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Tenofovir disoproxil fumarate
VIREAD is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV reverse transcriptase. The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl) oxy] methoxy] phosphinyl] methoxy] propyl] adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P•C4H4O4 and a molecular weight of 635.52. Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25°C. VIREAD tablets are for oral administration. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil,and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with a blue colored film (Opadry II Y-30-10671-A) that is made of FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910,lactose monohydrate, titanium dioxide, and triacetin. In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted. Microbiology Mechanism of Action: 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 diphos-phate. Tenofovir diphosphate inhibits the activity of HIV 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 a, ß, and mitochondrial DNA polymerase . Antiviral Activity In Vitro: The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentrations) for tenofovir was in the range of 0.04 µM to 8.5 µM. In drug combination studies of tenofovir with nucleoside and non-nucleoside analog inhibitors of HIV reverse transcriptase, and protease inhibitors, additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. In Vitro Resistance: HIV 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. In Vitro Cross-resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The in vitro activity of tenofovir against HIV-1 strains with zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N) was evaluated. Zidovudine-associated mutations may also confer reductions in susceptibility to other NRTIs and these mutations have been reported to emerge during combination therapy with stavudine and didanosine. In 20 samples that had multiple zidovudine-associated mutations (mean 3),a mean 3.1-fold increase of the IC50 of tenofovir was observed (range 0.8 to 8.4). The K65R mutation is selected both in vitro and in some HIV-infected subjects treated with didanosine, zalcitabine, or abacavir; therefore, some cross-resistance may occur in patients who develop this mutation following treatment with these drugs. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir. Genotypic and Phenotypic Analyses of VIREAD in Patients with Previous Antiretroviral Therapy (Studies 902 and 907): See Description of Clinical Studies In Vivo Resistance: Post baseline genotyping in Studies 902 and 907 showed that seven of 237 VIREAD-treated patients’ HIV (3%) developed the K65R mutation, a mutation selected by VIREAD and other NRTIs in vitro. Among VIREAD-treated patients whose HIV developed NRTI-associated mutations, there was continued HIV RNA suppression through 24 weeks. The rate and extent of tenofovir-associated resistance mutations has not been characterized in antiretroviral naïve patients initiating VIREAD treatment. Phenotypic analyses of HIV isolates after 48 weeks (Study 902,n=30) or 24 weeks (Study 907,n=35) of VIREAD therapy showed no significant changes in VIREAD susceptibility unless the K65R mutation had developed. Pharmacokinetics The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-infected individuals. Tenofovir pharmacokinetics are similar between these populations. Absorption: VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted patients is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hours. Cmax and AUC values are 296 ± 90 ng/mL and 2287 ± 685 ng*h/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing. Effects of Food on Oral Absorption: Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-¥ of approximately 40% and an increase in Cmax of approximately 14%. 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*h/mL following multiple doses of VIREAD 300 mg once daily in the fed state. VIREAD should be taken with a meal to enhance the bioavailability of tenofovir. 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 is 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 indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes. Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions),32 ± 10% of the administered dose is recovered in 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. Special Populations: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations. Tenofovir pharmacokinetics are similar in male and female patients. Pharmacokinetic studies have not been performed in children or in the elderly. The pharmacokinetics of tenofovir have not been studied in patients with hepatic impairment; however, tenofovir and tenofovir disoproxil are not metabolized by liver enzymes, so the impact of liver impairment should be limited. (See PRECAUTIONS, Hepatic Impairment) The pharmacokinetics of tenofovir have not been evaluated in patients with renal impairment (creatinine clearance < 60 mL/min). Because tenofovir is primarily renally eliminated, tenofovir pharmacokinetics are likely to be affected by renal impairment. (See WARNINGS, Renal Insufficiency) VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a controlled study of VIREAD of 24 weeks duration and in a controlled, dose ranging study of VIREAD of 48 weeks duration. Both studies were conducted in treatment experienced adults with evidence of HIV-1 viral replication despite ongoing antiretroviral therapy. Studies in antiretroviral naïve patients are ongoing; consequently, the risk-benefit ratio for this population has yet to be determined. Additional important information regarding the use of VIREAD for the treatment of HIV infection: • There are no study results demonstrating the effect of VIREAD on clinical progression of HIV. • The use of VIREAD should be considered for treating adult patients with HIV strains that are expected to be susceptible to tenofovir as assessed by laboratory testing or treatment history. Description of Clinical Studies: Treatment Experienced Patients Study 907: VIREAD + Standard Background Therapy (SBT) Compared to Placebo + SBT Study 907 was a 24 week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. Patients had a mean baseline CD4 cell count of 426 cells/mm3 (range 23-1385),median baseline plasma HIV RNA of 2340 (range 50-75,900) copies/mL,and mean duration of prior HIV treatment was 5.4 years. Mean age of the patients was 42 years,85% were male and 69% were Caucasian,17% African-American and 12% Hispanic. Mean Change from Baseline in Plasma HIV RNA (log10 copies/mL) Through Week 24: Study 907 (All Available Data) The percent of patients with HIV RNA <400 copies/mL,< 50 copies/mL and outcomes of patients through 24 weeks are summarized in Table 3. Table 3. Outcomes of Randomized Treatment at Week 24 (Study 907)
1. Includes discontinuations due to consent withdrawn, lost to follow up, non-compliance, protocol violations, pregnancy, and other reasons. Mean change in absolute CD4 counts by week 24 was -11 cells/mm3 for the VIREAD group and -5 cells/mm3 for the placebo group. One patient in the VIREAD group and no patients in the placebo arm experienced a new CDC Class C event. Study 902: VIREAD + Standard Background Therapy (SBT) Compared to Placebo + SBT Study 902 was a double-blind placebo-controlled multicenter study evaluating treatment with VIREAD at three dose levels (75 mg QD,150 mg QD and 300 mg QD) when added to a stable background regimen of antiretroviral agents in 186 treatment-experienced patients. Placebo patients received VIREAD 300 mg QD at week 24. All patients received open label VIREAD 300 mg QD after week 48. Patients had a mean baseline CD4 cell count of 374 cells/mm3 (range 9-1240),median baseline plasma HIV RNA of 5010 copies/mL (range 52-575,000),and mean duration of prior HIV treatment was 4.6 years. Mean age was 42 years,92% were male and 74% were Caucasian,13% African-American, and 11% Hispanic. At week 24, the rate of drug discontinuation was 11% for the VIREAD group versus 25% for the placebo group. * At week 24,21 placebo patients crossed over to receive VIREAD 300mg once daily. At week 48 mean change from week 24 was -0.56 log10 copies/mL. Through week 24 the proportion of patients achieving < 400 copies/mL was 19% VIREAD vs. 7% placebo and < 50 copies/mL was 11% VIREAD vs. 0% placebo. The differences for these secondary endpoints were not statistically significant. Mean change in absolute CD4 counts by week 24 were -14 cells/mm3 for the VIREAD group and +20 cells/mm3 for the placebo group. This result was not statistically significant. Mean change in CD4 count at week 48 was -11 cells/mm3 for the VIREAD group. No patients experienced a new CDC Class C event through week 24. Genotypic Analyses of VIREAD in Patients with Previous Antiretroviral Therapy (Studies 902 and 907) The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment experienced patients participating in trials 902 and 907. In both of these studies, 94% of the participants evaluated had baseline HIV isolates expressing at least one NRTI mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F or K219Q /E/N),the lamivudine/abacavir-associated mutation (M184V),and others. In addition the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall results in studies 902 and 907. The use of resistance testing and the clinical interpretation of genotypic mutations is a complex and evolving field. Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data. Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational patterns on virologic outcome. Descriptions of numerical differences in HIV RNA response are displayed in Table 4. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine-associated mutations were observed and appeared to depend on the number of specific mutations. VIREAD-treated patients whose HIV expressed 3 or more zidovudine-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N,K70R,T215Y/F or K219Q/E/N mutation did not appear to affect responses to VIREAD therapy. The HIV RNA responses by number and type of baseline zidovudine-associated mutations are shown in Table 4. Table 4. HIV RNA Response at Week 24 by Number of Baseline Zidovudine-Associated
Mutations in Studies 902 and 907 (Intent-To-Treat)1
1. Genotypic testing performed by Virco Laboratories and Visible Genetics TruGene™ technology 2. M41L,D67N,K70R,L210W,T215Y/F or K219Q/E/N in RT 3. Average HIV RNA change from baseline through week 24 (DAVG24) in log10 copies/mL In the protocol defined analyses, virologic response to VIREAD was not reduced in patients with HIV that expressed the lamivudine/abacavir-associated M184V mutation. In the absence of zidovudine-associated mutations, patients with the M184V mutation receiving VIREAD showed a –0.84 log10 copies/mL decrease in their HIV RNA relative to placebo. In the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV RNA responses to VIREAD treatment. More data are needed to determine the impact of M184V alone (in the absence of all other NRTI mutations) on subsequent virologic response in patients receiving VIREAD. There were limited data on patients expressing some primary nucleoside reverse transcriptase inhibitor mutations and multi-drug resistant mutations at baseline. However, patients expressing mutations at K65R (N=6),or L74V without zidovudine-associated mutations (N=6) appeared to have reduced virologic responses to VIREAD. The presence of at least one HIV protease inhibitor or non nucleoside reverse transcriptase inhibitor mutation at baseline did not appear to affect the virologic response to VIREAD. Cross-resistance between VIREAD and HIV protease inhibitors is unlikely because of the different enzyme targets involved. Phenotypic Analyses of VIREAD in Patients with Previous Antiretroviral Therapy (Studies 902 and 907) The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment experienced patients participating in trials 902 and 907. Phenotypic analysis of baseline HIV from patients in Studies 902 and 907 demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 5 summarizes the HIV RNA response by baseline VIREAD susceptibility. Table 5. HIV RNA Response at Week 24 by Baseline VIREAD Susceptibility
in Studies 902 and 907 (Intent-To-Treat)1
1. Tenofovir susceptibility was determined by recombinant phenotypic AntivirogramTM assay (Virco) 2. Fold change in susceptibility from wild-type 3. Average HIV RNA change from baseline through week 24 (DAVG24) in log10 copies/mL The dose of VIREAD (tenofovir disoproxil fumarate) is 300 mg once daily taken orally with a meal. VIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. The tablets are almond-shaped, light blue film-coated, and debossed with "GILEAD" and "4331" on one side and with "300" on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 61958-0401-1) containing a desiccant (silica gel canister or sachet) and closed with child-resistant closure. Store at 25°C (77°F),excursions permitted to 15-30°C (59-86°F) (see USP Controlled Room Temperature). Updated April 11, 2003 VIREAD™ is a trademark of Gilead Sciences, Inc. © Gilead Sciences, Inc. More than 1000 patients have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 143 weeks in Phase I-III clinical trials and a compassionate access study. Assessment of adverse reactions is based on two studies (902 and 907) in which 653 treatment experienced patients received double-blind treatment with VIREAD 300 mg (n=443) or placebo (n=210) for 24 weeks followed by extended treatment with VIREAD. Treatment-Related Adverse Events: The most common adverse events that occurred in patients receiving VIREAD with other antiretroviral agents in clinical trials were mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse events. A summary of treatment related adverse events is provided in Table 6 below. Table 6. Treatment-Related Adverse Events (Grades 1-4)
Reported in ³3% of VIREAD-Treated Patients
in the Pooled 902 - 907 Studies (0-24 weeks)
Laboratory Abnormalities: Laboratory abnormalities observed in these studies occurred with similar frequency in the VIREAD and placebo treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 7 below. Table 7: Grade 3/4 Laboratory Abnormalities Reported
in ³ 1% of VIREAD-Treated Patients in
the Pooled 902 - 907 Studies (0-24 weeks)
Observed During Clinical Practice In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD. Body as a whole: Asthenia Gastrointestinal: Pancreatitis Metabolic and nutritional: Hypophosphatemia, lactic acidosis Nervous: Dizziness Respiratory: Dyspnea Skin: Rash Urogenital: Increased creatinine, renal insufficiency, kidney failure, Fanconi syndrome At concentrations substantially higher (~ 300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP3A4, CYP2D6, CYP2C9 or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low. (See Pharmacokinetics) Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of VIREAD with drugs that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered drug, due to competition for this elimination pathway. Drugs that decrease renal function may also increase serum concentrations of tenofovir. VIREAD has been evaluated in healthy volunteers in combination with didanosine, lamivudine, indinavir, efavirenz, and lopinavir / ritonavir. Tables 1 and 2 summarize pharmacokinetic effects of co-administered drug on tenofovir pharmacokinetics and effects of tenofovir on the pharmacokinetics of co-administered drug. Table 1. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir1 in the Presence of the Co-administered Drug
1. Patients received VIREAD 300 mg once daily 2. Increase= ; Decrease= ¯ ; No Effect= Û 3. Buffered formulation Table 2. Drug Interactions: Changes in Pharmacokinetic
Parameters for Co-administered Drug in the Presence of VIREAD 300 mg Once
Daily
1. Increase= ; Decrease= ¯ ; No Effect= Û 2. Buffered formulation 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 factors. 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 VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Renal Impairment Tenofovir is principally eliminated by the kidney. VIREAD should not be administered to patients with renal insufficiency (creatinine clearance < 60 mL/min) until data become available describing the disposition of VIREAD in these patients. Renal impairment, which may include hypophosphatemia, has been reported with the use of VIREAD (see Adverse Reactions). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents. VIREAD 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.
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