Tenofovir Disoproxil Fumarate

Name: Tenofovir Disoproxil Fumarate

How supplied

Dosage Forms And Strengths

VIREAD is available as tablets or as an oral powder.

VIREAD tablets 150 mg contain 150 mg of tenofovir DF, 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 DF, 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 DF, 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 DF, 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 DF, which is equivalent to 33 mg of tenofovir disoproxil, per level scoop. Each level scoop contains 1 gram of oral powder.

Storage And Handling

Tablets

VIREAD tablets, 150 mg, are triangle-shaped, white, film-coated tablets containing 150 mg of tenofovir DF, which is equivalent to 123 mg of tenofovir disoproxil, and are debossed with “GSI” on one side and with “150” on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0404-1)

VIREAD tablets, 200 mg, are round-shaped, white, film-coated tablets containing 200 mg of tenofovir DF, which is equivalent to 163 mg of tenofovir disoproxil, and are debossed with “GSI” on one side and with “200” on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0405-1)

VIREAD tablets, 250 mg, are capsule-shaped, white, film-coated tablets containing 250 mg of tenofovir DF, which is equivalent to 204 mg of tenofovir disoproxil, and are debossed with “GSI” on one side and with “250” on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0406-1)

VIREAD tablets, 300 mg, are almond-shaped, light-blue, film-coated tablets containing 300 mg of tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil, and are debossed with “GILEAD” and “4331” on one side and with “300” on the other side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. (NDC 61958-0401-1)

Oral Powder

VIREAD oral powder consists of white, coated granules containing 40 mg of tenofovir DF, which is equivalent to 33 mg of tenofovir disoproxil, per gram of powder and is available in multi-use bottles containing 60 grams of oral powder, closed with a child-resistant closure, and co-packaged with a dosing scoop. (NDC 61958-0403-1)

Store VIREAD tablets and oral powder at 25 °C (77 °F), excursions permitted to 1530 °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.

Manufactured for and distributed by: Gilead Sciences, Inc. Foster City, CA 94404. Revised: April 2017

Clinical pharmacology

Mechanism Of Action

Tenofovir DF is an antiviral drug [See Microbiology].

Pharmacokinetics

The pharmacokinetics of tenofovir DF 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 (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax 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.

In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.

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 300 mg tablets 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%. 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 Cmax by approximately 1 hour. Cmax 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 (Table 11). 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.

Table 11 Mean (± SD) Tenofovir Pharmacokinetic Parameters by Age Groups for HIV-1-infected Pediatric Patients

Dose and Formulation 300 mg Tablet 8 mg/kg Oral Powder
12 to <18 Years (N=8) 2 to <12 Years (N=23)
Cmax (µg/mL) 0.38 ± 0.13 0.24 ± 0.13
AUCtau (µg•hr/mL) 3.39 ± 1.22 2.59 ± 1.06

Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of VIREAD 300 mg tablet were comparable to exposures achieved in HIV-1 infected adults and adolescents receiving once-daily doses of 300 mg.

Geriatric Patients

Pharmacokinetic trials have not been performed in the elderly (65 years and older).

Patients With Impaired Renal Function

The pharmacokinetics of tenofovir are altered in subjects with renal impairment [See WARNINGS AND PRECAUTIONS]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased (Table 12). It is recommended that the dosing interval for VIREAD be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis [See DOSAGE AND ADMINISTRATION].

Table 12 Pharmacokinetic Parameters (Mean ± SD) of Tenofovira in Subjects with Varying Degrees of Renal Function

Baseline Creatinine Clearance (mL/min) >80
(N=3)
50-80
(N=10)
30-49
(N=8)
12-29
(N=11)
Cmax (µg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19
AUC0-∞ (µg•hr/mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22
CL/F (mL/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1
CLrenal (mL/min) 243.5 ± 33.3 168.6 ± 27.5 100.6 ± 27.5 43.0 ± 31.2
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.

VIREAD has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 13 and 14 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug. Coadministration of VIREAD with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of VIREAD with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with VIREAD, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 14). The mechanism of this interaction is unknown.

No clinically significant drug interactions have been observed between VIREAD and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.

Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Coadministered Drug

Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parametersb
(90% CI)
Cmax AUC Cmin
Atazanavirc 400 once daily × 14 days 33 ↑ 14
(↑ 8 to ↑ 20)
↑ 24
(↑ 21 to ↑ 28)
↑ 22
(↑ 15 to ↑ 30)
Atazanavir/ Ritonavirc 300/100 once daily 12 ↑ 34
(↑ 20 to ↑ 51)
↑ 37
(↑ 30 to ↑ 45)
↑ 29
(↑ 21 to ↑ 36)
Darunavir/Ritonavird 300/100 twice daily 12 ↑ 24
(↑ 8 to ↑ 42)
↑ 22
(↑ 10 to ↑ 35)
↑ 37
(↑ 19 to ↑ 57)
Indinavir 800 three times daily × 7 days 13 ↑ 14
(↓ 3 to ↑ 33)
Ledipasvir/ Sofosbuvire,f 90/400 once daily × 10 days 24 ↑ 47
(↑ 37 to ↑ 58)
↑ 35
(↑ 29 to ↑ 42 )
↑ 47
(↑ 38 to ↑ 57)
Ledipasvir/ Sofosbuvire,g   23 ↑ 64
(↑ 54 to ↑ 74)
↑ 50
(↑ 42 to ↑ 59)
↑ 59
(↑ 49 to ↑ 70)
Ledipasvir/ Sofosbuvirh 90/400 once daily × 14 days 15 ↑ 79
(↑ 56 to ↑ 104)
↑ 98
(↑ 77 to ↑ 123)
↑ 163
(↑ 132 to↑197)
Ledipasvir/ Sofosbuviri 90/400 once daily × 10 days 14 ↑ 32
(↑ 25 to ↑ 39 )
↑ 40
(↑ 31 to ↑ 50 )
↑ 91
(↑ 74 to ↑ 110)
Ledipasvir/ Sofosbuvirj 90/400 once daily × 10 days 29 ↑ 61
(↑ 51 to ↑ 72)
↑ 65
(↑ 59 to ↑ 71)
↑ 115
(↑ 105 to ↑ 126)
Lopinavir/ Ritonavir 400/100 twice daily 14 days 24 ↑ 32
(↑ 25 to ↑ 38)
↑ 51
(↑ 37 to ↑ 66)
Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 ↑ 23
(↑ 16 to ↑ 30)
Sofosbuvirk 400 single dose 16 ↑ 25
(↑ 8 to ↑ 45)
Sofosbuvir/ Velpatasvirl 400/100 once daily 24 ↑ 55
(↑ 43 to ↑ 68)
↑ 30
(↑ 24 to ↑ 36)
↑ 39
(↑ 31 to ↑ 48)
Sofosbuvir/ Velpatasvirm 400/100 once daily 29 ↑ 55
(↑ 45 to ↑ 66)
↑ 39
(↑ 33 to ↑ 44)
↑ 52
(↑ 45 to ↑ 59)
Sofosbuvir/ Velpatasvirn 400/100 once daily 15 ↑ 77
(↑ 53 to ↑ 104)
↑ 81
(↑ 68 to ↑ 94)
↑ 121
(↑ 100 to ↑ 143)
Sofosbuvir/ Velpatasviro 400/100 once daily 24 ↑ 36
(↑ 25 to ↑ 47)
↑ 35
(↑ 29 to ↑ 42)
↑ 45
(↑ 39 to ↑ 51)
Sofosbuvir/ Velpatasvirp 400/100 once daily 24 ↑ 44
(↑ 33 to ↑ 55)
↑ 40
(↑ 34 to ↑ 46)
↑ 84
(↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasvirq 400/100 once daily 30 ↑ 46
(↑ 39 to ↑ 54)
↑ 40
(↑ 34 to ↑ 45)
↑ 70
(↑ 61 to ↑ 79)
Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ↑ 13
(↑ 1 to ↑ 27)
Tipranavir/ Ritonavirr 500/100 twice daily 22 ↓ 23
(↓ 32 to ↓ 13)
↓ 2
(↓ 9 to ↑ 5)
↑ 7
(↓ 2 to ↑ 17)
750/200 twice daily (23 doses) 20 ↓ 38
(↓ 46 to ↓ 29)
↑ 2
(↓ 6 to ↑ 10)
↑ 14
(↑ 1 to ↑ 27)
a. Subjects received VIREAD 300 mg once daily.
b. Increase = ↑; Decrease = ↓; No Effect = ⇔
c. Reyataz Prescribing Information.
d. Prezista Prescribing Information.
e. Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provide similar results.
f. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF.
g. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF.
h. Study conducted with ATRIPLA (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI.
i. Study conducted with COMPLERA (emtricitabine/rilpivirine/tenofovir DF) coadministered with HARVONI.
j. Study conducted with TRUVADA (emtricitabine/tenofovir DF) + dolutegravir coadministered with HARVONI.
k. Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir).
l. Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF.
m. Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF.
n. Study conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir).
o. Study conducted with STRIBILD (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA.
p. Study conducted with COMPLERA coadministered with EPCLUSA.
q. Administered as raltegravir + emtricitabine/tenofovir DF.
r. Aptivus Prescribing Information.

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with VIREAD: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.

Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIREAD

Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parametersa
(90% CI)
Cmax AUC Cmin
Abacavir 300 once 8 ↑ 12
(↓ 1 to ↑ 26)
NA
Atazanavirb 400 once daily × 14 days 34 ↓ 21
(↓ 27 to ↓ 14)
↓ 25
(↓ 30 to ↓ 19)
↓ 40
(↓ 48 to ↓ 32)
Atazanavirb Atazanavir/ Ritonavir 300/100 once daily × 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25c
(↓ 42 to ↓ 3)
↓ 23c
(↓ 46 to ↑ 10)
Darunavird Darunavir/Ritonavir 300/100 once daily 12 ↑ 16
(↓ 6 to ↑ 42)
↑ 21
(↓ 5 to ↑ 54)
↑ 24
(↓ 10 to ↑ 69)
Didanosinee 250 once, simultaneously with VIREAD and a light mealf 33 ↓ 20g
(↓ 32 to ↓ 7)
⇔g NA
Emtricitabine 200 once daily × 7 days 17 ↑ 20
(↑ 12 to ↑ 29)
Entecavir 1 mg once daily × 10 days 28 ↑ 13
(↑ 11 to ↑ 15)
Indinavir 800 three times daily × 7 days 12 ↓ 11
(↓ 30 to ↑ 12)
Lamivudine 150 twice daily × 7 days 15 ↓ 24
(↓ 34 to ↓ 12)
Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24
Ritonavir
Saquinavi Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22 (↑ 6 to ↑ 41) ↑ 29h
(↑ 12 to ↑ 48)
↑ 47h
(↑ 23 to ↑ 76)
Ritonavir ↑ 23
(↑ 3 to ↑ 46)
Tacrolimus 0.05 mg/kg twice daily × 7 days 21
Tipranaviri Tipranavir/Ritonavir 500/100 twice daily 22 ↓ 17
(↓ 26 to ↓ 6)
↓ 18
(↓ 25 to ↓ 9)
↓ 21
(↓ 30 to ↓ 10)
Tipranavir/Ritonavir 750/200 twice daily (23 doses) 20 ↓ 11
(↓ 16 to ↓ 4)
↓ 9
(↓ 15 to ↓ 3)
↓ 12
(↓ 22 to 0)
a. Increase = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable
b. Reyataz Prescribing Information.
c. In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3-and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
d. Prezista Prescribing Information.
e. Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules.
f. 373 kcal, 8.2 g fat
g. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.
h. Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.
i. Aptivus Prescribing Information.

Microbiology

Mechanism Of Action

Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF 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, tenofovir was not antagonistic 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). 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 2to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.

In Study 903 of treatment-naïve subjects (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) [See Clinical Studies], 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%) of analyzed patient isolates in the VIREAD arm and in 2/49 (4%) of analyzed patient isolates in the stavudine arm. Of the 8 subjects whose virus developed K65R in the VIREAD arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the VIREAD arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to VIREAD were not identified in this trial.

In Study 934 of treatment-naïve subjects (VIREAD + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz) [See Clinical Studies], genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 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 of analyzed subject isolates in the VIREAD + EMTRIVA group and in 10/29 of 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 and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three 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) [See Clinical Studies], 14/304 (5%) of the VIREAD-treated subjects with virologic failure through Week 96 had greater than 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 trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial 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 15 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

Table 15 HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (IntentTo-Treat)a

Baseline VIREAD Susceptibilityb Change in HIV-1 RNAc (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 greater than 100 µM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine, no antagonistic activity was observed.

Resistance

Cumulative VIREAD genotypic resistance has been evaluated annually for up to 384 weeks in Studies 0102, 0103, 0106, 0108, and 0121 with the paired HBV reverse transcriptase amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of VIREAD monotherapy and remained viremic with HBV DNA greater than or equal to 400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of VIREAD monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Studies 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on VIREAD monotherapy (15% versus 5%, respectively).

HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 16); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to VIREAD (genotypic and phenotypic analyses).

Table 16 Amino Acid Substitutions in Viremic Subjects across HBV Trials of VIREAD

  Compensated Liver Disease Decompensated Liver Disease
(N=39)d
Nucleotide-Naïve
(N=417)a
HEPSERA-Experienced
(N=247)b
Lamivudine-Resistant
(N=136)c
Viremic at Last Time Point on VIREAD 38/417 (9%) 37/247 (15%) 9/136 (7%) 7/39 (18%)
Treatment-Emergent Amino Acid Substitutionse 18f/32 (56%) 11g/31 (35%) 6h/8 (75%) 3/5 (60%)
a. Nucleotide-naïve subjects from Studies 0102 (N=246) and 0103 (N=171) receiving up to 384 weeks of treatment with VIREAD.
b. HEPSERA-experienced subjects from Studies 0102/0103 (N=195) and 0106 (N=52) receiving up to 336 weeks of treatment with VIREAD after switching to VIREAD from HEPSERA. Study 0106, a randomized, double-blind, 168-week Phase 2 trial, has been completed.
c. Lamivudine-resistant subjects from Study 0121 (N=136) receiving up to 96 weeks of treatment with VIREAD after switching to VIREAD from lamivudine.
d. Subjects with decompensated liver disease from Study 0108 (N=39) receiving up to 48 weeks of treatment with VIREAD.
e. Denominator includes those subjects who were viremic at last time point on VIREAD monotherapy and had evaluable paired genotypic data.
f. Of the 18 subjects with treatment-emergent amino acid substitutions during Studies 0102 and 0103, 5 subjects had substitutions at conserved sites and 13 subjects had substitutions only at polymorphic sites, and 8 subjects had only transient substitutions that were not detected at the last time point on VIREAD.
g. Of the 11 HEPSERA-experienced subjects with treatment-emergent amino acid substitutions, 2 subjects had substitutions at conserved sites and 9 had substitutions only at polymorphic sites.
h. Of the 6 lamivudine-resistant subjects with treatment-emergent substitutions during Study 0121, 3 subjects had substitutions at conserved sites and 3 had substitutions only at polymorphic sites.

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.

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.

One hundred fifty-two subjects initiating VIREAD therapy in Studies 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 384 weeks of VIREAD treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir-and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA less than 400 copies/mL [69 IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.

Animal Toxicology And/Or Pharmacology

Tenofovir and tenofovir DF administered in toxicology studies to rats, dogs, and monkeys at exposures (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 exposures (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.

Clinical Studies

Clinical Efficacy In Adults With HIV-1 Infection

Treatment-Naïve Adult Patients

Study 903

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18−64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3−956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417−5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 17.

Table 17 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)

Outcomes At Week 48 At Week 144
VIREAD+3TC +EFV
(N=299)
d4T+3TC +EFV
(N=301)
VIREAD+3TC +EFV
(N=299)
d4T+3TC +EFV
(N=301)
Respondera 79% 82% 68% 62%
Virologic failureb 6% 4% 10% 8%
  Rebound 5% 3% 8% 7%
  Never suppressed 0% 1% 0% 0%
  Added an antiretroviral agent 1% 1% 2% 1%
Death <1% 1% <1% 2%
Discontinued due to adverse event 6% 6% 8% 13%
Discontinued for other reasons c 8% 7% 14% 15%
a. Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144.
b. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.
c. Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons.

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the VIREAD and stavudine arms, respectively, achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the VIREAD arm and 283 cells/mm3 for the stavudine arm.

Through 144 weeks, 11 subjects in the VIREAD group and 9 subjects in the stavudine group experienced a new CDC Class C event.

Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD with efavirenz. Subjects had a mean age of 38 years (range 18−80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2−1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56−6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.

Table 18 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)

Outcomes At Week 48 At Week 144
FTC +VIREAD +EFV
(N=244)
AZT/3TC +EFV
(N=243)
FTC +VIREAD +EFV
(N=227)a
AZT/3TC +EFV
(N=229)a
Responderb 84% 73% 71% 58%
Virologic failurec 2% 4% 3% 6%
  Rebound 1% 3% 2% 5%
  Never suppressed 0% 0% 0% 0%
  Change in antiretroviral regimen 1% 1% 1% 1%
Death <1% 1% 1% 1%
Discontinued due to adverse event 4% 9% 5% 12%
Discontinued for other reasonsd 10% 14% 20% 22%
a. Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the trial after Week 48 or Week 96 were excluded from analysis.
b. Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
c. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.
d. Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.

Through Week 48, 84% and 73% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA + VIREAD group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the emtricitabine + VIREAD group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Treatment-Experienced Adult Patients

Study 907

Study 907 was a 24-week, double-blind, placebo-controlled multicenter trial of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label VIREAD for an additional 24 weeks. Subjects had a mean baseline CD4+ cell count of 427 cells/mm3 (range 23−1385), median baseline plasma HIV-1 RNA of 2340 (range 50−75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years; 85% were male, 69% Caucasian, 17% Black, and 12% Hispanic.

The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.

Table 19 Outcomes of Randomized Treatment (Study 907)

Outcomes 0-24 weeks 0-48 weeks 24-48 weeks
VIREAD
(N=368)
Placebo
(N=182)
VIREAD
(N=368)
Placebo Crossover to VIREAD
(N=170)
HIV-1 RNA <400 copies/mL a 40% 11% 28% 30%
Virologic failureb 53% 84% 61% 64%
Discontinued due to adverse event 3% 3% 5% 5%
Discontinued for other reasons c 3% 3% 5% 1%
a. Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48, respectively.
b. Subjects with HIV-1 RNA .400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48, respectively.
c. Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation, and other reasons.

At 24 weeks of therapy, there was a higher proportion of subjects in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the VIREAD group and −5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the VIREAD group.

Through Week 24, one subject in the VIREAD group and no subjects in the placebo arm experienced a new CDC Class C event.

Clinical Efficacy In Adults With Chronic Hepatitis B

HBeAg-Negative Chronic Hepatitis B

Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg-(anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years; 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy, and 18% were nucleosideexperienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.

HBeAg-Positive Chronic Hepatitis B

Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of VIREAD 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years; 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.

The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.

The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).

Table 20 Histological, Virological, Biochemical, and Serological Response at Week 48

  0102 (HBeAg-) 0103 (HBeAg+)
VIREAD
(N=250)
HEPSERA
(N=125)
VIREAD
(N=176)
HEPSERA
(N=90)
Complete Response 71% 49% 67% 12%
Histology
Histological Responsea
72% 69% 74% 68%
HBV DNA
<400 copies/mL (<69 IU/mL)
93% 63% 76% 13%
ALT
Normalized ALTb
76% 77% 68% 54%
Serology
HBeAg Loss/ Seroconversion
NAc NAc 20%/19% 16%/16%
HBsAg Loss/ Seroconversion 0/0 0/0 3%/1% 0/0
a. Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.
b. The population used for analysis of ALT normalization included only subjects with ALT above ULN at baseline.
c. NA = Not Applicable

Treatment Beyond 48 Weeks

In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.

In Study 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the study through Week 384. Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384. At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.

In Study 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the study through Week 384. Among subjects randomized to VIREAD, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384. At Week 384, HBsAg loss and seroconversion were 11% and 8%, respectively, in subjects initially randomized to VIREAD and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48, and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0−4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5−6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Patients With Lamivudine-Resistant Chronic Hepatitis B

Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of VIREAD compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/-rtL180M). One hundred forty-one adult subjects were randomized to the VIREAD treatment arm. The mean age of subjects randomized to VIREAD was 47 years (range 18−73); 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.

After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to VIREAD had HBV DNA <400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to VIREAD, 10 of 65 subjects (15%) experienced HBeAg loss and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the VIREAD monotherapy and the comparator arms.

Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

Patients With Chronic Hepatitis B And Decompensated Liver Disease

VIREAD was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of VIREAD compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).

Forty-five adult subjects (37 males and 8 females) were randomized to the VIREAD treatment arm. At baseline, 69% subjects were HBeAg-negative and 31% were HBeAgpositive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL, and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥0.5 mg/dL or confirmed serum phosphorus of <2 mg/dL [See ADVERSE REACTIONS].

At 48 weeks, 31/44 (70%) and 12/26 (46%) VIREAD-treated subjects achieved an HBV DNA <400 copies/mL (69 IU/mL), and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.

What is tenofovir (viread)?

Tenofovir is an antiviral medication that prevents human immunodeficiency virus (HIV) or hepatitis B virus cells from multiplying in your body.

Tenofovir is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Tenofovir is not a cure for HIV or AIDS. Tenofovir is also used to treat chronic hepatitis B.

Tenofovir may also be used for purposes not listed in this medication guide.

What should i avoid while taking tenofovir (viread)?

Avoid drinking alcohol. It may increase your risk of liver damage.

Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 230 232 233 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 230 232 233

  • Importance of using tenofovir DF (Viread) or emtricitabine/tenofovir DF (Truvada) in conjunction with other antiretrovirals for treatment of HIV-1not for monotherapy.1 230

  • Efavirenz/emtricitabine/tenofovir DF (Atripla) or emtricitabine/rilpivirine/tenofovir DF (Complera) can be used alone as a complete treatment regimen.232 233

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications of HIV disease may still occur.1 230 232 233

  • Advise HIV-infected patients that effective antiretroviral treatment regimens can decrease HIV-1 concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200 230 232 233

  • Emtricitabine/tenofovir DF (Truvada) medication guide must be provided to and reviewed with all HIV-negative individuals each time emtricitabine/tenofovir DF is dispensed for HIV-1 PrEP.37 230 (See REMS.) Advise such individuals of the importance of confirming that they are HIV-1-negative before starting PrEP, importance of regular HIV-1 testing (at least every 3 months) during PrEP, importance of strictly adhering to recommended dosage schedule and not missing any doses, and importance of using a complete prevention strategy that also includes other measures (e.g., consistent condom use, testing for other sexually transmitted infections such as syphilis and gonorrhea that may facilitate HIV-1 transmission, reducing sexual risk behavior).230 Advise uninfected individuals that emtricitabine/tenofovir DF PrEP does not protect all individuals from acquiring HIV-1 and to report any symptoms of acute HIV-1 infection (e.g., fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, cervical and inguinal adenopathy) immediately to a clinician.230

  • Importance of reading patient information provided by the manufacturer.1 230 232 233

  • Redistribution/accumulation of body fat may occur; cause and long-term health effects unknown.1 230 232 233

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as concomitant medical problems such as renal or hepatic impairment.1 230 232 233

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 230 232 233 Advise HIV-infected women not to breast-feed.1 230 232 233

  • Importance of advising patients of other important precautionary information.1 230 232 233 (See Cautions.)

Brand Names U.S.

  • Viread

Special Populations Renal Function Impairment

In patients with CrCl <50 mL/minute or with ESRD requiring dialysis, Cmax and AUC of tenofovir were increased. Following a single 300 mg dose, a 4-hour hemodialysis session removed ~10% of the administered tenofovir dose.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to tenofovir or any component of the formulation

Dosing Adult

Hepatitis B infection: Oral: 300 mg once daily

Note: Concurrent use with adefovir and/or tenofovir combination products should be avoided.

Treatment duration (AASLD practice guidelines): Treatment duration for nucleos(t)ide analog-based therapy (eg, tenofovir) is variable and influenced by HBeAg status, duration of HBV suppression, and presence of cirrhosis/decompensation (AASLD [Terrault 2016]):

Patients without cirrhosis:

Hepatitis B e antigen (HBeAg) positive immune-active chronic hepatitis: Treat until HBeAg seroconversion; after seroconversion, prolonged duration of therapy is often required in patients treated with nucleos(t)ide anaglogues,. Optimal duration is unknown; however, consolidation therapy is generally a minimum of 12 months of persistently normal ALT and undetectable serum HBV DNA levels after HBeAg seroconversion

HBeAg-negative immune-active chronic hepatitis: Indefinite antiviral therapy is suggested unless there is competing rationale for discontinuation (risk/benefit decision); treatment discontinuation may be considered in patients with loss of HBsAg; however, there is insufficient evidence to guide decisions in these patients.

Patients with cirrhosis:

HBeAg-positive immune-active chronic hepatitis: In patients who seroconvert on therapy, continue antiviral therapy indefinitely due to concerns with decompensation and death, unless there is a strong competing rationale for discontinuation.

HBeAg-negative immune-active chronic hepatitis: Treatment discontinuation is not recommended due to potential for decompensation and death (limited data).

HIV-1 infection, treatment: Oral: 300 mg once daily (in combination with other antiretrovirals). Note: Tenofovir is a component of recommended initial regimens in treatment-naive patients (when coadministered with emtricitabine plus dolutegravir, with emtricitabine plus darunavir/ritonavir, or with emtricitabine plus raltegravir; lamivudine may be substituted for emtricitabine in any of these regimens) and is a component of a recommended initial regimen in treatment-naive patients with pre-ART CrCl >70 mL/minute (when coadministered with emtricitabine plus elvitegravir/cobicistat) (HHS [adult] 2015).

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use): Oral: 300 mg once daily for 28 days (in combination with other antiretroviral agents). Initiate therapy within 72 hours of exposure. Note: The fixed dose emtricitabine and tenofovir disoproxil fumarate combination product is recommended for these components of the 3-drug regimen (HHS [nPEP] 2016)

HIV-1 occupational postexposure, prophylaxis (oPEP) (off-label use): Oral: 300 mg once daily in combination with emtricitabine and raltegravir; initiate therapy as soon as possible after occupational exposure (and within 72 hours) and continue for 4 weeks. Note: The fixed dose emtricitabine and tenofovir disoproxil fumarate combination product is recommended for these components of the 3-drug regimen (Kuhar 2013)

Dosing Geriatric

Refer to adult dosing.

Use in specific populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tenofovir Disoproxil Fumarate should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tenofovir Disoproxil Fumarate, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Risk Summary

Animal Data

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.

Nursing Mothers

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.  Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. 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 breastfeed if they are receiving Tenofovir Disoproxil Fumarate.

Pediatric Use

Pediatric Patients 2 Years of Age and Older with HIV-1 infection

The safety of Tenofovir Disoproxil Fumarate in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which Tenofovir Disoproxil Fumarate was administered to HIV-1 infected treatment-experienced subjects. In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials [see Clinical Pharmacology (12.3)].

In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with Tenofovir Disoproxil Fumarate (N=44) or continue their original regimen (N=48) for 48 weeks. Five additional subjects over the age of 12 were enrolled and randomized (Tenofovir Disoproxil Fumarate N=4, original regimen N=1) but are not included in the efficacy analysis. After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label Tenofovir Disoproxil Fumarate. At Week 48, 89% of subjects in the Tenofovir Disoproxil Fumarate treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL. During the 48 week randomized phase of the study, 1 subject in the Tenofovir Disoproxil Fumarate group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the Tenofovir Disoproxil Fumarate group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.

In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with Tenofovir Disoproxil Fumarate (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the Tenofovir Disoproxil Fumarate and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to Tenofovir Disoproxil Fumarate and OBR.

Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of Tenofovir Disoproxil Fumarate in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to Tenofovir Disoproxil Fumarate. [see Warnings and Precautions (5.6), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

Safety and effectiveness of Tenofovir Disoproxil Fumarate in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.

Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B

In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with Tenofovir Disoproxil Fumarate 300 mg (N=52) or placebo (N=54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with Tenofovir Disoproxil Fumarate, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the Tenofovir Disoproxil Fumarate group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving Tenofovir Disoproxil Fumarate had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One Tenofovir Disoproxil Fumarate-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.

Safety and effectiveness of Tenofovir Disoproxil Fumarate in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

Geriatric Use


Clinical trials of Tenofovir Disoproxil Fumarate 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 Tenofovir Disoproxil Fumarate be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

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