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VIREAD Label and VIREAD General Information

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viread (tenofovir disoproxil fumarate)  tablet, coated 
[Gilead]

Rx Only

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.

The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.

VIREAD tablets are for oral administration. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.

MICROBIOLOGY

Mechanism of Action

Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases a, ß, and mitochondrial DNA polymerase ?.

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 4.9 µM).

Resistance

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

In Study 903 of treatment-naïve patients (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from patients with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation 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 patients 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 mutations resulting in resistance to VIREAD were not identified in this study.

In Study 934 of treatment-naïve patients (VIREAD + EMTRIVA® + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis performed on HIV isolates from all patients with >400 copies/mL of HIV-1 RNA at Week 48 or early discontinuation showed development of efavirenz resistance-associated mutations occurred most frequently and was similar between the two treatment arms. The M184V mutation, associated with resistance to EMTRIVA and lamivudine, was observed in 2/12 (17%) analyzed patient isolates in the VIREAD + EMTRIVA group and in 7/22 (32%) analyzed patient isolates in the zidovudine/lamivudine group. Through 48 weeks of Study 934, no patients have developed a detectable K65R mutation in their HIV as analyzed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.

Cross-resistance

Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R mutation selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV isolates with this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R mutation. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir.

In Studies 902 and 907 conducted in treatment-experienced patients (VIREAD + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the VIREAD-treated patients 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 mutation 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 patients 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. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), the abacavir/emtricitabine/lamivudine resistance-associated mutation (M184V), and others. In addition the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall study results.

Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational 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 mutations were observed and appeared to depend on the number of specific mutations. VIREAD-treated patients whose HIV-1 expressed 3 or more zidovudine resistance-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N mutation did not appear to affect responses to VIREAD therapy.

In the protocol defined analyses, virologic response to VIREAD was not reduced in patients with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V mutation. In the presence of zidovudine resistance-associated mutations, the M184V mutation did not affect the mean HIV-1 RNA responses to VIREAD treatment. HIV-1 RNA responses among these patients were durable through Week 48.

Studies 902 and 907 Phenotypic Analyses

The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment-experienced patients participating in two controlled trials. Phenotypic analysis of baseline HIV-1 from patients in these studies demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 1 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

Table 1 HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (Intent-To-Treat)*

Baseline VIREAD Susceptibility†	Change in HIV-1 RNA‡ (N)
* Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco). † Fold change in susceptibility from wild-type. ‡ Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL.
<1	-0.74 (35)
>1 and ≤3	-0.56 (49)
>3 and ≤4	-0.3 (7)
>4	-0.12 (9)

CLINICAL PHARMACOLOGY

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 patients is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 296 ± 90 ng/mL and 2287 ± 685 ng·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.

Effects of Food on Oral Absorption

Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0–∞ of approximately 40% and an increase in Cmax of approximately 14%. 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 326 ± 119 ng/mL and 3324 ± 1370 ng·hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Distribution

In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.

Metabolism and Elimination

In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes.

Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. 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.

Special Populations

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

Tenofovir pharmacokinetics are similar in male and female patients.

Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (>65 years).

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

The pharmacokinetics of tenofovir are altered in patients with renal impairment (see WARNINGS, Renal Impairment). In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0–∞ of tenofovir were increased (Table 2). 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 (see DOSAGE AND ADMINISTRATION).

Table 2 Pharmacokinetic Parameters (Mean ± SD) of Tenofovir* in Patients 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)
* 300 mg, single dose of VIREAD
Cmax (ng/mL)	335.4 ± 31.8	330.4 ± 61.0	372.1 ± 156.1	601.6 ± 185.3
AUC 0–∞ (ng·hr/mL)	2184.5 ± 257.4	3063.8 ± 927.0	6008.5 ± 2504.7	15984.7 ± 7223.0
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

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.

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 CYP450 isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low (see Pharmacokinetics).

Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of VIREAD with drugs that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the coadministered drug, due to competition for this elimination pathway. Drugs that decrease renal function may also increase serum concentrations of tenofovir.

VIREAD has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir. Tables 3 and 4 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.

Table 5 summarizes the drug interaction between VIREAD and didanosine. When administered with multiple doses of VIREAD, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with VIREAD, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

Table 3 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir* in the Presence of the Coadministered Drug

Coadministered Drug	Dose of Coadministered Drug (mg)	N	% Change of Tenofovir Pharmacokinetic Parameters† (90% CI)
			Cmax	AUC	Cmin
* Patients received VIREAD 300 mg once daily. † Increase = ↑; Decrease = ↓; No Effect = ; NC = Not Calculated ‡ Reyataz Prescribing Information
Abacavir	300 once	8			NC
Adefovir dipivoxil	10 once	22			NC
Atazanavir‡	400 once daily x 14 days	33	↑ 14 (↑ 8 to ↑ 20)	↑ 24 (↑ 21 to ↑ 28)	↑ 22 (↑ 15 to ↑ 30)
Didanosine (enteric-coated)	400 once	25
Didanosine (buffered)	250 or 400 once daily × 7 days	14
Efavirenz	600 once daily × 14 days	29
Emtricitabine	200 once daily × 7 days	17
Indinavir	800 three times daily × 7 days	13	↑ 14 (↓ 3 to ↑ 33)
Lamivudine	150 twice daily × 7 days	15
Lopinavir/Ritonavir	400/100 twice daily × 14 days	24		↑ 32 (↑ 25 to ↑ 38)	↑ 51 (↑ 37 to ↑ 66)
Nelfinavir	1250 twice daily × 14 days	29
Saquinavir/Ritonavir	1000/100 twice daily × 14 days	35			↑ 23 (↑ 16 to ↑ 30)

Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and VIREAD.

Table 4 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 Parameters* (90% CI)
			Cmax	AUC	Cmin
* Increase = ↑; Decrease = ↓; No Effect = ; NA = Not Applicable † Reyataz Prescribing Information ‡ In HIV-infected patients, 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. § R-(active), S-and total methadone exposures were equivalent when dosed alone or with VIREAD. ¶ Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported. # Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD. Þ 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.
Abacavir	300 once	8	↑ 12 (↓ 1 to ↑ 26)		NA
Adefovir dipivoxil	10 once	22			NA
Atazanavir†	400 once daily × 14 days	34	↓ 21 (↓ 27 to ↓ 14)	↓ 25 (↓ 30 to ↓ 19)	↓ 40 (↓ 48 to ↓ 32)
Atazanavir†	Atazanavir/Ritonavir 300/100 once daily × 42 days	10	↓ 28 (↓ 50 to ↑ 5)	↓ 25‡ (↓ 42 to ↓ 3)	↓ 23‡ (↓ 46 to ↑ 10)
Efavirenz	600 once daily × 14 days	30
Emtricitabine	200 once daily × 7 days	17			↑ 20 (↑ 12 to ↑ 29)
Indinavir	800 three times daily × 7 days	12	↓ 11 (↓ 30 to ↑ 12)
Lamivudine	150 twice daily × 7 days	15	↓ 24 (↓ 34 to ↓ 12)
Lopinavir Ritonavir	Lopinavir/Ritonavir 400/100 twice daily × 14 days	24
Methadone§	40–110 once daily × 14 days¶	13
Nelfinavir	1250 twice daily × 14 days	29
M8 metabolite
Oral Contraceptives#	Ethinyl Estradiol/Norgestimate (Ortho-Tricyclen) once daily × 7 days	20
Ribavirin	600 once	22			NA
Saquinavir	Saquinavir/Ritonavir 1000/100 twice daily × 14 days	32	↑ 22 (↑ 6 to ↑ 41)	↑ 29Þ (↑ 12 to ↑ 48)	↑ 47Þ (↑ 23 to ↑ 76)
Ritonavir					↑ 23 (↑ 3 to ↑ 46)

Table 5 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD

Didanosine* Dose (mg)/Method of Administration†	VIREAD Method of Administration†	N	% Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted‡
			Cmax	AUC
* See PRECAUTIONS regarding use of didanosine with VIREAD. † Administration with food was with a light meal (~373 kcal, 20% fat). ‡ Increase = ↑; Decrease = ↓; No Effect = § Includes 4 subjects weighing <60 kg receiving ddI 250 mg.
Buffered tablets
400 once daily§ × 7 days	Fasted 1 hour after didanosine	14	↑ 28 (↑ 11 to ↑ 48)	↑ 44 (↑ 31 to ↑ 59)
Enteric coated capsules
400 once, fasted	With food, 2 hours after didanosine	26	↑ 48 (↑ 25 to ↑ 76)	↑ 48 (↑ 31 to ↑ 67)
400 once, with food	Simultaneously with didanosine	26	↑ 64 (↑ 41 to ↑ 89)	↑ 60 (↑ 44 to ↑ 79)
250 once, fasted	With food, 2 hours after didanosine	28	↓ 10 (↓ 22 to ↑ 3)
250 once, fasted	Simultaneously with didanosine	28		↑ 14 (0 to ↑ 31)
250 once, with food	Simultaneously with didanosine	28	↓ 29 (↓ 39 to ↓ 18)	↓ 11 (↓ 23 to ↑ 2)

INDICATIONS AND USAGE

VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Additional important information regarding the use of VIREAD for the treatment of HIV-1 infection:

• VIREAD should not be used in combination with TRUVADA® or ATRIPLA™.

Description of Clinical Studies

Treatment-Naïve Patients

Study 903: VIREAD + Lamivudine +Efavirenz Compared to Stavudine + Lamivudine + Efavirenz

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing VIREAD (300 mg QD) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve patients. Patients 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). Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm3. Treatment outcomes through 144 weeks are presented in Table 6.

Table 6 Outcomes of Randomized Treatment (Study 903)

	At Week 48		At Week 144
Outcomes	VIREAD + 3TC + EFV (N=299)	d4T + 3TC + EFV (N=301)	VIREAD + 3TC + EFV (N=299)	d4T + 3TC + EFV (N=301)
	%	%	%	%
* Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144. † Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144. ‡ Includes lost to follow-up, patient's withdrawal, noncompliance, protocol violation and other reasons.
Responder*	79%	82%	68%	62%
Virologic failure†	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‡	8%	7%	14%	15%

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 patients 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, eleven patients in the VIREAD group and nine patients in the stavudine group experienced a new CDC Class C event.

Study 934: VIREAD + EMTRIVA + Efavirenz Compared with Zidovudine/Lamivudine + Efavirenz

Data through 48 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing VIREAD + EMTRIVA administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve patients. Patients 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). Patients were stratified by baseline CD4 count (< or ≥200 cells/mm3); 41% had CD4 cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 7.

Table 7 Outcomes of Randomized Treatment at Week 48 (Study 934)

Outcome at Week 48	VIREAD + FTC + EFV (N=244)	AZT/3TC + EFV (N=243)
	%	%
* Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48. † Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48. ‡ Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
Responder*	84%	73%
Virologic failure†	2%	4%
Rebound	1%	3%
Never suppressed	0%	0%
Change in antiretroviral regimen	1%	1%
Death	<1%	1%
Discontinued due to adverse event	4%	9%
Discontinued for other reasons‡	10%	14%

The difference in the proportion of patients 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 study. In addition, 80% and 70% of patients in the VIREAD + EMTRIVA group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm3 in the VIREAD + EMTRIVA group and 158 cells/mm3 in the zidovudine/lamivudine group.

Through 48 weeks, 7 patients in the VIREAD + EMTRIVA group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

Treatment-Experienced Patients

Study 907: VIREAD + Standard Background Therapy (SBT) Compared to Placebo + SBT

Study 907 was a 24-week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label VIREAD for an additional 24 weeks. Patients 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 patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

Changes from baseline in log10 copies/mL plasma HIV-1 RNA levels over time up to Week 48 are presented below in Figure 1.

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 8.

Table 8 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) %
	* Patients with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively. † Patients with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively. ‡ Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
HIV-1 RNA <400 copies/mL*	40%	11%	28%	30%
Virologic failure†	53%	84%	61%	64%
Discontinued due to adverse event	3%	3%	5%	5%
Discontinued for other reasons‡	3%	3%	5%	1%

At 24 weeks of therapy, there was a higher proportion of patients 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 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 counts by Week 48 was +4 cells/mm3 for the VIREAD group.

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

CONTRAINDICATIONS

VIREAD is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

WARNINGS

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV and Hepatitis B Virus

It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. VIREAD is not approved for the treatment of chronic HBV infection and the safety and efficacy of VIREAD have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV and have discontinued VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV and HBV and discontinue VIREAD. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

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 in association with the use of VIREAD (see Adverse Reactions, Post Marketing Experience).

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.

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 dysfunction who received VIREAD using these dosing guidelines, and 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.

Other

VIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since it is a component of these products.

PRECAUTIONS

Drug Interactions

When administered with VIREAD, Cmax and AUC of didanosine (Videx, Videx EC) administered as either the buffered or enteric-coated formulation increased significantly (see Table 5). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. Suppression of CD4 cell counts has been observed in patients receiving tenofovir DF with didanosine at a dose of 400 mg daily. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions. Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.

Since tenofovir is primarily eliminated by the kidneys, 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 adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir.

Higher tenofovir concentrations could potentiate VIREAD-associated adverse events, including renal disorders.

Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated adverse events. VIREAD should be discontinued in patients who develop VIREAD-associated adverse events.

VIREAD decreases the AUC and Cmin 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.

Bone Effects

In Study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with patients 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 study and this reduction was sustained through Week 144. Twenty-eight percent of VIREAD-treated patients vs. 21% of the stavudine-treated patients 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 patients in the VIREAD group and 6 patients 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. 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) have been reported in association with the use of VIREAD (see Adverse Reactions, Post Marketing Experience).

Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. 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.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in 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.

Animal Toxicology

Tenofovir and tenofovir disoproxil fumarate 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.

There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.

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

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. 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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD.

Pediatric Use

Safety and effectiveness in patients less than 18 years of age have not been established.

Geriatric Use

Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Clinical Trials

More than 12,000 patients have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in Phase I-III clinical trials and expanded access studies. A total of 1,544 patients have received VIREAD 300 mg once daily in Phase I–III clinical trials; over 11,000 patients have received VIREAD in expanded access studies.

Treatment-Naïve Patients

Study 903 - Treatment-Emergent Adverse Events

The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve patients received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.

Mild adverse events (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse events are summarized in Table 9.

Table 9 Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 903 (0–144 Weeks)

	VIREAD + 3TC + EFV	d4T + 3TC + EFV
	N=299	N=301
* Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. † Peripheral neuropathy includes peripheral neuritis and neuropathy. ‡ Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
Body as a Whole
Headache	14%	17%
Pain	13%	12%
Fever	8%	7%
Abdominal pain	7%	12%
Back pain	9%	8%
Asthenia	6%	7%
Digestive System
Diarrhea	11%	13%
Nausea	8%	9%
Dyspepsia	4%	5%
Vomiting	5%	9%
Metabolic Disorders
Lipodystrophy*	1%	8%
Musculoskeletal
Arthralgia	5%	7%
Myalgia	3%	5%
Nervous System
Depression	11%	10%
Insomnia	5%	8%
Dizziness	3%	6%
Peripheral neuropathy†	1%	5%
Anxiety	6%	6%
Respiratory
Pneumonia	5%	5%
Skin and Appendages
Rash event‡	18%	12%

Laboratory Abnormalities

With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 10.

Table 10 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Study 903 (0–144 Weeks)

	VIREAD + 3TC + EFV	d4T + 3TC + EFV
	N=299	N=301
Any ≥ Grade 3 Laboratory Abnormality	36%	42%
Fasting Cholesterol (>240 mg/dL)	19%	40%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	12%	12%
Serum Amylase (>175 U/L)	9%	8%
AST (M: >180 U/L) (F: >170 U/L)	5%	7%
ALT (M: >215 U/L) (F: >170 U/L)	4%	5%
Hematuria (>100 RBC/HPF)	7%	7%
Neutrophils (<750/mm3)	3%	1%
Fasting Triglycerides (>750 mg/dL)	1%	9%

Study 934 - Treatment Emergent Adverse Events

In Study 934, 511 antiretroviral-naïve patients received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 11).

Table 11 Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 934 (0–48 Weeks)

	VIREAD + FTC + EFV	AZT/3TC + EFV
	N=257	N=254
Gastrointestinal Disorder
Diarrhea	7%	4%
Nausea	8%	6%
Vomiting	1%	4%
General Disorders and Administration Site Condition
Fatigue	7%	6%
Infections and Infestations
Sinusitis	4%	2%
Upper respiratory tract infections	3%	3%
Nasopharyngitis	3%	1%
Nervous System Disorders
Somnolence	3%	2%
Headache	5%	4%
Dizziness	8%	7%
Psychiatric Disorders
Depression	4%	7%
Insomnia	4%	5%
Abnormal dreams	4%	3%
Skin and Subcutaneous Tissue Disorders
Rash	5%	4%

Laboratory Abnormalities

Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 12).

Table 12 Significant Laboratory Abnormalities Reported in ≥1% of Patients in Any Treatment Group in Study 934 (0–48 Weeks)

	VIREAD + FTC + EFV	AZT/3TC + EFV
	N=257	N=254
Any ≥ Grade 3 Laboratory Abnormality	25%	22%
Fasting Cholesterol (>240 mg/dL)	15%	17%
Creatine Kinase (M: >990 U/L) (F: >845 U/L)	7%	6%
Serum Amylase (>175 U/L)	7%	3%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST (M: >180 U/L) (F: >170 U/L)	3%	2%
ALT (M: >215 U/L) (F: >170 U/L)	2%	2%
Hemoglobin (<8.0 mg/dL)	0%	3%
Hyperglycemia (>250 mg/dL)	1%	1%
Hematuria (>75 RBC/HPF)	2%	2%
Neutrophils (<750/mm3)	3%	4%
Fasting Triglycerides (>750 mg/dL)	4%	2%

Treatment-Experienced Patients

Treatment-Emergent Adverse Events

The adverse reactions seen in treatment experienced patients were generally consistent with those seen in treatment naïve patients including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse events (Study 907).

A summary of moderate to severe, treatment-emergent adverse events that occurred during the first 48 weeks of Study 907 is provided in Table 13.

Table 13 Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 907 (0–48 Weeks)

	VIREAD (N=368) (Week 0–24)	Placebo (N=182) (Week 0–24)	VIREAD (N=368) (Week 0–48)	Placebo Crossover to VIREAD (N=170) (Week 24–48)
* Peripheral neuropathy includes peripheral neuritis and neuropathy. † Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
Body as a Whole
Asthenia	7%	6%	11%	1%
Pain	7%	7%	12%	4%
Headache	5%	5%	8%	2%
Abdominal pain	4%	3%	7%	6%
Back pain	3%	3%	4%	2%
Chest pain	3%	1%	3%	2%
Fever	2%	2%	4%	2%
Digestive System
Diarrhea	11%	10%	16%	11%
Nausea	8%	5%	11%	7%
Vomiting	4%	1%	7%	5%
Anorexia	3%	2%	4%	1%
Dyspepsia	3%	2%	4%	2%
Flatulence	3%	1%	4%	1%
Respiratory
Pneumonia	2%	0%	3%	2%
Nervous System
Depression	4%	3%	8%	4%
Insomnia	3%	2%	4%	4%
Peripheral neuropathy*	3%	3%	5%	2%
Dizziness	1%	3%	3%	1%
Skin and Appendage
Rash event†	5%	4%	7%	1%
Sweating	3%	2%	3%	1%
Musculoskeletal
Myalgia	3%	3%	4%	1%
Metabolic
Weight loss	2%	1%	4%	2%

Laboratory Abnormalities

Laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 14.

Table 14 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Study 907 (0–48 Weeks)

	VIREAD (N=368) (Week 0–24)	Placebo (N=182) (Week 0–24)	VIREAD (N=368) (Week 0–48)	Placebo Crossover to VIREAD (N=170) (Week 24–48)
	(%)	(%)	(%)	(%)
Any ≥ Grade 3 Laboratory Abnormality	25%	38%	35%	34%
Triglycerides (>750 mg/dL)	8%	13%	11%	9%
Creatine Kinase (M: >990U/L) (F: >845 U/L)	7%	14%	12%	12%
Serum Amylase (>175 U/L)	6%	7%	7%	6%
Urine Glucose (≥3+)	3%	3%	3%	2%
AST (M: >180 U/L) (F: >170 U/L)	3%	3%	4%	5%
ALT (M: >215 U/L) (F: >170 U/L)	2%	2%	4%	5%
Serum Glucose (>250 U/L)	2%	4%	3%	3%
Neutrophils (<750/mm3)	1%	1%	2%	1%

Post Marketing Experience

The following events have been identified during post-approval