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Nevirapine

Pronunciation

(ne VYE ra peen)

Index Terms

  • NVP

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

Viramune: 50 mg/5 mL (240 mL) [contains methylparaben, propylparaben]

Generic: 50 mg/5 mL (240 mL)

Tablet, Oral:

Viramune: 200 mg [scored]

Generic: 200 mg

Tablet Extended Release 24 Hour, Oral:

Viramune XR: 100 mg, 400 mg

Generic: 100 mg, 400 mg

Brand Names: U.S.

  • Viramune
  • Viramune XR

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)

Pharmacology

As a non-nucleoside reverse transcriptase inhibitor, nevirapine has activity against HIV-1 by binding to reverse transcriptase. It consequently blocks the RNA-dependent and DNA-dependent DNA polymerase activities including HIV-1 replication. It does not require intracellular phosphorylation for antiviral activity.

Absorption

Rapid and readily absorbed; Immediate release: >90%

Distribution

Widely; Vd: 1.2 L/kg; CSF penetration approximates 40% to 50% of plasma

Metabolism

Extensively hepatic via CYP3A4 and CYP2B6 (hydroxylation to inactive compounds); may undergo enterohepatic recycling

Excretion

Urine (~81%, primarily as metabolites, <3% as unchanged drug); feces (~10%)

Clearance: Women have a 13.8% lower clearance compared to men; Body size does not totally explain the gender difference

Time to Peak

Serum: Immediate release: 4 hours; Extended release:~24 hours

Half-Life Elimination

Decreases over 2- to 4-week time with chronic dosing due to autoinduction (ie, half-life = 45 hours initially [single dose] and decreases to 25 to 30 hours [multiple dosing])

Protein Binding

Plasma: ~60%

Special Populations: Renal Function Impairment

No change in pharmacokinetics in patients with mild, moderate, or severe renal impairment. Patients on dialysis showed a 44% reduction in AUC over a 1-week exposure. Use of extended release dosage tablets has not been studied in patients with renal dysfunction.

Special Populations: Hepatic Function Impairment

Patients with hepatic fibrosis had trough concentrations above 9,000 mcg/mL (twofold the usual mean trough). Do not administer to patients with moderate or severe (Child-Pugh class B or C, respectively) hepatic impairment. Use of extended release dosage tablets has not been studied in patients with hepatic impairment.

Special Populations: Children

Plasma concentrations were within the range observed in adults, but were more variable between patients, particularly in the second month of age.

Special Populations: Race

Black patients showed ~30% to 35% higher trough concentrations than white patients.

Use: Labeled Indications

In combination therapy with other antiretroviral agents for the treatment of HIV-1

Contraindications

Moderate-to-severe hepatic impairment (Child-Pugh class B or C); use in occupational or nonoccupational postexposure prophylaxis (PEP) regimens

Canadian labeling: Additional contraindications (not in US labeling): Clinically significant hypersensitivity to nevirapine or any component of the formulation; therapy rechallenge in patients with prior hypersensitivity reactions, severe rash, rash accompanied by constitutional symptoms, or clinical hepatitis due to nevirapine; severe hepatic dysfunction or AST or ALT >5 times ULN (pretreatment or during prior use of nevirapine); hereditary conditions of galactose intolerance (eg, galactosemia, Lapp lactase deficiency, glucose-galactose malabsorption); concomitant use of herbal products containing St John’s wort

Dosing: Adult

HIV infection: Oral:

Note: Therapy in antiretroviral naive patients should not be initiated in patients with elevated CD4+-cell counts unless the benefit of therapy outweighs the risk of serious hepatotoxicity (adult/postpubertal females: CD4+-cell counts >250 cells/mm3; adult males: CD4+-cell counts >400 cells/mm3).

Initial: Immediate release: 200 mg once daily for 14 days

Maintenance:

Immediate release: 200 mg twice daily (in combination with additional antiretroviral agents) if there is no rash or untoward effects during initial dosing period

Extended release: 400 mg once daily; maintenance therapy using the extended release must follow a 14-day initial dosing period (lead-in) using the immediate release formulation unless patient is already maintained on a nevirapine immediate release regimen

Note: If patient experiences a rash during the 14-day lead-in period, dose should not be increased until the rash has resolved. A lead-in period must always be done with immediate release formulation and regimen should not exceed 28 days; alternative treatment should be considered at that point. If a rash occurs within the first 18 weeks of therapy, immediately check serum transaminases. Discontinue if severe rash, rash with constitutional symptoms, or rash with elevated hepatic transaminases is noted. Coadministration of prednisone during the first 6 weeks of therapy increases incidence and severity of rash; concomitant prednisone is not recommended to prevent rash. Permanently discontinue if symptomatic hepatic events occur. If therapy with any formulation is interrupted for >7 days, restart with initial dose of immediate release formulation for 14 days.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV infection: Oral: Note: If patient experiences a rash during the 14-day lead-in period, dose should not be increased until the rash has resolved. A lead-in period must always be done with immediate release formulation and regimen should not exceed 28 days; alternative treatment should be considered at that point. If a rash occurs within the first 18 weeks of therapy, immediately check serum transaminases. Discontinue if severe rash, rash with constitutional symptoms, or rash with elevated hepatic transaminases is noted. Coadministration of prednisone during the first 6 weeks of therapy increases incidence and severity of rash; concomitant prednisone is not recommended to prevent rash. Permanently discontinue if symptomatic hepatic events occur. If therapy with any formulation is interrupted for >7 days, restart with initial dose of immediate release formulation for 14 days. Use of nevirapine in children <15 years of age is not approved in the Canadian labeling.

Manufacturer's labeling:

Infants and Children: Immediate release: 150 mg/m2/dose once daily for first 14 days (maximum: 200 mg daily); increase dose to 150 mg/m2/dose twice daily if no rash or untoward effects (maximum: 400 mg daily).

Children 6 to <18 years: Extended release: Dose based on body surface area (Mosteller formula); maintenance therapy using the extended release must follow a 14-day initial dosing period (lead-in) using the immediate release formulation unless patient is already maintained on a nevirapine immediate release regimen.

0.58 m2 to 0.83 m2: 200 mg once daily

0.84 m2 to 1.16 m2: 300 mg once daily

≥1.17 m2: 400 mg once daily (do not exceed 400 mg daily)

Alternate recommendations (HHS [pediatric], 2014):

Note: Children <3 years of age: Nevirapine-based initial regimens should not be used in children previously exposed to nevirapine during prevention of maternal-to-child transmission of HIV

Children <8 years: Immediate release: 200 mg/m2/dose once daily for first 14 days (maximum dose: 200 mg); increase dose to 200 mg/m2/dose twice daily if no rash or untoward effects (maximum: 400 mg daily)

Children ≥8 years: Immediate release: 120-150 mg/m2/dose once daily for 14 days (maximum dose: 200 mg); increase dose to 120-150 mg/m2/dose twice daily if no rash or untoward effects (maximum: 400 mg daily)

Adolescents: Immediate release: Refer to adult dosing.

Prevention of perinatal HIV transmission (HHS [perinatal], 2015): Note: Nevirapine is used in combination with a 6-week course of zidovudine in infants at higher risk of HIV acquisition (eg, infants born to mothers with suboptimal viral suppression [>1,000 copies/mL] near delivery, only intrapartum therapy, or no therapy). Use is not recommended in newborns of women receiving effective antenatal antiretroviral prophylaxis. Initiate dosing as soon after delivery as possible. A total of three doses should be given during the first week of life. The first as soon as possible after birth (within 48 hours), the second dose 48 hours after the first dose, the third dose 96 hours after the second dose. Dose is based on birth weight:

Birth weight 1.5 to 2 kg: Oral: 8 mg/dose

Birth weight >2kg: Oral: 12 mg/dose

Dosing: Renal Impairment

Immediate release:

CrCl ≥20 mL/minute: No dosage adjustment necessary.

CrCl <20 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Extended release: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hemodialysis: An additional 200 mg immediate release dose is recommended following dialysis.

Dosing: Hepatic Impairment

Permanently discontinue if symptomatic hepatic events occur.

US labeling:

Mild impairment (Child-Pugh class A):

Immediate release: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Extended release: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Moderate-to-severe impairment (Child-Pugh class B or C): Use is contraindicated.

Canadian labeling:

Mild impairment (Child-Pugh class A): No dosage adjustment is necessary.

Moderate impairment (Child-Pugh class B): There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution.

Severe impairment (Child-Pugh class C): Use is contraindicated.

Administration

Oral: May be administered with or without food; may be administered with an antacid or didanosine. Shake suspension gently prior to administration; the use of an oral dosing syringe is recommended, especially if the dose is ≤5 mL; if using a dosing cup, after administration, rinse cup with water and also administer rinse. Extended release tablets must be swallowed whole and not crushed, chewed, or divided.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Artemether: Nevirapine may decrease the serum concentration of Artemether. Nevirapine may also increase or decrease serum concentrations of lumefantrine. Monitor therapy

Artesunate: Nevirapine may decrease serum concentrations of the active metabolite(s) of Artesunate. Nevirapine may increase the serum concentration of Artesunate. Monitor therapy

Atazanavir: May increase the serum concentration of Nevirapine. Nevirapine may decrease the serum concentration of Atazanavir. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of CarBAMazepine. This mechanism applies specifically to efavirenz. Avoid combination

Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Consider therapy modification

Contraceptives (Estrogens): Nevirapine may decrease the serum concentration of Contraceptives (Estrogens). Consider therapy modification

Contraceptives (Progestins): Nevirapine may decrease the serum concentration of Contraceptives (Progestins). Management: Instruct patients receiving nevirapine to use an alternative or additional nonhormonal contraceptive. Nevirapine product labeling however suggests that depo-medroxyprogesterone acetate may be used as a sole method of contraception. Consider therapy modification

CYP2B6 Substrates: CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: Nevirapine may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily. Consider therapy modification

Darunavir: May increase the serum concentration of Nevirapine. Nevirapine may increase the serum concentration of Darunavir. Management: No action is required if darunavir/ritonavir is combined with nevirapine. The combination of darunavir/cobicistat and nevirapine should be avoided. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dolutegravir: Nevirapine may decrease the serum concentration of Dolutegravir. Avoid combination

Efavirenz: May enhance the adverse/toxic effect of Nevirapine. Nevirapine may enhance the adverse/toxic effect of Efavirenz. Nevirapine may decrease the serum concentration of Efavirenz. Avoid combination

Elvitegravir: Nevirapine may decrease the serum concentration of Elvitegravir. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Fluconazole: May increase the serum concentration of Nevirapine. Monitor therapy

Fosamprenavir: Nevirapine may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Management: Coadministration of nevirapine and fosamprenavir is not recommended without concurrent ritonavir. However, when nevirapine and fosamprenavir/ritonavir (twice daily) are used in combination, no dose adjustment is required. Consider therapy modification

Hydrocodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hydrocodone. Monitor therapy

Indinavir: Nevirapine may decrease the serum concentration of Indinavir. Management: Increased indinavir doses may be needed when used with nevirapine; however, specific dosing guidelines have not been established. Consider therapy modification

Itraconazole: Nevirapine may decrease the serum concentration of Itraconazole. Avoid combination

Ketoconazole (Systemic): Nevirapine may decrease the serum concentration of Ketoconazole (Systemic). Avoid combination

Lopinavir: Nevirapine may decrease the serum concentration of Lopinavir. Management: Avoid once daily use of lopinavir/ritonavir with nevirapine. Avoid use of this combination in patients less than 6 months of age. See lopinavir/ritonavir prescribing information for recommended dose increases in other patients. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nelfinavir: Nevirapine may decrease serum concentrations of the active metabolite(s) of Nelfinavir. Nevirapine may decrease the serum concentration of Nelfinavir. Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Rifabutin: May decrease the serum concentration of Nevirapine. Nevirapine may decrease the serum concentration of Rifabutin. Nevirapine may increase the serum concentration of Rifabutin. Monitor therapy

Rifampin: May decrease the serum concentration of Nevirapine. Management: Avoid whenever possible. When this combination is necessary, use immediate-release nevirapine (avoid extended-release nevirapine) at a dose of 200 mg twice daily with no lead-in (per adult/adolescent HIV guidelines). Monitor nevirapine response closely. Consider therapy modification

Rilpivirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Rivaroxaban: Nevirapine may decrease the serum concentration of Rivaroxaban. Monitor therapy

Saquinavir: Nevirapine may decrease the serum concentration of Saquinavir. Monitor therapy

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: Nevirapine may decrease the serum concentration of Simeprevir. Avoid combination

St John's Wort: May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Specifically, St. Johns Wort may increase the metabolism of Reverse Transcriptase Inhibitors (Non-Nucleoside). Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Voriconazole: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Management: Consider avoiding when possible. Use efavirenz with voriconazole only if voriconazole is dosed at 400 mg every 12 hours and efavirenz is dosed at 300 mg daily (adult doses) throughout therapy. Avoid Atripla (efavirenz/emtricitabine/tenofovir). Consider therapy modification

Adverse Reactions

Note: Potentially life-threatening nevirapine-associated adverse effects may present with the following symptoms: Abrupt onset of flu-like symptoms, abdominal pain, jaundice, or fever with or without rash; may progress to hepatic failure with encephalopathy. Skin rash is present in ~50% of cases.

>10%:

Dermatologic: Rash (1% to 7%; grade 1/2: 13%; grade 3/4: 2%)

Endocrine & metabolic: Cholesterol increased (240-300 mg/dL: 18% to 19%; >300 mg/dL: 3% to 4%), LDL increased (160-190 mg/dL: 15%; >190 mg/dL: 5%)

Hematologic: Neutropenia (4% to 13%; grades 3/4: 1% to 2%)

Hepatic: ALT increased (2.6-5 x ULN: 10% to 13%; ≥5.1 x ULN: 6% to 7%), symptomatic hepatic events (including hepatitis and hepatic failure: 2% to 11%; risk higher in ARV-naive women with CD4 counts >250 cells/mm3 and ARV-naive men with CD4 counts >400 cells/mm3)

1% to 10%:

Central nervous system: Fatigue (≤5%), headache (1% to 4%), fever (1% to 2%)

Gastrointestinal: Nausea (<1% to 9%), amylase increased (1.6-5 x ULN: 7% to 8%; ≥5.1 x ULN: <1%), abdominal pain (≤2%), diarrhea (≤2%)

Hepatic: AST increased (2.6-5 x ULN: 7% to 9%; ≥5.1 x ULN: 4% to 5%)

Neuromuscular & skeletal: Arthralgia (2%)

<1% (Limited to important or life-threatening): Allergic reactions, anaphylaxis, anemia, angioedema, bullous eruptions, cholestatic hepatitis, conjunctivitis, drug reaction with eosinophilia and systemic symptoms (DRESS), eosinophilia, fulminant hepatitis, granulocytopenia, hepatic necrosis, hypersensitivity syndrome, hypophosphatemia, immune reconstitution syndrome, jaundice, lymphadenopathy, oral lesions, redistribution/accumulation of body fat, renal dysfunction, rhabdomyolysis, Stevens-Johnson syndrome, toxic epidermal necrolysis, ulcerative stomatitis

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Severe, life-threatening, and, in some cases, fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Women and patients with higher CD4+ cell counts at initiation of therapy are at increased risk. Women with CD4+ cell counts higher than 250 cells/mm3, including pregnant women receiving nevirapine in combination with other antiretrovirals for treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with nevirapine use can occur in both genders, at all CD4+ cell counts, and at any time during treatment. Hepatic failure has also been reported in patients without HIV taking nevirapine for postexposure prophylaxis. Use of nevirapine for occupational and nonoccupational postexposure prophylaxis is contraindicated. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately.

Skin reactions:

Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Check transaminase levels immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with nevirapine 200 mg immediate release daily dosing has been observed to decrease the incidence of rash and must be followed.

Monitoring:

Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these reactions. Do not restart nevirapine following clinical hepatitis, transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment.

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hepatotoxicity: [US Boxed Warning]: Severe hepatotoxic reactions may occur (fulminant and cholestatic hepatitis, hepatic necrosis) and, in some cases, have resulted in hepatic failure and death. The greatest risk of these reactions is within the initial 6 weeks of treatment; intensive monitoring is required during the initial 18 weeks of therapy to detect potentially life-threatening hepatic reactions. Patients with a history of chronic hepatitis (B or C) or increased baseline transaminase levels may be at increased risk of hepatotoxic reactions. Female gender and patients with increased CD4+-cell counts may be at substantially greater risk of hepatic events (often associated with rash). Therapy in antiretroviral naive patients should not be started with elevated CD4+-cell counts unless the benefit of therapy outweighs the risk of serious hepatotoxicity. If signs and symptoms of hepatitis occur, nevirapine should be permanently discontinued with immediate evaluation of liver function.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Rhabdomyolysis: Has been observed in conjunction with skin and/or hepatic adverse events during postmarketing surveillance. Termination of therapy is warranted with evidence of severe skin or liver toxicity.

• Skin reactions: [US Boxed Warning]: Severe life-threatening skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, hypersensitivity reactions with rash and organ dysfunction), including fatal cases, have occurred. The greatest risk of these reactions is within the initial 6 weeks of treatment; intensive monitoring is required during the initial 18 weeks of therapy to detect potentially life-threatening dermatologic and hypersensitivity reactions. If a rash occurs within the first 18 weeks of therapy, immediately check serum transaminases. Risk is greatest in African-Americans, Asian, or Hispanic race/ethnicity or in females (DHHS, 2011). If a severe dermatologic or hypersensitivity reaction occurs, nevirapine should be permanently discontinued; these events may include a severe rash, or a rash associated with fever, blisters, oral lesions, conjunctivitis, facial edema, muscle or joint aches, transaminase increases, general malaise, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. Use of the 14-day lead-in dosing period is necessary to decrease the incidence of rash events. If nonsevere rash (in absence of transaminase elevations) occurs, do not increase dose until resolution of rash. If rash continues beyond 28 days, consider an alternative regimen. Coadministration of prednisone during the first 6 weeks of therapy increases incidence and severity of rash; concomitant prednisone is not recommended to prevent rash.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with pre-existing dysfunction; monitor closely for drug-induced hepatotoxicity. US labeling contraindicates use in patients with moderate-to-severe impairment (Child-Pugh class B or C). Canadian labeling contraindicates use in severe impairment.

Concurrent drug therapy issues:

• Efavirenz: Use with nevirapine may increase the risk for adverse effects without increasing efficacy; concurrent use is not recommended.

• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions. Concurrent use of St John's wort is not recommended (Canadian labeling contraindicates concurrent use) as it may decrease the therapeutic efficacy of nevirapine.

Special populations:

• Pediatric: Nevirapine-based initial regimens should not be used in children <3 years of age if previously exposed to nevirapine during prevention of maternal-to-child transmission of HIV due to increased risk of resistance and treatment failure. Protease inhibitor-based initial regimens preferred in this population.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Appropriate use: When initiating therapy, a 14-day lead-in dose with the immediate release formulation should be used to decrease risk of skin reactions. If rash appears during the 14-day lead-in period, do not increase the dose or initiate the extended release formulation until the rash has resolved. An alternative regimen should be used if the lead-in dose period exceeds 28 days. Therapy in antiretroviral naive patients should not be initiated in patients with elevated CD4+-cell counts unless the benefit of therapy outweighs the risk of serious hepatotoxicity (adult/postpubertal females: CD4+-cell counts >250 cells/mm3; adult males: CD4+-cell counts >400 cells/mm3). If CD4+-cell counts increase above these thresholds as a result of nevirapine-containing therapy, therapy may be continued. After the lead-in period, patients may be switched to the extended-release formulation.

• Resistance: Due to rapid emergence of resistance, nevirapine should not be used as monotherapy or the only agent added to a failing regimen for the treatment of HIV. Resistance may occur with a single mutation and cross-resistance may be conferred to other non-nucleoside reverse transcriptase inhibitors (HHS [adult] 2015).

Monitoring Parameters

Monitor CBC and viral load. Baseline liver function tests should be obtained prior to nevirapine’s initiation. HHS adult guidelines recommend serum transaminase monitoring every 2 weeks for the first 4 weeks of therapy, monthly for the first 18 weeks, then frequently thereafter. Patients receiving maintenance immediate release nevirapine who change to the extended release formulation should adhere to their regular monitoring schedule. HHS adult guidelines recommend serum transaminase monitoring every 2 weeks for the first 4 weeks of therapy, then monthly for 3 months, followed by every 3-4 months. HHS pediatric guidelines recommend serum transaminase monitoring every 2 weeks for the first 4 weeks of therapy, followed by every 4 months. Assess/evaluate AST/ALT immediately in any patients with a rash. Permanently discontinue if patient experiences severe rash, constitutional symptoms associated with rash, rash with elevated AST/ALT, or clinical hepatitis. Mild-to-moderate rash without AST/ALT elevation may continue treatment per discretion of prescriber. If mild-to-moderate urticarial rash, do not restart if treatment is interrupted.

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic effects were not observed in animal reproduction studies. Nevirapine has a high level of transfer across the human placenta. No increased risk of overall birth defects has been observed following first trimester exposure according to data collected by the antiretroviral pregnancy registry. Hypersensitivity reactions (including severe life-threatening hepatic toxicity and rash) are more common in women than men, and the greatest risk is within the first 6 to 18 weeks of therapy; pregnancy does not appear to increase this risk. The HHS Perinatal HIV Guidelines do not recommend nevirapine as an initial NNRTI for use in antiretroviral-naive pregnant patients because of the potential for adverse events, complex dosing, and low barrier to resistance. Pharmacokinetics are not altered during pregnancy and dose adjustment is not needed. Women who become pregnant while on therapy and are tolerating it well may continue. Frequent monitoring is recommended.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2015).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, lipodystrophy, or tablet shell in stool. Have patient report immediately to prescriber considerable asthenia, urinary retention, oliguria, flu-like symptoms, arthralgia, myalgia, enlarged lymph nodes, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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