VIREAD (tenofovir disoproxil fumarate) Tablets part 3
DRUG INTERACTIONS: Didanosine: Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with VIREAD, Cmax and AUC of didanosine (administered as either the buffered or enteric-coated formulation) increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir disoproxil fumarate (tenofovir DF) with didanosine 400 mg daily. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions. Atazanavir: Atazanavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. VIREAD decreases the AUC and Cmm of atazanavir. When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with VIREAD. Lopinavir/Ritonavir: Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. Drugs Affecting Renal Function: Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir. In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).
USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD (tenofovir disoproxil fumarate) should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers: Studies
in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD. Pediatric Use: Safety and effectiveness in patients less than 18 years of age have not been established. Geriatric Use: Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients with Impaired Renal Function: It is recommended that the dosing interval for VIREAD be modified in patients with creatinine clearance <50 mL/min or in patients with end-stage renal disease (ESRD) who require dialysis (See Dosage and Administration).
NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice. There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
PATIENT COUNSELING INFORMATION: Information for Patients
Patients should be advised that:
- The use of VIREAD has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any blood fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.
- The long-term effects of VIREAD are unknown.
- VIREAD Tablets are for oral ingestion only.
- VIREAD should not be discontinued without first informing their physician.
- If you have HIV-1 infection, with or without HBV coinfection, it is important to take VIREAD with combination therapy.
- It is important to take VIREAD on a regular dosing schedule and to avoid missing doses.
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with VIREAD should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness (See Warnings and Precautions).
- Patients with HIV-1 should be tested for hepatitis B virus (HBV) before initiating antiretroviral therapy (See Warnings and Precautions).
- Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued VIREAD (See Warnings and Precautions).
- In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating VIREAD (See Warnings and Precautions).
- Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent (See Warnings and Precautions). Dosing interval of VIREAD may need adjustment in patients with renal impairment (See Dosage and Administration).
- VIREAD should not be coadministered with the fixed-dose combination products TRUVADA and ATRIPLA since it is a component of these products (See Warnings and Precautions).
- VIREAD should not be administered in combination with HEPSERA (See Warnings and Precautions).
- Decreases in bone mineral density have been observed with the use of VIREAD in patients with HIV. Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia (See Warnings and Precautions).
- 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.