Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti–hepatitis B therapy, including adefovir. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who discontinue anti–hepatitis B therapy. If appropriate, resumption of anti–hepatitis B therapy may be warranted.
In patients at risk of or having underlying renal dysfunction, long-term administration of adefovir may result in nephrotoxicity. Closely monitor renal function in these patients; they may require dose adjustment.
HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection treated with anti–hepatitis B therapies that may have activity against HIV (eg, adefovir).
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.
Hepatitis B, chronic:
Note: Adefovir is not preferred in the management of chronic hepatitis B due to high rate of resistance with long-term use (AASLD [Terrault 2018]); other guidelines do not recommend adefovir therapy (EASL 2017). Other antiviral agents with a high barrier to drug resistance are preferred (eg, tenofovir, entecavir) (AASLD [Terrault 2018]; EASL 2017).
Oral: 10 mg once daily; may be used as part of a combination regimen (concurrent use with tenofovir should be avoided) (AASLD [Terrault 2018]).
Treatment duration: Treatment duration is variable and influenced by hepatitis B e antigen (HBeAg) status, duration of HBV suppression, and presence of cirrhosis/decompensation (AASLD [Terrault 2018):
Patients without cirrhosis:
Hepatitis B e antigen positive (HBeAg-positive) immune-active chronic hepatitis: Treat until HBeAg seroconversion; after seroconversion, prolonged duration of therapy is often required in patients treated with nucleos(t)ide analogues. Optimal duration is unknown; however, consolidation therapy is generally a minimum of 12 months of persistently normal ALT and undetectable serum HBV DNA levels after HBeAg seroconversion if patient can be closely monitored. An alternative approach is to treat until hepatitis B surface antigen (HBsAg) loss (AASLD [Terrault 2018]; EASL 2017).
HBeAg-negative immune-active chronic hepatitis: Indefinite antiviral therapy is suggested unless there is competing rationale for discontinuation (risk/benefit decision); treatment discontinuation may be considered in patients with loss of HBsAg who have achieved long-term (≥3 years) virologic suppression; however, there is insufficient evidence to guide decisions in these patients (AASLD [Terrault 2018]; EASL 2017).
Patients with cirrhosis:
HBeAg-positive immune-active chronic hepatitis: In patients who seroconvert on therapy, continue antiviral therapy indefinitely due to concerns with decompensation and death, unless there is a strong competing rationale for discontinuation (AASLD [Terrault 2018]; EASL 2017).
HBeAg-negative immune-active chronic hepatitis: Treatment discontinuation is not recommended due to potential for decompensation and death (limited data) (AASLD [Terrault 2018]; EASL 2017).
Viral breakthrough: Patients with confirmed viral breakthrough (HBV DNA ≥100 IU/mL with previously undetectable levels [<10 IU/mL] or >1 log increase in HBV DNA) should either be switched to an alternative antiviral monotherapy agent with a high genetic barrier to resistance or receive a second antiviral agent with a complementary resistance profile; consult current clinical practice guidelines for recommended agents (AASLD [Terrault 2018]).
CrCl ≥50 mL/minute: No dosage adjustment necessary.
CrCl 30 to 49 mL/minute: 10 mg every 48 hours.
CrCl 10 to 29 mL/minute: 10 mg every 72 hours.
CrCl <10 mL/minute (nonhemodyalisis): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Hemodialysis: Dialyzable (~35%): 10 mg every 7 days (following dialysis)
No dosage adjustment necessary.
(For additional information see "Adefovir: Pediatric drug information")
Hepatitis B infection, chronic: Note: Optimal duration of treatment not established, continuation of therapy for at least 12 months after seroconversion has been suggested. Prolonged therapy (up to 4 years) has been reported to be safe and well-tolerated in pediatric patients (2 to 18 years). 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 (AASLD [Terrault 2016]; Jonas 2012; Lok 2009).
Children 2 to <7 years: Limited data available; efficacy results variable: Oral: 0.3 mg/kg/dose once daily; maximum dose: 10 mg (Jonas 2008; Jonas 2012)
Children ≥7 to <12 years: Limited data available; efficacy results variable: Oral: 0.25 mg/kg/dose once daily; maximum dose: 10 mg (Jonas 2008; Jonas 2012)
Children ≥12 years and Adolescents: Oral: 10 mg once daily; in HIV-exposed/-infected patients not requiring combination antiretroviral therapy or receiving a lamivudine- or emtricitabine-containing HIV-suppressive regimen, adefovir may be considered as HBV alternate therapy (interferon is preferable) (HHS [pediatric 2016])
Children ≥12 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; no data available; consider dosage reduction.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral, as dipivoxil:
Hepsera: 10 mg [DSC]
Generic: 10 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as dipivoxil:
Hepsera: 10 mg
Generic: 10 mg
Oral: Administer without regard to food.
Oral: May be administered without regard to food.
Hepatitis B, chronic: Treatment of chronic hepatitis B in patients ≥12 years of age with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. Note: Adefovir is not preferred in the management of chronic hepatitis B due to high rate of resistance with long-term use (AASLD [Terrault 2018]); other guidelines do not recommend adefovir therapy (EASL 2017). Other antiviral agents with a high barrier to drug resistance are preferred (eg, tenofovir, entecavir) (AASLD [Terrault 2018]; EASL 2017).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
In liver transplant recipients 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.
>10%:
Central nervous system: Headache (24% to 25%)
Gastrointestinal: Abdominal pain (15%), diarrhea (≤13%)
Genitourinary: Hematuria (grade ≥3: 11%)
Hepatic: Hepatitis (exacerbation; ≤25% within 12 weeks of adefovir discontinuation)
Neuromuscular & skeletal: Weakness (≤25%)
1% to 10%:
Dermatologic: Pruritus, skin rash
Endocrine & metabolic: Hypophosphatemia (<2 mg/dL: 1% and 3% in pre-/post-liver transplant patients, respectively)
Gastrointestinal: Flatulence (≤8%), dyspepsia (5% to 9%), nausea, vomiting
Neuromuscular & skeletal: Back pain (≤10%)
Renal: Increased serum creatinine (≥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
Respiratory: Cough (6% to 8%), rhinitis (≤5%)
<1%, postmarketing, and/or case reports: Fanconi's syndrome, hepatitis, myopathy, nephrotoxicity, osteomalacia, pancreatitis, proximal tubular nephropathy
Hypersensitivity to adefovir or any component of the formulation.
Disease-related concerns:
• Renal impairment: 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 of age or adolescents with renal impairment.
Concurrent drug therapy:
• Tenofovir: Do not use concurrently with tenofovir (tenofovir disoproxil fumarate or tenofovir alafenamide) or any tenofovir-containing product.
Efficacy in pediatric patients <12 years has not been reported; in clinical trials of children 2 to 12 years, positive responses to adefovir therapy were observed (13% to 17% of subjects evaluated); however, findings did not reach statistical significance (Jonas 2008).
Substrate of OAT1/3; Inhibits MRP2
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ataluren: May increase the serum concentration of Adefovir. Risk C: Monitor therapy
Betibeglogene Autotemcel: Antiretroviral Agents may diminish the therapeutic effect of Betibeglogene Autotemcel. Risk X: Avoid combination
Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Risk C: Monitor therapy
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Elivaldogene Autotemcel: Antiretroviral Agents may diminish the therapeutic effect of Elivaldogene Autotemcel. Management: Avoid use of antiretroviral medications for at least one month, or for the amount of time required for elimination of the retroviral medication, prior to stem cell mobilization and until the all apheresis cycles are finished Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Management: Avoid use of fexinidazole with OAT1/3 substrates when possible. If combined, monitor for increased OAT1/3 substrate toxicities. Risk D: Consider therapy modification
Leflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Nitisinone: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Orlistat: May decrease the serum concentration of Antiretroviral Agents. Risk C: Monitor therapy
Pretomanid: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk X: Avoid combination
Tenofovir Products: Adefovir may diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Risk X: Avoid combination
Teriflunomide: May increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Food does not have a significant effect on adefovir absorption. Management: Administer without regard to meals.
Treatment for hepatitis B should be evaluated prior to pregnancy. Adefovir is not recommended for use in pregnant patients (AASLD [Terrault 2018]; EASL 2017).
Outcome data following maternal or paternal use of adefovir during pregnancy is limited (Funk 2021; Gao 2022; Gu 2014; Yang 2022; Yi 2012). Agents other than adefovir are recommended when hepatitis B treatment is needed in pregnant patients. Patients who become pregnant while taking adefovir should be switched to the preferred agent (AASLD [Terrault 2018]; EASL 2017).
Data collection to monitor pregnancy and infant outcomes following exposure to adefovir is ongoing. Health care providers are encouraged to enroll patients exposed to adefovir during pregnancy in the Hepsera pregnancy registry (800-258-4263).
It is not known if adefovir is present in breast milk.
Patients requiring antivirals for hepatitis B may breastfeed if the infant received immunoprophylaxis at birth; however, recommendations are not specific to adefovir and other agents may be preferred (AASLD [Terrault 2018]; EASL 2017; SMFM 2016). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
HIV status, CrCl (prior to initiation of therapy), HBV DNA and ALT (HBV DNA usually done every 3 months until undetectable and then every 3 to 6 months thereafter); HBeAg; anti-HBe (in patients who are HBeAg-positive to monitor for seroconversion); HBsAg; if at risk for renal impairment, CrCl, serum phosphate, urine glucose, and urine protein at baseline and at least annually; consider monitoring bone density in patients with risk factors for osteopenia or fracture history (prior to initiation and during therapy); lactic acid levels especially in patients with kidney dysfunction; following discontinuation, monitor for recurrent viremia, ALT flares, seroreversion, and clinical decompensation every 3 months for at least 1 year. Monitor for development of hepatocellular carcinoma as clinically indicated (ie, prolonged viremia, hepatitis C virus co-infection or cirrhosis) (AASLD [Terrault 2018]; EASL 2017; manufacturer’s labeling).
Acyclic nucleotide reverse transcriptase inhibitor (adenosine analog) which interferes with HBV viral RNA-dependent DNA polymerase resulting in inhibition of viral replication.
Note: Pharmacokinetic data reported in pediatric patients (12-18 years) similar to reported adult data.
Distribution: 0.35 to 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: Median: 1.75 hours (range: 0.58 to 4 hours)
Excretion: Urine (45% as active metabolite within 24 hours); Dialysis: ~35% of dose (10 mg) removed during 4 hours hemodialysis session
Altered kidney function: Cmax and AUC increased in those with moderate or severe renal function impairment or with end-stage renal disease.
Tablets (Adefovir Dipivoxil Oral)
10 mg (per each): $37.89
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
