Nevirapine

NEVIRAPINE- nevirapine tablet
Mylan Pharmaceuticals Inc.

WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS

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) ]. 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 nevirapine 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed [see Warnings and Precautions (5.2)].

MONITORING FOR HEPATOTOXICITY AND SKIN REACTIONS: 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

Nevirapine 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, nevirapine is not recommended to be initiated, unless the benefit outweighs the risk, in:

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)].

2 DOSAGE AND ADMINISTRATION

2.1 Adult Patients

The recommended dose for nevirapine is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The 14-day lead-in period with nevirapine 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. For concomitantly administered antiretroviral therapy, the manufacturer’s recommended dosage and monitoring should be followed.

2.2 Pediatric Patients

The recommended oral dose for 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.

Mosteller Formula
(click image for full-size original)
Table 1 Calculation of the Volume of Nevirapine Oral Suspension (50 mg per 5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m2

BSA range (m2)

Volume (mL)

0.06-0.12

1.25

0.12-0.25

2.5

0.25-0.42

5

0.42-0.58

7.5

0.58-0.75

10

0.75-0.92

12.5

0.92-1.08

15

1.08-1.25

17.5

1.25+

20

Nevirapine suspension 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.

2.3 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 at baseline, prior to dose escalation, and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

2.4 Dosage Adjustment

Patients with Rash

Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2)]. Do not increase nevirapine 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.

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