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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)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
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]: 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.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <12 years of age.
Adverse Reactions
>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%)
Postmarketing and/or case reports: Fanconi syndrome, hepatitis, myopathy, nephrotoxicity, osteomalacia
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.
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. Note: Usual treatment duration is at least 1 year and varies with HBeAg status, consult current guidelines and literature.
Dosage adjustment in 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)
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 preexisting real insufficiency detected [Lok, 2007]); viral load; LFTs for several months following discontinuation of adefovir
Dietary Considerations
May be taken without regard to food.
Patient Education
Do not take any new prescription or OTC medications or herbal products during therapy without consulting prescriber. Use appropriate precautions to prevent spread to other persons. Take as directed. Do not discontinue medication without consulting prescriber. You will require frequent blood tests; follow recommended schedule. Maintain adequate hydration unless instructed to restrict fluid intake. You may be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause headache or abdominal pain (consult prescriber for approved analgesia); or nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report unusual bleeding (blood in urine, tarry stools, or easy bruising); unresolved nausea or vomiting; signs of infection (eg, fever, chills, sore throat, burning urination, flu-like symptoms); persistent fatigue; muscle weakness; changes in urinary pattern; or other persistent adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
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 other pharmacological or herbal products patient may be taking for potential interactions or toxicity (especially any nephrotoxic agents). Assess results of laboratory tests, patient response (viral load), and adverse reactions (eg, lactic acidosis, altered hepatic status) on a regular basis throughout therapy. Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as dipivoxil:
Hepsera®: 10 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Hepsera)
10 mg (30): $882.35
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,” Hepatology, 2007, 45(2):507-39.
Lok AS and McMahon BJ, “Corrections to AASLD Guidelines on Chronic Hepatitis B,” Hepatology, 2007, 45(6):1347.
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
Lexi-Comp.com
Last full review/revision July 2009
Content last modified July 2009
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