Tenofovir Disoproxil Fumarate

Pronunciation: (ten-OF-oh-vir DYE-soe-PROX-il FUE-ma-rate)
Class: Nucleotide analog reverse transcriptase inhibitor

Trade Names

Viread
- Tablets, oral 300 mg (equivalent to tenofovir disoproxil 245 mg)

Pharmacology

Tenofovir disoproxil fumarate is a prodrug of tenofovir that 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 0.3 mcg/mL and AUC is approximately 2.29 mcg•h/mL. T _max is approximately 1 h, and bioavailability is approximately 25%. Administration following a high-fat meal increases the oral bioavailability, with an increase in AUC of approximately 40% and an increase in C _max of approximately 14%.

Distribution

Vd of tenofovir is approximately 1.3 L/kg. Binding to plasma or serum proteins is less than 0.7% and 7.2%, respectively.

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. Elimination half-life is approximately 17 h.

Special Populations

Renal Function Impairment

In patients with CrCl less than 50 mL/min or with ESRD requiring dialysis, C _max and AUC of tenofovir were increased to approximately 0.37 to 0.6 mcg/mL and 6.01 to 15.98 mcg•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.

Hepatic Function Impairment

No substantial alterations in tenofovir pharmacokinetics were observed in patients with hepatic impairment.

Elderly

Pharmacokinetic studies have not been performed.

Children

Tenofovir exposures in children 12 to younger than 18 y of age are similar to exposures achieved in adults. Pharmacokinetic studies have not been performed in children younger than 12 y of age.

Gender

Tenofovir pharmacokinetics are similar in men and women.

Race

There were insufficient numbers from racial and ethnic groups other than white patients to adequately determine potential pharmacokinetic differences among these populations.

Indications and Usage

Treatment of HIV-1 infection in adults and children 12 y of age and older in combination with other antiretroviral agents; treatment of chronic hepatitis B infection in adults.

Contraindications

None well documented.

Dosage and Administration

Adults and Children 12 y of Age and Older

PO 300 mg/day. The optimal duration of therapy for chronic hepatitis B is not known.

Renal Function Impairment
Adults

PO CrCl at least 50 mL/min, 300 mg every 24 h; CrCl 30 to 49 mL/min, 300 mg every 48 h; CrCl 10 to 29 mL/min, 300 mg every 72 to 96 h; CrCl less than 10 mL/min and on hemodialysis, 300 mg every 7 days or after a total of approximately 12 h of dialysis (administer following completion of dialysis); CrCl 10 mL/min and nonhemodialysis, no recommendation is available.

Children 12 y of Age and Older

PO No data available to make recommendations.

General Advice

Instruct patients to take with or without food.
Use in combination with other antiretroviral agents.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Abacavir

Coadministration increased abacavir C _max 12%.

Atazanavir, indinavir

May increase tenofovir plasma levels. Tenofovir may decrease plasma levels of atazanavir and indinavir, 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. Reduce the didanosine dose to 250 mg when administered with tenofovir in adults weighing more than 60 kg. Monitor patients closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop an adverse reaction. Administer under fasting conditions.

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

May increase serum levels of tenofovir and/or increase the levels of other renally eliminated drugs. Avoid coadministration with adefovir.

Entecavir

Coadministration increased entecavir AUC 13%.

Lamivudine

Concurrent use decreased lamivudine C _max 24%, but the AUC remained unchanged.

Lopinavir/Ritonavir

May increase tenofovir plasma levels. Monitor closely.

Nephrotoxic agents

Risk of nephrotoxicity may be increased; avoid tenofovir in patients who are currently receiving or have recently received nephrotoxic agents.

NSAIDs (eg, ibuprofen)

May increase the pharmacologic and toxic effects of tenofovir. Coadminister with caution.

Saquinavir/Ritonavir

Concurrent use increased saquinavir AUC 29% and C _max 22%. These changes are not expected to be clinically relevant.

Tacrolimus

Coadministration increased C _max of tenofovir by 13%.

Adverse Reactions

CNS

Insomnia (18%); dizziness (13%); asthenia (11%); depression, headache (10% or more); fatigue (more than 5%); peripheral neuropathy (5%).

Dermatologic

Pruritus (16%); rash, including maculopapular rash, pustular rash, urticaria, and vesiculobullous rash (10% or more); sweating (3%).

GI

Abdominal pain (22%); nausea (20%); diarrhea (16%); vomiting (13%); anorexia, dyspepsia, flatulence (4%); hepatic steatosis, 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 serum creatinine (9%); 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%); hypokalemia, hypophosphatemia, lactic acidosis (postmarketing).

Musculoskeletal

Back pain (more than 5%), myalgia (4%); muscular weakness, myopathy, osteomalacia, rhabdomyolysis (postmarketing).

Respiratory

Nasopharyngitis (more than 5%); pneumonia (3%); dyspnea (postmarketing).

Miscellaneous

Pain (12%); fever (11%); chest pain (3%); allergic reaction, including angioedema (postmarketing).

Precautions

Warnings

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) were reported with the use of nucleoside analogs 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 antihepatitis B therapy may be warranted.

Monitor

Monitor renal function and serum phosphorous in patients at risk for or with history of renal dysfunction and in 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 hepatic function closely with both clinical and laboratory follow-up for at least several months in patients who discontinue tenofovir and are coinfected with HIV and HBV. Monitor patient for signs and symptoms of lactic acidosis.

Pregnancy

Category B .

Lactation

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

Children

Safety and efficacy not established in children younger than 12 y of age.

Elderly

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

Renal Function

Dosing adjustments are required for patients with renal impairment.

Hepatic Function

Use with caution in patients with risk factors for liver disease.

Bone effects

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

Early virologic failure

Early virologic failure and high rates of resistance substitutions have been reported in patients on triple nucleoside regimens. Use these regimens with caution and carefully monitor patients receiving these regimens, or consider therapy modification for these patients.

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

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 or residual opportunistic infections.

Renal effects

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported.

Overdosage

Symptoms

None well documented.

Patient Information

Inform patients that tenofovir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a health care provider when using tenofovir.
Inform patients that the use of tenofovir has not been shown to reduce the risk of transmission of HIV-1 or HBV to others through sexual contact or blood contamination. Advise patients to continue to practice safe sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids, such as semen, vaginal secretions, or blood. Advise patients never to reuse or share needles.
Inform patients that the long-term effects of tenofovir are unknown.
Advise patients not to discontinue tenofovir without first informing their health care provider.
Inform patients with HIV-1 infection, with or without HBV coinfection, that it is important to take tenofovir with combination therapy.
Advise patients that it is important to take tenofovir on a regular dosing schedule and to avoid missing doses.
Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Suspend treatment with tenofovir in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness).
Advise patients with HIV-1 to be tested for HBV before initiating antiretroviral therapy.
Inform patients with chronic hepatitis B to obtain HIV antibody testing prior to initiating therapy with tenofovir.
Inform patients that severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and who have discontinued tenofovir.
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent. The dosing interval of tenofovir may need adjustment in patients with renal impairment.
Advise patients not to coadminister tenofovir with the fixed-dose combination products emtricitabine/tenofovir and efavirenz/emtricitabine/tenofovir because it is a component of these products.
Advise patients not to administer tenofovir in combination with adefovir.
Inform patients that decreases in bone mineral density have been observed with the use of tenofovir in patients with HIV and that supplementation with calcium and vitamin D may be beneficial.
Inform patients that in the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.
Advise HIV-infected mothers not to breast-feed to prevent infecting infant with HIV.