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Adefovir

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Adefovir

Copyright 1978-2011 Lexicomp, Inc. All rights reserved.

Brand Names: U.S.

  • Hepsera®
Brand Names: Canada

  • Hepsera™
Pharmacologic Category

  • Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleotide)
Dosing: AdultHepatitis B (chronic): Oral: 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 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).

Dosing: PediatricHepatitis B (chronic): Children ≥12 years: Oral: 10 mg once daily

Dosing: GeriatricRefer to adult dosing.

Dosing: Renal ImpairmentAdult recommendations only (no dosage adjustment recommendations available for patients <18 years with renal impairment):

Clcr ≥50 mL/minute: No dosage adjustment necessary

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

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

Hemodialysis: 10 mg every 7 days (following dialysis)

Dosing: Hepatic ImpairmentNo adjustment required.

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral, as dipivoxil:

Hepsera®: 10 mg

Generic Equivalent Available: U.S.No

AdministrationMay be administered without regard to food.

UseTreatment 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%), 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

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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

ContraindicationsHypersensitivity to adefovir or any component of the formulation

Warnings/PrecautionsBoxed 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.

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• 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®).

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).

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 InteractionsEthanol: Should be avoided in hepatitis B infection due to potential hepatic toxicity.

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

Pregnancy Risk FactorPregnancy Implications

LactationExcretion in breast milk unknown/not recommended

Dietary ConsiderationsMay be taken without regard to food.

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

10 mg (30): $1013.97

Monitoring ParametersHIV 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

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)
Mechanism of ActionAcyclic nucleotide reverse transcriptase inhibitor (adenosine analog) which interferes with HBV viral RNA-dependent DNA polymerase resulting in inhibition of viral replication.

Pharmacodynamics/KineticsDistribution: 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)

REFERENCES
  1. 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. [PubMed 12606734]
  2. Lok AS and McMahon BJ, “Chronic Hepatitis B: Update 2009,” Hepatology, 2009, 50(3):661-2. [PubMed 19714720]
  3. 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. [PubMed 12606735]
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