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Drugs reference index «Tenofovir Disoproxil Fumarate»

Tenofovir Disoproxil Fumarate

Pronunciation: (ten-OH-foe-vir DYE-soe-PROX-il fue-MAR-ate)Class: Nucleotide analog reverse transcriptase inhibitor

Trade Names:Viread- Tablets 300 mg (equivalent to tenofovir disoproxil 245 mg)

Pharmacology

Tenofovir disoproxil fumarate is a prodrug of tenofovir, which inhibits the activity of HIV-1 reverse transcriptase and hepatitis B virus (HBV) polymerase by competing with deoxyadenosine 5′-triphosphate and by DNA chain termination after incorporation into DNA.

Pharmacokinetics

Absorption

Tenofovir C max is approximately 296 ng/mL and approximately 326 ng/mL in fasting and fed states, respectively. AUC is approximately 2,287 ng•h/mL and approximately 3,324 ng•h/mL in fasting and fed states, respectively. T max is about 1.5 h, and bioavailability is approximately 25%. Administration following a high-fat meal increases the oral bioavailability, with an increase in AUC of about 40% and C max increase of about 14%.

Distribution

Vd of tenofovir is approximately 1.3 L/kg.

Metabolism

Tenofovir is not a CYP-450 substrate.

Elimination

Elimination of tenofovir is by glomerular filtration and tubular secretion. Approximately 70% to 80% is recovered in urine as unchanged drug.

Special Populations

Renal Function Impairment

In patients with CrCl less than 50 mL/min or with end-stage renal disease requiring dialysis, C max and AUC of tenofovir were increased to approximately 372 to 601 ng/mL and 6,008 to 15,984 ng•h/mL, respectively. It is recommended that the dosing interval be modified in these patients. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose, a 4-h hemodialysis session removed approximately 10% of the administered tenofovir dose.

Indications and Usage

Treatment of HIV-1 infection in combination with other antiretroviral agents; treatment of chronic hepatitis B infection in adults.

Contraindications

Standard considerations.

Dosage and Administration

Adults

PO 300 mg/day without regard to food. The optimal duration of therapy for chronic hepatitis B is not known.

Renal Function ImpairmentAdults

PO CrCl at least 50 mL/min, give 300 mg every 24 h; CrCl 30 to 49 mL/min, give 300 mg every 48 h; CrCl 10 to 29 mL/min, give 300 mg every 72 to 96 h.

Hemodialysis

Give 300 mg every 7 days or after a total of about 12 h of dialysis.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Drug Interactions

Atazanavir

May increase tenofovir plasma levels. Tenofovir may decrease AUC and C min of atazanavir, decreasing the therapeutic effect. Do not administer atazanavir without ritonavir in patients receiving tenofovir.

Didanosine

Plasma concentrations of didanosine may be increased, increasing the risk of adverse reactions.

Drugs that reduce renal function or compete for active tubular secretion (eg, acyclovir, adefovir, dipivoxil, ganciclovir)

May increase serum levels of tenofovir and/or increase the levels of other renally eliminated drugs.

Lopinavir/Ritonavir

May increase tenofovir plasma levels.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Asthenia (11%); depression, headache (8%); peripheral neuropathy (5%); insomnia (4%); dizziness (3%).

Dermatologic

Rash including maculopapular rash, pruritus, pustular rash, urticaria, and vesiculobullous rash (7%); sweating (3%).

GI

Diarrhea (16%); nausea (11%); abdominal pain, vomiting (7%); anorexia, dyspepsia, flatulence (4%); hepatitis, increased liver enzymes, pancreatitis (postmarketing).

Genitourinary

Acute renal failure, acute tubular necrosis, Fanconi syndrome, interstitial nephritis, nephrogenic diabetes insipidus, polyuria, proteinuria, proximal tubulopathy, renal failure, renal insufficiency (postmarketing).

Lab Tests

Increased creatine kinase (12%); increased triglycerides (11%); increased ALT (10%); increased serum amylase (7%); increased AST (4%); glycosuria, increased serum glucose (3%); decreased neutrophils (2%).

Metabolic-Nutritional

Weight loss (4%); hypophosphatemia, lactic acidosis (postmarketing).

Musculoskeletal

Back pain, myalgia (4%); myopathy, osteomalacia (postmarketing).

Respiratory

Pneumonia (3%), dyspnea (postmarketing).

Miscellaneous

Pain (12%); fever (4%); chest pain (3%); allergic reaction (postmarketing).

Precautions

Warnings

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) were reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.

Severe acute exacerbations of HBV have been reported in HBV-infected patients who have discontinued anti–hepatitis B therapy, including tenofovir. Monitor hepatic function closely with clinical and laboratory follow-up for at least several months in patients who discontinue tenofovir. If appropriate, resumption of anti–hepatitis B therapy may be warranted.

Monitor

Monitor renal function and serum phosphorous in patients at risk for, or with history of, renal dysfunction and patients receiving nephrotoxic agents. Monitor bone density in HIV-infected patients with history of pathologic bone fracture or who are at risk for osteopenia. Ensure that liver enzymes are evaluated before starting therapy and periodically thereafter during prolonged treatment. Monitor patient for signs and symptoms of lactic acidosis. If patient develops any of the following, withhold drug: profound weakness or tiredness; unexpected stomach discomfort; fatty diarrhea; feelings of coldness, dizziness, or light-headedness; slow or irregular heartbeat.

Pregnancy

Category B .

Lactation

Undetermined. HIV-infected mothers should not breast-feed infants.

Children

Safety and efficacy not established.

Elderly

Select dose with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function and comorbidity.

Renal Function

See Route/Dosage section for recommended adjustments. Renal function impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported. If possible, avoid using tenofovir in patients with concurrent or recent use of nephrotoxic agent.

Bone effects

Reduction in bone mineral density and fractures have been reported. Ensure that supplementation with calcium and vitamin D has been considered in patient with HIV-associated osteopenia or osteoporosis.

Fat redistribution

Accumulation and redistribution of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, may occur.

Hepatitis B

Discontinuation of anti–hepatitis B therapy may cause severe acute exacerbations of hepatitis. Test HIV patients for chronic HBV before starting antiretroviral therapy.

HIV-1

Test HBV patients for HIV-1 before starting therapy.

Immune reconstitution syndrome

During initial phase of therapy, patients whose immune system responds may develop an inflammatory response to indolent of residual opportunistic infections.

Lactic acidosis/severe hepatomegaly with stenosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Use with caution in patients with risk factors for liver disease.

Patient Information

  • Advise patient or caregiver to review the patient information leaflet before starting therapy and with each refill.
  • Advise patient to take tenofovir once daily without regard to meals but to take with food if stomach upset occurs.
  • Instruct patient that if a dose is missed, to take it as soon as possible and take the next dose at the regularly scheduled time. If it is almost time for the next dose, advise patient to not take the missed dose and to take the next dose as scheduled. Caution patient not to double the next dose to catch up.
  • Warn patient that this drug is not to be used by itself for HIV, but is combined with other antiviral agents.
  • Instruct patient to report these symptoms immediately to health care provider: abdominal swelling or enlargement; fatty diarrhea; profound weakness or tiredness; unexpected stomach discomfort; feeling cold, dizzy, or light-headed; or slow or irregular heartbeat.
  • Inform patient that drug does not completely eliminate HIV virus and therefore does not reduce risk of transmitting HIV to others. Appropriate precautions must still be followed.
  • Advise patient that drug is not a cure for HIV infection and that illnesses associated with HIV infection, including opportunistic infections, may continue to be acquired. Patients should remain under a health care provider's care.
  • Advise patient with HIV-associated osteopenia or osteoporosis to discuss need for supplementation with calcium and vitamin D with health care provider
  • Advise HIV-infected mothers not to breast-feed to prevent infecting infants with HIV.

Copyright © 2009 Wolters Kluwer Health.