NEVIRAPINE Drug Interactions: What You Need to Know

INTERACTIONS Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine. The results of drug interactions studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology , Table 4. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 3. The data in Tables 3 and 4 are based on the results of drug interaction studies conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 3. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 3, additional clinical monitoring may be warranted when co-administering these drugs. The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently.

Table

3 Established and Potential Drug Interactions: Use with Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3) , Table 4 for Magnitude of Interaction.

Drug Name

Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment HIV Antiviral Agents: Protease Inhibitors (PIs)

Atazanavir/Ritonavir

The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. Fosamprenavir ↓ Amprenavir ↑ Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir ↓ Amprenavir ↑ Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. Indinavir ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. Lopinavir/Ritonavir ↓ Lopinavir Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra ® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Nelfinavir ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C min The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.

Saquinavir/Ritonavir

The interaction between nevirapine and saquinavir/ritonavir has not been evaluated. The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.

Hiv

Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz ↓ Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established.

Etravirine Rilpivirine

Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.

Other Agents

Analgesics: Methadone ↓ Methadone Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Antiarrhythmics: Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established. Antibiotics: Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin ↑ Rifabutin Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Rifampin ↓ Nevirapine Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. Anticonvulsants: Carbamazepine, clonazepam, ethosuximide Plasma concentrations of nevirapine and the anticonvulsant may be decreased. Use with caution and monitor virologic response and levels of anticonvulsants. Antifungals: Fluconazole ↑ Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Itraconazole ↓ Itraconazole Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. Antithrombotics: Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium Channel

Blockers: Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.

Cancer

Chemotherapy: Cyclophosphamide Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.

Ergot

Alkaloids: Ergotamine Plasma concentrations may be decreased. Appropriate doses for this combination have not been established. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus Plasma concentrations may be decreased. Appropriate doses for these combinations have not been established.

Opiate

Agonists: Fentanyl Plasma concentrations may be decreased. Appropriate doses for this combination have not been established.

Oral

Contraceptives: Ethinyl Estradiol and Norethindrone ↓ Ethinyl Estradiol ↓ Norethindrone Despite lower ethinyl estradiol and norethindrone exposures when co-administered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When co-administered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablet therapy, the therapeutic effect of the hormonal therapy should be monitored. Co-administration of nevirapine extended-release tablets can alter the concentrations of other drugs, and other drugs may alter the concentration of nevirapine. The potential for drug interactions must be considered prior to and during therapy. ( 5.4 , 7 , 12.3 )

Drug

Interactions [see Drug Interactions (7)] Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine extended-release tablets and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects. While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated K i for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A. Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.

Table

4 (see below) contains the results of drug interaction trials performed with immediate-release nevirapine and other drugs likely to be co-administered. The effects of nevirapine on the AUC, C max , and C min of co-administered drugs are summarized. Results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets.

Table

4 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Immediate-Release Nevirapine (All interaction studies were conducted in HIV-1 positive subjects) § = Cmin below detectable level of the assay ↑ = Increase, ↓ = Decrease, ↔ = No Effect Co-administered Drug Dose of Co-administered Drug Dose Regimen of Immediate-release Nevirapine n % Change of Co-administered Drug Pharmacokinetic Parameters (90% CI) Antiretrovirals AUC C max C min Atazanavir/Ritonavir For information regarding clinical recommendations, [see Drug Interactions (7) ] . , Parallel group design; n = 23 for atazanavir/ritonavir + nevirapine, n = 22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. 300/100 mg QD day 4-13, then 400/100 mg QD, day 14-23 200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry. 23 Atazanavir 300/100 mg ↓ 42 (↓ 52 to ↓ 29)

Atazanavir

300/100 mg ↓ 28 (↓ 40 to ↓ 14)

Atazanavir

300/100 mg ↓ 72 (↓ 80 to ↓ 60)

Atazanavir

400/100 mg ↓ 19 (↓ 35 to ↑ 2)

Atazanavir

400/100 mg ↑ 2 (↓ 15 to ↑ 24)

Atazanavir

400/100 mg ↓ 59 (↓ 73 to ↓ 40)

Darunavir/Ritonavir

Based on between-trial comparison. 400/100 mg BID 200 mg BID 8 ↑ 24 (↓ 3 to ↑57) ↑ 40 (↑ 14 to ↑ 73) ↑ 2 (↓ 21 to ↑ 32)

Didanosine

100-150 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ↔ ↔ § Efavirenz 600 mg QD 200 mg QD x 14 days; 400 mg QD x 14 days 17 ↓ 28 (↓ 34 to ↓ 14) ↓ 12 (↓ 23 to ↑ 1) ↓ 32 (↓ 35 to ↓ 19)

Fosamprenavir

1400 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 ↓ 33 (↓ 45 to ↓ 20) ↓ 25 (↓ 37 to ↓ 10) ↓ 35 (↓ 50 to ↓ 15)

Fosamprenavir/Ritonavir

700/100 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 ↓ 11 (↓ 23 to ↑ 3) ↔ ↓ 19 (↓ 32 to ↓ 4)

Indinavir

800 mg q8H 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↓ 31 (↓ 39 to ↓ 22) ↓ 15 (↓ 24 to ↓ 4) ↓ 44 (↓ 53 to ↓ 33) Lopinavir , Pediatric subjects ranging in age from 6 months to 12 years. 300/75 mg/m 2 (lopinavir/ritonavir) 7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week 12, 15 Parallel group design; n for nevirapine + lopinavir/ritonavir, n for lopinavir/ritonavir alone. ↓ 22 (↓ 44 to ↑ 9) ↓ 14 (↓ 36 to ↑ 16) ↓ 55 (↓ 75 to ↓ 19)

Lopinavir

400/100 mg BID (lopinavir/ritonavir) 200 mg QD x 14 days; 200 mg BID > 1 year 22, 19 ↓ 27 (↓ 47 to ↓ 2) ↓ 19 (↓ 38 to ↑ 5) ↓ 51 (↓ 72 to ↓ 26)

Maraviroc

Based on historical controls. 300 mg SD 200 mg BID 8 ↑ 1 (↓ 35 to ↑ 55) ↑ 54 (↓ 6 to ↑ 151) ↔ Nelfinavir 750 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 23 ↔ ↔ ↓ 32 (↓ 50 to ↑ 5) Nelfinavir-M8 metabolite ↓ 62 (↓ 70 to ↓ 53) ↓ 59 (↓ 68 to ↓ 48) ↓ 66 (↓74 to ↓ 55)

Ritonavir

600 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ↔ ↔ ↔ Stavudine 30-40 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 22 ↔ ↔ § Zalcitabine 0.125-0.25 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 6 ↔ ↔ § Zidovudine 100-200 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 11 ↓ 28 (↓ 40 to ↓ 4) ↓ 30 (↓ 51 to ↑ 14) § Other Medications AUC C max C min Clarithromycin 500 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 15 ↓ 31 (↓ 38 to ↓ 24) ↓ 23 (↓ 31 to ↓ 14) ↓ 56 (↓ 70 to ↓ 36)

Metabolite

14-OH-clarithromycin ↑ 42 (↑ 16 to ↑ 73) ↑ 47 (↑ 21 to ↑ 80) ↔ Ethinyl Estradiol and Norethindrone 0.035 mg (as Ortho-Novum ® 1/35) 1 mg (as Ortho-Novum ® 1/35) 200 mg QD x 14 days; 200 mg BID x 14 days 10 ↓ 20 (↓ 33 to ↓ 3) ↔ § ↓ 19 (↓ 30 to ↓ 7) ↓ 16 (↓ 27 to ↓ 3) § Depomedroxy- Progesterone Acetate 150 mg every 3 months 200 mg QD x 14 days; 200 mg BID x 14 days 32 ↔ ↔ ↔ Fluconazole 200 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↔ ↔ ↔ Ketoconazole 400 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 21 ↓ 72 (↓ 80 to ↓ 60) ↓ 44 (↓ 58 to ↓ 27) § Methadone Individual Subject Dosing 200 mg QD x 14 days; 200 mg BID ≥ 7 days 9 In a controlled pharmacokinetic trial with 9 subjects receiving chronic methadone to whom steady-state nevirapine therapy was added, the clearance of methadone was increased by 3-fold, resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in 7 of the 9 subjects. Methadone did not have any effect on nevirapine clearance.

Rifabutin

150 or 300 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↑ 17 (↓ 2 to ↑ 40) ↑ 28 (↑ 9 to ↑ 51) ↔ Metabolite 25-O-desacetyl-rifabutin ↑ 24 (↓ 16 to ↑ 84) ↑ 29 (↓ 2 to ↑ 68) ↑ 22 (↓ 14 to ↑ 74)

Rifampin

600 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 14 ↑ 11 (↓ 4 to ↑ 28) ↔ § Because of the design of the drug interaction trials (addition of 28 days of nevirapine therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by comparison to historical controls. Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and C max by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [see Drug Interactions (7) ]. The effect of other drugs listed in Table 4 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment (4.1, 5.1, 8.7) Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved use (4.2, 5.1)

4.1 Hepatic Impairment Nevirapine, USP is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ].

4.2 Post-Exposure Prophylaxis Nevirapine, USP is contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [ see Warnings and Precautions (5.1) ].

AND PRECAUTIONS

• Monitor patients for immune reconstitution syndrome and fat redistribution. ( 5.5 , 5.6 )

5.1 Hepatotoxicity and Hepatic Impairment Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups in controlled clinical trials through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests. The first 18 weeks of therapy with nevirapine extended-release tablets are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events. 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, 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 extended-release tablets treatment. Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>. If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment. The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 + cell counts. In a retrospective analysis of pooled clinical trials with immediate-release nevirapine tablets, during the first 6 weeks of treatment women had a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%). Patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events. Women with CD4 + cell counts greater than 250 cells/mm 3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4 + cell counts less than 250 cells/mm 3 (11% versus 1%). An increased risk was observed in men with CD4 + cell counts greater than 400 cells/mm 3 (6% versus 1% for men with CD4 + cell counts less than 400 cells/mm 3 ). However, all patients, regardless of sex, CD4 + cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 + cell counts. Co-infection with hepatitis B or C or transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT. In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of immediate-release nevirapine tablets in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine extended-release tablets for occupational and non-occupational PEP is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )]</span>. Nevirapine extended-release tablets have not been evaluated in subjects with hepatic impairment.

5.2 Skin Reactions Severe and life-threatening skin reactions, including fatal cases, have been reported in patients taking nevirapine. These have occurred most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction. The first 18 weeks of therapy with nevirapine extended-release tablets are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening skin reactions. 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, 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 extended-release tablets treatment. In addition, the 14-day lead-in period with immediate-release nevirapine tablets 200 mg daily dosing has been demonstrated to reduce the frequency of rash <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Patients must initiate therapy with immediate-release nevirapine tablets daily for the first 14 days. This lead-in period has been shown to reduce the frequency of rash. Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not initiate nevirapine extended-release tablets if patient is experiencing a mild to moderate rash without constitutional symptoms during the 14-day immediate-release nevirapine tablets lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) until the rash has resolved. The total duration of the immediate-release nevirapine tablets lead-in dosing period must not exceed 28 days, at which point an alternative regimen should be sought <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span>. Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction. Women appear to be at higher risk than men of developing rash with nevirapine. In a clinical trial of immediate-release nevirapine tablets, concomitant prednisone use (40 mg per day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.

5.3 Resistance Nevirapine extended-release tablets must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing nevirapine extended-release tablets, the long half-life of nevirapine should be considered; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop <span class="opacity-50 text-xs">[see Microbiology ( 12.4 )]</span>.

5.4 Drug Interactions See Table 3 for listings of established and potential drug interactions <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span>. Concomitant use of St. John&apos;s wort (Hypericum perforatum) or St. John&apos;s wort-containing products and nevirapine is not recommended. Co-administration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. Co-administration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

5.5 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.