DIRA 1.0: Atlas of Drug-induced Rhabdomyolysis

NEVIRAPINE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Less-DIR concern

Severity Score:1

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

WARNINGS AND PRECAUTIONS
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. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received Nevirapine 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 Nevirapine 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 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.
Skin Reaction
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 Nevirapine use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of Nevirapine 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 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)].
Therapy with Nevirapine must be initiated with a 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients), which 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 increase Nevirapine dose to a patient experiencing a 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. 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 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, 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.
ADVERSE REACTIONS
Post-Marketing Experience
In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of 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.
In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

Rhabdomyolysis

42868

Other ADRs

9096

14108183

Odds Ratio = 1.592

Drug Property Information

ATC Code(s):

J05AR05 - nevirapine

J05AR - "Antivirals for treatment of HIV infections, combinations"
J05A - DIRECT ACTING ANTIVIRALS
J05 - ANTIVIRALS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

J05AG01 - nevirapine

J05AG - Non-nucleoside reverse transcriptase inhibitors
J05A - DIRECT ACTING ANTIVIRALS
J05 - ANTIVIRALS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

J05AR07 - nevirapine

J05AR - "Antivirals for treatment of HIV infections, combinations"
J05A - DIRECT ACTING ANTIVIRALS
J05 - ANTIVIRALS FOR SYSTEMIC USE
J - ANTIINFECTIVES FOR SYSTEMIC USE

Active Ingredient:nevirapine

Active Ingredient UNII:99DK7FVK1H

Drugbank ID:DB00238

PubChem Compound:4463

CAS Number:129618-40-2

Dosage Form(s):tablet

Route(s) Of Administrator:oral

Daily Dose:

400.0 mg/day J05AG01

Chemical Structure:

SMILE Code:
CC1=C2C(=NC=C1)N(C3=C(C=CC=N3)C(=O)N2)C4CC4

Reference

COHORT STUDY:

N/A

OTHER REFERENCE(S):

1: No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database.

[Napoli Andrew A,Wood Jennifer J,Coumbis John J,Soitkar Amit M,Seekins Daniel W,Tilson Hugh H]
J Int AIDS Soc.2014 Sep 4;17:19214. doi: 10.7448/IAS.17.1.19214. eCollection 2014. PMID: 25192857

2: From the Centers for Disease Control and Prevention. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures--worldwide, 1997-2000.

JAMA.2001 Jan 24-31;285(4):402-3. PMID: 11263401

3: Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures--worldwide, 1997-2000.

[Centers for Disease Control and Prevention (CDC)]
MMWR Morb Mortal Wkly Rep.2001 Jan 5;49(51-52):1153-6. PMID: 11198946

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