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VIREAD® TABLETS

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

VIREAD® TABLETS

COMPOSITION:
Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil.

WARNING LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS (SEE WARNINGS).
TENOFOVIR IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF TENOFOVIR HAS 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 TENOFOVIR.
HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE TENOFOVIR AND ARE COINFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).

PHARMACOLOGICAL CLASSIFICATION:
A 20.2.8 Antimicrobial (Chemotherapeutic) Agents. Antiviral Agents

PHARMACOLOGICAL ACTION:
Mechanism of Action: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analogue 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 alpha, beta, and mitochondrial DNA polymerase Y.
Drug Resistance:
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2-4 fold reduction in susceptibility to tenofovir.
Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir in combination with certain antiretroviral agents. In treatment-naïve patients treated with tenofovir + lamivudine + efavirenz, viral isolates from 8/47 (17%) patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-experienced patients, 14/304 (4.6%) of the tenofovir-treated patients with virologic failure through week 96 showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 reverse transcriptase gene resulting in the K65R amino acid substitution.
Cross-resistance: Cross-resistance among certain reverse transcriptase inhibitors has been recognised. 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.
Pharmacodynamics: The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentration) values for tenofovir were in the range of 0.04 microM to 8.5 microM. 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 vitro against HIV1 clades A, B, C, D, E, F, G, and O (IC50 values ranged from 0.5 microM to 2.2 microM). The IC50 values of tenofovir against HIV-2 ranged from 1.6 microM to 4.9 microM.
Pharmacokinetics:
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption: Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients is approximately 25%. Following oral administration of a single dose of tenofovir 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*h/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over a dose range of 75 to 600 mg and are not affected by repeated dosing.
Effects of Food on Oral Absorption: Administration of tenofovir following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-8 of approximately 40% and an increase in Cmax of approximately 14%. However, administration of tenofovir 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*h/mL following multiple doses of tenofovir 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 micrograms/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 tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir 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 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 tenofovir dosing is required in patients with hepatic impairment. The pharmacokinetics of tenofovir are altered in patients with renal impairment. In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-8 of tenofovir were increased (Table 1). It is recommended that the dosing interval for tenofovir be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (see DOSAGE AND DIRECTIONS FOR USE).

Table 1.

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)	12-28 (N=11)
Cmax (ng/mL)	335.4+31.8	330.4+61.0	372.1+156.1	601.6+185.3
AUCO-oo (ng*hr/mL)	2184.5+257.4	3063.8+972.0	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

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

DESCRIPTION OF CLINICAL STUDIES
Treatment-Experienced Patients:
Study 907: Tenofovir + Standard Background Therapy (SBT) Compared to Placebo + SBT
Study 907 was a 24 week, double-blind placebo-controlled multicenter study of tenofovir 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 tenofovir 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.

{PLEASE SEE ORIGINAL PACKAGE INSERT FOR Figure 1}

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 2.

Table 2.

Outcomes of Randomized Treatment (Study 907)

Outcomes	0-24 weeks		0-48 weeks	24-48 weeks
	Tenofovir (N=368)%	Placebo (N=182)%	Tenofovir (N=368)%	Placebo Crossover to Tenofovir (N=170)%
HIV-1 RNA <400 copies/mL(1)	40%	11%	28%	30%
Virologic failure (2)	53%	84%	61%	64%
Discontinued due to adverse event	3%	3%	5%	5%
Discontinued for other reasons (3)	3%	3%	5%	1%

(1.) Patients with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively
(2.) Patients with HIV-1 RNA >400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively
(3.) Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
At 24 weeks of therapy, there was a higher proportion of patients in the tenofovir 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 tenofovir group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4 counts by week 48 was +4 cells/mm3 for the tenofovir group. Through week 24, one patient in the tenofovir group and no patients in the placebo arm experienced a new CDC Class C event.

Treatment-Naïve Patients:
Study 903: Tenofovir + Lamivudine +Efavirenz Compared to Stavudine + Lamivudine + Efavirenz
Data through 144-weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing tenofovir (300 mg QD) administered in combination with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz in 600 antiretroviral naïve patients. Patients had a mean age of 36 years (range 18 to 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/mL.
Treatment outcomes through 144 weeks are presented in Table 3 below.

Table 3.

Outcomes of Randomised Treatment (Study 903)

Outcomes	At Week48	At Week48	At Week 144	At Week 144
	Tenofivir+3TC +EFV (N=299)	Stavudine+3TC +EFV (N=301)	Tenofivir+3TC +EFV (N=299)	Stavudine+3TC +EFV (N=301)
	%	%	%	%
Responder (1)	79%	82%	68%	62%
Virologic failure (2)	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 (3)	8%	7%	14%	15%

(1.) Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144
(2.) Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144
(3.) Includes lost to follow-up, patient’s withdrawal, noncompliance, protocol violation and other reasons 12
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 tenofovir and stavudine arms, respectively achieved HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 263 cells/mm3 for the tenofovir arm and 283 cells/mm3 for the stavudine arm. Through 144
weeks, eleven patients in the tenofovir group and nine patients in the stavudine group experienced a new CDC Class C event.

Resistance Analyses of Tenofovir in Treatment Naïve Patients:
Genotypic analyses of patients with virologic failure showed development of efavirenz associated and lamivudine-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation occurred in 8 patients on the tenofovir arm and in 2 patients on the stavudine arm. Of the 8 patients who developed K65R in the tenofovir 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 tenofovir were not identified in this study.

Genotypic Analyses of Tenofovir in Patients with Previous Antiretroviral Therapy:
The virologic response to tenofovir therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment experienced patients participating in two controlled trials.
In two 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 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. Descriptions of numerical differences in HIV-1 RNA response are displayed in Table 4. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of tenofovir to pre-existing zidovudine-associated mutations were observed and appeared to depend on the number of specific mutations.
Tenofovir-treated patients whose HIV-1 expressed 3 or more zidovudine-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to tenofovir 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 tenofovir therapy. The HIV-1 RNA responses by number and type of baseline zidovudine-associated mutations are shown in Table 4.

Table 4.

HIV-1 RNA Response at Week 24 by Number of Baseline Zidovudine-Associated Mutations (Intent-To-Treat) (1)

Number of Baseline zidovudine-associated mutations (2)	Change in HIV-1 RNA (3) (N)
	Tenofovir 300 mg	Placebo
None	-0.80 (68)	-0.11 (29)
Any	-0.50 (154)	0 (81)
1-2	-0.66 (55)	-0.04 (33)
>3 including M41L or L210W	-0.21 (57)	+0.01 (29)
>3 without M41L or L210W	-0.67 (42)	+0.07 (19)

(1.) Genotypic testing performed by Virco Laboratories and Visible Genetics TruGene^TM technology
(2.) M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N in RT
(3.) Average HIV-1 RNA change from baseline through week 24 (DAVG24) in log10 copies/mL
In the protocol defined analyses, virologic response to tenofovir was not reduced in patients with HIV-1 that expressed the abacavir/emtricitabine/lamivudine-associated M184V mutation. In the absence of zidovudine-associated mutations, patients with the M184V mutation receiving tenofovir showed a –0.84 log10 copies/mL decrease in their HIV-1 RNA relative to placebo. In the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV-1 RNA responses to tenofovir treatment. HIV-1 RNA responses among these patients were durable through week 48.
Phenotypic Analyses of tenofovir in Patients with Previous Antiretroviral Therapy:
The virologic response to tenofovir 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 tenofovir and response to tenofovir therapy.
Table 5 summarizes the HIV-1 RNA response by baseline tenofovir susceptibility.

Table 5.

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

Baseline Tenofovir Susceptibility (2)	Change in HIV-1 RNA(3) (N)
<1	-0.74 (35)
>1 and <3	-0.56 (49)
>3 and <4	-0.3 (7)
<4	-0.61 (91)
>4	-0.12 (9)

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

INDICATIONS:
VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of VIREAD in treatment-naïve adults and in treatment-experienced adults.

CONTRA-INDICATIONS:
VIREAD is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
Uncontrolled renal failure.
Pregnancy and lactation.

WARNINGS:
There are no study results demonstrating the effect of VIREAD on clinical progression of HIV-1.
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 such as VIREAD 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 such as VIREAD to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Renal Impairment VIREAD is principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with creatinine clearance <50 mL/min. No safety data are available in patients with renal dysfunction who received VIREAD using these dosing guidelines.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of VIREAD.
VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk of, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
Patients with HIV and Hepatitis B Virus Coinfection It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. VIREAD is not indicated for the treatment of chronic HBV infection and the safety and efficacy of VIREAD have not been established in patients co-infected with HBV and HIV. Severe, acute exacerbations of HBV have been reported in patients after the discontinuation of VIREAD. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping VIREAD treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

INTERACTIONS:
At concentrations substantially higher (~300-fold) than those observed in vivo, VIREAD 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 VIREAD, the potential for CYP450 mediated interactions involving VIREAD with other medicinal products is low.
VIREAD is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of VIREAD with drugs that are eliminated by active tubular secretion may increase serum concentrations of either VIREAD or the coadministered drug, due to competition for this elimination pathway. Drugs that decrease renal function may also increase serum concentrations of VIREAD. VIREAD has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, oral contraceptives, and ribavirin. Tables 6 and 7 summarise pharmacokinetic effects of co-administered drug on VIREAD pharmacokinetics and effects of VIREAD on the pharmacokinetics of co-administered drug.
Table 8 summarises 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 6.

Drug Interactions: Changes in Pharmacokinetic Parameters for VIREAD (1) in the Presence of the Co-administered Drug.

Co-administered Drug	Dose of Co-administered Drug (mg)	N	% Change of VIREAD Pharmacokinetic Parameters (2)         (90% CI)
			Cmax	AUC	Cmin
Abavacavir	300 once	8	<=>	<=>	NC
Adefovir dipivoxil	10 once	22	<=>	<=>	<=>
Atazanavir (3)	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 x 7 days	14	<=>	<=>	<=>
Efavirenz	600 once daily x 14 days	29	<=>	<=>	<=>
Emtricitabine	200 once daily x 7 days	17	<=>	<=>	<=>
Indinavir	800 three times daily x 7 days	13	^14 (v3 to^33)	<=>	<=>
Lamivudine	150 twice daily x 7 days	15	<=>	<=>	<=>
Lopinavir/ Ritonavir	400/100 twice daily x 14 days	24	<=>	^32 (^26 to ^38)	^29 (^32 to^66)

(1.) Patients received VIREAD 300 mg once daily
(2.) Increase = ^; decrease = v; No Effect = <=> ; NC = Not Calculated
(3.) REYETAZ® Prescribing information (Bristol-Myers Squibb)

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 7.

Drug Interactions: Changes in Pharmacokinetic parameters for Co-administered Drug in the Presence of VIREAD.

Co-administered Drug	Dose of Co-administered Drug (mg)	N	% Change of Co-administered Drug Pharmacokinetic Parameters (1)         (90% CI)
			Cmax	AUC	Cmin
Abavacavir	300 once	8	^12 (v1 to ^26)	<=>	NA
Adefovir dipivoxil	10 once	22	<=>	<=>	NA
Efavirenz	600 once daily x 14 days	30	<=>	<=>	<=>
Emtricitabine	200 once daily x 7 days	17	<=>	<=>	^20 (^12 to ^29)
Indinavir	800 three times daily x 7 days	12	v11 (v30 to^12)	<=>	<=>
Lamivudine	150 twice daily x 7 days	15	v24 (v34 to v12)	<=>	<=>
Lopinavir	Lopinavir/Ritonavir 400/100 twice daily x 14 days	21	<=>	<=>	<=>

Co-administered Drug	Dose of Co-administered Drug (mg)	N	% Change of Co-administered Drug Pharmacokinetic Parameters (1)         (90% CI)
			Cmax	AUC	Cmin
Methadone (2)	40-110 once daily x 14 days (3)	13	<=>	<=>	<=>
Oral Contraceptives (4)	Ethinyl Estradiol /Norgestimate (Ortho-Tricyclen®) Once daily x 7 days	20	<=>	<=>	<=>
Ribavirin	600 once	22	<=>	<=>	NA
Ritonavir	Lopinavir/Ritonavir 400/100 twice daily x 14 days	24	<=>	<=>	<=>
Atazanavir (5)	400 once daily x 14 days	34	v21 (v27 tov14)	v25 (v30 to v19)	v40 (v48 to v32)
Atazanavir (5)	Atazanavir/ Ritonavir 300/100 once daily x 42 days.	10	v28 (v50 to ^5)	v25 (6) (v42 to v3)	v23 (6) (v46 to ^10)

(1.)Increase = ^; Decrease = v; No Effect = <=>; NA = Not Applicable
(2.) R-(active), S-and total methadone exposures were equivalent when dosed alone or with VIREAD
(3.) Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
(4.) Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.
(5.) REYETAZ® Prescribing information (Bristol-Myers Squibb)
(6.) In HIV-infected patients, addition of TFD 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.

Table 8.

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

Didanosine (1) Dose (mg)/ Method of Administration (2)	VIREAD Method of Administration (2)	N	% Difference (90% CI) vs. Didanosine 400 mg alone, Fasted (3)
			Cmax	AUC
Buffered tablets
400 once daily (4) x 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 hr 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 hr after didanosine	28	v10 (v22 to ^3)	<=>
250 once, fasted	Simultaneously with didanosine	28	<=>	^14 (0 to ^31)
250 once, with food	Simultaneously with didanosine	28	v29 (v39 to v18)	v11 (v23 to ^2)

(1) See "PRECAUTIONS" regarding use of didanosine with VIREAD
(2.) Administration with food was with a light meal ( ~ 373 kcal, 20% fat)
(3.) Increase = ^; Decrease = v; No Difference = <=>
(4.) Includes 4 subjects weighing <60kg receiving ddi 250 mg

PREGNANCY AND LACTATION:
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should not be used during pregnancy (See CONTRA-INDICATIONS)
Nursing Mothers: HIV-infected mothers should not breast-feed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that VIREAD is secreted in milk. It is not known whether VIREAD 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 (See CONTRA-INDICATIONS)

DOSAGE AND DIRECTION FOR USE:
The dose of VIREAD (tenofovir disoproxil fumarate) is 300 mg once daily taken orally, without regard to food.
Dose Adjustment for Renal Impairment:
Significantly increased exposure occurred when VIREAD was administered to patients with moderate to severe renal impairment (See CONTRA-INDICATIONS)
The pharmacokinetics of VIREAD have not been evaluated in non-haemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-Effects: Clinical trials:
Treatment-Naïve Patients:
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, diarrhoea and nausea. Selected treatment-emergent moderate to severe adverse events are summarised in Table 9.

Table 9.

Selected Treatment-Emergent Adverse Events (Grade 2-4) Reported in >5% in Any Treatment Group in Study 903 (0-144 weeks)

	VIREAD+3TC+EFV	D4T+3TC+EFV
Number of Patients Treated	N=299	N=301
Body as a Whole
Headache	14%	17%
Pain	13%	12%
Fever	8%	7%
Abdominal pain	7%	12%
Back Pain	9%	8%
Asthaenia	6%	7%
Digestive System
Diarrhoea	11%	13%
Nausea	8%	9%
Dyspepsia	4%	5%
Vomiting	5%	9%

	VIREAD+3TC+EFV	D4T+3TC+EFV
Number of Patients Treated	N=299	N=301
Metabolic Disorders
Lipodystrophy(1)	1%	8%
Musculoskeletal
Arthralgia	5%	7%
Myalgia	3%	5%
Nervous System
Depression	11%	10%
Insomnia	5%	8%
Dizziness	3%	6%
Peripheral neuropathy (2)	1%	5%
Anxiety	6%	6%
Respiratory
Pneumonia	5%	5%
Skin and Appendages
Rash Event (3)	18%	12%

(1.) Lipodystrophy represents a variety of investigator- described adverse events not a protocol-defined syndrome
(2.) Peripheral neuropathy includes peripheral neuritis and neuropathy
(3.) Rash event includes rash, pruritus, maculo-paular rash, urticaria, vesiculobullous rash, and pustular rash

Laboratory Abnormalities: With the exception of cholesterol and triglyceride elevations that were more common in the stavudine group (15% and 14%) compared with VIREAD (5% and 3%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and stavudine 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
Number of Patients Treated	N=299	N=301
Any >Grade 3 Laboratory Abnormality	36%	42%
Total Cholesterol (>7.77 mmol/L)	5%	15%
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 elevation (M: >215 U/L) (F: >170 U/L)	4%	5%
Haematuria (>100 RBC/HPF)	7%	7%
Neutrophil (>750.000/cm3)	3%	1%
Triglyceride (>8.475 mmol/L)	3%	14%

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, diarrhoea, 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 11.

Table 11.

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)
Body as a Whole
Asthaenia	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%

	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)
Digestive System
Diarrhoea	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 (1)	3%	3%	5%	2%
Dizziness	1%	3%	3%	1%

	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)
Skin and Appendages
Rash Event (2)	5%	4%	7%	1%
Sweating	3%	2%	3%	1%
Musculoskeletal
Myalgia	3%	3%	4%	1%
Metabolic
Weight Loss	2%	1%	4%	2%

(1.) Peripheral neuropathy includes peripheral neuritis and neuropathy
(2.) Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash

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 12.

Table 12

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%
Triglyceride (>8.475 mmol/L)	8%	13%	11%	9%
Creatine kinase                 (M: >990 U/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%

	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)
	(%)	(%)	(%)	(%)
ALT elevation (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: In addition to adverse events reported from clinical trials, the following adverse events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD.

IMMUNE SYSTEM DISORDERS Allergic reaction
METABOLISM AND NUTRITION DISORDERS Hypophosphataemia, Lactic Acidosis
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnoea
GASTROINTESTINAL DISORDERS Abdominal pain, Increased amylase, Pancreatitis
HEPATOBILIARY DISORDERS Increased liver enzymes, Hepatitis
RENAL AND URINARY DISORDERS Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus

Special Precautions:
Drug Interactions When administered with VIREAD, Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly (see Table 8). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine associated adverse events, including pancreatitis and neuropathy.
In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is co-administered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When co-administered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Co administration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions. Co-administration 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 VIREAD is primarily eliminated by the kidneys, co-administration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of VIREAD 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 VIREAD concentrations could potentiate VIREAD-associated adverse events, including renal disorders. Atazanavir and lopinavir/ritonavir have been shown to increase VIREAD 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. 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.
Paediatric Use
Safety and effectiveness in paediatric patients and patients < 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.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In Study 901, 600 mg VIREAD was administered to 8 patients orally for 28 days. The effects of higher doses are not known. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. VIREAD is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.

IDENTIFICATION:
VIREAD tablets are almond-shaped, white, film-coated, and debossed with “GILEAD”and “4331”on one side.

PRESENTATION:
VIREAD Tablets are supplied as follows:
Bottles of 30 tablets containing a desiccant (silica gel canister or sachet) and closed with a child resistant cap. Bottles are sealed with an aluminium induction seal.
Cartons of 30 blister-packed tablets : blister size 58 x 98 mm; 6 blisters per strip; 5 blister strips per unit carton; silver aluminium foil with black text; aluminium foil on foil is silver in colour.

STORAGE INSTRUCTIONS:
Store below 30°C.
Do not use if seal over bottle opening is broken or missing or if there is evidence of tampering with the blister pack. Do not remove from carton until required for use.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
A40/20.2.8/0681

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
PHARMACARE LIMITED Building 12 Healthcare Park Woodlands Drive Woodmead Sandton 2148

DATE OF PUBLICATION OF THE PACKAGE INSERT:
23 February 2007

575193/070205

New addition to this site: January 2008
Source: Pharmaceutical Industry
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