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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(a DEF o veer)

Generic Available (U.S.)

No

Index Terms

• Adefovir Dipivoxil
• Bis-POM PMEA

Brand Names: U.S.

• Hepsera®

Brand Names: Canada

• Hepsera™

Pharmacologic Category

• Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleotide)

Pharmacologic Category Synonyms

• Nucleotide Reverse Transcriptase Inhibitor
• Reverse Transcriptase Inhibitor, Nucleotide

Use: Labeled Indications

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

Pregnancy Risk Factor

C

Pregnancy Considerations

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

Contraindications

Hypersensitivity to adefovir or any component of the formulation

Warnings/Precautions

Boxed warnings:

• Chronic hepatitis B: See “Disease-related concerns” below.

• Human immunodeficiency virus (HIV): See “Disease-related concerns” below.

• Lactic acidosis/hepatomegaly: See “Concerns related to adverse effects” below.

• Renal impairment: See “Disease-related concerns” below.

Concerns related to adverse effects:

• Lactic acidosis/hepatomegaly: [U.S Boxed Warning]: Fatal cases of lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals; 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.

• 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. Calculation of creatinine clearance in all patients is recommended prior to initiating therapy.

Concurrent drug therapy:

• Tenofovir: Do not use concurrently with tenofovir (Viread®) or any product containing tenofovir (eg, Truvada®, Atripla®, Complera®).

Special populations:

• Pediatrics: Safety and efficacy have not been established in children <12 years of age.

Other warnings/precautions:

• Appropriate use: Not recommended as first line therapy of chronic HBV due to weak antiviral activity and high rate of resistance after first year. May be more appropriate as second-line agent in treatment-naïve patients. Combination therapy with lamivudine in nucleoside-naïve patients has not been shown to provide synergistic antiviral effects. However, in patients with lamivudine-resistant HBV, switching to adefovir monotherapy was associated with a higher risk of adefovir resistance compared to adding adefovir to lamivudine therapy (Lok, 2009).

Adverse Reactions

>10%:

Central nervous system: Headache (24% to 25%)

Gastrointestinal: Abdominal pain (15%), diarrhea (up to 13%)

Hepatic: Hepatitis exacerbation (up to 25% within 12 weeks of adefovir discontinuation)

Neuromuscular & skeletal: Weakness (up 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

Neuromuscular & skeletal: Back pain (up to 10%)

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%)

Postmarketing and/or case reports: Fanconi syndrome, hepatitis, myopathy, nephrotoxicity, osteomalacia, pancreatitis, proximal renal tubulopathy

Metabolism/Transport Effects

None known.

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. Adefovir may increase the serum concentration of Tenofovir. Tenofovir may increase the serum concentration of Adefovir. Risk X: Avoid combination

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.

Storage

Store controlled room temperature of 25°C (77°F).

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)

Dosage

Oral: Children ≥12 years and Adults: 10 mg once daily

Treatment duration (AASLD practice guidelines): Adults:

Hepatitis Be antigen (HBeAg) positive chronic hepatitis: Treat ≥1 year until HBeAg seroconversion and undetectable serum HBV DNA; continue therapy for ≥6 months after HBeAg seroconversion

HBeAg negative chronic hepatitis: Treat >1 year until hepatitis B surface antigen (HBsAg) clearance

Note: Patients not achieving a <2 log decrease in serum HBV DNA after at least 6 months of therapy should either receive additional treatment or be switched to an alternative therapy (Lok, 2009).

Dosage adjustment in renal impairment: Adult recommendations only (no dosage adjustment recommendations available for patients <18 years with renal impairment):

Cl_cr ≥50 mL/minute: No dosage adjustment necessary

Cl_cr 20-49 mL/minute: 10 mg every 48 hours

Cl_cr 10-19 mL/minute: 10 mg every 72 hours

Hemodialysis: 10 mg every 7 days (following dialysis)

Dosage adjustment in hepatic impairment: No adjustment required

Administration: Oral

May be administered without regard to food.

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 pre-existing real insufficiency detected [Lok, 2009]); LFTs for several months following discontinuation of adefovir; HBV DNA (every 3-6 months during therapy); HBeAg and anti-HBe

Dietary Considerations

May be taken without regard to food.

Patient Education

Use appropriate precautions to prevent spread to other persons. You will require frequent blood tests; follow recommended schedule. Maintain adequate hydration, unless instructed to restrict fluid intake. May cause headache, abdominal pain, diarrhea, or weakness. Report unusual bleeding (blood in urine, tarry stools, or easy bruising), unresolved diarrhea, signs of infection (eg, fever, chills, sore throat, burning urination, flu-like symptoms), persistent fatigue, muscle weakness, or changes in urinary pattern.

Additional Information

Adefovir dipivoxil is a prodrug, rapidly converted to the active component (adefovir). It was previously investigated as a treatment for HIV infections (at dosages substantially higher than the approved dose for hepatitis B). The NDA was withdrawn, and no further studies in the treatment of HIV are anticipated (per manufacturer).

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

Chronic administration may cause nephrotoxicity. In patients receiving lithium, gabapentin, or levetiracetam, a dosage adjustment may be needed; monitor.

Nursing: Physical Assessment/Monitoring

Use with caution in presence of renal dysfunction or risk of renal toxicity. Assess viral load. Monitor for lactic acidosis and altered hepatic status on a regular basis throughout therapy.

Dosage Forms

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

Tablet, oral, as dipivoxil:

Hepsera®: 10 mg

Pricing: U.S. (www.drugstore.com)

Tablets (Hepsera)

10 mg (30): $1056.04

References

Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al, “Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen-Negative Chronic Hepatitis B,” N Engl J Med, 2003, 348(9):800-7.

Lok AS and McMahon BJ, “Chronic Hepatitis B: Update 2009,” Hepatology, 2009, 50(3):661-2.

Marcellin P, Chang T-T, Lim SG, et al, “Adefovir Dipivoxil for the Treatment of Hepatitis B e Antigen-Positive Chronic Hepatitis B,” N Engl J Med, 2003, 348(9):808-16.

International Brand Names

• Adepam (KP)
• Adeptin (KP)
• Adesera (IN)
• Adesil (KP)
• Adevir (KP)
• Afoliva (KP)
• Baihepa (KP)
• Everhepa (KP)
• Hepovir (PK)
• Hepsera (AR, AT, AU, BE, BG, BR, CH, CL, CN, CO, CR, CZ, DE, DK, DO, EE, ES, FI, FR, GB, GR, GT, HK, HN, ID, IE, IL, IT, KP, MT, MY, NI, NL, NO, NZ, PA, PE, PH, PK, PL, PT, RU, SE, SG, SK, SV, TH, TR, TW, VE)
• Hepssel (KP)

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Last full review/revision March 2012

Content last modified March 2012