nevirapine
Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION
HEPATOTOXICITY:
Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patients at increased risk; women with CD4+ cell counts greater than 250 cells/mm3, including pregnant women receiving nevirapine in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4+ cell counts and at any time during treatment. Hepatic failure has also been reported in patients without HIV taking nevirapine for post-exposure prophylaxis (PEP). Use of nevirapine for occupational and non-occupational PEP is contraindicated [see Contraindications (4.2)]. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately [see Warnings and Precautions (5.1)].
SKIN REACTIONS:
Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with immediate-release Viramune 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed [see Warnings and Precautions (5.2)].
MONITORING:
Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart nevirapine following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment.
1 INDICATIONS AND USAGE
Viramune XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. This indication is based on one principal clinical trial (1100.1486) that demonstrated prolonged suppression of HIV-1 RNA through 48-weeks and a supportive trial (1100.1526).
Additional important information regarding the use of Viramune XR for the treatment of HIV-1 infection:
- Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 unless the benefit outweighs the risk [see Boxed Warning and Warnings and Precautions (5.1)].
- The 14-day lead-in period with immediate-release Viramune 200 mg daily dosing must be strictly followed; it has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
- If rash persists beyond the 14-day lead-in period with immediate-release Viramune, do not begin dosing with Viramune XR. The lead-in dosing with 200 mg once-daily immediate-release Viramune should not be continued beyond 28 days, at which point an alternative regimen should be sought.
2 DOSAGE AND ADMINISTRATION
Adults
Patients not currently taking immediate-release Viramune
Patients must initiate therapy with one 200 mg tablet of immediate-release Viramune daily for the first 14 days in combination with other antiretroviral agents (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg tablet of Viramune XR once daily. Patients must swallow Viramune XR tablets whole. They must not be chewed, crushed, or divided. For concomitantly administered therapy, the manufacturer's recommended dosage and monitoring should be followed. Viramune XR can be taken with or without food.
Switching Patients from immediate-release Viramune to Viramune XR
Patients already on a regimen of immediate-release Viramune twice daily in combination with other antiretroviral agents can be switched to Viramune XR 400 mg once daily in combination with other antiretroviral agents without the 14-day lead-in period of immediate-release Viramune.
Patients must never take more than one form of nevirapine at the same time.
Monitoring of Patients
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 Viramune, prior to initiation of Viramune XR, and at two weeks after initiation of Viramune XR therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout Viramune XR 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 Viramune twice daily who switch to Viramune XR once daily should continue with their ongoing clinical and laboratory monitoring.
Dosage Adjustment
Patients with Rash
Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings [see Boxed Warning, Warnings and Precautions (5.2), and Patient Counseling Information (17.1)]. Do not initiate therapy with Viramune XR if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of immediate-release Viramune (200 mg once daily) until the rash has resolved [see Warnings and Precautions (5.2) and Patient Counseling Information (17.1)]. 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 nevirapine. Do not restart nevirapine after recovery [see Warnings and Precautions (5.1)].
Patients with Dose Interruption
For patients who interrupt Viramune XR dosing for more than 7 days restart the recommended lead-in dosing with immediate-release Viramune, using one 200 mg tablet daily for the first 14 days.
Patients with Renal Impairment
Patients with CrCL greater than or equal to 20 mL/min and not requiring dialysis do not require an adjustment in dosing. An additional 200 mg dose of immediate-release 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)]. Viramune XR has not been studied in patients with renal dysfunction.
3 DOSAGE FORMS AND STRENGTHS
Tablets: 400 mg, yellow, oval, biconvex, tablets debossed with "V04" on one side and the Boehringer Ingelheim logo on the other side.
4 CONTRAINDICATIONS
Hepatic Impairment
Viramune XR is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].
Post-Exposure Prophylaxis
Viramune XR is contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS
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 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.
The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events and skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests prior to beginning the 14-day lead-in period with immediate-release Viramune, prior to initiation of Viramune XR (during the lead-in period), and at two weeks after initiation of Viramune XR therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout Viramune XR 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)].
For patients already on a regimen of immediate-release Viramune twice daily who switch to Viramune XR therapy, continue with their ongoing clinical and laboratory monitoring.
Hepatotoxicity and Hepatic Impairment
Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine.
The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups in controlled clinical trials through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.
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 Boxed Warning, Dosage and Administration (2.2), and Patient Counseling Information (17.1)].
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 Viramune, during the first 6 weeks of treatment women had a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% vs 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% vs 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% vs 1% for men with CD4+ cell counts less than 400 cells/mm3). However, all patients, regardless of gender, 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 and/or increased 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 Viramune in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of Viramune XR for occupational and non-occupational PEP is contraindicated [see Contraindications (4.2)].
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 (4.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. Viramune XR has not been evaluated in subjects with hepatic impairment.
Skin Reactions
Severe and life-threatening skin reactions, including fatal cases, have been reported in patients taking nevirapine. These have occurred most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately [see Boxed Warning and Patient Counseling Information (17.1)]. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.
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 one 200 mg tablet of immediate-release Viramune 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 Viramune XR if a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day immediate-release Viramune lead-in period of 200 mg/day until the rash has resolved. The total duration of the immediate-release Viramune lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [see Dosage and Administration (2.3)]. 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 Viramune, concomitant prednisone use (40 mg/day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended.
Resistance
Viramune XR 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 XR, the long half-life of nevirapine should be taken into account; 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 Clinical Pharmacology (12.4)].
Drug Interactions
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
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 (PCP), or tuberculosis), which may necessitate further evaluation and treatment.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
6 ADVERSE REACTIONS
Clinical Trials Experience
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 Viramune XR clinical trials contains data from 800 subjects treated with Viramune XR and 654 subjects treated with immediate release Viramune.
Trial 1100.1486 (VERxVE)
In Trial 1100.1486 (VERxVE) treatment-naïve subjects received a lead-in dose of immediate-release Viramune 200 mg once daily for 14 days (n=1068) and then were randomized to receive either immediate-release Viramune 200 mg twice daily (n=506) or Viramune XR 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 48 week primary endpoint in the trial (mean observation period 61 weeks).
After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release Viramune group and 6% in the Viramune XR group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 7% in the immediate-release Viramune group and 6% in the Viramune XR 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 Viramune, and in 1% of subjects in either treatment group during the randomization phase. In addition, five cases of Stevens-Johnson syndrome were reported in the trial, all of which occurred within the first 30 days of nevirapine treatment.
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 Viramune (200 mg once daily), with the exception of rash which occurred in 4% of subjects.
Adverse reactions of at least moderate intensity (Grades 2 or above) and considered to be related to treatment by the investigator in at least 2% of treatment-naive subjects receiving either immediate-release Viramune or Viramune XR after randomization in Trial 1100.1486 are shown in Table 1.
| Adverse Drug Reaction (%) | Viramune Immediate-Release N=506 | Viramune XR N=505 |
| 1 Includes adverse drug reactions considered by the investigator to be at least possibly, probably, or definitely related to the drug. 2 Mean observation period 61 weeks. 3 Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), and allergic dermatitis. 4 Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, jaundice. | ||
| Rash3 | 3% | 3% |
| Clinical hepatitis4 | 3% | 2% |
Liver enzyme test abnormalities (AST, ALT) were observed in subjects receiving Viramune XR. 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. Selected laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 2.
| Laboratory Parameter (unit) | Limit | Viramune Immediate-Release N=506 (%) | Viramune XR N=505 (%) |
| Chemistry | |||
| SGPT/ALT (U/L) | |||
| Grade 2 | 2.6-5.0 x ULN | 52 (10) | 44 (9) |
| Grade 3 | 5.1-10.0 x ULN | 18 (4) | 14 (3) |
| Grade 4 | >10.0 x ULN | 18 (4) | 10 (2) |
SGOT/AST (U/L) | |||
| Grade 2 | 2.6-5.0 x ULN | 43 (9) | 31 (6) |
| Grade 3 | 5.1-10.0 x ULN | 11 (2) | 13 (3) |
| Grade 4 | >10.0 x ULN | 10 (2) | 7 (1) |
Total Bilirubin (mg/dL) | |||
| Grade 2 | 1.6-2.5 x ULN | 2 (<1) | 4 (1) |
| Grade 3 | 2.6-5.0 x ULN | 3 (1) | 3 (1) |
| Grade 4 | >5.0 x ULN | 1 (<1) | 5 (1) |
Alkaline Phosphatase (U/L) | |||
| Grade 2 | 2.6-5.0 x ULN | 18 (4) | 11 (2) |
| Grade 3 | 5.1-10.0 x ULN | 1 (<1) | 4 (1) |
| Grade 4 | >10.0 x ULN | 0 | 0 |
| Hematology | |||
| Neutrophils | |||
| Grade 2 | 750-999/mm3 | 33 (7) | 22 (4) |
| Grade 3 | 500-749/mm3 | 13 (3) | 8 (2) |
| Grade 4 | <500/mm3 | 3 (1) | 2 (<1) |
| Lipids | |||
| LDL (mg/dL) | |||
| Grade 2 | 160-190 mg/dL | 66 (13) | 66 (13) |
| Grade 3 | >190 mg/dL | 21 (4) | 20 (4) |
Cholesterol (mg/dL) | |||
| Grade 2 | 240-300 mg/dL | 81 (16) | 83 (16) |
| Grade 3 | >300 mg/dL | 14 (4) | 9 (2) |
Triglycerides (mg/dL) | |||
| Grade 2 | 500-750 mg/dL | 10 (2) | 15 (3) |
| Grade 3 | 751-1,200 mg/dL | 9 (2) | 4 (1) |
| Grade 4 | >1,200 mg/dL | 1 (<1) | 2 (<1) |
In Trial 1100.1526 (TRANxITION) subjects on immediate-release Viramune 200 mg twice daily for at least 18 weeks were randomized to either receive Viramune XR 400 mg once daily (n=295) or remain on their immediate-release Viramune treatment (n=148). There were no adverse reactions of Grades 2 or above and considered to be related to treatment by the investigator that occurred in more than 1% of subjects (24 week analysis).
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of immediate-release 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 [see Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.
7 DRUG INTERACTIONS
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine.
The results of drug interactions studies with immediate-release Viramune are expected to also apply to Viramune XR. 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.
| Drug Name | Effect on Concentration of Nevirapine or Concomitant Drug | Clinical Comment |
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine | Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin | Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4)]. |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone | Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓Amprenavir ↑Nevirapine | Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓Amprenavir ↑Nevirapine | No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | Lopinavir/ritonavir 400/100 mg tablets can be used twice-daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin | The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
Potential Drug Interactions: | ||
| Drug Class | Examples of Drugs | |
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
8 USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects, Pregnancy Category B.
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
There are no adequate and well-controlled studies of nevirapine in pregnant women. The Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.
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 Boxed Warning].
Viramune XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to immediate-release Viramune and Viramune XR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Nevirapine is excreted in breast milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Viramune XR.
Pediatric Use
The safety and efficacy of Viramune XR in pediatric patients have not been established. Please consult the complete prescribing information for immediate-release Viramune tablets and Viramune Oral Suspension for dosage and administration of nevirapine to pediatric patients.
Geriatric Use
Clinical studies of Viramune XR 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.
Renal Impairment
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 extensiv
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