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Product Name
:
HEPSOVIR
Chemical Name
:
Adefovir
Therapeutic Category
:
Antifungal drugs & Antiviral drugs
Pharmacologic Category
:
Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleotide)
Pharmaceutical Form
:
Tablets
Composition
:
Adefovir 10mg
Dosing
 
Dosing: Adult

Hepatitis 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 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).

Dosing: Pediatric

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

Dosing: Geriatric

Refer to adult dosing.


Dosing: 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

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
 

>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

Contraindications
 
Hypersensitivity to adefovir or any component of the formulation
Warnings / Precautions Drug
 

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).

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.

Pregnancy
 
Pregnancy Risk Factor

C

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
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

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)

 
   
 
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