Adefovir Dipivoxil

Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: [[[2-(6-Amino-9-H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene) ester 2,2-dimethyl propanoic acid
Molecular Formula: C20H32N5O8P
CAS Number: 142340-99-6
Brands: Hepsera

Warning(s)

  • Severe acute exacerbations of hepatitis may occur in patients who discontinue adefovir.1 (See Exacerbations of Hepatitis under Cautions.) Closely monitor hepatic function in such patients.1

  • In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir may result in nephrotoxicity.1 Closely monitor renal function in such patients; dosage adjustments may be required.1

  • HIV resistance may emerge in chronic HBV patients who have unrecognized or untreated HIV infection.1 (See Individuals Coinfected with HBV and HIV under Cautions.)

  • Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs.1 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

Introduction

Antiviral; acyclic nucleotide.1

Uses for Adefovir Dipivoxil

Chronic Hepatitis B Virus (HBV) Infection

Treatment of chronic HBV infection in adults and adolescents ≥12 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransferases (ALT or AST) or histologic evidence of active disease.1 The relationship between treatment response (histologic, virologic, biochemical, serologic) to adefovir and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis is not known.1

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May be effective in HBeAg-positive patients;1 3 23 HBeAg-negative (anti-HBe- and HBV-DNA-positive) patients;1 4 11 16 and pre- and post-liver transplantation patients.1 11 16 21

May be effective in patients with lamivudine-resistant HBV.1 8 11 18

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.9

Adefovir Dipivoxil Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.1

Dosage

Available as adefovir dipivoxil; dosage expressed in terms adefovir dipivoxil.1

Pediatric Patients

Chronic Hepatitis B Virus (HBV) Infection
Oral

Adolescents 12–17 years of age: 10 mg once daily.1

Optimal duration of treatment unknown.1 9 Has been continued for up to 5 years in adults in controlled clinical studies.1 12 17

Adults

Chronic Hepatitis B Virus (HBV) Infection
Oral

10 mg once daily.1

Optimal duration of treatment unknown.1 9 Has been continued for up to 5 years in adults in controlled clinical studies.1 12 17

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in hepatic impairment.1 5

Renal Impairment

Decrease dosage in adults with baseline Clcr <50 mL/minute.1

Dosage for Adults with Renal Impairment1

Clcr (mL/min)

Dosage

30–49

10 mg once every 48 hours

10–29

10 mg once every 72 hours

<10 (not undergoing hemodialysis)

Dosage recommendations not available

Hemodialysis patients

10 mg once every 7 days following dialysis

These dosage guidelines for adults with renal impairment have not been clinically evaluated.1 In addition, these dosages were derived from data involving patients with preexisting renal impairment and may not be appropriate for those in whom renal impairment evolves during adefovir therapy.1 Closely monitor clinical response and renal function.1

Safety and efficacy not studied in adolescents with renal impairment.1 Data insufficient to make dosage recommendations for adolescents 12–17 years of age with underlying renal impairment;1 use caution and closely monitor renal function.1

Cautions for Adefovir Dipivoxil

Contraindications

  • Known hypersensitivity to adefovir or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Clinical and laboratory evidence of severe acute exacerbations of hepatitis have occurred following discontinuance of HBV therapy, including adefovir therapy.1

Exacerbations of hepatitis (ALT elevations at least 10 times the ULN) reported in up to 25% of patients following discontinuance of adefovir, usually within 12 weeks after discontinuance.1 These exacerbations generally occurred in the absence of HBeAg seroconversion and presented as elevations in ALT and reemergence of viral replication.1

Although these exacerbations may be self-limited or resolve with reinitiation of therapy, severe exacerbations (including fatalities) have been reported.1

In patients with compensated liver function, exacerbations have not generally been accompanied by hepatic decompensation.1 However, patients with advanced liver disease or cirrhosis may be at higher risk for hepatic decompensation than those with compensated liver function.1

Closely monitor hepatic function at repeated intervals with both clinical and laboratory follow-up for several months or longer after adefovir is discontinued.1 If appropriate, resumption of anti-HBV therapy may be warranted.1

Nephrotoxicity

Nephrotoxicity, characterized by a delayed onset, is the principal dose-limiting toxicity of adefovir and also may occur in patients receiving chronic (long-term) therapy with recommended dosage of the drug.1

Delayed onset of gradual increases in serum creatinine and decreases in serum phosphorus were the treatment-limiting toxicities of adefovir in clinical studies evaluating use of high dosages for treatment of HIV infection (60 or 120 mg daily) or use of high dosages for treatment of chronic HBV infection (30 mg daily).1

Long-term administration in dosages recommended for the treatment of HBV infection (10 mg daily) also may result in delayed nephrotoxicity.1 By week 96 or week 240, 2 or 3% of patients who received adefovir had serum creatinine increases of ≥0.5 mg/dL from baseline (by Kaplan Meier estimates), respectively.1

In pre- or post-liver transplantation patients receiving the usually recommended dosage (10 mg daily), most of whom had some degree of baseline renal insufficiency, 37 or 32% had increases in serum creatinine concentrations of 0.3 mg/dL or greater from baseline by week 48, respectively, and 53 or 51% had serum creatinine increases of 0.3 mg/dL or greater from baseline by week 96, respectively.1

Although overall risk of nephrotoxicity is low in patients with adequate renal function, consider possibility of nephrotoxicity in patients at risk of or having underlying renal dysfunction and in those receiving concomitant therapy with nephrotoxic agents.1 (See Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion under Interactions.)

Closely monitor renal function in all patients receiving adefovir, especially those with preexisting renal impairment or other risks for renal impairment.1 Dosage adjustments may be necessary.1 (See Renal Impairment under Dosage and Administration.)

Individuals Coinfected with HBV and HIV

Use of adefovir for the treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV resistance.1 Although adefovir has in vitro activity against HIV,22 dosage of the drug used for treatment of HBV infection (10 mg daily) has not been shown to suppress HIV RNA levels in HIV-infected patients.1 14 16

Offer HIV antibody testing to all patients prior to initiating adefovir.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.1

Nucleoside analogs should be used with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.1

Discontinue adefovir in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).1

Clinical Resistance

Resistance to adefovir may result in viral load rebound of HBV, which may lead to exacerbation of HBV infection; if the patient has impaired hepatic function, this may lead to liver decompensation and death.1

To reduce risk of clinical resistance in patients with lamivudine-resistant HBV, use adefovir in conjunction with lamivudine; do not use adefovir monotherapy1 9

Patients with serum HBV DNA levels >1000 copies/mL after 48 weeks of adefovir treatment are at greater risk of developing clinical resistance.1 To reduce risk of clinical resistance in patients receiving monotherapy with the drug, consider treatment modification if serum HBV DNA levels remain >1000 copies/mL with continued treatment.1

Specific Populations

Pregnancy

Category C.1

Pregnancy registry at 800-258-4263.1

Data not available regarding the effect of adefovir therapy during pregnancy on transmission of HBV to the infant;1 such infants should receive HBV vaccine according to the usual childhood immunization schedule to prevent neonatal acquisition of HBV.1

Lactation

Not known whether adefovir is distributed into milk.1 Discontinue nursing or drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Renal Impairment

Dosage adjustments recommended for adults if Clcr <50 mL/minute.1 5 (See Renal Impairment under Dosage and Administration.)

Has not been evaluated in adolescents 12–17 years of age with renal impairment.1 Use caution in such adolescents and monitor renal function closely.1

Common Adverse Effects

Asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, dyspepsia.1

Interactions for Adefovir Dipivoxil

Adefovir does not inhibit CYP isoenzymes, including CYP1A2, 2C9, 2C19, 2D6, and 3A4.1 Adefovir is not a substrate for CYP isoenzymes; potential of the drug to induce these enzymes is unknown.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs affecting or metabolized by CYP isoenzymes unlikely.1

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir and/or the other drug.1 Monitor closely for adverse effects if adefovir is used concomitantly with drugs excreted renally or with drugs known to affect renal function.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

No pharmacokinetic interaction1

Co-trimoxazole

No pharmacokinetic interaction1

Didanosine

No pharmacokinetic interaction with didanosine delayed-release capsules containing enteric-coated pellets1

Entecavir

No pharmacokinetic interaction24

Ibuprofen

No effect on pharmacokinetics of ibuprofen;1 increased adefovir plasma concentrations and AUC;1 may occur because of increased oral bioavailability of adefovir;1

Clinical importance unknown1

Immunosuppressive agents (cyclosporine, tacrolimus)

Cyclosporine: Effect on adefovir concentrations unknown1

Tacrolimus: No pharmacokinetic interaction1

Lamivudine

No pharmacokinetic interaction1

Additive antiviral effects against HBV1

Telbivudine

No pharmacokinetic interaction25

In vitro evidence of additive antiviral effects against HBV25

Tenofovir

No pharmacokinetic interaction1

Should not be used concomitantly for treatment of chronic HBV infection20

Adefovir Dipivoxil Pharmacokinetics

Absorption

Bioavailability

Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%.1 Peak plasma concentration of adefovir attained within 0.58–4 hours.1

Food

Food does not affect AUC of adefovir.1

Special Populations

Adolescents 12–17 years of age with compensated liver disease: Peak plasma concentrations and AUC similar to those reported in adults.1

Distribution

Extent

Not known whether adefovir distributed into human milk.1

Plasma Protein Binding

≤4%.1

Elimination

Metabolism

Following oral administration, adefovir dipivoxil is converted to the active adefovir.1

Adefovir is not metabolized by CYP isoenzymes.1

Elimination Route

Adefovir is excreted in urine by glomerular filtration and active tubular secretion.1

Following oral administration of adefovir dipivoxil, 45% of dose eliminated in urine as adefovir over 24 hours at steady-state.1

Removed by hemodialysis; effect of peritoneal dialysis unknown.1

Half-life

Terminal elimination half-life of adefovir: 7.48 hours.1

Special Populations

In adults with nonchronic HBV infection and hepatic impairment, no substantial differences in pharmacokinetics in those with moderate to severe hepatic impairment compared with those without hepatic impairment.1

In adults with moderate to severe renal impairment or end-stage renal disease requiring hemodialysis, clearance decreased and half-life prolonged.1

Pharmacokinetics not studied in geriatric adults.1

Pharmacokinetics not studied in adolescents 12–17 years of age with renal impairment.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Adefovir available as adefovir dipivoxil, a diester prodrug that is inactive until converted in vivo to adefovir and phosphorylated to adefovir diphosphate.1

  • An acyclic nucleotide antiviral.1

  • Active in vitro and in vivo against HBV.1 2

  • Also has some in vitro activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), HIV-1 and HIV-2, human papillomavirus (HPV), Epstein-Barr virus, and varicella zoster virus, but has not been shown to be effective in clinical infections caused by these viruses.2 15 22

  • HBV with reduced susceptibility to adefovir can develop in some patients during long-term use.1 9 12 16 17

  • Cross-resistance can occur among the nucleoside antivirals used for treatment of HBV.26 28

  • Some strains of HBV may be cross-resistant to both adefovir and lamivudine,26 27 28 but some lamivudine-resistant HBV may be susceptible to adefovir and some adefovir-resistant isolates may be susceptible to lamivudine.1 9 16 19 21 26

  • In vitro studies indicate that some HBV with mutations associated with adefovir resistance may have decreased susceptibility to entecavir.24

Advice to Patients

  • Advise patient of the risks and benefits of adefovir and other alternatives for treatment of HBV infection and importance of reading the adefovir patient package insert before starting treatment.1

  • Importance of remaining under the care of a clinician while taking adefovir and not discontinuing the drug without first informing a clinician.1

  • Importance of following a regular dosage schedule and avoiding missed doses.1

  • Risk of exacerbations of hepatitis when adefovir is discontinued and importance of close monitoring of liver function and HBV levels for several months or longer after the drug is stopped.1

  • Risk of nephrotoxicity and importance of monitoring renal function during treatment, especially in those with preexisting renal impairment or other risks for renal impairment.1

  • Importance of immediately reporting to clinicians any signs or symptoms of lactic acidosis (e.g., weakness/fatigue, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, cold intolerance especially in the arms and legs, dizziness or feeling light-headed, fast or irregular heart beat) or any signs or symptoms of hepatotoxicity (e.g., jaundice, dark urine, bowel movements light in color, anorexia, nausea, stomach pain).1 Importance of reporting any other unusual symptoms or if any known symptom persists or worsens.1

  • Risk of emergence of HIV resistance in patients with unrecognized or untreated HIV infection; importance of HIV antibody testing prior to initiation of adefovir therapy and anytime during therapy if possible exposure to HIV occurs.1

  • Advise patients with lamivudine-resistant HBV that they should receive adefovir in conjunction with lamivudine and should not receive adefovir monotherapy.1

  • Advise patients that it is not known whether adefovir will prevent transmission of HBV to others and that appropriate measures should be taken to prevent sexual or other transmission of the virus.1

  • Advise patients that the optimal duration of treatment and the relationship between treatment response and long-term outcomes (hepatocellular carcinoma, decompensated cirrhosis) are not known.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Adefovir Dipivoxil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg

Hepsera

Gilead

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Hepsera 10MG Tablets (GILEAD SCIENCES): 30/$1,056.04 or 90/$3,055.13

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Gilead Sciences, Inc. Hepsera (adefovir dipivoxil) tablet prescribing information. Foster City, CA; 2008 May.

2. Dusheiko G. Adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. Paper presented at the European Association for the Study of the Liver (EASL) international consensus conference on hepatitis B. Geneva, Switzerland, 2002 Sep 13-14. From the EASL website. Accessed 2003 Jan.

3. Marcellin P, Chung TT, Lim SG et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003; 348:808-16. [IDIS 494875] [PubMed 12606735]

4. 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; 348:800-7. [IDIS 494874] [PubMed 12606734]

5. Knight W, Hayashi S, Behnhamou Y et al. Dosing guidelines for adefovir dipivoxil in the treatment of chronic hepatitis B patients with renal or hepatic impairment. In: Posters of the 37th Annual Meeting of the European Association for the Study of the Liver (EASL), Madrid, Spain, 2002 Apr 17–21. Poster #308.

7. Anon. Gilead adefovir hep B resistance potential shows need for combo trials. FDC Rep. 2002; (Aug 12):5-6.

8. Perrillo R, Schiff E, Yoshida E et al. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology. 2000; 32:129-34. [PubMed 10869300]

9. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007; 45:507-39. [PubMed 17256718]

10. Anon. FDA approves new treatment for chronic hepatitis B. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2002 Sep 20.

11. Hadziyannis SJ. Papatheodoridis GV. Treatment of HBeAg negative chronic hepatitis B: treatment with new drugs (adefovir and others). Paper presented at the European Association for the Study of the Liver (EASL) international consensus conference on hepatitis B. Geneva, Switzerland, 2002 Sep 13-14. From the EASL website. Accessed 2003 Jan.

12. Marcellin P, Chang TT, Lim SG et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008; 48:750-8. [PubMed 18752330]

14. Fisher EJ, Chaloner K, Cohn DL et al. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial. AIDS. 2001; 15:1695-700. [PubMed 11546945]

15. Kamp W, Schokker J, Cambridge E et al. Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a phase I/II study. Antivir Ther. 1999; 4:101-7. [PubMed 10682155]

16. Gilead Sciences, Inc, Foster City, CA: Personal communication.

17. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006; 131:1743-51. [PubMed 17087951]

18. Peters MG, Hann Hw H, Martin P et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004; 126:91-101. [PubMed 14699491]

19. Xiong S, Yang H, Westland C et al. Resistance surveillance of HBeAg negative chronic hepatitis B patients treated for two years with adefovir dipivoxil. Presented at the 11th international symposium on viral hepatitis and liver disease, 2003. Sydney, Australia, 2003 Apr 6-10.

20. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2008 Aug.

21. Schiff E, Lai CL, Hadziyannis S et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007; 13:349-60. [PubMed 17326221]

22. Balzarini J, Schols D, Laethem KV et al. Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethyoxy] pyrimidines. J Antimicrob Chemother. 2007; 59:80-6. [PubMed 17124193]

23. Jonas MM, Kelly D, Pollack H et al. Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B. Hepatology. 2008; 47:1863-71. [PubMed 18433023]

24. Bristol-Myers Squibb Company. Baraclude (entecavir) tablets and oral solution prescribing information. Princeton, NJ; 2008 Feb.

25. Idenix Pharmaceuticals. Tyzeka (telbivudine) tablets prescribing information. Cambridge, MA; 2006 Oct.

26. Gerolami R, Bourliere M, Colson P et al. Unusual selection of rtA181V HBV mutants cross-resistant to adefovir following prolonged lamivudine monotherapy: report of two cases. Antivir Ther. 2006; 11:1103-6. [PubMed 17302381]

27. Karatayli E, Karayalçin S, Karaaslan H et al. A novel mutation pattern emerging during lamivudine treatment shows cross-resistance to adefovir dipivoxil treatment. Antivir Ther. 2007; 12:761-8. [PubMed 17713159]

28. Villet S, Pichoud C, Billioud G et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol. 2008; 48:747-55. [PubMed 18331765]

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