Tenofovir

Pronunciation

(te NOE fo veer)

U.S. Brand Names

Viread®

Synonyms

PMPA; TDF; Tenofovir Disoproxil Fumarate

Generic Available

No

Use

Management of HIV infections in combination with at least two other antiretroviral agents

Pregnancy Risk Factor

B

Pregnancy Implications

There are no adequate and well-controlled studies in pregnant women. Animal studies have shown decreased fetal growth and reduced fetal bone porosity. Clinical studies in children have shown bone demineralization with chronic use. Use in pregnancy only if clearly needed. Cases of lactic acidosis/hepatic steatosis syndrome have been reported in pregnant women receiving nucleoside analogues. It is not known if pregnancy itself potentiates this known side effect; however, pregnant women may be at increased risk of lactic acidosis and liver damage. Hepatic enzymes and electrolytes should be monitored frequently during the 3rd trimester of pregnancy in women receiving nucleoside analogues. Health professionals are encouraged to contact the Antiretroviral Pregnancy Registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to tenofovir or any component of the formulation

Warnings/Precautions

Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues, including fatal cases; use with caution in patients with risk factors for liver disease (risk may be increased in obese patients or prolonged exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis (transaminase elevation may/may not accompany hepatomegaly and steatosis).

Use caution in renal impairment (Clcr<50 mL/minute); dosage adjustment required. May cause osteomalacia and/or renal toxicity; monitor renal function and possible bone abnormalities during therapy. Use caution in hepatic impairment. All patients with HIV should be tested for HBV prior to initiation of treatment. Safety and efficacy of tenofovir during co-infection of HIV and HBV have not been established; acute, severe exacerbations of HBV have been reported following tenofovir discontinuation. In HBV co-infected patients, monitor hepatic function closely for several months following discontinuation. Safety and efficacy have not been established in pediatric patients.

Adverse Reactions

Clinical trials involved addition to prior antiretroviral therapy. Frequencies listed are treatment-emergent adverse effects noted at higher frequency than in the placebo group.

>10%: Gastrointestinal: Nausea (8% to 11%), diarrhea (11% to 16%)

1% to 10%:

Central nervous system: Headache (5% to 8%), depression (5% to 8%), dizziness (1% to 3%), insomnia (1% to 4%)

Endocrine & metabolic: Glycosuria (3%, frequency equal to placebo); other metabolic effects (hyperglycemia, hypertriglyceridemia) noted at frequencies less than placebo

Gastrointestinal: Vomiting (4% to 7%), flatulence (3% to 4%), abdominal pain (4% to 7%), anorexia (3% to 4%)

Hematologic: Neutropenia (1% to 2%)

Hepatic: Transaminases increased (2% to 4%)

Neuromuscular & skeletal: Weakness (7% to 11%), back pain (3% to 4%), myalgia (3% to 4%), neuropathy (1% to 3%)

Postmarketing and/or case reports: Serum creatinine increased, dyspnea, Fanconi syndrome, hypophosphatemia, lactic acidosis, pancreatitis, rash, renal failure, allergic reaction

Note: Uncommon, but significant adverse reactions reported with other reverse transcriptase inhibitors include pancreatitis, peripheral neuropathy, and myopathy.

Overdosage/Toxicology

Limited experience with overdose. Treatment is supportive.

Drug Interactions

Inhibits CYP1A2 (weak)

Atazanavir: Tenofovir may decrease serum concentrations of atazanavir, resulting in a loss of virologic response and/or resistance to atazanavir. Atazanavir-specific dosing recommendations are provided by the manufacturer.

Didanosine: Concomitant use of tenofovir with didanosine has been noted to increase exposure to didanosine and/or its active metabolite, potentially increasing the risk of pancreatitis, peripheral neuropathy, or lactic acidosis. Specific dosing adjustment is recommended. Use caution and monitor closely. Suspend therapy if signs/symptoms of toxicity are present.

Lopinavir: Serum levels of lopinavir may be decreased by tenofovir.

Nephrotoxic agents: Drugs causing nephrotoxicity may reduce elimination of tenofovir.

Ritonavir: Serum concentrations of ritonavir may be decreased by tenofovir. Lopinavir/ritonavir may increase serum concentrations of tenofovir.

Note: Drugs which may compete for renal tubule secretion (including acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir) may increase the serum concentrations of tenofovir.

Ethanol/Nutrition/Herb Interactions

Food: Fatty meals may increase the bioavailability of tenofovir. Tenofovir may be taken with or without food.

Stability

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Mechanism of Action

Tenofovir disoproxil fumarate (TDF) is an analog of adenosine 5'-monophosphate; it interferes with the HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication. TDF is first converted intracellularly by hydrolysis to tenofovir and subsequently phosphorylated to the active tenofovir diphosphate; nucleotide reverse transcriptase inhibitor.

Pharmacodynamics/Kinetics

Distribution: 1.2-1.3 L/kg

Protein binding: 7% to serum proteins

Metabolism: Tenofovir disoproxil fumarate (TDF) is converted intracellularly by hydrolysis (by non-CYP enzymes) to tenofovir, then phosphorylated to the active tenofovir diphosphate

Bioavailability: 25% (fasting); increases ~40% with high-fat meal

Time to peak, serum: Fasting: 1 hour; With food: 2 hours

Excretion: Urine (70% to 80%) via filtration and active secretion, primarily as unchanged tenofovir

Dosage

Oral: Adults: HIV infection: 300 mg once daily

Dosage adjustment in renal impairment:

Clcr 30-49 mL/minute: 300 mg every 48 hours

Clcr 10-29 mL/minute: 300 mg twice weekly

Clcr<10 mL/minute without dialysis: No recommendation available.

Hemodialysis: 300 mg every 7 days or after ~12 hours of dialysis

Administration

May be administered with or without food.

Monitoring Parameters

CBC with differential, reticulocyte count, serum creatine kinase, CD4 count, HIV RNA plasma levels, renal and hepatic function tests, bone density (long-term), serum phosphorus; testing for HBV is recommended prior to the initiation of antiretroviral therapy

Patients with HIV and HVB co-infection should be monitored for several months following tenofovir discontinuation.

Dietary Considerations

May be taken with or without food. Consider calcium and vitamin D supplementation in patients with history of bone fracture or osteopenia.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking (especially anything that may cause drowsiness), and any allergies you have. Take exactly as directed with food (space other medications as instructed). This drug will not cure HIV; use appropriate precautions to prevent spread to other persons. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea, vomiting, loss of appetite (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or diarrhea (boiled milk, yogurt, or buttermilk may help). Report immediately any loss of sensation, numbness, or tingling in fingers, toes, or feet; persistent unresolved abdominal distress (nausea, vomiting, diarrhea); signs of opportunistic infection (burning on urination, perineal itching, white plaques in mouth, unhealed sores, persistent sore throat or cough) Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant and do not get pregnant while taking this medicine. Do not breast-feed.

Additional Information

Approval was based on two clinical trials involving patients who were previously treated with antiretrovirals with continued evidence of HIV replication despite therapy. The risk:benefit ratio for untreated patients has not been established (studies currently ongoing), however, patients who received tenofovir showed significant decreases in HIV replication as compared to continuation of standard therapy.

A high rate of early virologic nonresponse was observed when abacavir, lamivudine, and tenofovir were used as the initial regimen in treatment-naive patients. A high rate of early virologic nonresponse was also observed when didanosine, lamivudine, and tenofovir were used as the initial regimen in treatment-naive patients. Use of either of these combinations is not recommended; patients currently on either of these regimens should be closely monitored for modification of therapy. Early virologic failure was also observed with tenofovir and didanosine delayed release capsules, plus either efavirenz or nevirapine; use caution in treatment-naive patients with high baseline viral loads.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

None reported

Mental Health: Effects on Psychiatric Treatment

Nausea is common; use caution with SSRIs, lithium, and valproic acid.

Dosage Forms

Tablet, as disoproxil fumarate: 300 mg [equivalent to 245 mg tenofovir disoproxil]

References

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents. Panel on Clinical Practices for Treatment of HIV Infection," March 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed June 1, 2004.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.