Drug Description

Nevirapine is a dipyridodiazepine derivative non-nucleoside reverse transcriptase inhibitor (NNRTI). [1]

References

[1] AHFS Drug Information 2008; p. 714

HIV/AIDS-Related Uses

Nevirapine was approved by the U.S. Food and Drug Administration (FDA) on June 21, 1996, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. [1] Nevirapine is approved for use in adults and in pediatic patients 15 days and older. [2] Nevirapine extended-release tablets received FDA approval on March 25, 2011. [3]

Administration of single-dose nevirapine to the mother intrapartum and to the infant postpartum effectively reduces vertical transmission of HIV-1. [4] This regimen, recommended only for use in HIV-infected treatment-naive women in labor who have had no prior therapy for HIV, includes a single nevirapine dose given to the mother at the onset of labor and a single nevirapine dose given to the neonate 48 to 72 hours after birth. [5]

References

[1] Wolters Kluwer Health, Inc. Nevirapine, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 03/12/09.

[2] FDA Viramune Prescribing Information, 06/24/08, p. 2. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[3] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[4] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[5] AHFS Drug Information 2008; p. 709

Dosing Information

Oral (tablet [immediate-release and extended-release], suspension). [1] [2]

Dosage Form

Tablets containing nevirapine 200 mg. [3]

Extended-release tablets containing nevirapine 400 mg. [4]

Oral suspension containing nevirapine 50 mg (as nevirapine hemihydrate) per 5 ml. [5]


Dosage and Administration of Nevirapine (Immediate-Release)

The recommended adult dose of nevirapine is one 200 mg tablet once daily for the first 14 days, followed by one 200 mg tablet twice daily. As of June 2008, the recommended dose of nevirapine 50 mg/5 ml oral suspension for pediatric patients is based on body surface area (BSA) rather than on weight. Pediatric patients who are 15 days and older should receive 150 mg/m2 once daily for 14 days (lead-in period) and 150mg/m2 twice daily thereafter, with a maximum total daily dose of 400 mg. The decision to calculate pediatric dosing by BSA instead of weight was based on pharmacokinetic data from more than 600 participants in a 48-week pediatric trial and in an analysis of five Pediatric AIDS Clinical Trial Group protocols. BSA-calculated doses for these studies provided nevirapine trough concentrations that were comparable to those achieved with weight-based doses; however, BSA dosing was found to allow for smoother dose transitions between pediatric age groups. [6] [7] [8]


Dosage and Administration of Extended-Release Nevirapine

Patients Not Currently Taking Immediate-Release Nevirapine:

Patients must initiate therapy with one 200 mg tablet of immediate-release nevirapine daily for the first 14 days in combination with other antiretroviral agents (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg tablet of  extended release nevirapine once daily. Patients must swallow nevirapine extended-release tablets whole. They must not be chewed, crushed, or divided. For concomitantly administered therapy, the manufacturer’s recommended dosage and monitoring should be followed. Nevirapine extended-release tablets can be taken with or without food. [9]

Switching Patients from Immediate-Release Nevirapine to Extended-Release Nevirapine:

Patients already on a regimen of immediate-release nevirapine twice daily in combination with other antiretroviral agents can be switched to extended-release nevirapine 400 mg once daily in combination with other antiretroviral agents without the 14-day lead-in period of immediate-release nevirapine. [10]

Patients must never take more than one form of nevirapine at the same time. [11]

Monitoring of patients receiving extended-release nevirapine is the same as immediate-release nevirapine and includes intensive clinical and laboratory monitoring, including liver enzyme tests at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release nevirapine, prior to initiation of extended-release nevirapine, and at two weeks after initiation of extended-release nevirapine therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout extended-release nevirapine treatment. [12]

Patients already on a regimen of immediate-release nevirapine twice daily who switch to extended-release nevirapine once daily should continue with their ongoing clinical and laboratory monitoring. [13]
 

Storage

Store tablets and oral suspension at 25 C (77F), with excursions permitted between 15 C to 30 C (59 F to 86 F). [14]

References

[1] Wolters Kluwer Health, Inc. Nevirapine, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 03/12/09.

[2] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[3] FDA Viramune Prescribing Information, 06/24/08, p. 14. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[4] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[5] FDA Viramune Prescribing Information, 06/24/08, p. 14. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[6] FDA Viramune Prescribing Information, 06/24/08, pp. 2-3. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[7] FDA Listserve Archive, June 24, 2008. Available at: http://www.fda.gov/oashi/aids/listserve/listserve2008.html. Accessed 03/12/09.

[8] FDA Viramune Prescribing Information, 06/24/08, pp. 2-3. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[9] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[10] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[11] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[12] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[13] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[14] FDA Viramune Prescribing Information, 06/24/08, p. 14. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

Pharmacology

Nevirapine exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase (RT) inhibitor. The drug binds directly to heterodimeric HIV-1 RT and appears to inhibit RT activity by disrupting the catalytic site of the enzyme. Nevirapine has a very limited spectrum of antiviral activity. The drug has in vitro virustatic activity against HIV-1, but is inactive against HIV-2 and animal retroviruses. [1]

Nevirapine is more than 90% absorbed after oral administration in healthy adults and adults with HIV-1 infection. Absolute bioavailability in a trial of 12 healthy adults following single-dose administration was 93% for a 50 mg oral tablet and 91% for 5 mL (nevirapine hemihydrate 50 mg) of oral suspension. When nevirapine was administered to 24 healthy adults with either a high-fat breakfast or an antacid, the extent of absorption was comparable to that seen under fasting conditions. [2]

Although distribution of nevirapine into body tissues and fluids has not been fully characterized, animal studies indicate that nevirapine is widely distributed into most tissues after administration. Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. A nevirapine peak plasma concentration (C_max) of approximately 2 mcg/mL was measured by 4 hours after a single 200 mg dose. Following IV administration of nevirapine in healthy adults, the apparent volume of distribution is 1.21 L/kg, suggesting that the drug is widely distributed in humans. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 10 mcg/mL. [3] Nevirapine concentrations in cerebrospinal fluid were 45% of the concentrations in plasma at a ratio approximately equal to the fraction not bound to plasma protein. [4] [5]

Nevirapine is extensively biotransformed via cytochrome P450 (CYP) metabolism to several hydroxylated metabolites. Biotransformation is primarily by isozymes from the CYP3A family, but other isozymes may be involved with nevirapine metabolism. [6] In a pharmacokinetic study, approximately 81% of a radiolabeled dose was recovered in the urine, with greater than 80% of that made up of glucuronide conjugates of hydroxylated metabolites. Approximately 10% of a radiolabeled dose was recovered in the feces. Less than 5% of the recovered radiolabeled dose was made up of the parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound. [7] In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood. [8]

Nevirapine is in FDA Pregnancy Category B. There are no adequate and well-controlled studies of nevirapine in pregnant women. Nevirapine readily crosses the placenta and achieves neonatal blood concentrations comparable to those in the mother (cord-to-maternal blood ratio approximately 0.9). Evidence of impaired fertility was seen in female rats at doses providing systemic exposure approximately equivalent to that attained with the recommended clinical dose of nevirapine. Teratogenic effects of nevirapine have not been observed in reproductive studies with rats and rabbits. However, in rats, a significant decrease in fetal weight occurred at doses producing systemic concentrations approximately 50% higher than human therapeutic exposure. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In order to monitor maternal-fetal outcomes of pregnant women exposed to nevirapine and other antiretrovirals, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by either calling 800-258-4263 or accessing the website at http://www.APRegistry.com. [9] [10]

Nevirapine is readily distributed into breast milk. Following administration of a single 100- to 200-mg dose of nevirapine to pregnant women several hours prior to delivery, postpartum concentrations of nevirapine in milk have been reported to be 25% to 122% of maternal serum concentrations. HIV infected mothers should not breastfeed their infants in order to avoid risk of HIV transmission and the potential for serious nevirapine-related adverse reactions in the nursing infant. [11]

The mechanism of resistance or reduced susceptibility to nevirapine has not been fully determined, but mutation of HIV RT appears to be involved. A single mutation may be sufficient to result in high-level resistance to nevirapine. Drug-resistant HIV emerges rapidly and uniformly when nevirapine is administered as monotherapy. Mutations conferring resistance to nevirapine could be observed after a single dose, even with a low level of viral replication. Therefore, nevirapine should always be administered in combination with at least one other antiretroviral agent. [12] Resistance to nevirapine usually confers class resistance to other NNRTIs (efavirenz and delavirdine). However, nevirapine-resistant isolates were susceptible to the nucleoside analogues zidovudine and didanosine. Similarly, zidovudine-resistant isolates were susceptible to nevirapine in vitro. [13]

Nevirapine demonstrated additive to synergistic in vitro activity against HIV-1 in combination regimens with zidovudine, didanosine, stavudine, lamivudine, saquinavir, and indinavir. [14] Because nevirapine and HIV protease inhibitors (PIs), such as amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, have different enzyme targets, cross resistance between nevirapine and these drugs is unlikely. [15]

The clinical efficacy of extended-release nevirapine is based on 48-week data from an ongoing, randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486, VERxVE) in treatment-naïve subjects and on 24-week data in an ongoing, randomized, open-label trial in subjects who switched from immediate-release nevirapine tablets administered twice daily to extended-release nevirapine tablets administered once daily (Trial 1100.1526, TRANxITION). [16]

References

[1] AHFS Drug Information 2008; pp. 712-3

[2] AHFS Drug Information 2008; p. 713

[3] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[4] AHFS Drug Information 2008; p. 713

[5] FDA Viramune Prescribing Information, 06/24/08, p. 9. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[6] AHFS Drug Information 2008; p. 714

[7] FDA Viramune Prescribing Information, 06/24/08, p. 9. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[8] Wolters Kluwer Health, Inc. Nevirapine, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 03/12/09.

[9] AHFS Drug Information 2008; p. 711

[10] Wolters Kluwer Health, Inc. Nevirapine, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 03/12/09.

[11] AHFS Drug Information 2008; p. 711

[12] AHFS Drug Information 2008; p. 713

[13] FDA Viramune Prescribing Information, 06/24/08, p. 13. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[14] FDA Viramune Prescribing Information, 06/24/08, p. 12. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[15] AHFS Drug Information 2008; p. 713

[16] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

Adverse Events/Toxicity

Granulocytopenia (occurring more frequently in children), skin rash, fever, hepatitis prodromal symptoms, hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, gastrointestinal effects, fatigue, and headache are the most common adverse effects seen with nevirapine use. [1]

Clinically symptomatic hepatotoxicity has been observed with initiation of and during continued use of nevirapine. Among the NNRTIs, nevirapine has the greatest potential for causing clinical hepatitis. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. [2] The greatest risk of severe and potentially fatal hepatic events, often associated with rash, occurs in the first 6 weeks of nevirapine treatment. Approximately two-thirds of the cases of nevirapine-associated clinical hepatitis occur within the first 12 weeks of use. [3] However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment. Clinical hepatitis and 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, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction. Patients who experience a clinical hepatitis event must seek medical evaluation immediately and should be advised to permanently discontinue nevirapine. In some cases, hepatic injury progresses despite discontinuation of treatment. [4] [5]

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, nevirapine, including extended-release nevirapine, should not be initiated in adult females with CD4 counts greater than 250 cells/mm³ or in adult males with CD4 counts greater than 400 cells/mm³ unless the benefit outweighs the risk. [6] [7]

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. Severe or life-threatening rash occurred in approximately 2% of clinically treated patients. [8] Fever, in the absence of any apparent cause, is a significant predictor for the development of rash in patients receiving nevirapine. [9] Patients who develop signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine as soon as possible and must limit the nevirapine-only treatment time to 28 days. [10] [11]

The first 18 weeks of therapy with nevirapine is a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme 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. [12]

Patients starting extended-release nevirapine and who are not currently taking immediate-release nevirapine, must strictly follow the 14-day lead-in period with immediate-release nevirapine 200 mg daily dosing to reduce the occurrence of rash. If rash persists beyond the 14-day lead-in period with immediate-release nevirapine, do not begin dosing with extended-release nevirapine. The lead-in dosing with 200 mg once-daily immediate-release nevirapine should not be continued beyond 28 days, at which point an alternative regimen should be sought. [13]

Because most occupational HIV exposures do not result in transmission of HIV, health care providers considering prescribing postexposure prophylaxis for exposed persons must balance the risk for HIV transmission represented by the exposure and the exposure source against the potential toxicity of the specific agents used for postexposure prophylaxis. In many circumstances, the risks associated with nevirapine as part of a postexposure prophylaxis regimen outweigh the anticipated benefits. However, no serious toxicity has been reported in women or infants receiving two-dose nevirapine (the HIVNET 012 clinical trial regimen) for prevention of perinatal transmission of HIV. [14]

Additional adverse reaction information related to extended-release nevirapine can be found in clinical trial data. In Trial 1100.1486 (VERxVE) treatment-naïve subjects received a lead-in dose of immediate-release nevirapine 200 mg once daily for 14 days (n=1068) and then were randomized to receive either immediate-release nevirapine 200 mg twice daily (n=506) or extended-release nevirapine 400 mg once daily (n=505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4+ counts less than 250 cells/mm³ for women and less than 400 cells/mm³ for men. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subjects’s completion of the 48 week primary endpoint in the trial (mean observation period 61 weeks). [15]

After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release nevirapine group and 6% in the extended-release nevirapine group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 7% in the immediate-release nevirapine group and 6% in the extended-release nevirapine group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE. [16]

Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release nevirapine, and in 1% of subjects in either treatment group during the randomization phase. In addition, five cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of nevirapine treatment. [17]

No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release nevirapine (200 mg once daily), with the exception of rash which occurred in 4% of subjects. [18]

Adverse reactions of at least moderate intensity (Grades 2 or above) and considered to be related to treatment by the investigator in at least 2% of treatment-naive subjects receiving either immediate-release nevirapine or extended-release nevirapine after randomization in Trial 1100.1486 are rash – 3% for each for nevirapine immediate release and extended-release nevirapine and clinical hepatitis 3% for nevirapine immediate release vs 2% extended-release nevirapine.[19]
 

References

[1] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[2] FDA Viramune Prescribing Information, 06/24/08, pp. 3-4 . Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[3] Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents MMWR 2002;51 (No.RR-7) Updated as a Living Document on November 3, 2008 [23]. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed 03/12/09.

[4] FDA Viramune Prescribing Information, 06/24/08, pp. 3-4. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[5] FDA Listserve Archive, June 24, 2008. Available at: http://www.fda.gov/oashi/aids/listserve/listserve2008.html. Accessed 03/12/09.

[6] FDA Viramune Prescribing Information, 06/24/08, p. 4. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[7] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[8] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[9] Wolters Kluwer Health, Inc. Nevirapine, Facts and Comparisons 4.0 [online]. Available at: http://www.factsandcomparisons.com. Accessed 03/12/09.

[10] FDA Viramune Prescribing Information, 06/24/08, p. 3. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[11] FDA Listserve Archive, June 24, 2008. Available at: http://www.fda.gov/oashi/aids/listserve/listserve2008.html. Accessed 03/12/09.

[12] FDA Viramune Prescribing Information, 06/24/08, p. 3. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[13] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[14] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[15] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[16] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[17] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[18] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

[19] FDA. For Patients and Patient Advocates: Approval of Viramune XR (nevirapine) 400 mg extended release tablet, March 29, 2011. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm248800.htm. Accessed 3/31/11.

Drug and Food Interactions

Nevirapine is metabolized by and induces the activity of CYP3A isoenzymes, with maximal induction occurring within 2 to 4 weeks of initiating multidose therapy. The induction of CYP3A by nevirapine may result in lower plasma concentrations of concurrently administered drugs that are extensively metabolized by CYP3A. [1]

Caution is required when nevirapine is administered concurrently with a PI, as the plasma concentrations of PIs may be reduced to subtherapeutic concentrations due to nevirapine-induced hepatic metabolism. Nevirapine decreases the area under the plasma concentration-time curve (AUC) and Cmax of indinavir, saquinavir, and ritonavir; nevirapine and nelfinavir do not appear to interact significantly. In contrast, PIs do not appear to affect the pharmacokinetics of nevirapine. No dosage adjustments are required when nevirapine is concurrently administered with ritonavir or nelfinavir. [2]

Concomitant use of nevirapine and hormonal contraceptives containing ethinyl estradiol or norethindrone may result in decreased plasma concentrations of the contraceptive. Therefore, hormonal contraceptives should not be used as the primary means of contraception when nevirapine is prescribed to women of childbearing potential. [3]

Concurrent use of ketoconazole with nevirapine is not recommended, as it results in significantly reduced plasma concentrations of ketoconazole and a modest increase in plasma concentrations of nevirapine. Nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concurrently. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Concurrent use of prednisone with nevirapine has resulted in increased incidence and severity of rash in the first 6 weeks of nevirapine therapy; concurrent use is not recommended. [4]

Rifampin and rifabutin accelerate the metabolism of NNRTIs through induction of CYP isoenzymes, resulting in subtherapeutic levels of nevirapine. Nevirapine retards the metabolism of rifampin and rifabutin, resulting in increased serum levels of these drugs. A dosage adjustment may be necessary when these drugs are administered with nevirapine. [5]

Concurrent use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products with nevirapine is expected to substantially decrease nevirapine concentrations and may result in suboptimal levels of nevirapine, loss of virologic response, and development of nevirapine resistance; concurrent use is not recommended. [6]

Based on data from an open-label randomized study and retrospective database analysis demonstrating the potential for early virologic failure, clinicians are advised to use caution when co-administering tenofovir disoproxil fumarate, enteric-coated didanosine, and either efavirenz or nevirapine in the treatment of treatment-naive HIV infected patients with high baseline viral loads. [7]

References

[1] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[2] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[3] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[4] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[5] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[6] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[7] AIDSinfo Important New Clinical Data, Potential Early Virologic Failure Associated With the Combination Antiretroviral Regimen of Tenofovir Disoproxil Fumarate, Didanosine, and Either Efavirenz or Nevirapine in HIV Treatment-Naive Patients with High Baseline Viral Loads. [Dear Healthcare Provider Letter]. New York: Bristol-Myers Squibb, November 2004. Available at: http://www.fda.gov/oashi/aids/listserv/bms.pdf. Accessed 03/12/09.

Contraindications

Nevirapine is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the tablet or the oral suspension. [1]

Nevirapine is contraindicated in patients with moderate or severe (child Pugh Class B or C, respectively) hepatic impairment. [2] Nevirapine is hepatotoxic and extensively metabolized by the liver. It is associated with a significant incidence of hepatotoxicity, usually occurring in the initial month of therapy. Risk-benefit should be considered in patients with renal function impairment, as nevirapine metabolites are extensively eliminated by the kidneys. [3]

References

[1] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

[2] FDA Viramune Prescribing Information, 06/24/08, p3. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[3] Pharm GKB The Pharmacogenetics and Pharmacogenomics Knowledge Base - Nevirapine. Available at: http://www.pharmgkb.org/do/serve?objId=PA450163&objCls=Drug. Accessed 03/12/09.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Nevirapina.

Chemistry

CAS Name

6H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one, 11-cyclopropyl-5,11-dihydro-4-methyl- [1]

CAS Number

129618-40-2 [2]

Molecular Formula

C15-H14-N4-O

Elemental Composition

C67.65%, H5.30%, N21.04%, O6.01%

Molecular Weight

266.30

Melting Point

247 to 249 C

Physical Description

Tablets: White, oval, biconvex tablets with 54 193 embossed on one side. [3]
Suspension: White to off-white suspension. [4]

Solubility

Solubility in water 0.1 mg/ml at neutral pH; highly soluble at pH less than 3. [5]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/12/09.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/12/09.

[3] FDA Viramune Prescribing Information, 06/24/08, p. 9. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[4] FDA Viramune Prescribing Information, 06/24/08, p. 9. Available at: http://www.fda.gov/cder/foi/label/2008/020636s027,020933s017lbl.pdf. Accessed 03/12/09.

[5] Merck Index 2006; p. 1123

Further Reading

Viramune Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha TE. Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis. 2006 Feb 15;193(4):479-81. Epub 2006 Jan 11.
Giaquinto C, Rampon O, De Rossi A. Antiretroviral therapy for prevention of mother-to-child HIV transmission: focus on single-dose nevirapine. Clin Drug Investig. 2006;26(11):611-27.
Gray GE, Urban M, Chersich MF, Bolton C, van Niekerk R, Violari A, Stevens W, McIntyre JA; for the PEP Study Group. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS. 2005 Aug 12;19(12):1289-97.
Wit FW, Kesselring AM, Gras L, Richter C, van der Ende ME, Brinkman K, Lange JM, de Wolf F, Reiss P. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study. Clin Infect Dis. 2008 Mar 15;46(6):933-40.
Verweel G, Sharland M, Lyall H, Novelli V, Gibb DM, Dumont G, Ball C, Wilkins E, Walters S, Tudor-Williams G. Nevirapine use in HIV-1-infected children. AIDS. 2003 Jul 25; 17(11): 1639-47.
Bannister WP, Ruiz L, Cozzi-Lepri A, Mocroft A, Kirk O, Staszewski S, Loveday C, Karlsson A, Monforte A, Clotet B, Lundgren JD; EuroSIDA study group. Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA. AIDS. 2008 Jan 30;22(3):367-76.

Manufacturer Information

Extended-Release Nevirapine

Boehringer Ingelheim Pharmaceuticals Inc
900 Ridgebury Rd / PO Box 368
Ridgefield, CT 06877-0368
Phone: 800-542-6257

Nevirapine

Boehringer Ingelheim Pharmaceuticals Inc
900 Ridgebury Rd / PO Box 368
Ridgefield, CT 06877-0368
Phone: 800-542-6257

Viramune

Boehringer Ingelheim Pharmaceuticals Inc
900 Ridgebury Rd / PO Box 368
Ridgefield, CT 06877-0368
Phone: 800-542-6257

Viramune XR

Boehringer Ingelheim Pharmaceuticals Inc
900 Ridgebury Rd / PO Box 368
Ridgefield, CT 06877-0368
Phone: 800-542-6257