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Accelerated Approval of Nevirapine

July 1996

Nevirapine was reviewed by the FDA Antiviral Drugs Advisory Committee on June 7, 1996. The Committee voted approval 8-0. When The Hopkins HIV Report went to press, the FDA had not yet cleared the accelerated approval of nevirapine, but the prior experience suggests this drug may be FDA-approved by the end of June. The following is a review of nevirapine:

  • Trade name (source): Viramune (Boehringer Ingelheim)
  • Form: 200 mg tabs
  • Price: (Not known)
  • Regimens: 200 mg po qd x 2 weeks, then 200 mg po bid.

Nevirapine must be used in combination with nucleoside analogues such as AZT (200 mg po bid) or ddC (0.75 mg tid). The greatest experience is with a) Nevirapine + AZT; b) Nevirapine + AZT + ddI; c) Nevirapine + AZT + ddC; experience is limited for Nevirapine + 3TC or d4T; protease inhibitors should not be given in combination with nevirapine.

Highlights of FDA presentation

  1. In vitro activity is excellent: the usual levels achieved (4-5 ug/ml) are 300-400x the IC50 levels (0.01 ug/ml). Strains resistant to nucleoside analogues are susceptible to nevirapine.
  2. The major side effect is rash - noted in 18% of all patients and sufficiently severe to require discontinuation of treatment in 6%. The cause of the rash is unknown.
  3. The pharmacokinetic profile is excellent - 90% absorption, minimal GI intolerance and low pill burden (2 tabs/day).
  4. Penetration across the blood brain barrier is excellent.
  5. Resistance is a major problemþresistance occurs early (within 2-8 weeks with monotherapy), it is high level, and multiple mutations are responsible (codons 103, 106, 108, 181, 188 and 190). Resistance is accompanied by return of CD4 count and HIV RNA levels to baseline, and it is unrelated to stage of disease or viral burden.
  6. Efficacy (based on studies in 1700 patients): Optimal results when NVP is combined with nucleoside analogues that have not been previously used. Compliance is critical: The drug should have durable effects if replication rates are consistently so low that mutations are rare.
Results of trials*
TrialNo.RegimenCD4 countHIV RNA
24 wks48 wks24 wks48 wks
ACTG
241
398NVP + AZT +ddI (exp)
AZT + ddI (exp)
+60
+5
+25
+3
-0.85
-0.52
-0.62
-0.26
103760NVP + AZT (exp)
AZT (exp)
+26
-20
---
---
0
+0.1
---
---
1046151NVP + AZT + ddI (naive)**
AZT + ddI (naive)
NVP + AZT (naive)
+90
+95
+30
---
---
---
-1.6
-1.3
-0.4
---
---
---

* Exp = nucleoside analogue experienced. CD4 reported as mean/ml above baseline. HIV RNA reported as mean/ml above baseline

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** 70% had no detectable HIV RNA by PCR (

Pharmacology

Bioavailability: >90%, not influenced by food

T½ (post induction): 25-30 hrs; CNS penetration: 50-60% of serum levels

Elimination: Induces cytochrome p450 (auto-induction) to reduce nevirapine levels

steady state achieved at 4 wks; gluconaride metabolite excreted in urine.

Side effects:

Rash in 18% - morbilliform and pruritic usually on trunk and extremities; most are noted during first 4 wks of therapy; dose related: 59% with 400 mg/day without lead-in; 18% with 400 mg/day after 200 mg/day x 2 wks; 9% with 200 mg/day. Stevens Johnson syndrome - 0.5%

Note: Rash during lead-in phase: delay full dose.

Rash during maintenance dose: treat through - most resolve;

Discontinue if rash is severe or is accompanied by systemic complications - fever, fatigue, etc.

Drug interactions:

No drug interactions noted with AZT, ddI or ddC

Induction of cytochrome p450 to produce action similar to rifampin, but weaker




  
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This article was provided by Johns Hopkins AIDS Service. It is a part of the publication Hopkins HIV Report.
 

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