VIRAMUNE is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older [see Clinical Studies (14.1, 14.2)].

{ "type": "p", "children": [], "text": "\nVIRAMUNE is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older [see Clinical Studies (14.1, 14.2)]." }

Limitations of Use:Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, VIRAMUNE is not recommended to be initiated, unless the benefit outweighs the risk, in:

{ "type": "p", "children": [], "text": "\nLimitations of Use:Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, VIRAMUNE is not recommended to be initiated, unless the benefit outweighs the risk, in:" }

{ "type": "ul", "children": [ "adult females with CD4+ cell counts greater than 250 cells/mm3 or", "adult males with CD4+ cell counts greater than 400 cells/mm3 [see Warnings and Precautions (5.1)]." ], "text": "" }

The recommended oral dosage for VIRAMUNE in adult patients is 200 mg (20 mL) once daily for the first 14 days, followed by 200 mg twice daily, in combination with other antiretroviral agents. The total daily dose should not exceed 400 mg for any patient. The 14-day lead-in period with VIRAMUNE 200 mg daily dosing must be strictly followed as the lead-in period has been observed to decrease the incidence of rash [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. If rash persists beyond the 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once-daily dosing regimen should not be continued beyond 28 days, at which point, an alternative regimen should be sought.

The recommended oral dosage for VIRAMUNE in pediatric patients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient.

<div class="scrollingtable"><table border="0" cellpadding="2" cellspacing="0" width="60%"> <caption> <span>Table 1 Calculation of the Volume of VIRAMUNE (50 mg per 5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m<span class="Sup">2</span></span> </caption> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Patient's BSA range (m<span class="Sup">2</span>)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Volume (mL) of VIRAMUNE</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.06 – 0.12</td><td class="Botrule Lrule Rrule Toprule">1.25</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.12 – 0.25</td><td class="Botrule Lrule Rrule Toprule">2.5</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.25 – 0.42</td><td class="Botrule Lrule Rrule Toprule">5</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.42 – 0.58</td><td class="Botrule Lrule Rrule Toprule">7.5</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.58 – 0.75</td><td class="Botrule Lrule Rrule Toprule">10</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.75 – 0.92</td><td class="Botrule Lrule Rrule Toprule">12.5</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">0.92 – 1.08</td><td class="Botrule Lrule Rrule Toprule">15</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">1.08 – 1.25</td><td class="Botrule Lrule Rrule Toprule">17.5</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">1.25+</td><td class="Botrule Lrule Rrule Toprule">20</td> </tr> </tbody> </table></div>

VIRAMUNE should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, 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.

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with VIRAMUNE. 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 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 VIRAMUNE treatment [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

Patients with Rash

Discontinue VIRAMUNE if a patient experiences severe rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2)]. Do not increase VIRAMUNE dose if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved [see Warnings and Precautions (5.2)]. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.

Patients with Hepatic Events

If a clinical (symptomatic) hepatic event occurs, permanently discontinue VIRAMUNE. Do not restart VIRAMUNE after recovery [see Warnings and Precautions (5.1)].

Patients with Dose Interruption

For patients who interrupt VIRAMUNE dosing for more than 7 days, restart the recommended dosing, using 200 mg once daily (150 mg/m2/day in pediatric patients) for the first 14 days (lead-in) followed by 200 mg twice daily (150 mg/m2 twice daily for pediatric patients).

Patients with Renal Impairment

Patients with CrCl greater than or equal to 20 mL per min do not require an adjustment in VIRAMUNE dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. An additional 200 mg dose of VIRAMUNE following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [see Clinical Pharmacology (12.3)].

Oral suspension: 50 mg per 5 mL, white to off-white oral suspension

{ "type": "p", "children": [], "text": "\nOral suspension: 50 mg per 5 mL, white to off-white oral suspension" }

VIRAMUNE is contraindicated:

{ "type": "p", "children": [], "text": "\nVIRAMUNE is contraindicated: " }

{ "type": "ul", "children": [ "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)].\n", "for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [see Warnings and Precautions (5.1)].\n" ], "text": "" }

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 VIRAMUNE. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received VIRAMUNE and 1% of subjects in control groups.

The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the VIRAMUNE groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects 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 subjects 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 VIRAMUNE 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 VIRAMUNE and immediately seek medical evaluation, which should include liver enzyme tests.

The first 18 weeks of therapy with VIRAMUNE 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 time 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 VIRAMUNE 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 [see Dosage and Administration (2.3)].

If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue VIRAMUNE. Do not restart VIRAMUNE 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 general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4+ cell counts at initiation of VIRAMUNE therapy are at higher risk for symptomatic hepatic events with VIRAMUNE. In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). 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 VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) 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 VIRAMUNE in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of VIRAMUNE for occupational and non-occupational PEP is contraindicated [see Contraindications (4)].

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 [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Severe and life-threatening skin reactions, including fatal cases, have been reported, occurring 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 VIRAMUNE use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of VIRAMUNE recipients compared to less than 1% of placebo subjects.

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 VIRAMUNE and seek medical evaluation immediately. Do not restart VIRAMUNE following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.

The first 18 weeks of therapy with VIRAMUNE 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 time 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 VIRAMUNE treatment. In addition, the 14-day lead-in period with VIRAMUNE 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.1)].

If patients present with a suspected VIRAMUNE-associated rash, measure transaminases immediately. Permanently discontinue VIRAMUNE in patients with rash-associated transaminase elevations [see Warnings and Precautions (5.1)].

Therapy with VIRAMUNE must be initiated with a 14-day lead-in period of 200 mg per day (150 mg/m2 per day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue VIRAMUNE if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase VIRAMUNE dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day (150 mg/m2/day in pediatric patients) until the rash has resolved. The total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [see Dosage and Administration (2.4)]. Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping VIRAMUNE 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 VIRAMUNE.

In a clinical trial, concomitant prednisone use (40 mg per day for the first 14 days of VIRAMUNE administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of VIRAMUNE therapy. Therefore, use of prednisone to prevent VIRAMUNE-associated rash is not recommended.

VIRAMUNE 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 VIRAMUNE, the long half-life of nevirapine should be considered; if antiretrovirals with shorter half-lives than VIRAMUNE are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [see Microbiology (12.4)].

See Table 4 for listings of established and potential drug interactions [see Drug Interactions (7)].

Concomitant use of St. John's wort (Hypericum perforatum) or St. John's wort-containing products and VIRAMUNE is not recommended. Co-administration of St. John's wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including VIRAMUNE, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of VIRAMUNE and lead to loss of virologic response and possible resistance to VIRAMUNE or to the class of NNRTIs. Co-administration of VIRAMUNE and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRAMUNE. 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.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Experience in Adult Patients

The most serious adverse reactions associated with VIRAMUNE are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/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, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

Hepatic Reaction

In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received VIRAMUNE and 1% of subjects in control groups. Female sex and higher CD4+ cell counts (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) place patients at increased risk of these events [see Boxed Warning and Warnings and Precautions (5.1)].

Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received VIRAMUNE and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving VIRAMUNE than in controls (see Table 3).

Skin Reaction

The most common clinical toxicity of VIRAMUNE is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving VIRAMUNE compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of VIRAMUNE recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of VIRAMUNE-associated rash [see Boxed Warning and Warnings and Precautions (5.2)].

Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving VIRAMUNE in placebo-controlled trials are shown in Table 2.

<div class="scrollingtable"><table border="0" cellpadding="2" cellspacing="0" width="100%"> <caption> <span>Table 2 Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials</span> </caption> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">1</span> Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4<span class="Sup">+</span> cell counts less than 200 cells/mm<span class="Sup">3</span>.<br/> <span class="Sup">2</span> Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some subjects. Subjects had CD4<span class="Sup">+</span> cell count greater than or equal to 200 cells/mm<span class="Sup">3</span>.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Trial 1090<span class="Sup">1</span></span></td><td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Trials 1037, 1038, 1046<span class="Sup">2</span></span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Toprule"><span class="Bold">VIRAMUNE</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Placebo</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">VIRAMUNE</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Placebo</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td><span class="Bold">(n=1,121)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=1,128)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=253)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=203)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Median exposure (weeks)</td><td class="Botrule Lrule Rrule Toprule">58</td><td class="Botrule Lrule Rrule Toprule">52</td><td class="Botrule Lrule Rrule Toprule">28</td><td class="Botrule Lrule Rrule Toprule">28</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Any adverse event</td><td class="Botrule Lrule Rrule Toprule">15%</td><td class="Botrule Lrule Rrule Toprule">11%</td><td class="Botrule Lrule Rrule Toprule">32%</td><td class="Botrule Lrule Rrule Toprule">13%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Rash</td><td class="Botrule Lrule Rrule Toprule">5</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">7</td><td class="Botrule Lrule Rrule Toprule">2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Nausea</td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">9</td><td class="Botrule Lrule Rrule Toprule">4</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Granulocytopenia</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">3</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Headache</td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">4</td><td class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Fatigue</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">5</td><td class="Botrule Lrule Rrule Toprule">4</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Diarrhea</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">1</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Abdominal pain</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">0</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Myalgia</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">0</td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">2</td> </tr> </tbody> </table></div>

Laboratory Abnormalities

Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving VIRAMUNE than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue VIRAMUNE therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing VIRAMUNE and control regimens (see Table 3).

<div class="scrollingtable"><table border="0" cellpadding="2" cellspacing="0" width="100%"> <caption> <span>Table 3 Percentage of Adult Subjects with Laboratory Abnormalities</span> </caption> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">1</span> Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4<span class="Sup">+</span> cell counts less than 200 cells/mm<span class="Sup">3</span>.<br/> <span class="Sup">2</span> Background therapy included ZDV and ZDV+ddI; VIRAMUNE monotherapy was administered in some subjects. Subjects had CD4<span class="Sup">+</span> cell count greater than or equal to 200 cells/mm<span class="Sup">3</span>.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Trial 1090<span class="Sup">1</span></span></td><td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Trials 1037, 1038, 1046<span class="Sup">2</span></span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">VIRAMUNE</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Placebo</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">VIRAMUNE</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Placebo</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Laboratory Abnormality</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=1,121)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=1,128)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=253)</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">(n=203)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Blood Chemistry</span></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  SGPT (ALT) &gt;250 U/L</td><td class="Botrule Lrule Rrule Toprule">5</td><td class="Botrule Lrule Rrule Toprule">4</td><td class="Botrule Lrule Rrule Toprule">14</td><td class="Botrule Lrule Rrule Toprule">4</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  SGOT (AST) &gt;250 U/L</td><td class="Botrule Lrule Rrule Toprule">4</td><td class="Botrule Lrule Rrule Toprule">3</td><td class="Botrule Lrule Rrule Toprule">8</td><td class="Botrule Lrule Rrule Toprule">2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  Bilirubin &gt;2.5 mg/dL</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">2</td><td class="Botrule Lrule Rrule Toprule">2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Hematology</span></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  Hemoglobin &lt;8.0 g/dL</td><td class="Botrule Lrule Rrule Toprule">3</td><td class="Botrule Lrule Rrule Toprule">4</td><td class="Botrule Lrule Rrule Toprule">0</td><td class="Botrule Lrule Rrule Toprule">0</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">  Platelets &lt;50,000/mm<span class="Sup">3</span></td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">1</td><td class="Botrule Lrule Rrule Toprule">&lt;1</td><td class="Botrule Lrule Rrule Toprule">2</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">  Neutrophils &lt;750/mm<span class="Sup">3</span></td><td class="Botrule Lrule Rrule Toprule">13</td><td class="Botrule Lrule Rrule Toprule">14</td><td class="Botrule Lrule Rrule Toprule">4</td><td class="Botrule Lrule Rrule Toprule">1</td> </tr> </tbody> </table></div>

Clinical Trial Experience in Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of VIRAMUNE (n=305) in which pediatric subjects received combination treatment with VIRAMUNE. In this trial, two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of VIRAMUNE (n=37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to VIRAMUNE in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE. Cases of allergic reaction, including one case of anaphylaxis, were also reported.

The safety of VIRAMUNE was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with VIRAMUNE, lamivudine and zidovudine for 48 weeks [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Rash (all causality) was reported in 21% of the subjects, 4 (3%) of whom discontinued drug due to rash. All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%) [see Use in Specific Populations (8.4) and Clinical Studies (14.2)].

Safety information on use of VIRAMUNE in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.

In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of VIRAMUNE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)] Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

In postmarketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

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.

{ "type": "p", "children": [], "text": "\nNevirapine 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 specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction trials 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 4. Although specific drug interaction trials in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs.

{ "type": "p", "children": [], "text": "\nThe specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables 4 and 5 are based on the results of drug interaction trials 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 4. Although specific drug interaction trials in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, 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.

{ "type": "p", "children": [], "text": "\nThe 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." }

<div class="scrollingtable"><table cellpadding="0" cellspacing="2" width="100%"> <caption> <span>Table 4 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 5 for Magnitude of Interaction.</span> </caption> <colgroup> <col valign="top" width="40%"/> <col valign="top" width="24%"/> <col valign="top" width="3%"/> <col valign="top" width="31%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td colspan="4"><span class="Bold">* </span>The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Drug Name</span></td><td class="Botrule Lrule Toprule"><span class="Bold">Effect on Concentration of <br/>Nevirapine or Concomitant Drug</span></td><td class="Botrule Toprule"></td><td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Clinical Comment</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">HIV Antiviral Agents: Protease Inhibitors (PIs)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Atazanavir/Ritonavir*<br/> </td><td class="Botrule Lrule Toprule">↓ Atazanavir<br/>↑ Nevirapine<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Lrule Rrule Toprule" valign="top">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.<br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule">Fosamprenavir*<br/> </td><td class="Lrule Toprule">↓ Amprenavir<br/>↑ Nevirapine<br/> </td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule">Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule">Fosamprenavir/Ritonavir*<br/> </td><td class="Botrule Lrule">↓ Amprenavir<br/> <br/>↑ Nevirapine<br/> </td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule">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.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Indinavir*<br/> </td><td class="Botrule Lrule Toprule">↓ Indinavir<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule">The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top">Lopinavir/Ritonavir*<br/> </td><td class="Botrule Lrule Toprule" valign="top">↓Lopinavir<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule">Dosing in adult patients:<br/> <br/>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.<br/> <br/>Dosing in pediatric patients:<br/> <br/>Please refer to the Kaletra<span class="Sup">®</span> 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.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Nelfinavir*<br/> </td><td class="Botrule Lrule Toprule">↓Nelfinavir M8 Metabolite<br/>↓Nelfinavir C<span class="Sub">min</span> <br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule">The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Saquinavir/Ritonavir<br/> </td><td class="Botrule Lrule Toprule">The interaction between nevirapine and saquinavir/ritonavir has not been evaluated<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule" valign="top">The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Efavirenz*<br/> </td><td class="Lrule Toprule">↓ Efavirenz<br/> </td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule">The appropriate doses of these combinations with respect to safety and efficacy have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule">Etravirine<br/>Rilpivirine<br/> </td><td class="Botrule Lrule"></td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule">Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="4"><span class="Bold">Other Agents</span></td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Analgesics:</span></td><td class="Lrule Toprule"></td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top">Methadone*<br/> </td><td class="Botrule Lrule" valign="top">↓ Methadone<br/> </td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule" valign="top">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.<br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Antiarrhythmics: </span></td><td class="Lrule Toprule"></td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule">Amiodarone, disopyramide, lidocaine<br/> </td><td class="Botrule Lrule">Plasma concentrations may be decreased.<br/> </td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule">Appropriate doses for this combination have not been established.<br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Antibiotics:</span></td><td class="Lrule Toprule"></td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule"></td> </tr> <tr> <td class="Lrule Rrule">Clarithromycin*<br/> </td><td class="Lrule">↓ Clarithromycin<br/>↑ 14-OH clarithromycin<br/> </td><td class="Rrule"></td><td class="Lrule Rrule">Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against <span class="Italics">Mycobacterium avium-intracellulare complex</span>, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.<br/> </td> </tr> <tr> <td class="Lrule Rrule">Rifabutin*<br/> </td><td class="Lrule">↑ Rifabutin<br/> </td><td class="Rrule"></td><td class="Lrule Rrule">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.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule">Rifampin*<br/> </td><td class="Botrule Lrule">↓ Nevirapine<br/> </td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule">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.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Anticonvulsants:</span> <br/>Carbamazepine, clonazepam, ethosuximide<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations of nevirapine and the anticonvulsant may be decreased.<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <br/>Use with caution and monitor virologic response and levels of anticonvulsants.<br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Antifungals:</span></td><td class="Lrule Toprule"></td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule"></td> </tr> <tr> <td class="Lrule Rrule">Fluconazole*<br/> </td><td class="Lrule">↑Nevirapine<br/> </td><td class="Rrule"></td><td class="Lrule Rrule">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.<br/> </td> </tr> <tr> <td class="Lrule Rrule">Ketoconazole*<br/> </td><td class="Lrule">↓ Ketoconazole<br/> </td><td class="Rrule"></td><td class="Lrule Rrule">Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule">Itraconazole<br/> </td><td class="Botrule Lrule">↓ Itraconazole<br/> </td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule">Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Antithrombotics:</span> <br/>Warfarin<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations may be increased.<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <br/>Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Calcium Channel blockers:</span> <br/>Diltiazem, nifedipine, verapamil<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations may be decreased.<br/> </td><td class="Botrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <br/>Appropriate doses for these combinations have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Cancer Chemotherapy:</span> <br/>Cyclophosphamide<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations may be decreased.<br/> </td><td class="Botrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <br/>Appropriate doses for this combination have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Ergot Alkaloids:</span> <br/>Ergotamine<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations may be decreased.<br/> </td><td class="Botrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <br/>Appropriate doses for this combination have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Immunosuppressants:</span> <br/>Cyclosporine, tacrolimus, sirolimus<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations may be decreased.<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <br/>Appropriate doses for these combinations have not been established.<br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Opiate Agonists:</span> <br/>Fentanyl<br/> </td><td class="Botrule Lrule Toprule"> <br/>Plasma concentrations may be decreased.<br/> </td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <br/>Appropriate doses for this combination have not been established.<br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule"><span class="Bold">Oral Contraceptives:</span></td><td class="Lrule Toprule"></td><td class="Rrule Toprule"></td><td class="Lrule Rrule Toprule"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule">Ethinyl estradiol and Norethindrone*<br/> </td><td class="Botrule Lrule">↓ Ethinyl Estradiol<br/>↓ Norethindrone<br/> </td><td class="Botrule Rrule"></td><td class="Botrule Lrule Rrule">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 VIRAMUNE, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.<br/> <br/>When these oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0\" cellspacing=\"2\" width=\"100%\">\n<caption>\n<span>Table 4 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 5 for Magnitude of Interaction.</span>\n</caption>\n<colgroup>\n<col valign=\"top\" width=\"40%\"/>\n<col valign=\"top\" width=\"24%\"/>\n<col valign=\"top\" width=\"3%\"/>\n<col valign=\"top\" width=\"31%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td colspan=\"4\"><span class=\"Bold\">* </span>The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Drug Name</span></td><td class=\"Botrule Lrule Toprule\"><span class=\"Bold\">Effect on Concentration of <br/>Nevirapine or Concomitant Drug</span></td><td class=\"Botrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">Clinical Comment</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\"><span class=\"Bold\">HIV Antiviral Agents: Protease Inhibitors (PIs)</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">Atazanavir/Ritonavir*<br/>\n</td><td class=\"Botrule Lrule Toprule\">↓ Atazanavir<br/>↑ Nevirapine<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\" valign=\"top\">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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">Fosamprenavir*<br/>\n</td><td class=\"Lrule Toprule\">↓ Amprenavir<br/>↑ Nevirapine<br/>\n</td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\">Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\">Fosamprenavir/Ritonavir*<br/>\n</td><td class=\"Botrule Lrule\">↓ Amprenavir<br/>\n<br/>↑ Nevirapine<br/>\n</td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\">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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">Indinavir*<br/>\n</td><td class=\"Botrule Lrule Toprule\">↓ Indinavir<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">Lopinavir/Ritonavir*<br/>\n</td><td class=\"Botrule Lrule Toprule\" valign=\"top\">↓Lopinavir<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">Dosing in adult patients:<br/>\n<br/>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.<br/>\n<br/>Dosing in pediatric patients:<br/>\n<br/>Please refer to the Kaletra<span class=\"Sup\">®</span> 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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">Nelfinavir*<br/>\n</td><td class=\"Botrule Lrule Toprule\">↓Nelfinavir M8 Metabolite<br/>↓Nelfinavir C<span class=\"Sub\">min</span>\n<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">Saquinavir/Ritonavir<br/>\n</td><td class=\"Botrule Lrule Toprule\">The interaction between nevirapine and saquinavir/ritonavir has not been evaluated<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. <br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\"><span class=\"Bold\">HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">Efavirenz*<br/>\n</td><td class=\"Lrule Toprule\">↓ Efavirenz<br/>\n</td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\">The appropriate doses of these combinations with respect to safety and efficacy have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\">Etravirine<br/>Rilpivirine<br/>\n</td><td class=\"Botrule Lrule\"></td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\">Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\"><span class=\"Bold\">Other Agents</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Analgesics:</span></td><td class=\"Lrule Toprule\"></td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">Methadone*<br/>\n</td><td class=\"Botrule Lrule\" valign=\"top\">↓ Methadone<br/>\n</td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\">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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Antiarrhythmics: </span></td><td class=\"Lrule Toprule\"></td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\">Amiodarone, disopyramide, lidocaine<br/>\n</td><td class=\"Botrule Lrule\">Plasma concentrations may be decreased.<br/>\n</td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\">Appropriate doses for this combination have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Antibiotics:</span></td><td class=\"Lrule Toprule\"></td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\">Clarithromycin*<br/>\n</td><td class=\"Lrule\">↓ Clarithromycin<br/>↑ 14-OH clarithromycin<br/>\n</td><td class=\"Rrule\"></td><td class=\"Lrule Rrule\">Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against <span class=\"Italics\">Mycobacterium avium-intracellulare complex</span>, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\">Rifabutin*<br/>\n</td><td class=\"Lrule\">↑ Rifabutin<br/>\n</td><td class=\"Rrule\"></td><td class=\"Lrule Rrule\">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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\">Rifampin*<br/>\n</td><td class=\"Botrule Lrule\">↓ Nevirapine<br/>\n</td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\">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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Anticonvulsants:</span>\n<br/>Carbamazepine, clonazepam, ethosuximide<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations of nevirapine and the anticonvulsant may be decreased.<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<br/>Use with caution and monitor virologic response and levels of anticonvulsants.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Antifungals:</span></td><td class=\"Lrule Toprule\"></td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\">Fluconazole*<br/>\n</td><td class=\"Lrule\">↑Nevirapine<br/>\n</td><td class=\"Rrule\"></td><td class=\"Lrule Rrule\">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.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\">Ketoconazole*<br/>\n</td><td class=\"Lrule\">↓ Ketoconazole<br/>\n</td><td class=\"Rrule\"></td><td class=\"Lrule Rrule\">Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\">Itraconazole<br/>\n</td><td class=\"Botrule Lrule\">↓ Itraconazole<br/>\n</td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\">Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Antithrombotics:</span>\n<br/>Warfarin<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations may be increased.<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<br/>Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Calcium Channel blockers:</span>\n<br/>Diltiazem, nifedipine, verapamil<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations may be decreased.<br/>\n</td><td class=\"Botrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<br/>Appropriate doses for these combinations have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Cancer Chemotherapy:</span>\n<br/>Cyclophosphamide<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations may be decreased.<br/>\n</td><td class=\"Botrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<br/>Appropriate doses for this combination have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Ergot Alkaloids:</span>\n<br/>Ergotamine<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations may be decreased.<br/>\n</td><td class=\"Botrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<br/>Appropriate doses for this combination have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Immunosuppressants:</span>\n<br/>Cyclosporine, tacrolimus, sirolimus<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations may be decreased.<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<br/>Appropriate doses for these combinations have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">Opiate Agonists:</span>\n<br/>Fentanyl<br/>\n</td><td class=\"Botrule Lrule Toprule\">\n<br/>Plasma concentrations may be decreased.<br/>\n</td><td class=\"Botrule Rrule Toprule\"></td><td class=\"Botrule Lrule Rrule Toprule\">\n<br/>Appropriate doses for this combination have not been established.<br/>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\"><span class=\"Bold\">Oral Contraceptives:</span></td><td class=\"Lrule Toprule\"></td><td class=\"Rrule Toprule\"></td><td class=\"Lrule Rrule Toprule\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\">Ethinyl estradiol and Norethindrone*<br/>\n</td><td class=\"Botrule Lrule\">↓ Ethinyl Estradiol<br/>↓ Norethindrone<br/>\n</td><td class=\"Botrule Rrule\"></td><td class=\"Botrule Lrule Rrule\">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 VIRAMUNE, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.<br/>\n<br/>When these oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored.</td>\n</tr>\n</tbody>\n</table></div>" }

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the risk of overall major birth defects for nevirapine compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

In literature reports, immediate-release nevirapine exposure (Cmin) can be up to 29% lower during pregnancy. However, as this reduction was not found to be clinically meaningful, dose adjustment is not necessary [see Data].

There is a risk for severe hepatic events in pregnant women exposed to VIRAMUNE [see Clinical Considerations]. In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of nevirapine during organogenesis in the rat and rabbit, at systemic exposures (AUC) to nevirapine approximately equal (rats) and 50% higher (rabbits) than the exposure in humans at the recommended 400 mg daily dose [see Data].

Clinical Considerations

Maternal adverse reactions

Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic VIRAMUNE therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate VIRAMUNE unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women [see Warnings and Precautions (5.1)].

Data

Human Data

Based on prospective reports to the APR of exposures to nevirapine during pregnancy resulting in live births (including over 1,100 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 2.1%, 4.1%) and 3.3% (95% CI: 2.4%, 4.3%) following first and second/third trimester exposure, respectively, to nevirapine-containing regimens, compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP.

There are several literature reports of chronic administration of immediate-release nevirapine during pregnancy, in which nevirapine pharmacokinetics were compared between pregnancy and postpartum. In these studies, the mean difference in nevirapine Cmin during pregnancy as compared to postpartum ranged from no difference to approximately 29% lower.

Animal Data

Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg per kg per day) and rabbits (at 0, 30, 100, and 300 mg per kg per day) through organogenesis (on gestation days 7 through 16, and 6 through 18, respectively). No adverse developmental effects were observed at doses producing systemic exposures (AUC) approximately equivalent to (rats) or approximately 50% higher (rabbits) than human exposure at the recommended daily dose. In rats, decreased fetal body weights were observed at a maternally toxic dose at an exposure approximately 50% higher than the recommended daily dose.

Risk Summary

Published data report that nevirapine is present in human milk [see Data]. There are limited data on the effects of nevirapine on the breastfed infant. There is no information on the effects of nevirapine on milk production. Potential risks of breastfeeding include (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults.

Data

Based on five publications, immediate-release nevirapine was excreted in breast milk at median concentrations ranging from 4,080 to 6,795 ng/mL, and the median maternal breast milk to maternal plasma concentration ratio range was 59 to 88%. Reported infant nevirapine median plasma concentrations were low, ranging from 734 to 1,140 ng/mL. The estimated nevirapine dose of 704 to 682 mcg/kg/day for infants fed exclusively with breast milk was lower than the daily recommended nevirapine dose for infants. Published literature indicates that rash and hyperbilirubinemia have been seen in infants exposed to nevirapine through breast milk.

Infertility

Limited human data are insufficient to determine the risk of infertility in humans. Based on results from animal fertility studies conducted in rats, VIRAMUNE may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

The safety, pharmacokinetic profile, and virologic and immunologic responses of VIRAMUNE have been evaluated in HIV-1 infected pediatric subjects aged 3 months to 18 years [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. The safety and pharmacokinetic profile of VIRAMUNE has been evaluated in HIV-1 infected pediatric subjects aged 15 days to less than 3 months [see Adverse Reactions (6.1) and Clinical Studies (14.2)].

The most frequently reported adverse events related to VIRAMUNE in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE [see Adverse Reactions (6.1) and Clinical Studies (14.2)].

Clinical trials of VIRAMUNE did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCl greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer VIRAMUNE to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

There is no known antidote for VIRAMUNE overdosage. Cases of VIRAMUNE overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease. All events subsided following discontinuation of VIRAMUNE.

{ "type": "p", "children": [], "text": "\nThere is no known antidote for VIRAMUNE overdosage. Cases of VIRAMUNE overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease. All events subsided following discontinuation of VIRAMUNE." }

VIRAMUNE is the brand name for nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds.

{ "type": "p", "children": [], "text": "\nVIRAMUNE is the brand name for nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds." }

The chemical name of nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O. Nevirapine has the following structural formula:

{ "type": "p", "children": [], "text": "\nThe chemical name of nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O. Nevirapine has the following structural formula:" }

VIRAMUNE is for oral administration. Each 5 mL of VIRAMUNE oral suspension contains 50 mg of nevirapine (as nevirapine hemihydrate). The suspension also contains the following inactive ingredients: carbomer 934P, methylparaben, polysorbate 80, propylparaben, purified water, sodium hydroxide, sorbitol, and sucrose.

{ "type": "p", "children": [], "text": "\nVIRAMUNE is for oral administration. Each 5 mL of VIRAMUNE oral suspension contains 50 mg of nevirapine (as nevirapine hemihydrate). The suspension also contains the following inactive ingredients: carbomer 934P, methylparaben, polysorbate 80, propylparaben, purified water, sodium hydroxide, sorbitol, and sucrose." }

Nevirapine is an antiretroviral drug [see Microbiology (12.4)].

Absorption and Bioavailability

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for a 50 mg immediate-release tablet and 91 ± 8% for an oral suspension. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dosage range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar), (n=242) were attained at 400 mg per day. Nevirapine immediate-release tablets and oral suspension have been shown to be comparably bioavailable and substitutable at doses up to 200 mg. When nevirapine 200 mg was administered to 24 healthy adults (12 female, 12 male), with either a high-fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate trial in HIV-1 infected subjects (n=6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. VIRAMUNE may be administered with or without food, antacid or didanosine.

Distribution

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk [see Use in Specific Populations (8.2)]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg per mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (±5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination

In vivo trials in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus, cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg per day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg per day.

Renal Impairment

HIV-1 seronegative adults with mild (CrCl 50-79 mL per min; n=7), moderate (CrCl 30-49 mL per min; n=6), or severe (CrCl less than 30 mL per min; n=4) renal impairment received a single 200 mg dose of nevirapine in a pharmacokinetic trial. These subjects did not require dialysis. The trial included six additional subjects with renal failure requiring dialysis.

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose following each dialysis treatment is indicated [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

Hepatic Impairment

In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity [see Warnings and Precautions (5.1)]. The subjects studied were receiving antiretroviral therapy containing VIRAMUNE 200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.

In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of nevirapine, a significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.7)].

Sex

In the multinational 2NN trial, a population pharmacokinetic substudy of 1,077 subjects was performed that included 391 female subjects. Female subjects showed a 13.8% lower clearance of nevirapine than did male subjects. Since neither body weight nor body mass index (BMI) had an influence on the clearance of nevirapine, the effect of sex cannot be explained solely by body size.

Race

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg per day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Black subjects (n=80/group) in Trial 1100.1486 showed approximately 30% to 35% higher trough concentrations than Caucasian subjects (250-325 subjects/group) in both immediate-release nevirapine and VIRAMUNE XR treatment groups over 96 weeks of treatment at 400 mg per day.

Geriatric Patients

Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18 to 68 years); however, nevirapine has not been extensively evaluated in subjects beyond the age of 55 years [see Use in Specific Populations (8.5)].

Pediatric Patients

Pharmacokinetic data for nevirapine have been derived from two sources: a 48-week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïve subjects aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 subjects aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, and pharmacokinetics of a weight-based and a body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric subjects up to 8 years of age received a dose of 4 mg/kg once daily for two weeks followed by 7 mg per kg twice daily thereafter. Subjects 8 years and older were dosed 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatric subjects received 150 mg/m2 once daily for two weeks followed by 150 mg/m2 twice daily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)]. Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead-in of 150 mg/m2 QD) produced geometric mean or mean trough nevirapine concentrations between 4-6 mcg per mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two dosing regimens studied (BSA- and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of pediatric subjects less than 3 months of age (n=17). The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the pediatric population, but were more variable between subjects, particularly in the second month of age. For dose recommendations for pediatric patients [see Dosage and Administration (2.2)].

Drug Interactions [see Drug Interactions (7)]

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE 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 Ki 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 5 (see below) contains the results of drug interaction trials performed with VIRAMUNE and other drugs likely to be co-administered. The effects of VIRAMUNE on the AUC, Cmax, and Cmin of co-administered drugs are summarized.

<div class="scrollingtable"><table border="0" cellpadding="1" cellspacing="0"> <caption> <span>Table 5 Drug Interactions:        Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIRAMUNE (All interaction trials were conducted in HIV-1 positive subjects)</span> </caption> <colgroup> <col valign="top" width="14*"/> <col valign="top" width="14*"/> <col valign="top" width="14*"/> <col valign="top" width="14*"/> <col valign="top" width="14*"/> <col valign="top" width="14*"/> <col valign="top" width="14*"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="7">§ = C<span class="Sub">min</span> below detectable level of the assay<br/>↑ = Increase, ↓ = Decrease, ⇔ = No Effect<br/> <span class="Sup">a</span> For information regarding clinical recommendations, see <span class="Italics">Drug Interactions <a href="#Section_7">(7)</a></span>.<br/> <span class="Sup">b</span> Pediatric subjects ranging in age from 6 months to 12 years. <br/> <span class="Sup">c</span> Parallel group design; n for nevirapine+lopinavir/ritonavir, n for lopinavir/ritonavir alone.<br/> <span class="Sup">d</span> 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.<br/> <span class="Sup">e</span> Based on between-trial comparison.<br/> <span class="Sup">f</span> Based on historical controls.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Toprule"><span class="Bold">Co-administered Drug</span></td><td align="left" class="Botrule Lrule Toprule"><span class="Bold">Dose of Co-administered Drug</span></td><td align="left" class="Botrule Lrule Toprule"><span class="Bold">Dose Regimen of VIRAMUNE</span></td><td align="left" class="Botrule Lrule Toprule"><span class="Bold">n</span></td><td align="left" class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)</span></td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"><span class="Bold">Antiretrovirals</span></td><td class="Rrule Toprule"><span class="Bold">AUC</span></td><td class="Rrule Toprule"><span class="Bold">C<span class="Sub">max</span></span></td><td class="Rrule Toprule"><span class="Bold">C<span class="Sub">min</span></span></td> </tr> <tr> <td class="Lrule Rrule Toprule" rowspan="2">Atazanavir/Ritonavir<span class="Sup">a, d</span></td><td class="Rrule Toprule" rowspan="2">300/100 mg QD<br/>day 4–13, then 400/100 mg QD, day 14–23</td><td class="Rrule Toprule" rowspan="2">200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry.</td><td class="Rrule Toprule" rowspan="2">23</td><td class="Rrule Toprule"><span class="Underline">Atazanavir<br/>300/100 mg</span> <br/> <br/>↓42<br/>(↓52 to ↓29)<br/> <br/> </td><td class="Rrule Toprule"><span class="Underline">Atazanavir<br/>300/100 mg <br/> </span> <br/>↓28<br/>(↓40 to ↓14)<br/> <br/> </td><td class="Rrule Toprule"><span class="Underline">Atazanavir<br/>300/100 mg <br/> </span> <br/>↓72<br/>(↓80 to ↓60)<br/> <br/> </td> </tr> <tr> <td class="Rrule Toprule"><span class="Underline">Atazanavir<br/>400/100 mg<br/> </span> <br/>↓19<br/> (↓35 to ↑2)<br/> <br/> </td><td class="Rrule Toprule"><span class="Underline">Atazanavir<br/>400/100 mg<br/> </span> <br/>↑2<br/>(↓15 to ↑24)<br/> <br/> </td><td class="Rrule Toprule"><span class="Underline">Atazanavir<br/>400/100 mg<br/> </span> <br/>↓59 <br/>(↓73 to ↓40)<br/> <br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule">Darunavir/Ritonavir<span class="Sup">e</span></td><td class="Rrule Toprule">400/100 mg BID</td><td class="Rrule Toprule">200 mg BID</td><td class="Rrule Toprule">8</td><td class="Rrule Toprule">↑24 <br/>(↓3 to ↑57)<br/> <br/> </td><td class="Rrule Toprule">↑40 <br/>(↑14 to ↑73)<br/> <br/> </td><td class="Rrule Toprule">↑2 <br/>(↓21 to ↑32)<br/> <br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule">Didanosine</td><td class="Rrule Toprule">100-150 mg BID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">18</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Lrule Rrule Toprule">Efavirenz<span class="Sup">a</span></td><td class="Rrule Toprule">600 mg QD</td><td class="Rrule Toprule">200 mg QD x 14 days; 400 mg QD x 14 days</td><td class="Rrule Toprule">17</td><td class="Rrule Toprule">↓28<br/>(↓34 to ↓14)</td><td class="Rrule Toprule">↓12<br/>(↓23 to ↑1)</td><td class="Rrule Toprule">↓32<br/>(↓35 to ↓19)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Fosamprenavir</td><td class="Rrule Toprule">1400 mg BID</td><td class="Rrule Toprule">200 mg BID. Subjects were treated with nevirapine prior to trial entry.</td><td class="Rrule Toprule">17</td><td class="Rrule Toprule">↓33 <br/>(↓45 to ↓20)<br/> <br/> </td><td class="Rrule Toprule">↓25 <br/>(↓37 to ↓10)<br/> <br/> </td><td class="Rrule Toprule">↓35  <br/>(↓50 to ↓15)<br/> <br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule">Fosamprenavir/Ritonavir</td><td class="Rrule Toprule">700/100 mg BID</td><td class="Rrule Toprule">200 mg BID.  Subjects were treated with nevirapine prior to trial entry.</td><td class="Rrule Toprule">17</td><td class="Rrule Toprule">↓11<br/>(↓23 to ↑3)<br/> <br/> </td><td class="Rrule Toprule">⇔<br/> <br/> </td><td class="Rrule Toprule">↓19 <br/>(↓32 to ↓4)<br/> <br/> </td> </tr> <tr> <td class="Lrule Rrule Toprule">Indinavir<span class="Sup">a</span></td><td class="Rrule Toprule">800 mg q8H</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">19</td><td class="Rrule Toprule">↓31<br/>(↓39 to ↓22)</td><td class="Rrule Toprule">↓15<br/>(↓24 to ↓4)</td><td class="Rrule Toprule">↓44<br/>(↓53 to ↓33)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Lopinavir<span class="Sup">a, b</span></td><td class="Rrule Toprule">300/75 mg/m<span class="Sup">2</span> (lopinavir/<br/>ritonavir) <span class="Sup">b</span></td><td class="Rrule Toprule">7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week</td><td class="Rrule Toprule">12, 15 <span class="Sup">c</span></td><td class="Rrule Toprule">↓22<br/>(↓44 to ↑9)</td><td class="Rrule Toprule">↓14<br/>(↓36 to ↑16)</td><td class="Rrule Toprule">↓55<br/>(↓75 to ↓19)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Lopinavir<span class="Sup">a</span></td><td class="Rrule Toprule">400/100 mg BID (lopinavir/ritonavir)</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID &gt;1 year</td><td class="Rrule Toprule">22, 19 <span class="Sup">c</span></td><td class="Rrule Toprule">↓27<br/>(↓47 to ↓2)</td><td class="Rrule Toprule">↓19<br/>(↓38 to ↑5)</td><td class="Rrule Toprule">↓51<br/>(↓72 to ↓26)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Maraviroc<span class="Sup">f</span></td><td class="Rrule Toprule">300 mg SD</td><td class="Rrule Toprule">200 mg BID</td><td class="Rrule Toprule">8</td><td class="Rrule Toprule">↑1 <br/>(↓35 to ↑55)</td><td class="Rrule Toprule">↑54 <br/>(↓6 to ↑151)</td><td class="Rrule Toprule">⇔ </td> </tr> <tr> <td class="Lrule Rrule Toprule">Nelfinavir<span class="Sup">a</span></td><td class="Rrule Toprule">750 mg TID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">23</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">↓32<br/>(↓50 to ↑5)</td> </tr> <tr> <td class="Lrule Rrule">Nelfinavir-M8 metabolite</td><td class="Rrule"></td><td class="Rrule"></td><td class="Rrule"></td><td class="Rrule Toprule">↓62<br/>(↓70 to ↓53)</td><td class="Rrule Toprule">↓59<br/>(↓68 to ↓48)</td><td class="Rrule Toprule">↓66<br/>(↓74 to ↓55)</td> </tr> <tr> <td class="Lrule Rrule Toprule">Ritonavir</td><td class="Rrule Toprule">600 mg BID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">18</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td> </tr> <tr> <td class="Lrule Rrule Toprule">Stavudine</td><td class="Rrule Toprule">30-40 mg BID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">22</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Lrule Rrule Toprule">Zalcitabine</td><td class="Rrule Toprule">0.125-0.25 mg TID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">6</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Lrule Rrule Toprule">Zidovudine</td><td class="Rrule Toprule">100-200 mg TID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">11</td><td class="Rrule Toprule">↓28<br/>(↓40 to ↓4)</td><td class="Rrule Toprule">↓30<br/>(↓51 to ↑14)</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="4"><span class="Bold">Other Medications</span></td><td class="Rrule Toprule"><span class="Bold">AUC</span></td><td class="Rrule Toprule"><span class="Bold">C<span class="Sub">max</span></span></td><td class="Rrule Toprule"><span class="Bold">C<span class="Sub">min</span></span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Clarithromycin<span class="Sup">a</span></td><td class="Rrule Toprule">500 mg BID</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">15</td><td class="Rrule Toprule">↓31<br/>(↓38 to ↓24)</td><td class="Rrule Toprule">↓23<br/>(↓31 to ↓14)</td><td class="Rrule Toprule">↓56<br/>(↓70 to ↓36)</td> </tr> <tr> <td class="Lrule Rrule">Metabolite <br/>14-OH-clarithromycin</td><td class="Rrule"></td><td class="Rrule"></td><td class="Rrule"></td><td class="Rrule Toprule">↑42<br/>(↑16 to ↑73)</td><td class="Rrule Toprule">↑47<br/>(↑21 to ↑80)</td><td class="Rrule Toprule">⇔</td> </tr> <tr> <td class="Lrule Rrule Toprule" rowspan="2">Ethinyl Estradiol<span class="Sup">a</span> <br/> <br/>and<br/> <br/>Norethindrone<span class="Sup">a</span></td><td class="Rrule Toprule">0.035 mg<br/>(as Ortho-Novum® 1/35)</td><td class="Rrule Toprule" rowspan="2">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule" rowspan="2"> <br/>10</td><td class="Rrule Toprule">↓20<br/>(↓33 to ↓3)</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Rrule">1 mg<br/>(as Ortho-Novum® 1/35)</td><td class="Rrule Toprule">↓19<br/>(↓30 to ↓7)</td><td class="Rrule Toprule">↓16<br/>(↓27 to ↓3)</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Lrule Rrule Toprule">Depomedroxy-Progesterone Acetate</td><td class="Rrule Toprule">150 mg every 3 months</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">32</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td> </tr> <tr> <td class="Lrule Rrule Toprule">Fluconazole</td><td class="Rrule Toprule">200 mg QD</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">19</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td><td class="Rrule Toprule">⇔</td> </tr> <tr> <td class="Lrule Rrule Toprule">Ketoconazole<span class="Sup">a</span></td><td class="Rrule Toprule">400 mg QD</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">21</td><td class="Rrule Toprule">↓72<br/>(↓80 to ↓60)</td><td class="Rrule Toprule">↓44<br/>(↓58 to ↓27)</td><td class="Rrule Toprule">§</td> </tr> <tr> <td class="Lrule Rrule Toprule">Methadone<span class="Sup">a</span></td><td class="Rrule Toprule">Individual Subject Dosing</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID ≥7 days</td><td class="Rrule Toprule">9</td><td class="Rrule Toprule" colspan="3">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.</td> </tr> <tr> <td class="Lrule Rrule Toprule">Rifabutin<span class="Sup">a</span></td><td class="Rrule Toprule">150 or 300 mg QD</td><td class="Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Rrule Toprule">19</td><td class="Rrule Toprule">↑17<br/>(↓2 to ↑40)</td><td class="Rrule Toprule">↑28<br/>(↑9 to ↑51)</td><td class="Rrule Toprule">⇔</td> </tr> <tr> <td class="Lrule Rrule">Metabolite<br/>25-O-desacetyl-rifabutin</td><td class="Rrule"></td><td class="Rrule"></td><td class="Rrule"></td><td class="Rrule Toprule">↑24<br/>(↓16 to ↑84)</td><td class="Rrule Toprule">↑29<br/>(↓2 to ↑68)</td><td class="Rrule Toprule">↑22<br/>(↓14 to ↑74)</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Rifampin<span class="Sup">a</span></td><td class="Botrule Rrule Toprule">600 mg QD</td><td class="Botrule Rrule Toprule">200 mg QD x 14 days; 200 mg BID x 14 days</td><td class="Botrule Rrule Toprule">14</td><td class="Botrule Rrule Toprule">↑11<br/>(↓4 to ↑28)</td><td class="Botrule Rrule Toprule">⇔</td><td class="Botrule Rrule Toprule">§</td> </tr> </tbody> </table></div>

Because of the design of the drug interaction trials (addition of 28 days of VIRAMUNE 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 Cmax 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 5 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) are not inhibited by nevirapine.

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2,923 wild-type isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14-302 nM, n=29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activity of nevirapine was not antagonistic in combination with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine, and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.

HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n=24) or nevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trials ranging from 1 to 12 weeks or longer. After 1 week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the subjects tested (n=24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline and had one or more of the nevirapine RT resistance-associated substitutions. Nineteen (80%) of these subjects had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: A98G, K101E, K103N, V106A/M, V108I, Y181C, Y188C/L, G190A/S, F227L, and M230L.

For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy isolates from 23 and 34 subjects who experienced virologic failure in the VIRAMUNE XR and immediate-release nevirapine treatment group, respectively. Nevirapine resistance-associated substitutions developed in the on-therapy isolates of 78% (18/23) of the subjects who had virologic failures in the VIRAMUNE XR treatment group and 88% (30/34) of the subjects in the immediate-release nevirapine treatment group, respectively. The Y181C nevirapine resistance-associated substitution was found alone or in combination with other nevirapine resistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjects failing VIRAMUNE XR treatment and 25 subjects failing immediate-release nevirapine treatment. On-therapy isolates from 1 subject in VIRAMUNE XR treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release nevirapine treatment group developed a novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively.

Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs efavirenz and etravirine. The Y188N conferred a 7-fold reduction in susceptibility to efavirenz but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to etravirine 8-fold, but did not reduce susceptibility to efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTI ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose. The mechanism of the carcinogenic potential is unknown.

Mutagenesis

However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.

Impairment of Fertility

In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose of VIRAMUNE.

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2,249 HIV-1 infected subjects with less than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with VIRAMUNE + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were VIRAMUNE, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1,309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV-1 RNA of 4.58 log10 copies per mL (38,291 copies per mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies per mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

<div class="scrollingtable"><table border="0" cellpadding="2" cellspacing="1" width="100%"> <caption> <span>Table 6 BI 1090 Outcomes Through 48 Weeks</span> </caption> <colgroup> <col width="50%"/> <col width="7%"/> <col width="7%"/> <col width="11%"/> <col width="7%"/> <col width="7%"/> <col width="11%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="7"><span class="Sup">1</span> including change to open-label nevirapine<br/> <span class="Sup">2</span> includes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Outcome</span></td><td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">VIRAMUNE <br/>(N=1,121)<br/>%</span></td><td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Placebo <br/>(N=1,128)<br/>%</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Responders at 48 weeks: HIV-1 RNA &lt;50 copies/mL </td><td class="Botrule Lrule Rrule Toprule" colspan="3">18</td><td class="Botrule Lrule Rrule Toprule" colspan="3">2</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Treatment Failure</td><td class="Botrule Lrule Rrule Toprule" colspan="3">82</td><td class="Botrule Lrule Rrule Toprule" colspan="3">98</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">    Never suppressed viral load</td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">45</td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">66</td><td class="Botrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">    Virologic failure after response</td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">7</td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">4</td><td class="Botrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">    CDC category C event or death</td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">10</td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">11</td><td class="Botrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">    Added antiretroviral therapy<span class="Sup">1</span> while &lt;50 copies/mL</td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">5</td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">1</td><td class="Botrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">    Discontinued trial therapy due to AE</td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">7</td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">6</td><td class="Botrule Rrule Toprule"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">    Discontinued trial &lt;48 weeks<span class="Sup">2</span></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">9</td><td class="Botrule Rrule Toprule"></td><td class="Botrule Lrule Toprule"></td><td align="right" class="Botrule Toprule">10</td><td class="Botrule Rrule Toprule"></td> </tr> </tbody> </table></div>

The change from baseline in CD4+ cell count through one year of therapy was significantly greater for the VIRAMUNE group compared to the placebo group for the overall trial population (64 cells/mm3 versus 22 cells/mm3, respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm3 versus 25 cells/mm3, respectively).

At two years into the trial, 16% of subjects on VIRAMUNE had experienced class C CDC events as compared to 21% of subjects in the control arm.

Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4+ cell counts of 200-600 cells/mm3 at baseline. BI 1046 compared treatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudine and zidovudine+didanosine. Treatment doses were VIRAMUNE at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log10 copies/mL (25,704 copies per mL) and mean baseline CD4+ cell count of 376 cells/mm3. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies per mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects treated with VIRAMUNE+zidovudine.

CD4+ cell counts in the VIRAMUNE+ZDV+ddI group increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increase of 87 cells/mm3 in the ZDV+ddI subjects. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm3 below baseline.

The pediatric safety and efficacy of VIRAMUNE was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received VIRAMUNE oral suspension for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years, and 12 to less than or equal to 16 years) and randomized to receive one of two VIRAMUNE doses, determined by 2 different dosing methods [body surface area (150 mg/m2) and weight-based dosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine [see Adverse Reactions (6.1), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)]. The total daily dose of VIRAMUNE did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log10 copies per mL and a median baseline CD4+ cell count of 527 cells/mm3 (range 37-2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies per mL at 48 weeks was 47% (58/123).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in a safe place out of the reach of children.

Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877 USA

Licensed from:Boehringer Ingelheim International GmbH

VIRAMUNE is a registered trademark of and used under license from Boehringer Ingelheim International GmbH.

The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc.

Copyright © 2024 Boehringer Ingelheim Pharmaceuticals, Inc. ALL RIGHTS RESERVED

COL10614BG262024SPL10654B

<div class="scrollingtable"><table border="0" width="100%"> <colgroup> <col/> <col/> <col/> </colgroup> <tfoot> <tr class="First Last"> <td align="left" class="Toprule">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td></td><td align="right">Revised: 07/2024</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="3"><span class="Bold">MEDICATION GUIDE</span></td> </tr> <tr> <td align="center" class="Botrule Lrule"><span class="Bold">VIRAMUNE<span class="Sup">®</span> (VIH-rah-mune)<br/>(nevirapine)<br/>oral suspension</span></td><td align="center" class="Botrule Rrule" colspan="2"><span class="Bold">VIRAMUNE XR<span class="Sup">®</span> (VIH-rah-mune)<br/>(nevirapine)<br/>extended-release tablets</span></td> </tr> <tr> <td class="Lrule Rrule" colspan="3"><span class="Bold">What is the most important information I should know about VIRAMUNE?</span> <br/> <span class="Bold">VIRAMUNE can cause severe liver and skin problems that may lead to death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment.</span> <br/> <span class="Bold">VIRAMUNE can cause serious side effects, including:</span> <ul class="Disc"> <li> <span class="Bold">Severe liver problems. </span>Some people taking VIRAMUNE may develop severe liver problems that can lead to liver failure and the need for a liver transplant, or death. If you have liver problems, you may get a rash.<ul class="Circle"> <li>Women have a higher risk of developing liver problems during treatment with VIRAMUNE than men.</li> <li>People who have abnormal liver test results before starting VIRAMUNE and people with hepatitis B or C also have a greater risk of getting liver problems.<br/> <span class="Bold">People who have higher CD4<span class="Sup">+</span> cell counts when they begin VIRAMUNE have a higher risk of liver problems, especially:</span> </li> <li>Women with CD4<span class="Sup">+</span> counts higher than 250 cells/mm<span class="Sup">3</span>. This group has the highest risk.</li> <li>Men with CD4<span class="Sup">+</span> counts higher than 400 cells/mm<span class="Sup">3</span>.<br/> <span class="Bold">Stop taking VIRAMUNE and call your doctor right away if you have any of the following symptoms of liver problems with or without a skin rash:</span> </li> </ul> </li> </ul> </td> </tr> <tr> <td class="Lrule" valign="top"> <ul class="Disc"> <li>dark (tea colored) urine</li> <li>light-colored bowel movements (stools)</li> <li>feeling sick to your stomach (nausea)</li> <li>pain or tenderness on your right side below your ribs</li> <li>loss of appetite</li> </ul> </td><td valign="top"> <ul class="Disc"> <li>yellowing of your skin or whites of your eyes</li> <li>fever</li> <li>feel unwell or like you have the flu</li> <li>tiredness</li> </ul> </td><td class="Rrule"></td> </tr> <tr> <td class="Lrule Rrule" colspan="3"> <ul class="Disc"> <li> <span class="Bold">Severe skin reactions and rash.</span> Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first 6 weeks of treatment with VIRAMUNE.<ul class="Circle"> <li>Women have a higher risk of developing a rash during treatment with VIRAMUNE than men.<br/> <span class="Bold">Stop taking VIRAMUNE and call your doctor right away if you get a rash with any of the following symptoms:</span> </li> </ul> </li> </ul> </td> </tr> <tr> <td class="Lrule"> <ul class="Disc"> <li>blisters</li> <li>red or inflamed eyes, like "pink eye" (conjunctivitis)</li> <li>swelling of your face</li> <li>feel unwell or like you have the flu</li> </ul> </td><td> <ul class="Disc"> <li>muscle or joint aches</li> <li>mouth sores</li> <li>fever</li> <li>tiredness</li> </ul> </td><td class="Rrule"></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3"> <ul class="Disc"> <li>Your doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with VIRAMUNE. You should continue to see your doctor and have your liver checked regularly during your treatment with VIRAMUNE. It is important for you to keep all of your doctor appointments.</li> <li> <span class="Bold">If your doctor tells you to stop treatment with VIRAMUNE because you have had any of the severe liver or skin symptoms listed above, you should never take VIRAMUNE again.</span> </li> </ul> <span class="Bold">See "What are the possible side effects of VIRAMUNE?" for more information about side effects.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">What is VIRAMUNE?</span> <br/>VIRAMUNE oral suspension is a prescription HIV-1 medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 15 days of age or older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).<br/>VIRAMUNE XR extended-release tablets is a prescription medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 6 years of age or older based on the child's weight and height.<ul class="Disc"> <li>If you are a woman with CD4<span class="Sup">+</span> counts higher than 250 cells/mm<span class="Sup">3</span> or a man with CD4<span class="Sup">+</span> counts higher than 400 cells/mm<span class="Sup">3</span>, you and your doctor will decide if starting VIRAMUNE is right for you.</li> <li>VIRAMUNE XR extended-release tablets are not recommended for use in children less than 6 years of age.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Do not take VIRAMUNE:</span> <ul class="Disc"> <li>if you have liver problems.</li> <li>as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. VIRAMUNE is only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take VIRAMUNE.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Before taking VIRAMUNE, tell your doctor about all your or your child's medical conditions, including if you or your child:</span> <ul class="Disc"> <li>have or have had hepatitis (inflammation of your liver) or problems with your liver. See <span class="Bold"><a href="#Section_18">"What is the most important information I should know about VIRAMUNE?"</a></span> </li> <li>receive dialysis</li> <li>have trouble swallowing pills</li> <li>are pregnant or plan to become pregnant. It is not known if VIRAMUNE will harm your unborn baby.<br/> <span class="Bold">Pregnancy Registry:</span> There is a pregnancy registry for women who take VIRAMUNE during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.</li> <li>are breastfeeding or plan to breastfeed. VIRAMUNE can pass into your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with VIRAMUNE:<ul class="Disc"> <li>the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.</li> <li>the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.</li> <li>your baby may get serious side effects from VIRAMUNE.</li> </ul> </li> </ul> <span class="Bold">Tell your doctor about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins and herbal supplements. <span class="Bold">Especially tell your doctor if you take St. John's wort.</span> <ul class="Disc"> <li>Some medicines interact with VIRAMUNE. Keep a list of your medicines to show your doctor or pharmacist.</li> <li>You can ask your doctor or pharmacist for a list of medicines that interact with VIRAMUNE.</li> <li> <span class="Bold">Do not start taking a new medicine without telling your doctor. </span>Your doctor can tell you if it is safe to take VIRAMUNE with other medicines.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">How should I take VIRAMUNE?</span> <ul class="Disc"> <li> <span class="Bold">Take VIRAMUNE exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to.</span> </li> <li>VIRAMUNE is always taken in combination with other antiretroviral medicines.</li> <li>VIRAMUNE comes in two different forms. Your doctor will prescribe the form of VIRAMUNE that is right for you.<ul class="Circle"> <li>VIRAMUNE oral suspension</li> <li>VIRAMUNE XR extended-release tablets</li> </ul> </li> <li>You should not take more than one form of VIRAMUNE (nevirapine) at the same time. Talk to your doctor if you have any questions.</li> <li>If your child is prescribed VIRAMUNE, your child's doctor will tell you exactly how VIRAMUNE should be taken.</li> <li>VIRAMUNE can be taken with or without food.</li> <li>Swallow VIRAMUNE XR extended-release tablets whole. Do not chew, crush, or divide VIRAMUNE XR extended-release tablets.</li> <li>Do not miss a dose of VIRAMUNE. If you miss a dose of VIRAMUNE, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take 2 doses at the same time.</li> <li>If you stop taking VIRAMUNE for more than 7 days, ask your doctor how much to take before you start taking it again. You may need to begin taking the starting dose again, which is taken 1 time each day for 14 days.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">Starting VIRAMUNE:</span> <ol class="Arabic"> <li>Your doctor should start you with 1 dose each day to lower your chance of getting a serious rash. <span class="Bold">It is important that you only take 1 dose of VIRAMUNE each day for the first 14 days.</span> <ul class="Disc"> <li> <span class="Bold">Call your doctor right away if you get a skin rash during the first 14 days of VIRAMUNE treatment.</span> </li> <li> <span class="Bold">Do not increase your dose to 2 times a day if you have a rash.</span> </li> <li>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of VIRAMUNE.</li> </ul> </li> <li>Day 15, you will take 1 dose of VIRAMUNE 2 times a day.</li> </ol> <p class="First"> <a name="p873938221491500508"></a><span class="Bold">Starting VIRAMUNE XR extended-release tablets when this is the first time you are taking any form of VIRAMUNE:</span> </p> <ol class="Arabic"> <li>Your doctor should start you with 1 dose of VIRAMUNE oral suspension or immediate-release nevirapine tablets each day to lower your risk of getting a serious rash. <span class="Bold">It is important that you only take 1 dose of VIRAMUNE or immediate-release nevirapine each day for the first 14 days.</span> <ul class="Disc"> <li> <span class="Bold">Call your doctor right away if you get a skin rash during the first 14 days of VIRAMUNE or immediate-release nevirapine treatment.</span> </li> <li>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of VIRAMUNE or immediate-release nevirapine.</li> <li> <span class="Bold">Do not start VIRAMUNE XR extended-release tablets if you have a rash.</span> </li> </ul> </li> <li>Day 15, take VIRAMUNE XR extended-release tablets 1 time a day as prescribed by your doctor.</li> </ol> <span class="Bold">Switching from VIRAMUNE oral suspension or immediate-release nevirapine tablets to VIRAMUNE XR extended-release tablets:</span> <ul class="Disc"> <li>Take VIRAMUNE XR extended-release tablets 1 time a day as prescribed by your doctor.</li> <li>You may sometimes pass a soft mass in your stools (bowel movement) that looks like your VIRAMUNE XR extended-release tablets. This will not affect the way your medicine works.</li> </ul> <span class="Bold">If you take VIRAMUNE oral suspension:</span> <ul class="Disc"> <li>If you or your child takes VIRAMUNE oral suspension (liquid), shake it gently before each use. Use an oral dosing syringe or dosing cup to measure the right dose. The oral dosing syringe and dosing cup are not provided with VIRAMUNE oral suspension. Ask your pharmacist for a syringe or cup if you do not have one.</li> <li>After drinking the medicine, fill the dosing cup with water and drink it to make sure you get all the medicine.</li> <li>If the dose is less than 1 teaspoon (5 mL), use the syringe instead of the dosing cup.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">What are the possible side effects of VIRAMUNE?</span> <br/> <span class="Bold">VIRAMUNE may cause serious side effects, including:</span> <br/>See "<span class="Bold">What is the most important information I should know about VIRAMUNE?</span>"<ul class="Disc"> <li> <span class="Bold">Changes in your immune system (Immune Reconstitution Syndrome) </span>can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.</li> <li> <span class="Bold">Changes in body fat</span> can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.</li> </ul> <span class="Bold">The most common side effect of VIRAMUNE is rash.</span> <br/>VIRAMUNE may cause decreased fertility in females. Talk to your doctor if you have concerns about fertility.<br/>These are not all the possible side effects of VIRAMUNE. For more information, ask your doctor or pharmacist.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">How should I store VIRAMUNE?</span> <ul class="Disc"> <li>Store VIRAMUNE at room temperature between 68°F to 77°F (20°C to 25°C).</li> </ul> <span class="Bold">Keep VIRAMUNE and all medicines out of the reach of children.</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"><span class="Bold">General information about the safe and effective use of VIRAMUNE.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VIRAMUNE for a condition for which it was not prescribed. Do not give VIRAMUNE to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or doctor for information about VIRAMUNE that is written for health professionals.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="3"><span class="Bold">What are the ingredients in VIRAMUNE?</span> <br/> <span class="Bold">Active ingredient:</span> nevirapine<br/> <span class="Bold">Inactive ingredients:</span> <br/> <span class="Bold">VIRAMUNE oral suspension: </span>carbomer 934P, methylparaben, polysorbate 80, propylparaben, purified water, sodium hydroxide, sorbitol, and sucrose<br/> <span class="Bold">VIRAMUNE XR tablets:</span> ferric oxide yellow, hypromellose, lactose monohydrate, and magnesium stearate<br/> <br/>For current prescribing information, including Medication Guide, for VIRAMUNE or VIRAMUNE XR, scan the codes or for additional information you may also call Boehringer Ingelheim Pharmaceuticals, Inc., at 1-800-542-6257.</td> </tr> <tr valign="top"> <td align="left" class="Lrule"><span class="Bold">VIRAMUNE oral suspension</span><img alt="viramune-tablets-and-oral-suspension-qr-code" src="/dailymed/image.cfm?name=viramune-tablets-and-oral-suspension-qr-code.jpg&amp;setid=5ec05500-6333-4bd0-ac83-464fad0d5162"/></td><td align="left"><span class="Bold">VIRAMUNE XR extended-release tablets</span><img alt="viramune-xr-qr-code" src="/dailymed/image.cfm?name=viramune-xr-qr-code.jpg&amp;setid=5ec05500-6333-4bd0-ac83-464fad0d5162"/></td><td align="left" class="Rrule"></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" colspan="3">Copyright © 2024 Boehringer Ingelheim Pharmaceuticals, Inc.<p class="First"> <a name="p371295301655490061"></a>ALL RIGHTS RESERVED</p> <br/>Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA<br/>Licensed from: Boehringer Ingelheim International GmbH<br/> <p> <a name="p279491301655499316"></a>VIRAMUNE is a registered trademark of and used under license from Boehringer Ingelheim International GmbH.</p> <br/> <p> <a name="p281611301655499316"></a>COL10614BG262024</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" width=\"100%\">\n<colgroup>\n<col/>\n<col/>\n<col/>\n</colgroup>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" class=\"Toprule\">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td></td><td align=\"right\">Revised: 07/2024</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">MEDICATION GUIDE</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\"><span class=\"Bold\">VIRAMUNE<span class=\"Sup\">®</span> (VIH-rah-mune)<br/>(nevirapine)<br/>oral suspension</span></td><td align=\"center\" class=\"Botrule Rrule\" colspan=\"2\"><span class=\"Bold\">VIRAMUNE XR<span class=\"Sup\">®</span> (VIH-rah-mune)<br/>(nevirapine)<br/>extended-release tablets</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What is the most important information I should know about VIRAMUNE?</span>\n<br/>\n<span class=\"Bold\">VIRAMUNE can cause severe liver and skin problems that may lead to death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment.</span>\n<br/>\n<span class=\"Bold\">VIRAMUNE can cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Severe liver problems. </span>Some people taking VIRAMUNE may develop severe liver problems that can lead to liver failure and the need for a liver transplant, or death. If you have liver problems, you may get a rash.<ul class=\"Circle\">\n<li>Women have a higher risk of developing liver problems during treatment with VIRAMUNE than men.</li>\n<li>People who have abnormal liver test results before starting VIRAMUNE and people with hepatitis B or C also have a greater risk of getting liver problems.<br/>\n<span class=\"Bold\">People who have higher CD4<span class=\"Sup\">+</span> cell counts when they begin VIRAMUNE have a higher risk of liver problems, especially:</span>\n</li>\n<li>Women with CD4<span class=\"Sup\">+</span> counts higher than 250 cells/mm<span class=\"Sup\">3</span>. This group has the highest risk.</li>\n<li>Men with CD4<span class=\"Sup\">+</span> counts higher than 400 cells/mm<span class=\"Sup\">3</span>.<br/>\n<span class=\"Bold\">Stop taking VIRAMUNE and call your doctor right away if you have any of the following symptoms of liver problems with or without a skin rash:</span>\n</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>dark (tea colored) urine</li>\n<li>light-colored bowel movements (stools)</li>\n<li>feeling sick to your stomach (nausea)</li>\n<li>pain or tenderness on your right side below your ribs</li>\n<li>loss of appetite</li>\n</ul>\n</td><td valign=\"top\">\n<ul class=\"Disc\">\n<li>yellowing of your skin or whites of your eyes</li>\n<li>fever</li>\n<li>feel unwell or like you have the flu</li>\n<li>tiredness</li>\n</ul>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Severe skin reactions and rash.</span> Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first 6 weeks of treatment with VIRAMUNE.<ul class=\"Circle\">\n<li>Women have a higher risk of developing a rash during treatment with VIRAMUNE than men.<br/>\n<span class=\"Bold\">Stop taking VIRAMUNE and call your doctor right away if you get a rash with any of the following symptoms:</span>\n</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Disc\">\n<li>blisters</li>\n<li>red or inflamed eyes, like \"pink eye\" (conjunctivitis)</li>\n<li>swelling of your face</li>\n<li>feel unwell or like you have the flu</li>\n</ul>\n</td><td>\n<ul class=\"Disc\">\n<li>muscle or joint aches</li>\n<li>mouth sores</li>\n<li>fever</li>\n<li>tiredness</li>\n</ul>\n</td><td class=\"Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>Your doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with VIRAMUNE. You should continue to see your doctor and have your liver checked regularly during your treatment with VIRAMUNE. It is important for you to keep all of your doctor appointments.</li>\n<li>\n<span class=\"Bold\">If your doctor tells you to stop treatment with VIRAMUNE because you have had any of the severe liver or skin symptoms listed above, you should never take VIRAMUNE again.</span>\n</li>\n</ul>\n<span class=\"Bold\">See \"What are the possible side effects of VIRAMUNE?\" for more information about side effects.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">What is VIRAMUNE?</span>\n<br/>VIRAMUNE oral suspension is a prescription HIV-1 medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 15 days of age or older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).<br/>VIRAMUNE XR extended-release tablets is a prescription medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 6 years of age or older based on the child's weight and height.<ul class=\"Disc\">\n<li>If you are a woman with CD4<span class=\"Sup\">+</span> counts higher than 250 cells/mm<span class=\"Sup\">3</span> or a man with CD4<span class=\"Sup\">+</span> counts higher than 400 cells/mm<span class=\"Sup\">3</span>, you and your doctor will decide if starting VIRAMUNE is right for you.</li>\n<li>VIRAMUNE XR extended-release tablets are not recommended for use in children less than 6 years of age.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Do not take VIRAMUNE:</span>\n<ul class=\"Disc\">\n<li>if you have liver problems.</li>\n<li>as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. VIRAMUNE is only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take VIRAMUNE.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Before taking VIRAMUNE, tell your doctor about all your or your child's medical conditions, including if you or your child:</span>\n<ul class=\"Disc\">\n<li>have or have had hepatitis (inflammation of your liver) or problems with your liver. See <span class=\"Bold\"><a href=\"#Section_18\">\"What is the most important information I should know about VIRAMUNE?\"</a></span>\n</li>\n<li>receive dialysis</li>\n<li>have trouble swallowing pills</li>\n<li>are pregnant or plan to become pregnant. It is not known if VIRAMUNE will harm your unborn baby.<br/>\n<span class=\"Bold\">Pregnancy Registry:</span> There is a pregnancy registry for women who take VIRAMUNE during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.</li>\n<li>are breastfeeding or plan to breastfeed. VIRAMUNE can pass into your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with VIRAMUNE:<ul class=\"Disc\">\n<li>the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.</li>\n<li>the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.</li>\n<li>your baby may get serious side effects from VIRAMUNE.</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">Tell your doctor about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins and herbal supplements. <span class=\"Bold\">Especially tell your doctor if you take St. John's wort.</span>\n<ul class=\"Disc\">\n<li>Some medicines interact with VIRAMUNE. Keep a list of your medicines to show your doctor or pharmacist.</li>\n<li>You can ask your doctor or pharmacist for a list of medicines that interact with VIRAMUNE.</li>\n<li>\n<span class=\"Bold\">Do not start taking a new medicine without telling your doctor. </span>Your doctor can tell you if it is safe to take VIRAMUNE with other medicines.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">How should I take VIRAMUNE?</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Take VIRAMUNE exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to.</span>\n</li>\n<li>VIRAMUNE is always taken in combination with other antiretroviral medicines.</li>\n<li>VIRAMUNE comes in two different forms. Your doctor will prescribe the form of VIRAMUNE that is right for you.<ul class=\"Circle\">\n<li>VIRAMUNE oral suspension</li>\n<li>VIRAMUNE XR extended-release tablets</li>\n</ul>\n</li>\n<li>You should not take more than one form of VIRAMUNE (nevirapine) at the same time. Talk to your doctor if you have any questions.</li>\n<li>If your child is prescribed VIRAMUNE, your child's doctor will tell you exactly how VIRAMUNE should be taken.</li>\n<li>VIRAMUNE can be taken with or without food.</li>\n<li>Swallow VIRAMUNE XR extended-release tablets whole. Do not chew, crush, or divide VIRAMUNE XR extended-release tablets.</li>\n<li>Do not miss a dose of VIRAMUNE. If you miss a dose of VIRAMUNE, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take 2 doses at the same time.</li>\n<li>If you stop taking VIRAMUNE for more than 7 days, ask your doctor how much to take before you start taking it again. You may need to begin taking the starting dose again, which is taken 1 time each day for 14 days.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">Starting VIRAMUNE:</span>\n<ol class=\"Arabic\">\n<li>Your doctor should start you with 1 dose each day to lower your chance of getting a serious rash. <span class=\"Bold\">It is important that you only take 1 dose of VIRAMUNE each day for the first 14 days.</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Call your doctor right away if you get a skin rash during the first 14 days of VIRAMUNE treatment.</span>\n</li>\n<li>\n<span class=\"Bold\">Do not increase your dose to 2 times a day if you have a rash.</span>\n</li>\n<li>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of VIRAMUNE.</li>\n</ul>\n</li>\n<li>Day 15, you will take 1 dose of VIRAMUNE 2 times a day.</li>\n</ol>\n<p class=\"First\">\n<a name=\"p873938221491500508\"></a><span class=\"Bold\">Starting VIRAMUNE XR extended-release tablets when this is the first time you are taking any form of VIRAMUNE:</span>\n</p>\n<ol class=\"Arabic\">\n<li>Your doctor should start you with 1 dose of VIRAMUNE oral suspension or immediate-release nevirapine tablets each day to lower your risk of getting a serious rash. <span class=\"Bold\">It is important that you only take 1 dose of VIRAMUNE or immediate-release nevirapine each day for the first 14 days.</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Call your doctor right away if you get a skin rash during the first 14 days of VIRAMUNE or immediate-release nevirapine treatment.</span>\n</li>\n<li>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of VIRAMUNE or immediate-release nevirapine.</li>\n<li>\n<span class=\"Bold\">Do not start VIRAMUNE XR extended-release tablets if you have a rash.</span>\n</li>\n</ul>\n</li>\n<li>Day 15, take VIRAMUNE XR extended-release tablets 1 time a day as prescribed by your doctor.</li>\n</ol>\n<span class=\"Bold\">Switching from VIRAMUNE oral suspension or immediate-release nevirapine tablets to VIRAMUNE XR extended-release tablets:</span>\n<ul class=\"Disc\">\n<li>Take VIRAMUNE XR extended-release tablets 1 time a day as prescribed by your doctor.</li>\n<li>You may sometimes pass a soft mass in your stools (bowel movement) that looks like your VIRAMUNE XR extended-release tablets. This will not affect the way your medicine works.</li>\n</ul>\n<span class=\"Bold\">If you take VIRAMUNE oral suspension:</span>\n<ul class=\"Disc\">\n<li>If you or your child takes VIRAMUNE oral suspension (liquid), shake it gently before each use. Use an oral dosing syringe or dosing cup to measure the right dose. The oral dosing syringe and dosing cup are not provided with VIRAMUNE oral suspension. Ask your pharmacist for a syringe or cup if you do not have one.</li>\n<li>After drinking the medicine, fill the dosing cup with water and drink it to make sure you get all the medicine.</li>\n<li>If the dose is less than 1 teaspoon (5 mL), use the syringe instead of the dosing cup.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">What are the possible side effects of VIRAMUNE?</span>\n<br/>\n<span class=\"Bold\">VIRAMUNE may cause serious side effects, including:</span>\n<br/>See \"<span class=\"Bold\">What is the most important information I should know about VIRAMUNE?</span>\"<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Changes in your immune system (Immune Reconstitution Syndrome) </span>can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.</li>\n<li>\n<span class=\"Bold\">Changes in body fat</span> can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (\"buffalo hump\"), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.</li>\n</ul>\n<span class=\"Bold\">The most common side effect of VIRAMUNE is rash.</span>\n<br/>VIRAMUNE may cause decreased fertility in females. Talk to your doctor if you have concerns about fertility.<br/>These are not all the possible side effects of VIRAMUNE. For more information, ask your doctor or pharmacist.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">How should I store VIRAMUNE?</span>\n<ul class=\"Disc\">\n<li>Store VIRAMUNE at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n</ul>\n<span class=\"Bold\">Keep VIRAMUNE and all medicines out of the reach of children.</span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">General information about the safe and effective use of VIRAMUNE.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VIRAMUNE for a condition for which it was not prescribed. Do not give VIRAMUNE to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or doctor for information about VIRAMUNE that is written for health professionals.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"3\"><span class=\"Bold\">What are the ingredients in VIRAMUNE?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> nevirapine<br/>\n<span class=\"Bold\">Inactive ingredients:</span>\n<br/>\n<span class=\"Bold\">VIRAMUNE oral suspension: </span>carbomer 934P, methylparaben, polysorbate 80, propylparaben, purified water, sodium hydroxide, sorbitol, and sucrose<br/>\n<span class=\"Bold\">VIRAMUNE XR tablets:</span> ferric oxide yellow, hypromellose, lactose monohydrate, and magnesium stearate<br/>\n<br/>For current prescribing information, including Medication Guide, for VIRAMUNE or VIRAMUNE XR, scan the codes or for additional information you may also call Boehringer Ingelheim Pharmaceuticals, Inc., at 1-800-542-6257.</td>\n</tr>\n<tr valign=\"top\">\n<td align=\"left\" class=\"Lrule\"><span class=\"Bold\">VIRAMUNE oral suspension</span><img alt=\"viramune-tablets-and-oral-suspension-qr-code\" src=\"/dailymed/image.cfm?name=viramune-tablets-and-oral-suspension-qr-code.jpg&amp;setid=5ec05500-6333-4bd0-ac83-464fad0d5162\"/></td><td align=\"left\"><span class=\"Bold\">VIRAMUNE XR extended-release tablets</span><img alt=\"viramune-xr-qr-code\" src=\"/dailymed/image.cfm?name=viramune-xr-qr-code.jpg&amp;setid=5ec05500-6333-4bd0-ac83-464fad0d5162\"/></td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" colspan=\"3\">Copyright © 2024 Boehringer Ingelheim Pharmaceuticals, Inc.<p class=\"First\">\n<a name=\"p371295301655490061\"></a>ALL RIGHTS RESERVED</p>\n<br/>Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA<br/>Licensed from: Boehringer Ingelheim International GmbH<br/>\n<p>\n<a name=\"p279491301655499316\"></a>VIRAMUNE is a registered trademark of and used under license from Boehringer Ingelheim International GmbH.</p>\n<br/>\n<p>\n<a name=\"p281611301655499316\"></a>COL10614BG262024</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Viramune Oral Suspension 50 mg/5mL240 mLNDC 0597-0047-24

{ "type": "p", "children": [], "text": "\nViramune Oral Suspension 50 mg/5mL240 mLNDC 0597-0047-24" }

Viramune Oral Suspension 50 mg/5mL240 mLNDC 0597-0047-24

{ "type": "p", "children": [], "text": "\nViramune Oral Suspension 50 mg/5mL240 mLNDC 0597-0047-24" }

Nevirapine extended-release tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m2 or greater [see Clinical Studies (14.1, 14.2)].

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Limitations of Use:

{ "type": "p", "children": [], "text": "Limitations of Use:" }

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine extended-release tablets are not recommended to be initiated, unless the benefit outweighs the risk, in:

{ "type": "p", "children": [], "text": "Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine extended-release tablets are not recommended to be initiated, unless the benefit outweighs the risk, in:" }

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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. The 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed (the lead-in period has been observed to decrease the incidence of rash), followed by one 400-mg tablet of nevirapine extended-release once daily [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. If rash persists beyond the 14-day lead-in period with immediate-release nevirapine, do not begin dosing with nevirapine extended-release tablets. 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.

Patients already on a regimen of immediate-release nevirapine twice daily in combination with other antiretroviral agents can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period. Patients already on a regimen of immediate-release nevirapine twice daily who switch to nevirapine extended-release tablet therapy should continue with their ongoing clinical and laboratory monitoring.

Nevirapine extended-release tablets in pediatric patients are dosed based on body surface area (BSA) calculated using the Mosteller formula. All pediatric patients must initiate therapy with immediate-release nevirapine (as 150 mg/m2 of nevirapine oral suspension or as nevirapine tablets), at a dose not to exceed 200 mg per day, administered once daily for the first 14 days. This lead-in period should be used because it has been demonstrated to reduce the frequency of rash. This lead-in period is not required if the patient is already on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents.

The recommended oral dosage of nevirapine extended-release tablets for pediatric patients with a BSA of 1.17 m2 or greater is 400 mg following the lead-in period with immediate-release nevirapine. The total daily dose should not exceed 400 mg for any patient.

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential 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 nevirapine extended-release tablets, and at two weeks after initiation of nevirapine extended-release tablet therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine extended-release tablet treatment [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

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

Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2)]. Do not initiate therapy with nevirapine extended-release tablets if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of immediate-release nevirapine until the rash has resolved [see Warnings and Precautions (5.2)]. The total duration of the once daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen should be sought.

If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine. Do not restart nevirapine after recovery [see Warnings and Precautions (5.1)].

For patients who interrupt nevirapine extended-release tablet dosing for more than 7 days, restart the recommended lead-in dosing with immediate-release nevirapine, using one 200-mg tablet daily for the first 14 days.

Patients with CrCl greater than or equal to 20 mL per min and not requiring dialysis do not require an adjustment in dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. An additional 200 mg dose of immediate-release nevirapine following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [see Clinical Pharmacology (12.3)]. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

Nevirapine Extended-Release Tablets, USP are available containing 400 mg of nevirapine, USP.

{ "type": "p", "children": [], "text": "Nevirapine Extended-Release Tablets, USP are available containing 400 mg of nevirapine, USP." }

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Nevirapine extended-release tablets are contraindicated:

{ "type": "p", "children": [], "text": "Nevirapine extended-release tablets are contraindicated:" }

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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 tablet 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 [see Dosage and Administration (2.4)].

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, 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/mm3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). 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 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 [see Contraindications (4)].

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 [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. Nevirapine extended-release tablets have not been evaluated in subjects with hepatic impairment.

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 tablet treatment. In addition, the 14-day lead-in period with immediate-release nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.2)].

If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations [see Warnings and Precautions (5.1)].

Patients must initiate therapy with immediate-release nevirapine 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 a patient is experiencing a mild to moderate rash without constitutional symptoms during the 14-day immediate-release nevirapine lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved. The total duration of the immediate-release nevirapine lead-in dosing period must not exceed 28 days, at which point an alternative regimen should be sought [see Dosage and Administration (2.5)]. 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, 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.

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 [see Microbiology (12.4)].

See Table 3 for listings of established and potential drug interactions [see Drug Interactions (7)].

Concomitant use of St. John’s wort (Hypericum perforatum) or St. John’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.

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.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most serious adverse reactions associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/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, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities.

The safety database in nevirapine extended-release tablet clinical trials contains data from 800 subjects treated with nevirapine extended-release tablets and 654 subjects treated with immediate-release nevirapine.

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 = 1,068) and then were randomized to receive either immediate-release nevirapine 200 mg twice daily (n = 506) or nevirapine extended-release tablets 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 [see Indications and Usage (1)]. 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 subject’s completion of the 96-week endpoint in the trial (mean observation period 98 weeks).

After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release nevirapine group and 6% in the nevirapine extended-release tablets 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 8% in both the immediate-release nevirapine group and nevirapine extended-release tablets group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.

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 randomized phase. In addition, six cases of Stevens-Johnson syndrome were reported; all but one occurred within the first 30 days of nevirapine treatment.

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), except for rash which occurred in 4% of subjects.

Adverse reactions of at least moderate intensity (Grades 2 or above) occurring in 2% or more of treatment-naïve subjects receiving either immediate-release nevirapine or nevirapine extended-release tablets after randomization in Trial 1100.1486 are shown in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1 Selected Clinical Adverse Drug Reactions<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> of at least Moderate Intensity (Grade 2 or above) Occurring in 2% or more of Adult Subjects - Week 96 Analysis of Trial 1100.1486<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></span> </caption> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Excludes laboratory abnormalities reported as ADRs</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Mean observation period 98 weeks.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS).</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, jaundice.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Drug Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Immediate-Release Nevirapine</span> <br/> <span class="Bold">N = 506 (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Nevirapine Extended-Release Tablets </span> <br/> <span class="Bold">N = 505 (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rash<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Clinical Hepatitis<a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal Pain</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Arthralgia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pyrexia</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

Liver enzyme test abnormalities (AST, ALT) were observed in subjects receiving nevirapine extended-release tablets. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue therapy with nevirapine in the absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 2.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2 Grade 2 to Grade 4 Laboratory Abnormalities that Represent a Worsening from Baseline Observed in at least 5% of Subjects in Either Treatment Group - Trial 1100.1486</span> </caption> <col width="26%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Laboratory Parameter</span> <br/> <span class="Bold">(unit) </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Limit</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Immediate-Release<br/>Nevirapine</span> <br/> <span class="Bold">(%) </span> <br/> <span class="Bold">(N = 506)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Nevirapine</span> <br/> <span class="Bold">Extended-Release Tablets</span> <br/> <span class="Bold">(%) </span> <br/> <span class="Bold">(N = 505)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Chemistry</span></span> </p> <p> <span class="Bold"><span class="Italics"> </span></span> </p> <p>SGPT/ALT (U/L)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.6-5.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5.1-10.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&gt; 10.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> </p> <p>SGOT/AST (U/L)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.6-5.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">9</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5.1-10.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&gt; 10.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> </p> <p>Amylase (U/L)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.6-2.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.1-5.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&gt; 5.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt; 1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> </p> <p>Phosphate (mg/dL)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2.0-2.4 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">38</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">33</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1.0-1.9 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt; 1.0 x ULN</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt; 1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Hematology</span></span> </p> <p> <span class="Bold"><span class="Italics"> </span></span> </p> <p>Neutrophils</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">750-999/mm<span class="Sup">3</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">500-749/mm<span class="Sup">3</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt; 500/mm<span class="Sup">3</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Lipids</span></span> </p> <p> <span class="Bold"><span class="Italics"> </span></span> </p> <p>LDL (mg/dL)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">160-190 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">15</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&gt; 190 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <p class="First"> </p> <p>Cholesterol (mg/dL)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 2</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">240-300 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">19</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Grade 3</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&gt; 300 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">3</p> </td> </tr> </tbody> </table></div>

In Trial 1100.1526 (TRANxITION) subjects on immediate-release nevirapine 200 mg twice daily for at least 18 weeks were randomized to either receive nevirapine extended-release tablets 400 mg once daily (n = 295) or remain on their immediate-release nevirapine treatment (n = 148). Adverse reactions observed for nevirapine extended-release tablet subjects (48-week analysis) were similar to those observed in trial 1100.1486, as displayed in Table 1.

Adverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, non-randomized, cross-over trial to evaluate the safety and steady-state pharmacokinetic parameters of nevirapine extended-release tablets in HIV-1-infected pediatric subjects 3 to less than 18 years of age. Safety was further examined in an optional extension phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were treated with nevirapine extended-release tablets once daily in combination with other antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse reactions related to nevirapine extended-release tablets in pediatric subjects were similar to those observed in adults. In pediatric subjects the incidence of Grade 2 or higher drug-related rash was 1%. There were no adverse reactions of Grade 2 or above which were considered to be related to treatment by the investigator that occurred in more than 1% of subjects [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

The following adverse reactions have been identified during post-approval use of immediate-release nevirapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)] Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities [see Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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." }

<div class="scrollingtable"><table width="100%"> <caption> <span>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 <a href="#ID_0206a610-8c26-4ebc-84bc-fc6d0373ac80">Clinical Pharmacology (12.3)</a>, Table 4 for Magnitude of Interaction.</span> </caption> <col width="30%"/> <col width="29%"/> <col width="41%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>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.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Drug Name </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Effect on Concentration of Nevirapine or Concomitant Drug</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Clinical Comment </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">HIV Antiviral Agents: Protease Inhibitors (PIs) </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Atazanavir/Ritonavir<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ Atazanavir<br/>↑ Nevirapine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First">Fosamprenavir<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First">↓ Amprenavir<br/>↑ Nevirapine</p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First">Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fosamprenavir/Ritonavir<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">↓ Amprenavir<br/>↑ Nevirapine</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Indinavir<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ Indinavir</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Lopinavir/Ritonavir<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ Lopinavir</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Dosing in adult patients: </p> <p> </p> <p>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.</p> <p> </p> <p>Dosing in pediatric patients: </p> <p> </p> <p>Please refer to the Kaletra<span class="Sup">®</span> 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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Nelfinavir<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ Nelfinavir M8 Metabolite <br/>↓ Nelfinavir C<span class="Sub">min</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Saquinavir/Ritonavir</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The interaction between nevirapine and saquinavir/ritonavir has not been evaluated.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) </span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First">Efavirenz<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First">↓ Efavirenz </p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First">The appropriate doses of these combinations with respect to safety and efficacy have not been established.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Etravirine <br/>Rilpivirine</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Other Agents </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Analgesics:</span> <br/>Methadone<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>↓ Methadone</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Antiarrhythmics:</span> <br/>Amiodarone, disopyramide, lidocaine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Plasma concentrations may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Appropriate doses for this combination have not been established.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Antibiotics:</span> <br/>Clarithromycin<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>↓ Clarithromycin<br/>↑ 14-OH clarithromycin</p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against <span class="Italics">Mycobacterium avium-intracellulare complex</span>, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.<br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Rifabutin<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Lrule Rrule" valign="top"> <p class="First">↑ Rifabutin</p> </td><td class="Lrule Rrule" valign="top"> <p class="First">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.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rifampin<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">↓ Nevirapine</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Anticonvulsants:</span> <br/>Carbamazepine, clonazepam, ethosuximide</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> <p>Plasma concentrations of nevirapine and the anticonvulsant may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> </p> <p>Use with caution and monitor virologic response and levels of anticonvulsants.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Antifungals:</span> <br/>Fluconazole<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>↑ Nevirapine</p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>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.<br/> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Ketoconazole<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Lrule Rrule" valign="top"> <p class="First">↓ Ketoconazole</p> </td><td class="Lrule Rrule" valign="top"> <p class="First">Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.<br/> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Itraconazole</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">↓ Itraconazole</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Antithrombotics:</span> <br/>Warfarin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Plasma concentrations may be increased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Calcium Channel Blockers:</span> <br/>Diltiazem, nifedipine, verapamil</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Plasma concentrations may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Appropriate doses for these combinations have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Cancer Chemotherapy:</span> <br/>Cyclophosphamide</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Plasma concentrations may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Appropriate doses for this combination have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Ergot Alkaloids:</span> <br/>Ergotamine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Plasma concentrations may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Appropriate doses for this combination have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Immunosuppressants:</span> <br/>Cyclosporine, tacrolimus, sirolimus</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Plasma concentrations may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Appropriate doses for these combinations have not been established.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Opiate Agonists:</span> <br/>Fentanyl</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Plasma concentrations may be decreased.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>Appropriate doses for this combination have not been established.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Oral Contraceptives:</span> <br/>Ethinyl Estradiol and Norethindrone<a class="Sup" href="#footnote-5">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>↓ Ethinyl Estradiol <br/>↓ Norethindrone </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <br/>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.</p> <p> </p> <p>When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablet therapy, the therapeutic effect of the hormonal therapy should be monitored.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>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 <a href=\"#ID_0206a610-8c26-4ebc-84bc-fc6d0373ac80\">Clinical Pharmacology (12.3)</a>, Table 4 for Magnitude of Interaction.</span>\n</caption>\n<col width=\"30%\"/>\n<col width=\"29%\"/>\n<col width=\"41%\"/>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"3\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-5\" name=\"footnote-5\">*</a>\n</dt>\n<dd>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.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drug Name </span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Effect on Concentration of Nevirapine or Concomitant Drug</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Clinical Comment </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">HIV Antiviral Agents: Protease Inhibitors (PIs) </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Atazanavir/Ritonavir<a class=\"Sup\" href=\"#footnote-5\" name=\"footnote-reference-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">↓ Atazanavir<br/>↑ Nevirapine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Fosamprenavir<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">↓ Amprenavir<br/>↑ Nevirapine</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Fosamprenavir/Ritonavir<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">↓ Amprenavir<br/>↑ Nevirapine</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Indinavir<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">↓ Indinavir</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Lopinavir/Ritonavir<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">↓ Lopinavir</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Dosing in adult patients: </p>\n<p> </p>\n<p>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.</p>\n<p> </p>\n<p>Dosing in pediatric patients: </p>\n<p> </p>\n<p>Please refer to the Kaletra<span class=\"Sup\">®</span> 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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Nelfinavir<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">↓ Nelfinavir M8 Metabolite <br/>↓ Nelfinavir C<span class=\"Sub\">min</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Saquinavir/Ritonavir</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The interaction between nevirapine and saquinavir/ritonavir has not been evaluated.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Efavirenz<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">↓ Efavirenz </p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">The appropriate doses of these combinations with respect to safety and efficacy have not been established.<br/> </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Etravirine <br/>Rilpivirine</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Other Agents </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Analgesics:</span>\n<br/>Methadone<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>↓ Methadone</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antiarrhythmics:</span>\n<br/>Amiodarone, disopyramide, lidocaine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Plasma concentrations may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Appropriate doses for this combination have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antibiotics:</span>\n<br/>Clarithromycin<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>↓ Clarithromycin<br/>↑ 14-OH clarithromycin</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against <span class=\"Italics\">Mycobacterium avium-intracellulare complex</span>, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.<br/> </p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Rifabutin<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Lrule Rrule\" valign=\"top\">\n<p class=\"First\">↑ Rifabutin</p>\n</td><td class=\"Lrule Rrule\" valign=\"top\">\n<p class=\"First\">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.<br/> </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Rifampin<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">↓ Nevirapine</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Anticonvulsants:</span>\n<br/>Carbamazepine, clonazepam, ethosuximide</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> </p>\n<p>Plasma concentrations of nevirapine and the anticonvulsant may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> </p>\n<p>Use with caution and monitor virologic response and levels of anticonvulsants.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antifungals:</span>\n<br/>Fluconazole<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>↑ Nevirapine</p>\n</td><td class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>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.<br/> </p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Ketoconazole<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Lrule Rrule\" valign=\"top\">\n<p class=\"First\">↓ Ketoconazole</p>\n</td><td class=\"Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.<br/> </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Itraconazole</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">↓ Itraconazole</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antithrombotics:</span>\n<br/>Warfarin</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Plasma concentrations may be increased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Calcium Channel Blockers:</span>\n<br/>Diltiazem, nifedipine, verapamil</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Plasma concentrations may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Appropriate doses for these combinations have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Cancer Chemotherapy:</span>\n<br/>Cyclophosphamide</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Plasma concentrations may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Appropriate doses for this combination have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Ergot Alkaloids:</span>\n<br/>Ergotamine</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Plasma concentrations may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Appropriate doses for this combination have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Immunosuppressants:</span>\n<br/>Cyclosporine, tacrolimus, sirolimus</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Plasma concentrations may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Appropriate doses for these combinations have not been established.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Opiate Agonists:</span>\n<br/>Fentanyl</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Plasma concentrations may be decreased.</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>Appropriate doses for this combination have not been established.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Oral Contraceptives:</span>\n<br/>Ethinyl Estradiol and Norethindrone<a class=\"Sup\" href=\"#footnote-5\">*</a>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>↓ Ethinyl Estradiol <br/>↓ Norethindrone </p>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\"> <br/>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.</p>\n<p> </p>\n<p>When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablet therapy, the therapeutic effect of the hormonal therapy should be monitored.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Available data from the APR show no difference in the risk of overall major birth defects for nevirapine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at < 20 weeks gestation.

There is a risk for severe hepatic events in pregnant women exposed to nevirapine extended-release tablets [see Clinical Considerations]. In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of nevirapine during organogenesis in the rat and rabbit, at systemic exposures (AUC) to nevirapine approximately equal (rats) and 50% higher (rabbits) than the exposure in humans at the recommended 400 mg daily dose [see Data].

Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women [see Warnings and Precautions (5.1)].

Based on prospective reports to the APR of exposures to nevirapine during pregnancy resulting in live births (including over 1,100 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 2.1%, 4.1%) and 3.3% (95% CI: 2.4%, 4.3%) following first and second/third-trimester exposure, respectively, to nevirapine-containing regimens, compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP.

Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg/kg/day), and rabbits (at 0, 30, 100, and 300 mg/kg/day) through organogenesis (on gestation days 7 through 16 and 6 through 18, respectively). No adverse developmental effects were observed at doses producing systemic exposures (AUC) approximately equivalent to (rats) or approximately 50% higher (rabbits) than human exposure at the recommended daily dose. In rats, decreased fetal body weights were observed at a maternally toxic dose at an exposure approximately 50% higher than the recommended daily dose.

Published data report that immediate-release nevirapine is present in human milk. There are limited data on the effects of nevirapine on the breastfed infant. There is no information on the effects of nevirapine on milk production. Potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1-negative infants; (2) developing viral resistance in HIV-1-positive infants; and (3) serious adverse reactions in a breastfed infant similar to those seen in adults.

Limited human data are insufficient to determine the risk of infertility in humans. Based on results from animal fertility studies conducted in rats, nevirapine extended-release tablets may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Nevirapine extended-release tablets are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in children 6 years of age or older with a BSA of 1.17 m2 or greater [see Indications and Usage (1) and Dosage and Administration (2.3)].

The use of nevirapine extended-release tablets for the treatment of HIV-1 infection in pediatric patients 6 to less than 18 years of age is based on pharmacokinetic, safety, and antiviral activity data from an open-label trial with nevirapine extended-release tablets. The results of this trial were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Nevirapine extended-release tablets are not recommended for children less than 6 years of age. Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than 6 years of age to support the use of nevirapine extended-release tablets in this age group. Furthermore, nevirapine extended-release tablets are not recommended for children less than 3 years of age because they are not able to swallow tablets.

Clinical studies of nevirapine extended-release tablets did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCl greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional dose of immediate-release nevirapine (200 mg) following each dialysis treatment is indicated [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. Nevirapine extended-release tablets have not been evaluated in subjects with hepatic impairment.

There is no known antidote for nevirapine overdosage. Cases of immediate-release nevirapine overdose at doses ranging from 800 to 1,800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of immediate-release nevirapine.

{ "type": "p", "children": [], "text": "There is no known antidote for nevirapine overdosage. Cases of immediate-release nevirapine overdose at doses ranging from 800 to 1,800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of immediate-release nevirapine." }

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds.

{ "type": "p", "children": [], "text": "Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds." }

The chemical name of nevirapine is 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1, 4]diazepin-6-one. Nevirapine, USP (anhydrous) is a white to off-white, odorless to nearly odorless crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O. Nevirapine has the following structural formula:

{ "type": "p", "children": [], "text": "The chemical name of nevirapine is 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1, 4]diazepin-6-one. Nevirapine, USP (anhydrous) is a white to off-white, odorless to nearly odorless crystalline powder with the molecular weight of 266.30 and the molecular formula C15H14N4O. Nevirapine has the following structural formula:" }

Nevirapine extended-release tablets, USP are for oral administration. Each tablet contains 400 mg of nevirapine and the inactive ingredients hypromellose, lactose monohydrate and sodium stearyl fumarate.

{ "type": "p", "children": [], "text": "Nevirapine extended-release tablets, USP are for oral administration. Each tablet contains 400 mg of nevirapine and the inactive ingredients hypromellose, lactose monohydrate and sodium stearyl fumarate." }

Nevirapine is an antiretroviral drug [see Microbiology (12.4)].

The single-dose pharmacokinetics of nevirapine extended-release tablets was studied in 17 healthy volunteers. Nevirapine was absorbed with a median tmax of approximately 24 hrs. The mean Cmax and AUC0-∞ of nevirapine were 2060 ng per mL and 161,000 ng*hr/mL, respectively. The bioavailability of 400 mg of nevirapine extended-release tablets, relative to 400 mg of immediate-release nevirapine, was approximately 75%.

The multiple-dose pharmacokinetics of nevirapine extended-release tablets was studied in 24 HIV-1 infected subjects who switched from chronic immediate-release nevirapine to nevirapine extended-release tablets. The mean nevirapine AUC0-24,ss and Cmin,ss after 19 days of nevirapine extended-release tablet dosing under fasted conditions were 82,000 ng*hr/mL and 2,920 ng per mL, respectively. When nevirapine extended-release tablets were administered under fed conditions, the mean nevirapine AUC0-24,ss and Cmin,ss were 96,700 ng*hr/mL and 3,150 ng per mL, respectively. The bioavailability of 400 mg of nevirapine extended-release tablets, relative to 400 mg of immediate-release nevirapine, under fasted and fed conditions, was 80% and 94%, respectively. The difference in the bioavailability of nevirapine, when nevirapine extended-release tablets are dosed under fasted or fed conditions, is not considered clinically relevant. Nevirapine extended-release tablets can be taken with or without food.

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk [see Use in Specific Populations (8.2)]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg per mL. Nevirapine concentrations in human cerebrospinal fluid (n = 6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady-state with immediate-release nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus, cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg per day of immediate-release nevirapine. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg per day.

HIV-1 seronegative adults with mild (CrCl 50-79 mL per min; n = 7), moderate (CrCl 30-49 mL per min; n = 6), or severe (CrCl less than 30 mL per min; n = 4) renal impairment received a single 200 mg dose of immediate-release nevirapine in a pharmacokinetic trial. These subjects did not require dialysis. The trial included six additional subjects with renal failure requiring dialysis.

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose of immediate-release nevirapine following each dialysis treatment is indicated [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)]. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

In a steady-state trial comparing 46 subjects with mild (n = 17; expansion of some portal areas; Ishak Score 1-2), moderate (n = 20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n = 9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity [see Warnings and Precautions (5.1)]. The subjects studied were receiving antiretroviral therapy containing immediate-release nevirapine 200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.

In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n = 6) or moderate (Child-Pugh B; n = 4) hepatic impairment received a single 200 mg dose of immediate-release nevirapine, a significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.7)]. Nevirapine extended-release tablets have not been evaluated in patients with hepatic impairment.

In the multinational 2NN trial of immediate-release nevirapine, a population pharmacokinetic substudy of 1,077 subjects was performed that included 391 female subjects. Female subjects showed a 13.8% lower clearance of nevirapine than did male subjects. Since neither body weight nor body mass index (BMI) had an influence on the clearance of nevirapine, the effect of sex cannot be explained solely by body size.

The effects of sex on the pharmacokinetics of nevirapine extended-release tablets have been investigated in Trial 1100.1486. Female subjects tend to have higher (approximately 20-30%) trough concentrations in both nevirapine extended-release tablets and immediate-release nevirapine treatment groups.

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cmin,ss = 4.7 mcg per mL Black, 3.8 mcg per mL Hispanic, 4.3 mcg per mL Caucasian) with long-term treatment with immediate-release nevirapine at 400 mg per day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Black subjects (n = 80/group) in Trial 1100.1486 showed approximately 30% to 35% higher trough concentrations than Caucasian subjects (250-325 subjects/group) in both immediate-release nevirapine and nevirapine extended-release tablet treatment groups over 96 weeks of treatment at 400 mg per day.

Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18 to 68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years [see Use in Specific Populations (8.5)].

The pharmacokinetics of nevirapine extended-release tablets were assessed in HIV-1 infected children 3 to less than 18 years of age. Children enrolled received weight or body surface area dose-adjusted immediate-release nevirapine in combination with other antiretrovirals for a minimum of 18 weeks and then were switched to nevirapine extended-release tablets in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined.

Overall, the mean systemic nevirapine exposures in children 6 to less than 18 years of age following administration of nevirapine extended-release tablets and immediate-release nevirapine were similar. Based on intensive PK data (N = 17), the observed geometric mean ratios of nevirapine extended-release tablets to immediate-release nevirapine were approximately 97% for Cmin,ss and 94% for AUCss with 90% confidence intervals within 80% to 125%; the ratio for Cmax,ss was lower and consistent with a once daily extended-release dosage form.

Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than 6 years of age to support the use of nevirapine extended-release tablets in this age group.

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 Ki 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, Cmax, and Cmin 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.

<div class="scrollingtable"><table width="100%"> <caption> <span>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)</span> </caption> <col width="22%"/> <col width="19%"/> <col width="15%"/> <col width="5%"/> <col width="15%"/> <col width="12%"/> <col width="12%"/> <tfoot> <tr class="First"> <td align="left" colspan="7" valign="top">§ = Cmin below detectable level of the assay</td> </tr> <tr class="Last"> <td align="left" colspan="7" valign="top">↑ = Increase, ↓ = Decrease, ↔ = No Effect</td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>For information regarding clinical recommendations, <span class="Italics">[see <a href="#ID_83fd0ec9-aaf8-4bbd-84ac-f61275fd8110">Drug Interactions (7)</a>]</span>.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>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.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>Based on between-trial comparison.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">§</a> </dt> <dd>Pediatric subjects ranging in age from 6 months to 12 years.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">¶</a> </dt> <dd>Parallel group design; n for nevirapine + lopinavir/ritonavir, n for lopinavir/ritonavir alone.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">#</a> </dt> <dd>Based on historical controls.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Co-administered Drug</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose of Co-administered Drug</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose Regimen of Immediate-release Nevirapine</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">n</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First"> <span class="Bold">% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Antiretrovirals</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Lrule Rrule" rowspan="2" valign="top"> <p class="First">Atazanavir/Ritonavir<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a><span class="Sup">, </span><a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a> </p> </td><td rowspan="2" valign="top"> <p class="First">300/100 mg QD day 4-13, then </p> <p>400/100 mg QD, day 14-23</p> </td><td rowspan="2" valign="top"> <p class="First">200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry.</p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">23</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Atazanavir</span> </p> <p> <span class="Underline">300/100 mg</span> </p> <p>↓ 42</p> <p>(↓ 52 to ↓ 29)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Atazanavir</span> </p> <p> <span class="Underline">300/100 mg</span> </p> <p>↓ 28</p> <p>(↓ 40 to ↓ 14)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Atazanavir</span> </p> <p> <span class="Underline">300/100 mg</span> </p> <p>↓ 72</p> <p>(↓ 80 to ↓ 60)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Atazanavir</span> </p> <p> <span class="Underline">400/100 mg</span> </p> <p>↓ 19</p> <p>(↓ 35 to ↑ 2)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Atazanavir</span> </p> <p> <span class="Underline">400/100 mg</span> </p> <p>↑ 2</p> <p>(↓ 15 to ↑ 24)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Underline">Atazanavir</span> </p> <p> <span class="Underline">400/100 mg</span> </p> <p>↓ 59</p> <p>(↓ 73 to ↓ 40)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Darunavir/Ritonavir<a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400/100 mg BID</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg BID</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 24</p> <p>(↓ 3 to ↑57)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 40</p> <p>(↑ 14 to ↑ 73)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 2</p> <p>(↓ 21 to ↑ 32)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Didanosine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100-150 mg BID</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Efavirenz<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">600 mg QD </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 400 mg QD x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 28</p> <p>(↓ 34 to ↓ 14) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 12</p> <p>(↓ 23 to ↑ 1) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 32</p> <p>(↓ 35 to ↓ 19) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fosamprenavir </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1400 mg BID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg BID. Subjects were treated with nevirapine prior to trial entry. </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 33</p> <p>(↓ 45 to ↓ 20) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 25</p> <p>(↓ 37 to ↓ 10) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 35</p> <p>(↓ 50 to ↓ 15) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fosamprenavir/Ritonavir </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">700/100 mg BID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg BID. Subjects were treated with nevirapine prior to trial entry.</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 11</p> <p>(↓ 23 to ↑ 3) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 19</p> <p>(↓ 32 to ↓ 4) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Indinavir<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">800 mg q8H </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">19 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 31</p> <p>(↓ 39 to ↓ 22) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 15</p> <p>(↓ 24 to ↓ 4) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 44</p> <p>(↓ 53 to ↓ 33) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lopinavir<a class="Sup" href="#footnote-6">*</a><span class="Sup">, </span><a class="Sup" href="#footnote-9" name="footnote-reference-9">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">300/75 mg/m<span class="Sup">2</span> (lopinavir/ritonavir)<a class="Sup" href="#footnote-9">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12, 15<a class="Sup" href="#footnote-10" name="footnote-reference-10">¶</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 22</p> <p>(↓ 44 to ↑ 9) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 14</p> <p>(↓ 36 to ↑ 16) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 55</p> <p>(↓ 75 to ↓ 19) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lopinavir<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400/100 mg BID (lopinavir/ritonavir) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID &gt; 1 year </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22, 19<a class="Sup" href="#footnote-10">¶</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 27</p> <p>(↓ 47 to ↓ 2) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 19</p> <p>(↓ 38 to ↑ 5) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 51</p> <p>(↓ 72 to ↓ 26) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Maraviroc<a class="Sup" href="#footnote-11" name="footnote-reference-11">#</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">300 mg SD </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg BID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 1</p> <p>(↓ 35 to ↑ 55) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 54</p> <p>(↓ 6 to ↑ 151) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Nelfinavir<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">750 mg TID </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">23 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 32</p> <p>(↓ 50 to ↑ 5) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nelfinavir-M8 metabolite</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 62</p> <p>(↓ 70 to ↓ 53) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 59</p> <p>(↓ 68 to ↓ 48) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 66</p> <p>(↓74 to ↓ 55) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ritonavir </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">600 mg BID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">18 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Stavudine </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">30-40 mg BID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Zalcitabine </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.125-0.25 mg TID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Zidovudine </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">100-200 mg TID </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 28</p> <p>(↓ 40 to ↓ 4) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 30</p> <p>(↓ 51 to ↑ 14) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First"> <span class="Bold">Other Medications </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Clarithromycin<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">500 mg BID </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">15 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 31</p> <p>(↓ 38 to ↓ 24) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 23</p> <p>(↓ 31 to ↓ 14) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 56</p> <p>(↓ 70 to ↓ 36) </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Metabolite </p> <p>14-OH-clarithromycin </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 42</p> <p>(↑ 16 to ↑ 73) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 47</p> <p>(↑ 21 to ↑ 80) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="top"> <p class="First">Ethinyl Estradiol<a class="Sup" href="#footnote-6">*</a> </p> <p>and</p> <p>Norethindrone<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">0.035 mg (as Ortho-Novum<span class="Sup">®</span> 1/35)</p> <p>1 mg (as Ortho-Novum<span class="Sup">®</span> 1/35) </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">10 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 20</p> <p>(↓ 33 to ↓ 3)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 19</p> <p>(↓ 30 to ↓ 7) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 16</p> <p>(↓ 27 to ↓ 3) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§ </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Depomedroxy-</p> <p>Progesterone Acetate </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">150 mg every 3 months </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">32 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fluconazole </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">19 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ketoconazole<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">400 mg QD </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">21 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 72</p> <p>(↓ 80 to ↓ 60) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ 44</p> <p>(↓ 58 to ↓ 27) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§ </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Methadone<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Individual Subject Dosing </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID ≥ 7 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9 </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="3" valign="top"> <p class="First">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. </p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First">Rifabutin<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">150 or 300 mg QD </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First">19 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 17</p> <p>(↓ 2 to ↑ 40) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 28</p> <p>(↑ 9 to ↑ 51) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Metabolite 25-O-desacetyl-rifabutin </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 24</p> <p>(↓ 16 to ↑ 84) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 29</p> <p>(↓ 2 to ↑ 68) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 22</p> <p>(↓ 14 to ↑ 74) </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rifampin<a class="Sup" href="#footnote-6">*</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">600 mg QD </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">200 mg QD x 14 days; 200 mg BID x 14 days </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">14 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ 11</p> <p>(↓ 4 to ↑ 28) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">§</p> </td> </tr> </tbody> </table></div>

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 Cmax 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.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme’s catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, ß, γ, or δ) are not inhibited by nevirapine.

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2,923 wild-type isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14-302 nM, n = 29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n = 3) or HIV-2 isolates (n = 3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activity of nevirapine was not antagonistic in combination with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine, and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.

HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n = 24) or nevirapine and zidovudine (n = 14) were monitored in Phase 1 and 2 trials ranging from 1 to 12 weeks or longer. After 1 week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the subjects tested (n = 24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline and had one or more of the nevirapine RT resistance-associated substitutions. Nineteen (80%) of these subjects had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n = 71) receiving nevirapine once daily (n = 25) or twice daily (n = 46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: A98G, K101E, K103N, V106A/M, V108I, Y181C, Y188C/L, G190A/S, F227L, and M230L.

For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy isolates from 23 and 34 subjects who experienced virologic failure in the nevirapine extended-release tablet and immediate-release nevirapine treatment group, respectively. Nevirapine resistance-associated substitutions developed in the on-therapy isolates of 78% (18/23) of the subjects who had virologic failures in the nevirapine extended-release tablet treatment group and 88% (30/34) of the subjects in the immediate-release nevirapine treatment group, respectively. The Y181C nevirapine resistance-associated substitution was found alone or in combination with other nevirapine resistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjects failing nevirapine extended-release tablet treatment and 25 subjects failing immediate-release nevirapine treatment. On-therapy isolates from 1 subject in nevirapine extended-release tablet treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release nevirapine treatment group developed a novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively.

Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs efavirenz and etravirine. The Y188N conferred a 7-fold reduction in susceptibility to efavirenz but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to etravirine 8-fold, but did not reduce susceptibility to efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTI ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose of immediate-release nevirapine. The mechanism of the carcinogenic potential is unknown.

However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.

In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose.

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

The clinical efficacy of nevirapine extended-release tablets is based on 96-week data from a randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486, VERxVE) in treatment-naïve subjects and on 48-week data in a randomized, open-label trial in subjects who switched from immediate-release nevirapine tablets administered twice daily to nevirapine extended-release tablets administered once daily (Trial 1100.1526, TRANxITION).

Trial 1100.1486 (VERxVE) was a Phase 3 trial in which treatment-naïve subjects received immediate-release nevirapine 200 mg once daily for 14 days and then were randomized to receive either immediate-release nevirapine 200 mg twice daily or nevirapine extended-release tablets 400 mg once daily. All subjects received tenofovir + emtricitabine as background therapy. Randomization was stratified by screening HIV-1 RNA level (less than or equal to 100,000 copies per mL and greater than 100,000 copies per mL). Subject demographic and baseline disease characteristics were balanced between the two treatment groups. With respect to demographics: 85% of the subjects were male, 75% were white, 20% were black, and approximately 29% were from North America. With respect to baseline disease characteristics: mean viral load was 4.7 log10 copies per mL, mean CD4+ cell count was 228 cells/mm3 and 73% of subjects had clade B HIV-1 subtype. Approximately two-thirds of the subjects had a baseline HIV-RNA level of less than or equal to 100,000 copies per mL.

Table 5 describes week 96 outcomes in Trial 1100.1486 (VERxVE). These outcomes include all subjects who were randomized after the 14-day lead-in with immediate-release nevirapine and received at least one dose of blinded study medication.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5 Outcomes at Week 96 in Trial 1100.1486</span> </caption> <col width="42%"/> <col width="29%"/> <col width="29%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>Includes subjects who changed optimized background therapy (OBT) to new class or changed OBT not permitted per protocol or due to lack of efficacy prior to Week 96, subjects who discontinued prior to Week 96 for lack or loss of efficacy and subjects with HIV RNA greater than or equal to 50 copies/mL in the Week 96 window.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>Includes subjects who discontinued due to adverse events or death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the specified window.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">‡</a> </dt> <dd>Other includes: withdrew consent, lost to follow-up, moved away, etc.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Week 96</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Immediate-<br/>Release <br/>Nevirapine</span> <br/> <span class="Bold">N = 506</span> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nevirapine <br/>Extended-<br/>Release Tablets</span> <br/> <span class="Bold">N = 505</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Virologic Success - HIV RNA &lt; 50 copies/mL</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">67%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">69%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Virologic Failure<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">18%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">17%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">No Virologic Data at Week 96 Window</p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     <span class="Underline">Reasons</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Discontinued trial/study drug due to adverse event or death<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">10%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Discontinued trial/study drug for other reasons<a class="Sup" href="#footnote-14" name="footnote-reference-14">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">5%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Missing data during window but on trial</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">&lt; 1%</p> </td><td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First">1%</p> </td> </tr> </tbody> </table></div>

At 96 weeks, mean change from baseline in CD4+ cell count adjusting for baseline HIV-1 viral load stratum was 222 cells/mm3 and 244 cells/mm3 for the groups receiving immediate-release nevirapine and nevirapine extended-release tablets, respectively.

Trial 1100.1526 (TRANxITION) was a Phase 3 trial to evaluate safety and antiviral activity of switching from immediate-release nevirapine to nevirapine extended-release tablets. In this open-label trial, 443 subjects already on an antiviral regimen containing immediate-release nevirapine 200 mg twice daily with HIV-1 RNA less than 50 copies per mL were randomized in a 2:1 ratio to nevirapine extended-release tablets 400 mg once daily or immediate-release nevirapine 200 mg twice daily. Approximately half of the subjects had tenofovir + emtricitabine as their background therapy, with the remaining subjects receiving abacavir sulfate + lamivudine or zidovudine + lamivudine. Approximately half of the subjects had at least 3 years of exposure to immediate-release nevirapine prior to entering the trial.

At 48 weeks after randomization in Trial 1100.1526, 91% of subjects receiving immediate-release nevirapine 200 mg twice daily and 93% of subjects receiving nevirapine extended-release tablets 400 mg once daily continued to have HIV-1 RNA less than 50 copies per mL.

Trial 1100.1518 was an open-label, multiple-dose, non-randomized, crossover trial performed in 85 HIV-1 infected pediatric subjects 3 to less than 18 years of age who had received at least 18 weeks of immediate-release nevirapine and had plasma HIV-1 RNA less than 50 copies per mL prior to trial enrollment. Subjects were stratified according to age (3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years). Following a 10-day period with immediate-release nevirapine, subjects were treated with nevirapine extended-release tablets once daily in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined. Forty of the 80 subjects who completed the initial part of the study were enrolled in an optional extension phase of the trial which evaluated the safety and antiviral activity of nevirapine extended-release tablets through a minimum of 24 weeks of treatment. Zidovudine or stavudine plus lamivudine were the most commonly used background therapies in subjects who entered the optional extension phase.

Baseline demographics included: 55% of the subjects were female, 93% were black, 7% were white, and approximately 84% were from Africa. Subjects had a median baseline CD4+ cell count of 925 cells/mm3 (range 207 to 2,057 cells/mm3).

Of the 40 subjects who entered the treatment extension phase, 39 completed at least 24 weeks of treatment and one subject discontinued prematurely due to an adverse reaction. After 24 weeks or more of treatment with nevirapine extended-release tablets, all 39 subjects continued to have plasma HIV-1 RNA less than 50 copies per mL. Median CD4+ cell counts for the 3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years age groups were 1,113 cells/mm3, 853 cells/mm3, and 682 cells/mm3, respectively. These CD4+ cell counts were similar to those observed at baseline.

Nevirapine Extended-Release Tablets, USP are available containing 400 mg of nevirapine, USP.

{ "type": "p", "children": [], "text": "Nevirapine Extended-Release Tablets, USP are available containing 400 mg of nevirapine, USP." }

The 400 mg tablets are white to off-white, oval, unscored tablets debossed with M on one side of the tablet and N400 on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "The 400 mg tablets are white to off-white, oval, unscored tablets debossed with M on one side of the tablet and N400 on the other side. They are available as follows:" }

NDC 0378-4890-93bottles of 30 tablets

{ "type": "p", "children": [], "text": "NDC 0378-4890-93bottles of 30 tablets" }

Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "\nStorage\nStore at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]\n" }

Store in a safe place out of the reach of children.

{ "type": "p", "children": [], "text": "Store in a safe place out of the reach of children." }

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure." }

PHARMACIST: Dispense a Medication Guide with each prescription.

{ "type": "p", "children": [], "text": "\nPHARMACIST: Dispense a Medication Guide with each prescription. " }

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide)." }

Hepatotoxicity and Skin Reactions Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis.

{ "type": "p", "children": [], "text": "\nHepatotoxicity and Skin Reactions\n\nInform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis." }

Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C or increased transaminases 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 [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C or increased transaminases 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 [see Warnings and Precautions (5.1)].\n" }

The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-in period with immediate-release nevirapine, do not initiate nevirapine extended-release tablets until the rash resolves. The total duration of the lead-in dosing period with immediate-release nevirapine should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult a physician. Nevirapine should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash. For patients who interrupt nevirapine extended-release tablet dosing for more than 7 days and for whom restarting nevirapine therapy is not contraindicated, restart the recommended lead-in dosing with immediate-release nevirapine using one 200 mg tablet daily (150 mg/m2/day in pediatric patients) for the first 14 days [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-in period with immediate-release nevirapine, do not initiate nevirapine extended-release tablets until the rash resolves. The total duration of the lead-in dosing period with immediate-release nevirapine should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult a physician. Nevirapine should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash. For patients who interrupt nevirapine extended-release tablet dosing for more than 7 days and for whom restarting nevirapine therapy is not contraindicated, restart the recommended lead-in dosing with immediate-release nevirapine using one 200 mg tablet daily (150 mg/m2/day in pediatric patients) for the first 14 days [see Warnings and Precautions (5.2)].\n" }

Administration and Missed Dosage Inform patients to take nevirapine extended-release tablets every day as prescribed. Advise patients not to alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose.

{ "type": "p", "children": [], "text": "\nAdministration and Missed Dosage\n\nInform patients to take nevirapine extended-release tablets every day as prescribed. Advise patients not to alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. " }

Inform patients that they may occasionally see soft remnants of nevirapine extended-release tablets in their stool, which sometimes resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

{ "type": "p", "children": [], "text": "Inform patients that they may occasionally see soft remnants of nevirapine extended-release tablets in their stool, which sometimes resemble intact tablets. These occurrences have not been shown to affect drug levels or response." }

Instruct patients to swallow nevirapine extended-release tablets whole. They must not be chewed, crushed, or divided.

{ "type": "p", "children": [], "text": "Instruct patients to swallow nevirapine extended-release tablets whole. They must not be chewed, crushed, or divided." }

To avoid overdose, inform patients that they should never take immediate-release nevirapine tablets or nevirapine oral suspension and extended-release nevirapine tablets concomitantly.

{ "type": "p", "children": [], "text": "To avoid overdose, inform patients that they should never take immediate-release nevirapine tablets or nevirapine oral suspension and extended-release nevirapine tablets concomitantly." }

Drug Interactions Nevirapine extended-release tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John’s wort [see Warnings and Precautions (5.4) and Drug Interactions (7)].

{ "type": "p", "children": [], "text": "\nDrug Interactions\n\nNevirapine extended-release tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John’s wort [see Warnings and Precautions (5.4) and Drug Interactions (7)].\n" }

Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection, as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when nevirapine extended-release tablets are started [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "\nImmune Reconstitution Syndrome\nAdvise patients to inform their healthcare provider immediately of any signs or symptoms of infection, as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when nevirapine extended-release tablets are started [see Warnings and Precautions (5.5)]." }

Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "\nFat Redistribution\n\nInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.6)].\n" }

Pregnancy Registry Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to nevirapine extended-release tablets during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nPregnancy Registry\n\nAdvise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to nevirapine extended-release tablets during pregnancy [see Use in Specific Populations (8.1)]. " }

Lactation Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1-negative infants, (2) developing viral resistance in HIV-1-positive infants, and (3) serious adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "\nLactation\nInform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1-negative infants, (2) developing viral resistance in HIV-1-positive infants, and (3) serious adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]." }

Infertility Advise females of reproductive potential of the potential for impaired fertility from nevirapine extended-release tablets [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

{ "type": "p", "children": [], "text": "\nInfertility\nAdvise females of reproductive potential of the potential for impaired fertility from nevirapine extended-release tablets [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]." }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Nevirapine Extended-Release Tablets, USP<br/>(ne vir′ a peen)</span> </p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about nevirapine?</span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold">Nevirapine can cause severe liver and skin problems that may lead to death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment. </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold">Nevirapine can cause serious side effects, including: </span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Severe liver problems. </span>Some people taking nevirapine may develop severe liver problems that can lead to liver failure and the need for a liver transplant, or death. If you have liver problems, you may get a rash.<dl> <dt>o</dt> <dd>Women have a higher risk of developing liver problems during treatment with nevirapine than men.</dd> <dt>o</dt> <dd>People who have abnormal liver test results before starting nevirapine and people with hepatitis B or C also have a greater risk of getting liver problems. </dd> </dl> </dd> <dt> </dt> <dd> <span class="Bold">People who have higher CD4<span class="Sup">+</span> cell counts when they begin nevirapine have a higher risk of liver problems, especially:</span> <dl> <dt>o</dt> <dd>Women with CD4<span class="Sup">+</span> counts higher than 250 cells/mm<span class="Sup">3</span>. This group has the highest risk.</dd> <dt>o</dt> <dd>Men with CD4<span class="Sup">+</span> counts higher than 400 cells/mm<span class="Sup">3</span>.</dd> </dl> </dd> <dt> </dt> <dd> <span class="Bold">Stop taking nevirapine and call your doctor right away if you have any of the following symptoms of liver problems with or without a skin rash:</span> </dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>•</dt> <dd>dark (tea colored) urine</dd> <dt>•</dt> <dd>light-colored bowel movements (stools)</dd> <dt>•</dt> <dd>feeling sick to your stomach (nausea)</dd> <dt>•</dt> <dd>pain or tenderness on your right side below your ribs</dd> <dt>•</dt> <dd>loss of appetite</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>yellowing of your skin or whites of your eyes</dd> <dt>•</dt> <dd>fever</dd> <dt>•</dt> <dd>feel unwell or like you have the flu</dd> <dt>•</dt> <dd>tiredness</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Severe skin reactions and rash</span>. Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first 6 weeks of treatment with nevirapine.<dl> <dt>o</dt> <dd>Women have a higher risk of developing a rash during treatment with nevirapine than men. </dd> </dl> </dd> <dt> </dt> <dd> <span class="Bold">Stop taking nevirapine and call your doctor right away if you get a rash with any of the following symptoms:</span> </dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>•</dt> <dd>blisters</dd> <dt>•</dt> <dd>red or inflamed eyes, like “pink eye” (conjunctivitis)</dd> <dt>•</dt> <dd>swelling of your face</dd> <dt>•</dt> <dd>feel unwell or like you have the flu</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>muscle or joint aches</dd> <dt>•</dt> <dd>mouth sores</dd> <dt>•</dt> <dd>fever </dd> <dt>•</dt> <dd>tiredness</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd>Your doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with nevirapine. You should continue to see your doctor and have your liver checked regularly during your treatment with nevirapine. It is important for you to keep all of your doctor appointments. </dd> <dt>•</dt> <dd> <span class="Bold">If your doctor tells you to stop treatment with nevirapine because you have had any of the severe liver or skin symptoms listed above, you should never take nevirapine again. </span> </dd> </dl> <p class="First"> <span class="Bold">See “What are the possible side effects of nevirapine?” for more information about side effects.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What is nevirapine? </span> </p> <p> <span class="Bold"> </span> </p> <p>Nevirapine oral suspension is a prescription HIV-1 medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 15 days of age or older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).</p> <p> </p> <p>Nevirapine extended-release tablets are a prescription medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 6 years of age or older based on the child’s weight and height.</p> <dl> <dt>•</dt> <dd>If you are a woman with CD4<span class="Sup">+</span> counts higher than 250 cells/mm<span class="Sup">3</span> or a man with CD4<span class="Sup">+</span> counts higher than 400 cells/mm<span class="Sup">3</span>, you and your doctor will decide if starting nevirapine is right for you.</dd> <dt>•</dt> <dd>Nevirapine extended-release tablets are not recommended for use in children less than 6 years of age.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Do not take nevirapine:</span> </p> <dl> <dt>•</dt> <dd>if you have liver problems.</dd> <dt>•</dt> <dd>as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. Nevirapine is only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take nevirapine.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Before taking nevirapine, tell your doctor about all your or your child’s medical conditions, including if you or your child: </span> </p> <dl> <dt>•</dt> <dd>have or have had hepatitis (inflammation of your liver) or problems with your liver. See <span class="Bold">“What is the most important information I should know about </span><span class="Bold">nevirapine?”</span> </dd> <dt>•</dt> <dd>receive dialysis </dd> <dt>•</dt> <dd>have trouble swallowing pills </dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. It is not known if nevirapine will harm your unborn baby. <br/> <span class="Bold">Pregnancy Registry: </span>There is a pregnancy registry for women who take nevirapine during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry. </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. Nevirapine can pass into your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with nevirapine.<dl> <dt>•</dt> <dd>the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.</dd> <dt>•</dt> <dd>the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.</dd> <dt>•</dt> <dd>your baby may get serious side effects from nevirapine.</dd> </dl> </dd> </dl> <p> <span class="Bold">Tell your doctor about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins and herbal supplements. <span class="Bold">Especially tell your doctor if you take St. John’s wort.</span> </p> <dl> <dt>•</dt> <dd>Some medicines interact with nevirapine. Keep a list of your medicines to show your doctor or pharmacist. </dd> <dt>•</dt> <dd>You can ask your doctor or pharmacist for a list of medicines that interact with nevirapine. </dd> <dt>•</dt> <dd> <span class="Bold">Do not start taking a new medicine without telling your doctor. </span>Your doctor can tell you if it is safe to take nevirapine with other medicines.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">How should I take nevirapine?</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Take nevirapine exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to.</span> </dd> <dt>•</dt> <dd>Nevirapine is always taken in combination with other antiretroviral medicines.</dd> <dt>•</dt> <dd>Nevirapine comes in two different forms. Your doctor will prescribe the form of nevirapine that is right for you.<dl> <dt>o</dt> <dd>nevirapine oral suspension </dd> <dt>o</dt> <dd>nevirapine extended-release tablets</dd> </dl> </dd> <dt>•</dt> <dd>You should not take more than one form of nevirapine at the same time. Talk to your doctor if you have any questions.</dd> <dt>•</dt> <dd>If your child is prescribed nevirapine, your child’s doctor will tell you exactly how nevirapine should be taken.</dd> <dt>•</dt> <dd>Nevirapine can be taken with or without food. </dd> <dt>•</dt> <dd>Swallow nevirapine extended-release tablets whole. Do not chew, crush, or divide nevirapine extended-release tablets. </dd> <dt>•</dt> <dd>Do not miss a dose of nevirapine. If you miss a dose of nevirapine, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take 2 doses at the same time. </dd> <dt>•</dt> <dd>If you stop taking nevirapine for more than 7 days, ask your doctor how much to take before you start taking it again. You may need to begin taking the nevirapine starting dose again, which is taken 1 time each day for 14 days. </dd> </dl> <p> <span class="Bold">Starting nevirapine: </span> </p> <dl> <dt>1.</dt> <dd>Your doctor should start you with 1 dose each day to lower your chance of getting a serious rash. <span class="Bold">It is important that you only take 1 dose of </span><span class="Bold">nevirapine each day for the first 14 days.</span> <dl> <dt>•</dt> <dd> <span class="Bold">Call your doctor right away if you get a skin rash during the first 14 days of nevirapine treatment.</span> </dd> <dt>•</dt> <dd> <span class="Bold">Do not increase your dose to 2 times a day if you have a rash. </span> </dd> <dt>•</dt> <dd>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine. </dd> </dl> </dd> <dt>2.</dt> <dd>Day 15, you will take 1 dose of nevirapine 2 times a day.</dd> </dl> <p> <span class="Bold">Starting nevirapine extended-release tablets when this is the first time you are taking any form of nevirapine:</span> </p> <dl> <dt>1.</dt> <dd>Your doctor should start you with 1 dose of nevirapine oral suspension or immediate-release nevirapine tablets each day to lower your risk of getting a serious rash. <span class="Bold">It is important that you only take 1 dose of nevirapine or immediate-release nevirapine each day for the first 14 days.</span> <dl> <dt>•</dt> <dd> <span class="Bold">Call your doctor right away if you get a skin rash during the first 14 days of nevirapine or immediate-release nevirapine treatment. </span> </dd> <dt>•</dt> <dd>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine or immediate-release nevirapine.</dd> <dt>•</dt> <dd> <span class="Bold">Do not start nevirapine extended-release tablets if you have a rash. </span> </dd> </dl> </dd> <dt>2.</dt> <dd>Day 15, take nevirapine extended-release tablets 1 time a day as prescribed by your doctor. </dd> </dl> <p> <span class="Bold">Switching from nevirapine oral suspension or immediate-release nevirapine tablets to nevirapine extended-release tablets: </span> </p> <dl> <dt>•</dt> <dd>Take nevirapine extended-release tablets 1 time a day as prescribed by your doctor. </dd> <dt>•</dt> <dd>You may sometimes pass a soft mass in your stools (bowel movement) that looks like your nevirapine extended-release tablets. This will not affect the way your medicine works. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of nevirapine? </span> </p> <p> <span class="Bold"> </span> </p> <p> <span class="Bold">Nevirapine may cause serious side effects, including: </span> </p> <p>See <span class="Bold">“What is the most important information I should know about nevirapine?”</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Changes in your immune system (Immune Reconstitution Syndrome) </span>can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.</dd> <dt>•</dt> <dd> <span class="Bold">Changes in body fat </span>can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.</dd> </dl> <p> <span class="Bold">The most common side effect of nevirapine is rash.</span> </p> <p> <span class="Bold"> </span> </p> <p>Nevirapine may cause decreased fertility in females. Talk to your doctor if you have concerns about fertility.  These are not all the possible side effects of nevirapine. For more information, ask your doctor or pharmacist.  <span class="Bold">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">How should I store nevirapine extended-release tablets?</span> </p> <dl> <dt>•</dt> <dd>Store nevirapine extended-release tablets at room temperature between 20° to 25°C (68° to 77°F).</dd> </dl> <p> <span class="Bold">Keep nevirapine extended-release tablets and all medicines out of the reach of children. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of nevirapine extended-release tablets.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use nevirapine extended-release tablets for a condition for which they were not prescribed. Do not give nevirapine extended-release tablets to other people, even if they have the same condition you have. They may harm them. You can ask your pharmacist or doctor for information about nevirapine extended-release tablets that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in nevirapine extended-release tablets? </span> </p> <p> <span class="Bold">Active ingredient: </span>nevirapine </p> <p> <span class="Bold">Inactive ingredients: </span> </p> <p> <span class="Bold">Nevirapine extended-release tablets: </span>hypromellose, lactose monohydrate and sodium stearyl fumarate </p> <p> </p> <p>Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505   U.S.A.</p> <p>Manufactured by: Mylan Laboratories Limited, Hyderabad — 500 096, India</p> <p> </p> <p>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Nevirapine Extended-Release Tablets, USP<br/>(ne vir′ a peen)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about nevirapine?</span>\n</p>\n<p>\n<span class=\"Bold\"> </span>\n</p>\n<p>\n<span class=\"Bold\">Nevirapine can cause severe liver and skin problems that may lead to death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment. </span>\n</p>\n<p>\n<span class=\"Bold\"> </span>\n</p>\n<p>\n<span class=\"Bold\">Nevirapine can cause serious side effects, including: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Severe liver problems. </span>Some people taking nevirapine may develop severe liver problems that can lead to liver failure and the need for a liver transplant, or death. If you have liver problems, you may get a rash.<dl>\n<dt>o</dt>\n<dd>Women have a higher risk of developing liver problems during treatment with nevirapine than men.</dd>\n<dt>o</dt>\n<dd>People who have abnormal liver test results before starting nevirapine and people with hepatitis B or C also have a greater risk of getting liver problems. </dd>\n</dl>\n</dd>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">People who have higher CD4<span class=\"Sup\">+</span> cell counts when they begin nevirapine have a higher risk of liver problems, especially:</span>\n<dl>\n<dt>o</dt>\n<dd>Women with CD4<span class=\"Sup\">+</span> counts higher than 250 cells/mm<span class=\"Sup\">3</span>. This group has the highest risk.</dd>\n<dt>o</dt>\n<dd>Men with CD4<span class=\"Sup\">+</span> counts higher than 400 cells/mm<span class=\"Sup\">3</span>.</dd>\n</dl>\n</dd>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Stop taking nevirapine and call your doctor right away if you have any of the following symptoms of liver problems with or without a skin rash:</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>dark (tea colored) urine</dd>\n<dt>•</dt>\n<dd>light-colored bowel movements (stools)</dd>\n<dt>•</dt>\n<dd>feeling sick to your stomach (nausea)</dd>\n<dt>•</dt>\n<dd>pain or tenderness on your right side below your ribs</dd>\n<dt>•</dt>\n<dd>loss of appetite</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>yellowing of your skin or whites of your eyes</dd>\n<dt>•</dt>\n<dd>fever</dd>\n<dt>•</dt>\n<dd>feel unwell or like you have the flu</dd>\n<dt>•</dt>\n<dd>tiredness</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Severe skin reactions and rash</span>. Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first 6 weeks of treatment with nevirapine.<dl>\n<dt>o</dt>\n<dd>Women have a higher risk of developing a rash during treatment with nevirapine than men. </dd>\n</dl>\n</dd>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">Stop taking nevirapine and call your doctor right away if you get a rash with any of the following symptoms:</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>blisters</dd>\n<dt>•</dt>\n<dd>red or inflamed eyes, like “pink eye” (conjunctivitis)</dd>\n<dt>•</dt>\n<dd>swelling of your face</dd>\n<dt>•</dt>\n<dd>feel unwell or like you have the flu</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>muscle or joint aches</dd>\n<dt>•</dt>\n<dd>mouth sores</dd>\n<dt>•</dt>\n<dd>fever </dd>\n<dt>•</dt>\n<dd>tiredness</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>Your doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with nevirapine. You should continue to see your doctor and have your liver checked regularly during your treatment with nevirapine. It is important for you to keep all of your doctor appointments. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">If your doctor tells you to stop treatment with nevirapine because you have had any of the severe liver or skin symptoms listed above, you should never take nevirapine again. </span>\n</dd>\n</dl>\n<p class=\"First\">\n<span class=\"Bold\">See “What are the possible side effects of nevirapine?” for more information about side effects.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is nevirapine? </span>\n</p>\n<p>\n<span class=\"Bold\"> </span>\n</p>\n<p>Nevirapine oral suspension is a prescription HIV-1 medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 15 days of age or older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).</p>\n<p> </p>\n<p>Nevirapine extended-release tablets are a prescription medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 6 years of age or older based on the child’s weight and height.</p>\n<dl>\n<dt>•</dt>\n<dd>If you are a woman with CD4<span class=\"Sup\">+</span> counts higher than 250 cells/mm<span class=\"Sup\">3</span> or a man with CD4<span class=\"Sup\">+</span> counts higher than 400 cells/mm<span class=\"Sup\">3</span>, you and your doctor will decide if starting nevirapine is right for you.</dd>\n<dt>•</dt>\n<dd>Nevirapine extended-release tablets are not recommended for use in children less than 6 years of age.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Do not take nevirapine:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>if you have liver problems.</dd>\n<dt>•</dt>\n<dd>as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. Nevirapine is only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take nevirapine.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking nevirapine, tell your doctor about all your or your child’s medical conditions, including if you or your child: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have or have had hepatitis (inflammation of your liver) or problems with your liver. See <span class=\"Bold\">“What is the most important information I should know about </span><span class=\"Bold\">nevirapine?”</span>\n</dd>\n<dt>•</dt>\n<dd>receive dialysis </dd>\n<dt>•</dt>\n<dd>have trouble swallowing pills </dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. It is not known if nevirapine will harm your unborn baby. <br/>\n<span class=\"Bold\">Pregnancy Registry: </span>There is a pregnancy registry for women who take nevirapine during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry. </dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. Nevirapine can pass into your breast milk. Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with nevirapine.<dl>\n<dt>•</dt>\n<dd>the HIV-1 virus may pass to your baby if your baby does not have HIV-1 infection.</dd>\n<dt>•</dt>\n<dd>the HIV-1 virus may become harder to treat if your baby has HIV-1 infection.</dd>\n<dt>•</dt>\n<dd>your baby may get serious side effects from nevirapine.</dd>\n</dl>\n</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your doctor about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins and herbal supplements. <span class=\"Bold\">Especially tell your doctor if you take St. John’s wort.</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Some medicines interact with nevirapine. Keep a list of your medicines to show your doctor or pharmacist. </dd>\n<dt>•</dt>\n<dd>You can ask your doctor or pharmacist for a list of medicines that interact with nevirapine. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not start taking a new medicine without telling your doctor. </span>Your doctor can tell you if it is safe to take nevirapine with other medicines.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take nevirapine?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Take nevirapine exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to.</span>\n</dd>\n<dt>•</dt>\n<dd>Nevirapine is always taken in combination with other antiretroviral medicines.</dd>\n<dt>•</dt>\n<dd>Nevirapine comes in two different forms. Your doctor will prescribe the form of nevirapine that is right for you.<dl>\n<dt>o</dt>\n<dd>nevirapine oral suspension </dd>\n<dt>o</dt>\n<dd>nevirapine extended-release tablets</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>You should not take more than one form of nevirapine at the same time. Talk to your doctor if you have any questions.</dd>\n<dt>•</dt>\n<dd>If your child is prescribed nevirapine, your child’s doctor will tell you exactly how nevirapine should be taken.</dd>\n<dt>•</dt>\n<dd>Nevirapine can be taken with or without food. </dd>\n<dt>•</dt>\n<dd>Swallow nevirapine extended-release tablets whole. Do not chew, crush, or divide nevirapine extended-release tablets. </dd>\n<dt>•</dt>\n<dd>Do not miss a dose of nevirapine. If you miss a dose of nevirapine, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take 2 doses at the same time. </dd>\n<dt>•</dt>\n<dd>If you stop taking nevirapine for more than 7 days, ask your doctor how much to take before you start taking it again. You may need to begin taking the nevirapine starting dose again, which is taken 1 time each day for 14 days. </dd>\n</dl>\n<p>\n<span class=\"Bold\">Starting nevirapine: </span>\n</p>\n<dl>\n<dt>1.</dt>\n<dd>Your doctor should start you with 1 dose each day to lower your chance of getting a serious rash. <span class=\"Bold\">It is important that you only take 1 dose of </span><span class=\"Bold\">nevirapine each day for the first 14 days.</span>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Call your doctor right away if you get a skin rash during the first 14 days of nevirapine treatment.</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not increase your dose to 2 times a day if you have a rash. </span>\n</dd>\n<dt>•</dt>\n<dd>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine. </dd>\n</dl>\n</dd>\n<dt>2.</dt>\n<dd>Day 15, you will take 1 dose of nevirapine 2 times a day.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Starting nevirapine extended-release tablets when this is the first time you are taking any form of nevirapine:</span>\n</p>\n<dl>\n<dt>1.</dt>\n<dd>Your doctor should start you with 1 dose of nevirapine oral suspension or immediate-release nevirapine tablets each day to lower your risk of getting a serious rash. <span class=\"Bold\">It is important that you only take 1 dose of nevirapine or immediate-release nevirapine each day for the first 14 days.</span>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Call your doctor right away if you get a skin rash during the first 14 days of nevirapine or immediate-release nevirapine treatment. </span>\n</dd>\n<dt>•</dt>\n<dd>You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine or immediate-release nevirapine.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Do not start nevirapine extended-release tablets if you have a rash. </span>\n</dd>\n</dl>\n</dd>\n<dt>2.</dt>\n<dd>Day 15, take nevirapine extended-release tablets 1 time a day as prescribed by your doctor. </dd>\n</dl>\n<p>\n<span class=\"Bold\">Switching from nevirapine oral suspension or immediate-release nevirapine tablets to nevirapine extended-release tablets: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Take nevirapine extended-release tablets 1 time a day as prescribed by your doctor. </dd>\n<dt>•</dt>\n<dd>You may sometimes pass a soft mass in your stools (bowel movement) that looks like your nevirapine extended-release tablets. This will not affect the way your medicine works. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of nevirapine? </span>\n</p>\n<p>\n<span class=\"Bold\"> </span>\n</p>\n<p>\n<span class=\"Bold\">Nevirapine may cause serious side effects, including: </span>\n</p>\n<p>See <span class=\"Bold\">“What is the most important information I should know about nevirapine?”</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Changes in your immune system (Immune Reconstitution Syndrome) </span>can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Changes in body fat </span>can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.</dd>\n</dl>\n<p>\n<span class=\"Bold\">The most common side effect of nevirapine is rash.</span>\n</p>\n<p>\n<span class=\"Bold\"> </span>\n</p>\n<p>Nevirapine may cause decreased fertility in females. Talk to your doctor if you have concerns about fertility.  These are not all the possible side effects of nevirapine. For more information, ask your doctor or pharmacist.  <span class=\"Bold\">Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store nevirapine extended-release tablets?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store nevirapine extended-release tablets at room temperature between 20° to 25°C (68° to 77°F).</dd>\n</dl>\n<p>\n<span class=\"Bold\">Keep nevirapine extended-release tablets and all medicines out of the reach of children. </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of nevirapine extended-release tablets.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use nevirapine extended-release tablets for a condition for which they were not prescribed. Do not give nevirapine extended-release tablets to other people, even if they have the same condition you have. They may harm them. You can ask your pharmacist or doctor for information about nevirapine extended-release tablets that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in nevirapine extended-release tablets? </span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient: </span>nevirapine </p>\n<p>\n<span class=\"Bold\">Inactive ingredients: </span>\n</p>\n<p>\n<span class=\"Bold\">Nevirapine extended-release tablets: </span>hypromellose, lactose monohydrate and sodium stearyl fumarate </p>\n<p> </p>\n<p>Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505   U.S.A.</p>\n<p>Manufactured by: Mylan Laboratories Limited, Hyderabad — 500 096, India</p>\n<p> </p>\n<p>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration

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The brands listed are trademarks of their respective owners.

{ "type": "p", "children": [], "text": "The brands listed are trademarks of their respective owners." }

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505   U.S.A.

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Pharmaceuticals Inc.\nMorgantown, WV 26505   U.S.A." }

Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, India

{ "type": "p", "children": [], "text": "Manufactured by:\nMylan Laboratories Limited\nHyderabad — 500 096, India\n" }

75106830

{ "type": "p", "children": [], "text": "75106830" }

Revised: 10/2024MXA:NEV1:R8

{ "type": "p", "children": [], "text": "Revised: 10/2024MXA:NEV1:R8" }

NDC 0378-4890-93

{ "type": "p", "children": [], "text": "\nNDC 0378-4890-93\n" }

Nevirapine Extended-Release Tablets, USP 400 mg

{ "type": "p", "children": [], "text": "\nNevirapine\n\nExtended-Release\n\nTablets, USP\n\n400 mg\n" }

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "\nPHARMACIST: Dispense the accompanying\n\nMedication Guide to each patient.\n" }

Rx only     30 Tablets

{ "type": "p", "children": [], "text": "\nRx only     30 Tablets\n" }

Each tablet contains:Nevirapine, USP (anhydrous)    400 mg

{ "type": "p", "children": [], "text": "Each tablet contains:Nevirapine, USP (anhydrous)    400 mg" }

Usual Dosage: See accompanyingprescribing information.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See accompanyingprescribing information." }

Tablets must be swallowed whole and must not be chewed, crushed, or divided.

{ "type": "p", "children": [], "text": "\nTablets must be swallowed whole and\n\nmust not be chewed, crushed, or divided.\n" }

Keep this and all medication out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep this and all medication out of\n\nthe reach of children.\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F). [See\n\nUSP Controlled Room Temperature.]\n" }

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Pharmaceuticals Inc.\nMorgantown, WV 26505 U.S.A." }

Made in India

{ "type": "p", "children": [], "text": "Made in India" }

Mylan.com

{ "type": "p", "children": [], "text": "\nMylan.com\n" }

RMXA4890H4

{ "type": "p", "children": [], "text": "\nRMXA4890H4\n" }

Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure." }

Keep container tightly closed.

{ "type": "p", "children": [], "text": "Keep container tightly closed." }

Code No.: MH/DRUGS/AD/089

{ "type": "p", "children": [], "text": "Code No.: MH/DRUGS/AD/089" }