Jane S. Ricciuti, RPh, MS


October 23, 2002

In This Article

Antiviral Agents

(adefovir dipivoxil) Tablets

Manufacturer: Gilead Sciences, Inc

Drug Approval Classification: Original New Drug Application (Approval Date: 9/20/02)

Indication: Hepsera (adefovir dipivoxil) is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on histologic, virologic, biochemical, and serologic responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

Dosing: Hepsera in chronic hepatitis B patients with normal renal function is dosed at 10 mg once daily. The optimal duration of therapy is unknown.

Dose adjustment is necessary for patients with renal impairment (see Table).

Clinical Summary: Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analogue with activity against human hepatitis B virus (HBV). Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA.

Hepsera 10 mg was studied in HBeAg-positive chronic hepatitis B patients in a randomized, double-blind, placebo-controlled, 3-arm study. Hepsera was associated with a 53% histologic improvement, defined as a 2-point decrease in the Knodell necro-inflammatory score with no worsening of the Knodell fibrosis score. Placebo-controlled patients showed an improvement of 25%. No improvement was seen in 37% of Hepsera-treated patients vs in 67% of placebo patients.

In patients with HBeAg-negative (anti-HBe positive/HBV DNA positive) chronic hepatitis B, Hepsera demonstrated a 64% histologic improvement vs a 35% improvement in the placebo group in a randomized, double-blind, placebo-controlled study. No improvement was seen in 29% and 63% of Hepsera vs placebo patients, respectively.

In both HBeAg-positive and HBeAg-negative chronic hepatitis B patients, treatment was continued to 72 weeks with continued maintenance of mean reductions in HBV DNA observed at week 48.

The FDA is requiring Gilead Sciences, Inc. to conduct postmarketing studies. Some of the postmarketing commitments include obtaining 5-year long-term follow-up information from the submitted pivotal clinical trials to address the following factors: maintenance of virologic suppression; durability of HBeAg and HBsAg seroconversion and the rate of new events; risk of drug-related adverse effects, particularly nephrotoxicity; and risk for development of HBV resistance to adefovir. Other required studies are being conducted to determine the optimal dosing in renally impaired patients and pharmacokinetic data in nonwhite patients.

Warnings: Hepsera labeling contains significant warnings for acute exacerbations of hepatitis upon discontinuation, potential for nephrotoxicity in chronic administration, HIV resistance, and lactic acidosis and severe hepatomegaly.

Adverse Effects: The incidence of treatment-related adverse events observed in the pivotal trials include asthenia (13%), headache (9%), abdominal pain (9%), nausea (5%), flatulence (4%), diarrhea (3%), and dyspepsia (3%).

Pharmacokinetics: The peak adefovir plasma concentration (Cmax) was 18.4 ng/mL and occurred between 0.58 and 4.00 hours. The adefovir area under the plasma concentration-time curve (AUC) was 220 ng*h/mL. Food does not affect adefovir exposure. Adefovir is eliminated by the kidney.

In patients with moderately or severely impaired renal function or with end-stage renal disease requiring hemodialysis, Cmax, AUC, and half-life (T1/2) were increased compared with subjects with normal renal function. It is recommended that the dosing interval of Hepsera be modified in these patients (see Dosing).

Adefovir does not inhibit any of the common human CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The potential for adefovir to induce CYP450 enzymes is unknown.

Hepsera (adefovir dipivoxil) labeling.


Manufacturer: GlaxoSmithKline

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 9/9/02)

New Indication: Valtrex (valacyclovir) is indicated for the treatment of cold sores (herpes labialis) in adult and adolescent patients 12 years of age and older.

Prior to this supplemental indication, Valtrex was indicated for the treatment of herpes zoster and the treatment or suppression of genital herpes.

Dose: For the treatment of cold sores (herpes labialis), the recommended dose is 2 g twice daily for 1 day initiated at the earliest symptoms of a cold sore (eg, tingling, itching, or burning).

Clinical Summary: Valtrex was evaluated in 2 double-blind, placebo-controlled studies in 1856 subjects with a history of recurrent cold sores. Valtrex 2 g twice daily for 1 day was compared with placebo. The mean duration of the cold sore was about 1 day shorter with Valtrex than with placebo.

Adverse Effects: No new adverse effects have been reported. The most common side effects are headache, nausea, and abdominal pain.

Valtrex (valacyclovir) Letter

Valtrex (valacyclovir)


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