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Adefovir

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U.S. BRAND NAMES — Hepsera™

PHARMACOLOGIC CATEGORY
Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleoside)

DOSING: ADULTS — Hepatitis B (chronic): Oral: 10 mg once daily. Note: Usual treatment duration is at least 1 year and varies with HBeAg status, consult current guidelines and literature.

DOSING: PEDIATRIC — Hepatitis B (chronic): Oral: Children ≥ 12 years: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — Adult recommendations only (no dosage adjustment recommendations available for patients <18 years with renal impairment):
Clcr ≥ 50 mL/minute: No dosage adjustment necessary
Clcr 30-49 mL/minute: 10 mg every 48 hours
Clcr 10-29 mL/minute: 10 mg every 72 hours

Hemodialysis: 10 mg every 7 days (following dialysis)

DOSING: HEPATIC IMPAIRMENT — No adjustment required.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, as dipivoxil:
Hepsera®: 10 mg

DOSAGE FORMS: CONCISE
Tablet:
Hepsera®: 10 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — May be administered without regard to food.

USE — Treatment of chronic hepatitis B with evidence of active viral replication (based on persistent elevation of ALT/AST or histologic evidence), including patients with lamivudine-resistant hepatitis B

ADVERSE REACTIONS SIGNIFICANT
>10%:
Central nervous system: Headache (24% to 25%)
Gastrointestinal: Abdominal pain (15% to 18%), diarrhea (up to 13%)
Hepatic: Hepatitis exacerbation (up to 25% within 12 weeks of adefovir discontinuation)
Neuromuscular & skeletal: Weakness (13% to 25%)
Renal: Hematuria (grade ≥ 3: 11%)

1% to 10%:
Dermatologic: Rash, pruritus
Endocrine & metabolic: Hypophosphatemia (<2 mg/dL: 1% and 3% in pre-/post-liver transplant patients, respectively)
Gastrointestinal: Flatulence (up to 8%), dyspepsia (5% to 9%), nausea, vomiting
Renal: Serum creatinine increased (≥ 0.5 mg/dL: 2% to 3% in compensated liver disease; incidence may be higher in patients with decompensated cirrhosis or in liver transplant recipients), renal failure
Note: In liver transplant patients with baseline renal dysfunction, frequency of increased serum creatinine has been observed to be as high as 32% to 51% at 48 and 96 weeks post-transplantation, respectively; considering the concomitant use of other potentially nephrotoxic medications, baseline renal insufficiency, and predisposing comorbidities, the role of adefovir in these changes could not be established.
Respiratory: Cough (6% to 8%), rhinitis (up to 5%)

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Postmarketing and/or case reports: Fanconi syndrome, hepatitis, myopathy, nephrotoxicity, osteomalacia

CONTRAINDICATIONS — Hypersensitivity to adefovir or any component of the formulation

WARNINGS / PRECAUTIONS
Boxed warnings: Chronic hepatitis B: . Human immunodeficiency virus (HIV): . Lactic acidosis/hepatomegaly: . Renal impairment: .

Concerns related to adverse effects: Lactic acidosis/hepatomegaly: [U.S Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues, including fatal cases; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, obesity, pregnancy or prolonged exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).

Disease-related concerns: Chronic hepatitis B: [U.S. Boxed Warning]: Severe, acute exacerbation of hepatitis B may occur upon discontinuation. Exacerbations may occur in up to 25% of patients and usually within 12 weeks and may be self-limited or resolve upon resuming treatment; risk may be increased with advanced liver disease or cirrhosis. Monitor liver function several months after stopping treatment; reinitiation of antihepatitis B therapy may be required.

Resistant hepatitis B virus (HBV): In patients with lamivudine-resistant HBV, switching to adefovir was associated with a higher risk of adefovir-resistance compared to adding adefovir to lamivudine therapy (Lok, 2007).
Nonresponse to adefovir monotherapy (<2 log drop in HBV DNA after 6 months of treatment): Consider alternative treatment (Lok, 2007). HIV: [U.S. Boxed Warning]:May cause the development of HIV resistance in chronic hepatitis B patients with unrecognized or untreated HIV infection. Determine HIV status prior to initiating treatment with adefovir. Renal impairment: [U.S. Boxed Warning]: Use with caution in patients with renal dysfunction or in patients at risk of renal toxicity (including concurrent nephrotoxic agents or NSAIDs). Chronic administration may result in nephrotoxicity. Dosage adjustment is required in adult patients with renal dysfunction or in patients who develop renal dysfunction during therapy; no data available for use in children ≥ 12 years or adolescents with renal impairment.

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Special populations: Pediatrics: Safety and efficacy have not been established in children <12 years of age. DRUG INTERACTIONS
Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Hematologic toxicity is of specific concern. Risk D: Consider therapy modification

Ribavirin: May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Lactic acidosis may occur. Risk D: Consider therapy modification

Tenofovir: Adefovir may diminish the therapeutic effect of Tenofovir. Specifically, adefovir-associated mutations in Hepatitis B viral reverse transcriptase may decrease viral susceptibility to tenofovir. Tenofovir may increase the serum concentration of Adefovir. Similarly, Adefovir may increase the concentration of Tenofovir. Risk D: Consider therapy modification

ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: Should be avoided in hepatitis B infection due to potential hepatic toxicity.

Food: Does not have a significant effect on adefovir absorption.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Use in pregnancy only when clearly needed. Pregnant women exposed to adefovir should be registered with the pregnancy registry (800-258-4263).

LACTATION — Excretion in breast milk unknown/not recommended

DIETARY CONSIDERATIONS — May be taken without regard to food.

PRICING — (data from drugstore.com)
Tablets (Hepsera)
10 mg (30): $882.35

MONITORING PARAMETERS — HIV status (prior to initiation of therapy); serum creatinine (prior to initiation and during therapy; every 3 months in patients with medical conditions which predispose to renal insufficiency and in all patients treated for >1 year; more frequent monitoring required if preexisting real insufficiency detected [Lok, 2007]); viral load; LFTs for several months following discontinuation of adefovir

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CANADIAN BRAND NAMES — Hepsera™

INTERNATIONAL BRAND NAMES — Adesera (IN); Hepsera (AR, AT, AU, BE, BG, BR, CH, CL, CN, CO, CR, CZ, DE, DK, DO, ES, FI, FR, GB, GR, GT, HK, HN, ID, IE, IL, IT, KP, NI, NL, NO, PA, PE, PH, PK, PL, PT, RU, SE, SG, SV, TH, TR, TW, VE); Youheding (CL)

MECHANISM OF ACTION — Acyclic nucleotide reverse transcriptase inhibitor (adenosine analog) which interferes with HBV viral RNA-dependent DNA polymerase resulting in inhibition of viral replication.

PHARMACODYNAMICS / KINETICS
Distribution: 0.35-0.39 L/kg

Protein binding: ≤ 4%

Metabolism: Prodrug; rapidly converted to adefovir (active metabolite) in intestine

Bioavailability: 59%

Half-life elimination: 7.5 hours; prolonged in renal impairment

Time to peak: 1.75 hours

Excretion: Urine (45% as active metabolite within 24 hours)

PATIENT INFORMATION — Not a cure for hepatitis B, nor will it reduce the risk of transmission. Report persistent lethargy, acute headache, severe nausea or vomiting, difficulty breathing, loss of sensation, or rash. Do not discontinue unless instructed by prescriber; additional monitoring is required after discontinuation to ensure the disease does not recur.

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