL) in 90% at Week 1 and 87% at Week 2.

Infants, Children, and Adolescents
In pediatric patients, the mean nevirapine clearance adjusted for body weight is greater than in adults. Clearance adjusted for weight reached maximum values by age 1 to 2 years and then decreased with increasing age. Additionally, clearance adjusted for weight was at least 2-fold greater in children younger than 8 years compared to older children and adults which may require a higher dosage to achieve equivalent drug exposure.

Ethnic Differences
Certain ethnic groups (such as African Americans and Hispanics) may display genetic polymorphisms resulting in a slower rate of clearance of nevirapine. This appears to be clinically relevant only with a planned interruption of nevirapine therapy, as plasma concentrations of the drug persist and there is a greater potential for the development of antimicrobial resistance.