Tenofovir disoproxil fumarate.
Each tablet contains Tenoflovir Disoproxil Fumarate 300 mg equivalent to Tenofovir Disoproxil 245 mg.
Pharmacology: Pharmacodynamics: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and after incorporation into DNA by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Antiviral Activity in Vitro: The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nallinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. Tenofovir displayed antiviral activity in vitro against HIV-1 classes A, B, C, D, E, F, G, and O (IC50 values ranges from 0.5 μM to 2.2 μM).
Drug Resistance: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 3-4 fold reduction in susceptibility to tenofovir.
Cross-resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R mutation selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine, HIV isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R mutation. HIV-1 isolates from patients whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T695 double insertion mutation the reverse transcriptase showed reduced susceptibility to tenofovir.
Pharmacokinetics: The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption: Tenofovir disoproxil fumarate is a water soluble diester prodrug of active ingredient tenofovir. The oral bioavailability of tenofovir in fasted patients is approximately 25%. Following oral administration of a single dose of tenofovir disoproxil fumarate tablet 300 mg to HIV-1 infected patients in the fasted state maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 296 ± 90 ng/mL an 2287 ± 685 ng·h/mL respectively.
Effects of Food on Oral Absorption: Administration of tenofovir disoproxil fumarate tablets following a high-fat meal (-700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability with an increase in tenofovir AUC of approximately 40% and an increase in Cmax of approximately 14%. However, administration of the drug with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour, Cmax and AUC of tenofovir are 326 ± 119 ng/mL and 3324 ± 1370 ng·hr/mL following multiple doses of tenofovir disoproxil fumarate tablet 300 mg once daily in the fed state when meal content was not controlled.
Distribution: In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2% respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state are 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination: In vitro studies indicates that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes.
Following single dose administration, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate tablet 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in the urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
TENOFOVIR GPO is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
The dose of TENOFOVIR GPO is 300 mg once daily taken orally, without regard to food.
Dose Adjustment for Renal Impairment: Significantly increased drug exposure occurred when TENOFOVIR GPO was administered to patients with moderate to severe renal impairment. The dosing interval of TENOFOVIR GPO should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in the table. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated, therefore, clinical response to treatment and renal function should be closely monitored in these patients. (See Table.)
Click on icon to see table/diagram/image
Calculated using ideal (lean) body weight.
Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. TENOFOVIR GPO should be administered following completion of dialysis.
The pharmacokinetics of tenofovir have no been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min, therefore, no dosing recommendation is available for these patients.
No severe adverse reactions were reported. The effects of higher doses are not known. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TENOFOVIR GPO, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
TENOFOVIR GPO is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factor. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Treatment with TENOFOVIR GPO should be suspended in any patient who develops clinical or laboratory finding suggestive of lactic acidosis or pronounced hepatotoxity (which may include hepatomegaly and steatosis even in absence of marked transaminase elevation).
Renal Impairment: Tenofovir is principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with creatinine clearance < 50 mL/min. No safety data are available in patients with renal dysfunction who received TENOFOVIR GPO using these dosing guidelines.
Renal impairment including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported in association with the use of TENOFOVIR GPO. The majority of these cases occurred in patients with underlying systemic or renal disease or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors.
TENOFOVIR GPO should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for or with a history of renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
Patients with HIV and Hepatitis B Virus Co-infection: It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. TENOFOVIR GPO is not indicated for the treatment of chronic HBV infection and the safety and efficacy of TENOFOVIR GPO have not been established in patients co-infected with HBV and HIV. Exacerbations of HBV have been reported in patients after the discontinuation of TENOFOVIR GPO. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping TENOFOVIR GPO treatment.
Bone Effects: Decreased bone mineral density (BMD) were seen at the lumbar spine and hip. In addition, there were significant increases in levels of four biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels were also higher. The clinical significance of the changes in BMD and biochemical markers is unknown and follow-up is continuing to assess long-term impact.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at substantial risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected then appropriate consultation should be obtained.
Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Animal Toxicology: Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposure (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species, increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposure (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies of tenofovir disoproxil fumarate in rats and mice are in progress. 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 and female rats at a dose equivalent to 19 times the human dose based on body surface area comparisons. There was, however, an alteration of the estrous cycle in female rats.
Use in 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, TENOFOVIR GPO should be used during pregnancy only if clearly needed.
Use in Lactation: It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking potential transmission of HIV. Studies in rat have demonstrated that tenofovir is secreted in milk. It is not known when tenofovir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TENOFOVIR GPO.
Body as a Whole:
Asthenia, pain, headache, abdominal pain, back pain, chest pain, fever.
Diarrhea, nausea, vomiting, anorexia, dyspepsia; flatulence.
Depression, insomnia, peripheral neuropathy, dizziness, abnormal dreams, paresthesia.
Skin and Appendage:
Rash event, sweating.
When administered with TENOFOVIR GPO, Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly. The mechanism of the interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events including pancreatitis and neuropathy. In adults weighing >60 kg the didanosine dose should be reduced to 250 mg when it is co-administered with TENOPOVIR GPO. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When co-administered, TENOFOVIR GPO and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Co-administration of didanosine buffered tablet formulation with TENOFOVIR GPO should be under fasted conditions.
Co-administration of TENOFOVIR GPO and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.
Since tenofovir is primarily eliminated by the kidneys, co-administration of TENOFOVIR GPO 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 adefovir, dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir and valganciclovir.
J05AF07 - tenofovir disoproxil ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Tab 300 mg (light blue, oblong-shaped, one side bisected and other side "GT" marked, film coated) x 30's.