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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 reported in patients who have discontinued HBV therapy, including adefovir.1 29 (See Exacerbation of Hepatitis under Cautions.) Closely monitor hepatic function in patients who discontinue HBV therapy; if appropriate, resumption of therapy may be warranted.1 29

  • In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir may result in nephrotoxicity.1 29 Closely monitor renal function in such patients;1 29 dosage adjustments may be required.1 29

  • HIV resistance may emerge in chronic HBV patients receiving HBV treatment who have unrecognized or untreated HIV infection.1 29 (See HBV-infected Individuals Coinfected with HIV under Cautions.)

  • Lactic acidosis and severe hepatomegaly with steatosis (including fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 29 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

Introduction

Antiviral; acyclic nucleotide.1 29

Uses for Adefovir Dipivoxil

Chronic 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 29

Has been effective in hepatitis B e antigen (HBeAg)-positive adults and adolescents;1 3 23 29 HBeAg-negative adults;1 4 11 16 29 and pre- and postliver transplant patients.1 11 16 21 29 Also has been used in patients with lamivudine-resistant HBV.1 8 11 18 29

Treatment of chronic HBV infection is complex and evolving; consult specialized references and experts.97 98 Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of HBV infection, including recommendations for initial treatment, is available at .97

Adefovir Dipivoxil Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.1 29

Dosage

Available as adefovir dipivoxil;1 29 dosage expressed in terms adefovir dipivoxil.1 29

Pediatric Patients

Chronic HBV Infection
Oral

Adolescents 12–17 years of age: 10 mg once daily.1 29

Optimal duration of treatment unknown.1 29 Has been continued for up to 5 years in adults in controlled clinical studies.12 17

Adults

Chronic HBV Infection
Oral

10 mg once daily.1 29

Optimal duration of treatment unknown.1 29 Has been continued for up to 5 years in adults in controlled clinical studies.12 17

Special Populations

Hepatic Impairment

Dosage adjustments not needed.1 29

Renal Impairment

Adults with baseline Clcr <50 mL/minute: Adjust dosage.1 29 (See Table 1.)

Table 1: Dosage of Adefovir Dipivoxil for Treatment of HBV Infection in Adults with Renal Impairment129

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 29 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 29 Closely monitor clinical response and renal function.1 29

Adolescents ≥12 years of age with renal impairment: Safety and efficacy not studied.1 Data insufficient to make dosage recommendations for adolescents ≥12 years of age with underlying renal impairment;1 29 use caution and closely monitor renal function.1 29

Geriatric Patients

Select dosage with caution because of possible age-related decreases in renal function.1 29 (See Geriatric Use under Cautions.)

Cautions for Adefovir Dipivoxil

Contraindications

  • Known hypersensitivity to adefovir or any ingredient in the formulation.1 29

Warnings/Precautions

Warnings

Exacerbation of Hepatitis

Severe acute exacerbations of hepatitis reported following discontinuance of HBV therapy, including adefovir therapy.1 29

Exacerbations of hepatitis (ALT elevations ≥10 times ULN) reported in up to 25% of patients following discontinuance of adefovir, usually within 12 weeks after discontinuance;1 29 generally occurred in the absence of HBeAg seroconversion and presented as elevations in ALT and reemergence of viral replication.1 29

Although these exacerbations may be self-limited or resolve with reinitiation of therapy, severe exacerbations (including fatalities) reported.1 29

In patients with compensated liver function, exacerbations not generally 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 with both clinical and laboratory follow-up for at least several months after adefovir discontinued.1 29 If appropriate, resumption of HBV therapy may be warranted.1 29

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 29

Delayed onset of gradual increases in Scr 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 29

Long-term administration in dosages recommended for treatment of HBV infection (10 mg daily) also may result in delayed nephrotoxicity.1 29 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 29

In pre- or postliver transplant patients receiving usually recommended dosage (10 mg daily), most of whom had some degree of baseline renal insufficiency, 37 or 32% had increases in Scr concentrations of ≥0.3 mg/dL from baseline by week 48, respectively, and 53 or 51% had Scr increases of ≥0.3 mg/dL from baseline by week 96, respectively.1 29

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 29 (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 29 Dosage adjustments may be necessary.1 29 (See Renal Impairment under Dosage and Administration.)

HBV-infected Individuals Coinfected with HIV

Use of adefovir for treatment of chronic HBV infection in patients with unrecognized or untreated HIV infection may result in emergence of HIV resistance.1 29 Although adefovir has in vitro activity against HIV,30 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 29

Some experts state do not use adefovir alone or in conjunction with other antivirals for treatment of HBV infection in HIV-infected patients.200

Offer HIV antibody testing to all patients prior to initiating adefovir.1 29

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 29 Most reported cases have involved women; obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.1 29

Use nucleoside analogs 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 29

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 aminotransferase elevations).1 29

HBV Resistance

Resistance to adefovir may result in hepatitis B viral load rebound, which may lead to exacerbation of HBV infection; if the patient has impaired hepatic function, this may lead to liver decompensation and death.1 29

To reduce risk of clinical resistance in patients with lamivudine-resistant HBV, use adefovir in conjunction with lamivudine; do not use adefovir monotherapy1 29

Patients with serum HBV DNA levels >1000 copies/mL after 48 weeks of adefovir treatment are at greater risk of developing clinical resistance.1 29 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 29

Concomitant Use with Other Drugs

Do not use adefovir concomitantly with tenofovir disoproxil fumarate (tenofovir DF) or any fixed-combination preparation containing tenofovir DF.1 29

Specific Populations

Pregnancy

Category C.1 29

Pregnancy registry at 800-258-4263.1 29

No adequate, well-controlled studies in pregnant women.1 29 Use during pregnancy only if potential benefits justify potential risks to fetus.1 29

No evidence of embryotoxicity or teratogenicity in rats or rabbits at systemic exposures 23 or 40 times, respectively, exposures in humans at therapeutic dosage.1 29 However, embryotoxicity and increased incidence of fetal malformations occurred in rats at adefovir exposures 38 times human exposures at therapeutic dosage.1 29

Data not available regarding effect of adefovir therapy during pregnancy on transmission of HBV to the infant.1 Routine screening for HBV infection recommended for all pregnant women.105 For prevention of perinatal transmission of HBV, US Public Health Service Advisory Committee on Immunization Practices (ACIP), AAP, and others state that infants born to hepatitis B surface antigen (HBsAg)-positive women should receive first dose of hepatitis B vaccine and a dose of hepatitis B immune globulin (HBIG) within 12 hours of birth.9 105

Lactation

Not known whether distributed into milk.1 29

Discontinue nursing or the drug, taking into account importance of the drug to the woman.1 29

Pediatric Use

Safety and efficacy not established in children <12 years of age.1 29

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether geriatric adults respond differently than younger adults.1 29

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 29

Renal Impairment

Dosage adjustments recommended for adults with Clcr <50 mL/minute.1 29 (See Renal Impairment under Dosage and Administration.)

Not evaluated in adolescents ≥12 years of age with renal impairment.1 Use with 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 29 Adefovir is not a substrate for CYP isoenzymes; potential of the drug to induce these enzymes unknown.1 29

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs affecting or metabolized by CYP isoenzymes unlikely.1 29

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 29 Monitor closely for adverse effects if used concomitantly with drugs excreted renally or with drugs known to affect renal function.1 29 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

No pharmacokinetic interactions1 29

Aminoglycosides

Potential increased risk of nephrotoxicity1 29

Co-trimoxazole

No pharmacokinetic interactions1 29

Didanosine

No pharmacokinetic interactions with didanosine delayed-release capsules containing enteric-coated pellets1 29

Entecavir

No clinically important pharmacokinetic interactions24

Ibuprofen

No effect on pharmacokinetics of ibuprofen;1 29 increased adefovir plasma concentrations and AUC;1 29 may occur because of increased oral bioavailability of adefovir1 29

Clinical importance unknown1 29

Immunosuppressive agents (cyclosporine, tacrolimus)

Cyclosporine: Effect on adefovir concentrations unknown;1 29 potential increased risk of nephrotoxicity1 29

Tacrolimus: No pharmacokinetic interactions;1 29 potential increased risk of nephrotoxicity1 29

Lamivudine

No pharmacokinetic interactions1 29

Additive antiviral effects against HBV1 29

NSAIAs

Possible increased risk of nephrotoxicity1 29

Telbivudine

No pharmacokinetic interactions25

In vitro evidence of additive antiviral effects against HBV25

Tenofovir DF

Do not use concomitantly with any preparation containing tenofovir DF1 29

Vancomycin

Potential increased risk of nephrotoxicity1 29

Adefovir Dipivoxil Pharmacokinetics

Absorption

Bioavailability

Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%.1 29 Peak plasma concentration of adefovir attained within 0.58–4 hours.1 29

Food

Food does not affect AUC of adefovir.1 29

Special Populations

Adolescents 12–17 years of age with compensated liver disease: Peak plasma concentrations and AUC similar to those reported in adults.1 29

Distribution

Extent

Not known whether distributed into human milk.1 29

Plasma Protein Binding

≤4%.1 29

Elimination

Metabolism

Following oral administration, adefovir dipivoxil is converted to adefovir and then phosphorylated by cellular kinases to the active metabolite, adefovir diphosphate.1 29

Adefovir is not metabolized by CYP isoenzymes.1 29

Elimination Route

Adefovir is excreted in urine by glomerular filtration and active tubular secretion.1 29

Following oral administration of adefovir dipivoxil, 45% of dose eliminated in urine as adefovir over 24 hours at steady-state.1 29

Removed by hemodialysis;29 effect of peritoneal dialysis unknown.1 29

Half-life

Terminal elimination half-life: 7.48 hours.1 29

Special Populations

Adults with moderate or severe hepatic impairment (without chronic HBV infection): No substantial differences in pharmacokinetics compared with those without hepatic impairment.1 29

Adults with moderate to severe renal impairment or end-stage renal disease requiring hemodialysis (without chronic HBV infection): Decreased clearance and prolonged half-life.1 29

Geriatric patients: Pharmacokinetics not studied.1 29

Adolescents ≥12 years of age with renal impairment: Pharmacokinetics not studied.1 29

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 29

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 29

  • An acyclic nucleotide antiviral active in vitro and in vivo against HBV.1 29

  • 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.15 30

  • HBV with reduced susceptibility to adefovir can develop in some patients during long-term use.1 12 16 17 29 97

  • Cross-resistance can occur among the nucleoside and nucleotide antivirals used for treatment of HBV.25 26 28 36

  • 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 16 19 21 26 29

  • In vitro studies indicate that some HBV with mutations associated with adefovir resistance may have decreased susceptibility to entecavir.24 Some adefovir-resistant HBV have reduced susceptibility to telbivudine;25 other strains remain susceptible to telbivudine.25 HBV with single adefovir resistance-associated substitutions also have less than twofold reduced susceptibility to tenofovir alafenamide;36 HBV with certain double adefovir resistance-associated substitutions have 3.7-fold reduced susceptibility to tenofovir alafenamide.36

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 29

  • Importance of remaining under the care of a clinician while taking adefovir and not discontinuing the drug without first informing a clinician.1 29

  • Importance of following a regular dosage schedule and avoiding missed doses.1 29

  • 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 29

  • 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 29

  • Importance of immediately reporting 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 29 Importance of reporting any other unusual symptoms or if any known symptom persists or worsens.1 29

  • 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 29

  • Advise patients with lamivudine-resistant HBV that they should receive adefovir in conjunction with lamivudine and should not receive adefovir monotherapy.1 29

  • Advise patients that optimal duration of treatment and the relationship between treatment response and long-term outcomes (hepatocellular carcinoma, decompensated cirrhosis) are not known.1 29

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1 29

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 29

  • Importance of advising patients of other important precautionary information.1 29 (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Adefovir Dipivoxil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg*

Adefovir Dipivoxil Tablets

Hepsera

Gilead

AHFS DI Essentials. © Copyright 2017, Selected Revisions October 23, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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; 2012 Nov.

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. [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. [PubMed 12606734]

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. Centers for Disease Control and Prevention. Recommended immunization schedule for children and adolescents aged 18 years or younger—United States, 2017. Updates may be available at CDC website.

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.

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]

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; 2015 Aug.

25. Novartis Pharmaceuticals. Tyzeka (telbivudine) tablets prescribing information. Cambridge, MA; 2013 Jan.

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]

29. Sigmapharm Laboratories. Adefovir dipivoxil tablet prescribing information. Bensalem, PA;2016 Aug.

30. 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]

36. Gilead Sciences. Vemlidy (tenofovir alafenamide fumarate) tablets prescribing information. Foster City, CA; 2017 Apr.

97. Terrault NA, Bzowej NH, Chang KM et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016; 63:261-83. [PubMed 26566064]

98. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. March 2015. Geneva: World Health Organization; 2015.

105. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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