PRINCIPIOS DE FARMACOLOGIA

Description: Nevirapine is a first-generation oral non-nucleoside reverse transcriptase inhibitor (NNRTI). Nevirapine is structurally a member of the dipyridodiazepinone class of NNRTIs. It is approved for the treatment of human immunodeficiency virus (HIV) infection in combination with nucleoside analog antiretroviral agents. However, nevirapine is not recommended as monotherapy because of rapid emergence of resistant HIV isolates. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), nevirapine does not require phosphorylation for activity. Nevirapine was approved under the FDAs accelerated approval program June 24, 1996 based on changes in surrogate markers (e.g., CD4 cell counts and HIV viral load) in studies lasting up to 48 weeks. Nevirapine was approved for pediatric use on September 11, 1998 and is available as an oral suspension in addition to tablets. Mechanism of Action: Nevirapine inhibits HIV reverse transcriptase. Its mechanism differs from that of nucleoside reverse transcriptase inhibitors. Combination therapy with nevirapine and zidovudine has been shown to be synergistic against HIV replication. Nevirapine binds directly to reverse transcriptase. This binding 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. Resistant HIV emerges rapidly and uniformly when nevirapine is administered as monotherapy. Nevirapine plus zidovudine combination therapy did not alter the emergence rate of nevirapine-resistant virus or the magnitude of nevirapine resistance in vitro; however, a different mutation pattern was observed. The clinical relevance of this finding has not been established. Rapid emergence of HIV strains which are cross-resistant to NNRTIs has been observed in vitro. Limited data indicate that nevirapine is active against zidovudine-resistant HIV isolates. Cross-resistance between nevirapine and HIV protease inhibitors is unlikely because the enzyme targets involved are different. Pharmacokinetics: Nevirapine is administered orally. Following administration, nevirapine is readily absorbed with an absolute bioavailability of 91—93%. Peak plasma concentrations occur within 4 hours following a single 200 mg dose. After multiple doses, peak plasma concentrations increase linearly in the dose range of 200—400 mg/day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and are interchangeable at doses up to 200 mg. Nevirapine is highly lipophilic and is widely distributed throughout the body. The drug readily crosses the placenta and is excreted in breast milk. Protein binding is approximately 60%. The cerebrospinal fluid concentration is about 45% of the corresponding plasma concentration of nevirapine which is approximately equal to the fraction of nevirapine not bound to plasma protein. Metabolism of nevirapine to hydroxylated metabolites occurs primarily via the cytochrome P450 (CYP) 3A family of hepatic enzymes. These metabolites are then further metabolized by glucuronide conjugation. Elimination of nevirapine and its metabolites is mainly in the urine. In radiolabeled pharmacokinetic studies of nevirapine, 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 of nevirapine is excreted unchanged in the urine. Following a single dose, nevirapine terminal elimination half-life is about 45 hours. After multiple dosing with 200—400 mg/day, the elimination half-life is decreased to approximately 25—30 hours due to induction of hepatic cytochrome P450 enzymes. The clearance of nevirapine is also increased 1.5—2 fold because of autoinduction. •Special Populations: The pharmacokinetics of nevirapine have not been evaluated in patients with hepatic or renal dysfunction. Nevirapine pharmacokinetics in HIV-infected adults (18—68 years) do not appear to change with age; however, nevirapine has not been extensively studied in patients > 55 years of age. In pediatric patients, the mean nevirapine clearance adjusted for body weight is greater than adults. Nevirapine clearance adjusted for weight reached maximum values by age 1—2 years and then decreased with increasing age. Nevirapine clearance adjusted for weight was at least 2-fold greater in children younger than 8 years compared to adults. Current pediatric dosage regimens are designed to achieve steady state plasma concentrations similar to adults.

ndications...Dosage For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents: •in symptomatic adults or adolescents; or those with a CD4 count < 500 or with HIV RNA plasma levels > 10,000 bDNA or 20,000 RT-PCR copies; or a patient with detectable plasma HIV RNA levels who requests and is committed to adherence to the regimen: NOTE: The following abbreviations are used: nucleoside reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitor (PI). Oral dosage: Adults and adolescents: 200 mg PO once daily for the first 14 days, followed by 200 mg PO twice daily, in combination with 2 NRTIs (e.g., didanosine, lamivudine, stavudine, zidovudine, or zalcitabine). The combination of nevirapine and 2 NRTIs is an alternative to the preferred regimens of 2 NRTIs in combination with either a PI or efavirenz. Monotherapy with nevirapine is not recommended. Adolescents in early puberty (Tanner I—II) should be dosed using pediatric schedules.[1800] If rash is observed during the first 14 days of therapy, dose escalation should not occur until the rash has resolved. Treatment should be permenantly discontinued if severe hepatotoxicity, severe cutaneous reactions, or hypersensitivity reactions occur. •in children with clinical symptoms or evidence of immunosuppression; or any infant < 12 months; or in asymptomatic children >= 1 year with normal immune status unless other factors favor postponing treatment: Oral dosage: Children >= 8 years: 4 mg/kg PO once daily for 14 days, followed by 4 mg/kg PO twice daily thereafter. The total daily dose should not exceed 400 mg. Use of nevirapine in combination with zidovudine and didanosine is considered an alternative to regimens containing two nucleoside reverse transcriptase inhibitors in combination with a protease inhibitor.[1684] If rash is observed during the first 14 days of therapy, dose escalation should not occur until the rash has resolved. Treatment should be permenantly discontinued if severe hepatotoxicity, severe cutaneous reactions, or hypersensitivity reactions occur. Children and infants 2 months to < 8 years: 4 mg/kg PO once daily for the first 14 days, followed by 7 mg/kg PO twice daily thereafter. The total daily dose should not exceed 400 mg. Nevirapine in combination with 2 NRTIs is recommended as an alternative regimen; these regimens may be less likely than the preferred regimens (2 NRTIs plus a PI) to provide sustained virus suppression. In one study, the combination of nevirapine and didanosine produced substantial and sustained suppression of viral replication in two of six HIV-infected infants first treated at < 4 months of age.[1694] If rash is observed during the first 14 days of therapy, dose escalation should not occur until the rash has resolved. Treatment should be permenantly discontinued if severe hepatotoxicity, severe cutaneous reactions, or hypersensitivity reactions occur. Neonates† through 2 months of age: Nevirapine is currently under investigation in this age group. The dosage being evaluated in the Pediatric ACTG protocol 356 is 5 mg/kg PO once daily for 14 days, followed by 120 mg/m2 PO every 12 hours for 14 days, then 200 mg/m2 PO every 12 hours.[1684] Patients with hepatic impairment: Patients with underlying hepatic disease are at increased risk for toxicity and, possibly, decreased elimination of nevirapine. In patients who develop severe hepatotoxicity, nevirapine therapy should be discontinued. Patients with renal impairment: Dosing in patients with renal impairment has not been studied. However, less than 3% of nevirapine is excreted unchanged in the urine, and dosage modification is not expected to be needed. †non-FDA-approved indication

Administration Oral Administration •Nevirapine may be administered with or without food, antacids, or didanosine (ddI). •Nevirapine should be discontinued if patients experience hepatic toxicity, severe rash or rash accompanied by constitutional findings or hypersensitivity reactions (see Adverse Reactions). Patients who develop a rash during the initial 14 days of therapy should not have their nevirapine dose increased until the rash resolves. •Patients who interrupt dosing for more than 7 days should restart therapy with the intial recommended dosage. •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.

Contraindications Nevirapine has been associated with severe or life-threatening hepatotoxicity, including fatal cases (See Adverse Reactions). 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. 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 to nevirapine. Patients with signs or symptoms of hepatitis must seek medical attention immediately and should be advised to discontinue nevirapine therapy. The first 12 weeks of therapy with nevirapine are a critical period during which it is essential that patients be monitored intensely to detect severe hepatotoxicity or skin reactions. Monitoring should continue at frequent intervals thereafter. Nevirapine should not be restarted following severe hepatic reactions. In addition, the 14-day lead-in period must be strictly followed (see Dosage). Although no pharmacokinetic studies have been performed in patients with hepatic disease, nevirapine should be used with caution in these patients. Nevirapine is metabolized by the liver, so patients with hepatic impairment are more likely to have increased serum concentrations of nevirapine. Nevirapine has been associated with severe or life-threatening cutaneous toxicity and nevirapine hypersensitivity reactions, including fatal cases (See Adverse Reactions). Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine therapy immediately. Risk factors for developing severe cutaneous or hypersensitivity reactions include failure to follow the initial dosing and lead-in period (see Dosage) 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. The first 12 weeks of therapy with nevirapine are a critical period during which it is essential that patients be monitored intensely to detect severe skin or hypersensitivity reactions. Monitoring should continue at frequent intervals thereafter. Nevirapine should not be restarted following severe skin or nevirapine hypersensitivity reactions. Nevirapine is classified as FDA pregnancy risk category C. Nevirapine was shown to readily cross the placenta, but there have been no reports of teratogenic or other adverse effects on the human fetus. Because no adequate studies have been conducted in pregnant women, the use of nevirapine is not recommended unless the benefit to the mother outweighs the risk to the fetus. Nevirapine is also excreted in human breast milk. The U.S. Public Health Service Centers for Disease Control and Prevention recommend that HIV-infected women avoid breast-feeding to prevent postnatal transmission of HIV to a child who may not be infected. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263. Females of childbearing age should use other means of birth control besides hormonal contraceptives while on nevirapine. Nevirapine may decrease plasma concentrations of oral and other hormonal contraceptives. In reproductive toxicology studies with nevirapine, evidence of impaired fertility was seen in female rats at doses providing systemic exposure approximately equivalent to that provided with the recommended clinical dose of nevirapine. The safety of nevirapine has not been established in neonates.

nteractions Nevirapine is an inducer of the cytochrome P4503A (CYP3A) enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme may require dosage adjustments. Although no clinical studies examining these drug interactions have been conducted, other drugs metabolized by CYP3A include alfentanil, calcium-channel blockers, clonazepam, cyclosporine, dexamethasone, disopyramide, dronabinol, THC, erythromycin, ethosuximide, etoposide, VP-16, fentanyl, lidocaine, loratadine, lovastatin, nefazodone, ondansetron, paclitaxel, pravastatin, quinine, rifampin, sertraline, sirolimus, tacrolimus, tamoxifen, trazodone, vinblastine, vincristine, and warfarin. Autoinduction also occurs with a 1.5—2 fold increase in the clearance of nevirapine following 2—4 weeks of therapy. Nevirapine might decrease the plasma concentrations of certain highly metabolized sedatives and hypnotics due to induction of cytochrome P450 enzymes. Drugs affected include alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, and zolpidem. Higher doses of these drugs may be required to maintain sedation. Caution should also be observed when discontinuing nevirapine in patients stabilized on both nevirapine and a sedative/hypnotic agent metabolized by CYP3A. Nevirapine is hepatically metabolized by the CYP3A isoenzyme. Coadministration of nevirapine with drugs that increase the activity of CYP3A would be expected to increase the clearance of nevirapine, thereby decreasing nevirapine plasma concentrations. These drugs include carbamazepine, dexamethasone, phenobarbital, and phenytoin. In vivo reports from the manufacturer showed that steady-state nevirapine trough plasma concentrations were reduced by 16% and 37% in patients who received rifabutin and rifampin, respectively. Coadministration of nevirapine and usual-dose rifabutin is a possibility based on pharmacokinetic data; however there is no published clinical experience with this combination. Data are insufficient to assess whether dose adjustments are necessary when rifampin is given concurrently with nevirapine. Therefore, rifampin should only be used in combination if clearly indicated and with careful monitoring.[1299] Nevirapine is hepatically metabolized by the CYP3A isoenzyme. In vitro studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was significantly inhibited by ketoconazole. Data suggest that coadministration with ketoconazole may result in a 15—30% increase in nevirapine plasma concentrations. In addition, ketoconazole AUC and Cmax decreased by a median of 63% and 40%, respectively, in HIV-infected patients who were given nevirapine. The manufacturer of nevirapine recommends that ketoconazole not be administered concomitantly. Other known inhibitors of CYP3A that may inhibit nevirapine metabolism include cimetidine and macrolide antibiotics. Steady-state nevirapine trough plasma concentrations were elevated by 21% and 12% in patients who received cimetidine and macrolides, respectively, in combination with nevirapine. Nevirapine may decrease plasma concentrations of oral contraceptives and other hormonal contraceptives, including estrogens and progestins. According to the manufacturer of nevirapine, oral or other hormonal contraceptives should not be used as a method of birth control in females taking nevirapine. 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. Results from a 36-day study of HIV-infected patients who received nevirapine and indinavir indicated that their coadministration led to a 28% mean decrease in indinavir AUC and an 11% decrease in indinavir Cmax. Results from a 42-day study of HIV-infected patients who received nevirapine and saquinavir (hard gelatin capsules) indicated that their coadministration led to a 24% decrease in saquinavir AUC and a 28% decrease in saquinavir Cmax. The clinical significance of these interactions is not known. Clinical reports suggest that patients who are stabilized on methadone-maintenance therapy may experience narcotic withdrawal symptoms when they begin nevirapine therapy. Nevirapine may induce methadone metabolism via cytochrome P450 3A4. Opiate-withdrawal symptoms will generally begin during the first 2 weeks after initiating nevirapine, but may continue through day 28. Methadone-maintained patients should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly. St. John's wort, Hypericum perforatum appears to interact with anti-retroviral protease inhibitors (PIs). In one study of healthy volunteers, the concomitant administration of St. John's wort with indinavir substantially decreased mean indinavir plasma concentrations by 57% and trough concentrations by 81%.[2718] It appears that St. John's wort is an inducer of hepatic cytochrome P450 enzymes, particularly CYP3A4. It is expected that St. John's wort may significantly decrease the plasma concentrations of all currently marketed PIs (e.g., amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) and may also substantially reduce plasma concentrations of all marketed HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) (i.e., delavirdine, efavirenz, and nevirapine). Such reductions in plasma concentrations of these drugs could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV patients treated with these agents.

Adverse Reactions Rash (unspecified) is the most common adverse event associated with nevirapine. The rash is usually mild to moderate, erythematous, cutaneous eruptions, with or without pruritus. The rash may be located on the trunk, face, and extremities. Severe, life-threatening skin reactions, including fatalities, have occurred in patients treated with nevirapine. Severe cutaneous reactions include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions (anaphylactoid reactions) characterized by rash, constitutional findings, and organ dysfunction. The majority of severe rashes occurred within the first 6—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, conjunctivitis, eosinophilia, facial edema, fatigue, fever, granulocytopenia, lymphadenopathy, malaise, myalgia, ulcerative stomatitis, urticaria, and/or renal dysfunction) nevirapine should be discontinued immediately; nevirapine therapy should not be restarted in these patients. Nevirapine must be initiated with a 14-day dose escalation or lead-in period (see Dosage), which has been shown to reduce the frequency of rash. Severe cutaneous reactions have been associated with not improper dose escalation or delay in seeking medical attention when the cutaneous symptoms appeared. Elevated hepatic enzymes are a common adverse reaction in patients receiving nevirapine. Severe or life-threatening, and in some cases fatal, hepatotoxicity, including fulminant cholestatic hepatitis, hepatic necrosis, and hepatic failure has occurred. Serious hepatic events occur most frequently during the first 12 weeks of nevirapine therapy, and have been reported within the first few weeks. However, approximately one-third of cases have been reported after the critical 12-week period. Extensive monitoring of patients is required during the first 12 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, 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. These events progressed to hepatic failure with elevated liver enzymes, with or without hyperbilirubinemia, prolonged aPTT, or eosinophilia. Rash and fever accomanied 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. If clinical hepatotoxicity occures, nevirapine should be discontinued and not restarted after recovery. Other adverse drug reactions to nevirapine occurring in > 2% of patients include abdominal pain, diarrhea, headache, nausea/vomiting, and paresthesias. 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.[1316] 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).[1317] The most frequently reported adverse events related to nevirapine in pediatric patients were similar to those observed in adults, with the exception of granulocytopenia which was more commonly observed in children.

Nevirapine Viramune®

1800. Centers for Disease Control and Prevention et al. The Living Document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. May 5, 1999. Available on the World Wide Web at http://www.hivatis.org

1684. Centers for Disease Control and Prevention et al. The Living Document: Guidelines for the use of antiretroviral agents in pediatric HIV infection. Retrieved January 7, 2000. Available on the World Wide Web at http://www.hivatis.org

1694. Luzuiraga K, Bryson Y, Krogstad P et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med 1997;336:1343—9.

2718. Piscitelli SC, Burstein AH, Alfaro MS. Indinavir concentrations and St. John's wort. Lancet 2000;355:547—48.

1316. Havlir D, Cheeseman SH, Mclaughlin M, et al. High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Inf Dis 1995;171:537—45.

1317. Richman DD, Havlir D, Corbeil J, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994;68:1660—6.