Drug Description

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-1 reverse transcriptase.

VIREAD tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg tablets are coated with Opadry II Y–30–10671–A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

VIREAD oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil. The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.

HIV/AIDS-Related Uses

INDICATIONS AND USAGE

HIV-1 Infection
VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.

The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:

• VIREAD should not be used in combination with ATRIPLA®, COMPLERA®, or TRUVADA®

Chronic Hepatitis B
VIREAD is indicated for the treatment of chronic hepatitis B in adults.

The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection:

• This indication is based primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease
• VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease.
• The numbers of subjects in clinical trials who had lamivudine- or adefovirassociated substitutions at baseline were too small to reach conclusions of efficacy.

Dosing Information

Mode of Delivery

Oral.

Dosage Form

VIREAD is available as tablets or as an oral powder.

VIREAD tablets 150 mg contain 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil. The tablets are triangle-shaped, white, film-coated, and debossed with “GSI” on one side and “150” on the other side.

VIREAD tablets 200 mg contain 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil. The tablets are round-shaped, white, film-coated, and debossed with “GSI” on one side and “200” on the other side.

VIREAD tablets 250 mg contain 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil. The tablets are capsule-shaped, white, film-coated, and debossed with “GSI” on one side and “250” on the other side.

VIREAD tablets 300 mg contain 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.

The oral powder consists of white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per level scoop. Each level scoop contains 1 gram of oral powder.

DOSAGE AND ADMINISTRATION

Recommended Dose in Adults
For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.

For adults unable to swallow VIREAD tablets, the oral powder formulation (7.5 scoops) may be used.
In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.

Recommended Dose in Pediatric Patients (2 to Less Than 18 Years of Age)
For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of VIREAD is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.

VIREAD oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate. VIREAD oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer VIREAD oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer VIREAD oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).

VIREAD is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.

Dosing recommendations for VIREAD oral powder and tablets based on body weight are shown below. Weight should be monitored periodically and the VIREAD dose adjusted accordingly.

Dosing Recommendations for Pediatric Patients ≥2 Years of Age Using VIREAD Oral Powder

Body Weight (Kilogram [kg]):  Oral Powder Once Daily (Scoops of Powder)

10 to <12 kg:  2 scoops of powder
12 to <14 kg:  2.5 scoops of powder
14 to <17 kg:  3 scoops of powder
17 to <19 kg:  3.5 scoops of powder
19 to <22 kg:  4 scoops of powder
22 to <24 kg:  4.5 scoops of powder
24 to <27 kg:  5 scoops of powder
27 to <29 kg:  5.5 scoops of powder
29 to <32 kg:  6 scoops of powder
32 to <34 kg:  6.5 scoops of powder
34 to <35 kg:  7 scoops of powder
≥35 kg:  7.5 scoops of powder


Dosing Recommendations for Pediatric Patients ≥2 Years of Age and Weighing ≥17 kg Using VIREAD Tablets

Body Weight (Kilogram [kg]):  Tablets Once Daily

17 to <22 kg:  150 mg
22 to <28 kg:  200 mg
28 to <35 kg:  250 mg
≥35 kg:  300 mg

Dose Adjustment for Renal Impairment in Adults
Significantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment. Therefore, the dosing interval of VIREAD tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations shown below. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients. There are no data to recommend use of VIREAD tablets 150, 200 or 250 mg or VIREAD oral powder in patients with renal impairment.

No dose adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment. 

Dosage Adjustment for Patients with Altered Creatinine Clearance

• Creatinine Clearance  ≥50 mL/min^a: Every 24 hours
• Creatinine Clearance  30–49 mL/min^a: Every 48 hours
• Creatinine Clearance  10–29 mL/min^a: Every 72 to 96 hours
• Hemodialysis Patients: Every 7 days or after a total of approximately 12 hours of dialysis^b

a. Calculated using ideal (lean) body weight.
b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.

No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.

Storage

Store VIREAD tablets and oral powder at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).

Keep the bottle tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.

Pharmacology

Mechanism of Action
Tenofovir disoproxil fumarate is an antiviral drug.

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
VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted subjects is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C_max) are achieved in 1.0 ± 0.4 hrs. C_max and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg•hr/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.

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 CYP 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. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. 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.

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 AUC_0-∞ of approximately 40% and an increase in C_max of approximately 14%. However, administration of VIREAD 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 C_max by approximately 1 hour. C_max and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Special Populations

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

Gender: Tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (see below). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of VIREAD 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.

Mean (± SD) Tenofovir Pharmacokinetic Parameters by Age Groups for Pediatric Patients

300 mg Tablet
12 to <18 Year (N=8)
C_max (μg/mL): 0.38 ± 0.13
AUC_tau (μg•hr/mL): 3.39 ± 1.22

8 mg/kg Oral Powder
2 to <12 Years (N=23)
C_max (μg/mL): 0.24 ± 0.13
AUC_tau (μg•hr/mL): 2.59 ± 1.06

Geriatric Patients: Pharmacokinetic studies have not been performed in the elderly (>65 years).

Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, C_max, and AUC_0-∞ of tenofovir were increased (see below). It is recommended that the dosing interval for VIREAD be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis.

Pharmacokinetic Parameters (Mean ± SD) of Tenofovir^a in Subjects with Varying Degrees of Renal Function

Baseline Creatinine Clearance >80 mL/min (N=3) – C_max: 0.34 ± 0.03 μg/mL; AUC_0-∞: 2.18 ± 0.26 μg•hr/mL; CL/F: 1043.7 ± 115.4 mL/min; CL_renal: 243.5 ± 33.3 mL/min.

Baseline Creatinine Clearance 50–80 mL/min (N=10) – C_max: 0.33 ± 0.06 μg/mL; AUC_0-∞: 3.06 ± 0.93 μg•hr/mL; CL/F: 807.7 ± 279.2 mL/min; CL_renal: 168.6 ± 27.5 mL/min.

Baseline Creatinine Clearance 30–49 mL/min (N=8) – C_max: 0.37 ± 0.16 μg/mL; AUC_0-∞: 6.01 ± 2.50 μg•hr/mL; CL/F: 444.4 ± 209.8 mL/min; CL_renal: 100.6 ± 27.5 mL/min.

Baseline Creatinine Clearance 12–29 mL/min (N=11) – C_max: 0.60 ± 0.19 μg/mL; AUC_0-∞: 15.98 ± 7.22 μg•hr/mL; CL/F: 177.0 ± 97.1 mL/min; CL_renal: 43.0 ± 31.2 mL/min.

a. 300 mg, single dose of VIREAD

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in VIREAD dosing is required in patients with hepatic impairment.

Assessment of Drug Interactions
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 CYP 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 CYP mediated interactions involving tenofovir with other medicinal products is low.

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 diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV 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.

Activity against HIV

Antiviral Activity
The 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 EC₅₀ (50% effective 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, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC₅₀ values ranged from 0.5 μM to 2.2 μM) and strain specific activity against HIV-2 (EC₅₀ values ranged from 1.6 μM to 5.5 μM).

Resistance
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold reduction in susceptibility to tenofovir.

In Study 903 of treatment-naïve subjects (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the VIREAD arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 subjects whose virus developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in resistance to VIREAD were not identified in this study.

In Study 934 of treatment-naïve subjects (VIREAD + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the VIREAD + EMTRIVA group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

Cross Resistance
Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 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 substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.

In Studies 902 and 907 conducted in treatment-experienced subjects (VIREAD + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the VIREAD-treated subjects with virologic failure through Week 96 had >1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation. Virologic responses for subjects in the genotype substudy were similar to the overall study results.

Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. VIREAD-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution 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 substitution did not appear to affect responses to VIREAD therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

In the protocol defined analyses, virologic response to VIREAD was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.

Studies 902 and 907 Phenotypic Analyses
Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 13 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (IntentTo-Treat)^a

Baseline VIREAD Susceptibility^b     Change in HIV-1 RNA^c (N)
                 <1                                                       -0.74 (35)
                 >1 and ≤3                                          -0.56 (49)
                 >3 and ≤4                                           -0.3 (7)
                 >4                                                       -0.12 (9)

a. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).
b. Fold change in susceptibility from wild-type.
c. Average HIV-1 RNA change from baseline through Week 24 (DAVG₂₄) in log₁₀ copies/mL.

Activity against HBV

Antiviral Activity
The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC₅₀ values for tenofovir ranged from 0.14 to 1.5 μM, with CC₅₀ (50% cytotoxicity concentration) values >100 μM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside anti-HBV reverse transcriptase inhibitors emtricitabine, entecavir, lamivudine and telbivudine, no antagonistic activity was observed.

Resistance
Cumulative VIREAD genotypic resistance was evaluated annually with the paired HBV reverse transcriptase amino acid sequences of the pre-treatment and on-treatment isolates from subjects who received at least 24 weeks of VIREAD monotherapy and remained viremic with HBV DNA ≥400 copies/mL at the end of each study year (or at discontinuation of VIREAD monotherapy) using an as-treated analysis. From four ongoing VIREAD trials (Studies 102, 103, and 106 in subjects with compensated liver disease, and Study 108 in subjects with decompensated liver disease), 10% (69/660) of VIREAD recipients with compensated liver disease receiving up to 144 weeks of VIREAD monotherapy and 18% (7/39) of VIREAD recipients with decompensated liver disease receiving up to 48 weeks of VIREAD monotherapy remained viremic at their last time-point on VIREAD monotherapy. In the HEPSERA-naïve HBeAg+ subject population from Study 103, 74% (17/23) of the subjects with HBV DNA ≥400 copies/mL at their last time-point on VIREAD monotherapy had a baseline viral load of >9 log₁₀ copies/mL. Treatment emergent amino acid substitutions in the HBV reverse transcriptase were identified in 46% (32/69) of those subjects in Studies 102, 103, 106, and 108 with evaluable paired genotypic data; no specific substitutions occurred at a sufficient frequency to be associated with resistance to VIREAD (genotypic or phenotypic analyses).

Cross Resistance
Cross resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.

In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7 to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.

HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6 to 6.9-fold that of wild type virus. An HBV strain expressing rtL180M, rtT184G, rtS202I, and rtM204V together had a 6.9-fold reduction in susceptibility to tenofovir.

HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9 to 1.5-fold that of wild type virus.

In the four VIREAD-treatment studies, prior to treatment with VIREAD, 14, 15, and 2 subjects had HBV harboring either adefovir resistance-associated substitutions (rtA181T/V and/or rtN236T) or lamivudine resistance-associated substitutions (rtM204I/V), or both, respectively. Following up to 144 weeks of VIREAD treatment, 11 of the 14 subjects with adefovir-resistant HBV, 12 of the 15 subjects with lamivudineresistant HBV, and 1 of the 2 subjects with both adefovir- and lamivudine-resistant HBV achieved virologic suppression (HBV DNA <400 copies/mL). Two of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions and one of the 5 subjects whose virus harbored these substitutions and an rtM204I substitution remained viremic following up to 32 weeks of VIREAD monotherapy.

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 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
Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. 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.

(For additional information, consult the Viread complete prescribing information). 

Adverse Events/Toxicity

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals.
   
• Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

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, including VIREAD, 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).

Exacerbation of Hepatitis after Discontinuation of Treatment
Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment
Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD.

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA^®.

Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min (See Dosage and Administration). No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.

VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.

Patients Coinfected with HIV-1 and HBV
Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.
HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.

Decreases in Bone Mineral Density
Assessment of bone mineral density (BMD) should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

In HIV-1 infected adult subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range.

In clinical trials evaluating VIREAD in HIV-1 infected pediatric subjects 2 to less than 18 years of age, bone effects were similar to those observed in adult subjects. Under normal circumstances BMD increases rapidly in pediatric patients. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the VIREAD and the d4T or AZT treatment groups. Total body BMD gain was less in the VIREAD compared to the d4T or AZT treatment group. One VIREAD-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with VIREAD for 96 weeks. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the VIREAD compared to the placebo treatment group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with VIREAD for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects suggest increased bone turnover, consistent with the effects observed in adults.

The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD.

The bone effects of VIREAD have not been studied in patients with chronic HBV infection.

Fat Redistribution
In HIV-infected patients 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 combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.

Early Virologic Failure
Clinical studies in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

Clinical Trials in Adult Patients with HIV-1 Infection: More than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access studies. The most common adverse reactions (incidence ≥10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

Clinical Trials in Pediatric Subjects 2 Years of Age and Older with HIV-1 Infection: Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with VIREAD (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults.

Bone effects observed in pediatric subjects 2 years of age and older were consistent with those observed in adult clinical trials.

Eighty-nine pediatric subjects received VIREAD in Study 352 (48 who were initially randomized to VIREAD and 41 who were initially randomized to continue stavudine or zidovudine and then received VIREAD in the extension phase) for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.

In HBV-infected subjects with compensated liver disease, the most common adverse reaction (all grades) was nausea (9%). In HBV-infected subjects with decompensated liver disease, the most common adverse reactions (incidence ≥10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia.

Drug and Food Interactions

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 AUC_0-∞ of approximately 40% and an increase in C_max of approximately 14%. However, administration of VIREAD 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 C_max by approximately 1 hour. C_max and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Coadministration with Other Products
VIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir disoproxil fumarate is a component of these products.

VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

Drug Interactions

Didanosine
Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosineassociated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.

When administered with VIREAD, C_max 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 patients 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 adult or pediatric 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 C_min 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).

Contraindications

None. [1] [2]

References

[1] FDA Viread Prescribing Information, October 2010. Avialable at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021356s035lbl.pdf. Accessed 09/09/2011.

[2] Viread Full Prescribing Information, January 2012. Available at: http://www.viread.com/global_pdfs/Viread_FPI.pdf. Accessed 01/30/2012.

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Fumarato de disoproxilo de tenofovir .

Chemistry

CAS Name

Bis(hydroxymethyl) [[(R)-2(6-Amino- 9H-purin-9-yl)-1-methylethoxy] methyl]phosphonate,bis(isopropyl carbonate) (ester), fumarate (1:1). [1]

CAS Number

202138-50-9 [2]

Molecular Formula

C19-H30-N5-O10-P.C4-H4-O4 [3]

Molecular Weight

635.52 [4]

Physical Description

White to off-white crystalline powder. [5]

Solubility

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. [6]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 09/09/2011.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 09/09/2011.

[3] FDA Viread Prescribing Information, October 2010. Avialable at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021356s035lbl.pdf. Accessed 09/09/2011.

[4] FDA Viread Prescribing Information, October 2010. Avialable at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021356s035lbl.pdf. Accessed 09/09/2011.

[5] FDA Viread Prescribing Information, October 2010. Avialable at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021356s035lbl.pdf. Accessed 09/09/2011.

[6] FDA Viread Prescribing Information, October 2010. Avialable at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021356s035lbl.pdf. Accessed 09/09/2011.

Further Reading

Viread Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, Rozenbaum W, Le Teuff G, Trylesinski A, Piketty C; TECOVIR Study Group. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006 Mar;43(3):548-55.
Gerard L, Chazallon C, Taburet AM, Girard PM, Aboulker JP, Piketty C. Renal function in antiretroviral-experienced patients treated with tenofovir disoproxil fumarate associated with atazanavir/ritonavir. Antivir Ther. 2007;12(1):31-9.
Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, Lazzarin A, Schewe K, Lange J, Wyatt C, Curtis S, Chen SS, Smith S, Bischofberger N, Rooney JF. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS. 2007 Jun 19;21(10):1273-81.
Peterson L, Taylor D, Roddy R, Belai G, Phillips P, Nanda K, Grant R, Clarke EE, Doh AS, Ridzon R, Jaffe HS, Cates W. Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clin Trials. 2007 May 25;2(5):e27.
Pham PA, Gallant JE. Tenofovir disoproxil fumarate for the treatment of HIV infection. Expert Opin Drug Metab Toxicol. 2006 Jun;2(3):459-69.
Squires K, Pozniak AL, Pierone G Jr, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF, Cheng A; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med. 2003 Sep 2; 139(5 Pt 1):313-20. Summary for patients in: Ann Intern Med. 2003 Sep 2; 139(5 Pt 1):I22.

Manufacturer Information

Tenofovir disoproxil fumarate

Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264


Viread

Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Phone: (650) 574-3000
Fax: (650) 578-9264