Tenofovir Disoproxil Fumarate

(BANM, USAN, rINNM)
Synonyms: Fumarato de disoproxilo de tenofovir; GS-4331/05; Ténofovir Disoproxil. Fumarate de; Tenofovirum Disoproxilum Fumaras. 9{(R)-2-[(Bis{[(isopropoxycarbonyl)oxy]methoxy}phosphinyl)methoxy]propyl}adenine fumarate (1:1).
Cyrillic synonym: Тенофовир Дизопроксил Фумарат.

💊 Chemical information

Chemical formula: C19H30N5O10P, C4H4O4 = 635.5.
CAS — 202138-50-9.
ATC — J05AF07.
ATC Vet — QJ05AF07.

💊 Adverse Effects

Adverse effects commonly associated with tenofovir disoproxil fumarate either as monotherapy for the treatment of chronic hepatitis B or with other antiretrovirals for the treatment of HIV are mild to moderate gastrointestinal events such as anorexia, abdominal pain, diarrhoea, dyspepsia, flatulence, nausea, and vomiting. Other commonly reported adverse effects are dizziness, fatigue, and headache. Skin rashes may occur. Hypophosphataemia is also common. Serumamylase concentrations may be raised and pancreatitis has been reported rarely. There have also been reports of raised liver enzymes, hepatitis, nephritis, nephrogenic diabetes insipidus, renal impairment, acute renal failure, and effects on the renal proximal tubules, including Fanconi syndrome. Lactic acidosis, usually associated with severe hepatomegaly and steatosis, has been associated with treatment with nucleoside reverse transcriptase inhibitors. Immune reconstitution syndrome (an inflammatory immune response resulting in clinical deterioration) has been reported during the initial phase of treatment with combination antiretroviral therapy, including tenofovir disoproxil fumarate, in HIV-infected patients with severe immune deficiency. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been seen in patients receiving antiretroviral therapy, including tenofovir disoproxil fumarate. Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia have also been reported. NRTIs have also been associated with mitochondrial dysfunction manifesting as abnormal behaviour, anaemia, convulsions, hyperlipasaemia, hypertonia, and neutropenia. Elevated creatine phosphokinase, myalgia, myositis, and rarely rhabdomyolysis have been reported, particularly when nucleoside analogues have been given with HIVprotease inhibitors. Osteonecrosis has been reported, particularly in patients with advanced HIV disease or long-term exposure to combination antiretroviral therapy. For further information on adverse effects associated with NRTIs see Zidovudine.

Effects on the kidney.

Use of tenofovir in patients with HIV infection has been associated with renal toxicity,1 including Fanconi syndrome,2 interstitial nephritis,3 and acute renal failure.4,5The mechanism of acute renal failure appears to be tubular necrosis, which may not resolve on withdrawal of the drug.6Some studies have indicated that glomerular filtration rate or creatinine clearance was consistently decreased in patients given tenofovir-containing regimens;7,8 it has been reported that this is greater if combined with HIV-protease inhibitors than NNRTIs.8Other studies have not found renal toxicity to be a significant problem.9,10
1. Gitman MD, et al. Tenofovir-induced kidney injury. Expert Opin Drug Saf 2007; 6: 155–64.
2. Gupta SK. Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. AIDS Patient Care STDS 2008; 22: 99–103
3. Schmid S, et al. Acute interstitial nephritis of HIV-positive patients under atazanavir and tenofovir therapy in a retrospective analysis of kidney biopsies. Virchows Arch 2007; 450: 665–70
4. Hynes P, et al. Acute renal failure after initiation of tenofovir disoproxil fumarate. Ren Fail 2007; 29: 1063–6
5. Kapitsinou PP, Ansari N. Acute renal failure in an AIDS patient on tenofovir: a case report. J Med Case Reports 2008; 2: 94
6. Zimmermann AE, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006; 42: 283–90
7. Fux CA, et al. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study. Antivir Ther 2007; 12: 1165–73
8. Goicoechea M, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis 2008; 197: 102–8
9. Viganò A, et al. Renal safety of tenofovir in HIV-infected children: a prospective, 96-week longitudinal study. Clin Drug Investig 2007; 27: 573–81
10. Madeddu G, et al. Tenofovir renal safety in HIV-infected patients: results from the SCOLTA Project. Biomed Pharmacother 2008; 62: 6–11.

💊 Precautions

Treatment with tenofovir disoproxil fumarate should be stopped if there is a rapid increase in aminotransferase concentrations, progressive hepatomegaly or steatosis, or metabolic or lactic acidosis of unknown aetiology. It should be given with caution to patients with hepatomegaly or other risk factors for liver disease. In particular, extreme caution should be exercised in patients with co-existing hepatitis C infection who are receiving interferon alfa and ribavirin. In patients co-infected with hepatitis B, there is a risk of severe acute exacerbation of hepatitis when tenofovir is stopped, and liver function should be monitored closely in such patients for at least several months. Tenofovir should be used with caution, and doses modified, in patients with renal impairment. Renal function and serum phosphates should be monitored before treatment is started, every 4 weeks during the first year of therapy, and then every 3 months; in patients with a history of renal impairment or who are particularly at risk, more frequent monitoring may be needed. If serum-phosphate concentrations fall markedly or if creatinine clearance is below 50 mL/minute, renal function should be evaluated within a week, and the dose interval may need to be adjusted or treatment interrupted. Tenofovir disoproxil fumarate may be associated with reduction in bone density and patients should be observed for evidence of bone abnormalities; bone monitoring should be considered for patients with a history of bone fractures or those at risk of osteopenia.

💊 Interactions

Use of tenofovir disoproxil fumarate with nephrotoxic drugs or with other drugs eliminated by active tubular secretion is not recommended; if such use is unavoidable, renal function should be monitored weekly. Tenofovir increases the plasma concentrations of didanosine. Once daily triple nucleoside regimens of tenofovir and lamivudine with either abacavir or didanosine are associated with a high level of treatment failure and of emergence of resistance, and should be avoided. Decreased plasma concentrations of atazanavir and increased plasma concentrations of tenofovir occur when tenofovir is given with atazanavir; the effect is significantly reduced when ritonavir is added as a booster. Use of ritonavir-boosted lopinavir with tenofovir modestly increases the plasma concentrations of tenofovir.

Antidiabetics.

Fatal lactic acidosis has been reported1 in a patient given metformin with didanosine, stavudine, and tenofovir.
1. Worth L, et al. A cautionary tale: fatal lactic acidosis complicating nucleoside analogue and metformin therapy. Clin Infect Dis 2003; 37: 315–16.

💊 Antiviral Action

Tenofovir is converted intracellularly to the diphosphate. This diphosphate halts the DNA synthesis of HIV through competitive inhibition of reverse transcriptase and incorporation into viral DNA. Tenofovirresistant strains of HIV have been identified and crossresistance to other reverse transcriptase inhibitors may occur.

💊 Pharmacokinetics

Tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir after oral doses, with peak plasma concentrations occurring after 1 to 2 hours. Bioavailability in fasting patients is about 25%, but this is enhanced when tenofovir disoproxil fumarate is taken with a high fat meal. Tenofovir is widely distributed into body tissues, particularly the kidneys and liver. Binding to plasma proteins is less than 1% and that to serum proteins about 7%. The terminal elimination half-life of tenofovir is 12 to 18 hours. Tenofovir is excreted mainly in the urine by both active tubular secretion and glomerular filtration. It is removed by haemodialysis.
1. Kearney BP, et al. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 2004; 43: 595–612
2. Kearney BP, et al. Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment. Clin Pharmacokinet 2006; 45: 1115–24.

💊 Uses and Administration

Tenofovir is a nucleotide reverse transcriptase inhibitor with antiviral activity against HIV-1 and hepatitis B. It is used in the treatment of HIV infection and AIDS and chronic hepatitis B infection. Viral resistance emerges rapidly when tenofovir is used alone in the treatment of HIV infection, and it is therefore used with other antiretrovirals. It is given orally as the disoproxil fumarate ester. Tenofovir disoproxil fumarate 300 mg is equivalent to about 245 mg of tenofovir disoproxil and to about 136 mg of tenofovir. For the treatment of either HIV or chronic hepatitis B infection the usual dose is 300 mg of the disoproxil fumarate ester once daily with food. For details of doses of tenofovir disoproxil fumarate to be used in patients with renal impairment, see below. Fixed-dose combination products for the treatment of HIV infection and AIDS have been developed in order to improve patient adherence and avoid monotherapy, thereby decreasing the risk of acquired drug resistance. Products containing tenofovir disoproxil fumarate in combination with emtricitabine, and with efavirenz plus emtricitabine are available in some countries. A gel containing tenofovir is under investigation as a topical microbicide in the prevention of HIV infection.
1. Grim SA, Romanelli F. Tenofovir disoproxil fumarate. Ann Pharmacother 2003; 37: 849–59
2. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis 2003; 37: 944–50
3. Dando TM, Wagstaff AJ. Emtricitabine/tenofovir disoproxil fumarate. Drugs 2004; 64: 2075–82
4. Lyseng-Williamson KA, et al. Tenofovir disoproxil fumarate: a review of its use in the management of HIV infection. Drugs 2005; 65: 413–32
5. Wong SN, Lok AS. Tenofovir disoproxil fumarate: role in hepatitis B treatment. Hepatology 2006; 44: 309–13
6. Reijnders JGP, Janssen HLA. Potency of tenofovir in chronic hepatitis B: mono or combination therapy? J Hepatol 2008; 48: 383–6
7. Stephan C. Experience with tenofovir disoproxil fumarate for antiretroviral therapy. Expert Opin Pharmacother 2008; 9: 1197–209
8. Pozniak A. Tenofovir: what have over 1 million years of patient experience taught us? Int J Clin Pract 2008; 62: 1285–93.

Administration in renal impairment.

Doses of tenofovir disoproxil fumarate should be modified by adjustment of the dosing interval in patients with renal impairment according to their creatinine clearance (CC):
CC 50 mL or more per minute: usual once-daily dosage (above)
CC 30 to 49 mL/minute: every 48 hours
CC 10 to 29 mL/minute: every 72 to 96 hours
haemodialysis patients: a dose every 7 days or after a cumulative total of 12 hours of dialysis

💊 Preparations

Proprietary Preparations

Arg.: Viread; Austral.: Viread; Austria: Viread; Belg.: Viread; Canad.: Viread; Chile: Viread; Cz.: Viread; Denm.: Viread; Fin.: Viread; Fr.: Viread; Ger.: Viread; Gr.: Viread; Hung.: Viread; Irl.: Viread; Israel: Viread; Ital.: Viread; Mex.: Viread; Neth.: Viread; Norw.: Viread; NZ: Viread; Pol.: Viread; Spain: Viread; Swed.: Viread; Switz.: Viread; UK: Viread; USA: Viread. Multi-ingredient: Arg.: Truvada; Austral.: Truvada; Cz.: Truvada; Fin.: Truvada; Fr.: Truvada; Ger.: Truvada; Gr.: Truvada; Irl.: Truvada; Ital.: Truvada; Mex.: Truvada; Neth.: Tr uvada; NZ: Truvada; Port.: Truvada; Spain: Truvada; Swed.: Truvada; UK: Atripla; Truvada; USA: Atripla; Truvada.
Published December 23, 2018.