Submission Control Number: 117342

Date of Revision: August 14, 2008

TABLE OF CONTENTS

TITLE PAGE 1

PART I. HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3

INDICATIONS AND CLINICAL USE 3

CONTRAINDICATIONS 4

WARNINGS AND PRECAUTIONS 4

ADVERSE REACTIONS. 9

DRUG INTERACTIONS 20

DOSAGE AND ADMINISTRATION 25

OVERDOSAGE 26

ACTION AND CLINICAL PHARMACOLOGY 26

STORAGE AND STABILITY 30

SPECIAL HANDLING INSTRUCTIONS 30

DOSAGE FORMS, COMPOSITION AND PACKAGING 30

PART II. SCIENTIFIC INFORMATION 31

CLINICAL TRIALS 31

DETAILED PHARMACOLOGY 39

VIROLOGY (MICROBIOLOGY) 42

PHARMACEUTICAL INFORMATION 44

TOXICOLOGY 44

REFERENCES 47

PART III. CONSUMER INFORMATION 49

PrViread(r)

(Tenofovir Disoproxil Fumarate Tablets)

PART I. HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

For a complete listing, see Dosage Forms, Composition and Packaging section.

CONTRAINDICATIONS

VIREAD (tenofovir disoproxil fumarate) is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, alone or in combination with other antiretrovirals (see WARNINGS AND PRECAUTIONS).

Post-Treatment Exacerbation of Hepatitis

Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VIREAD. If appropriate, resumption of anti-hepatitis B therapy may be warranted (see WARNINGS AND PRECAUTIONS).

Nephrotoxicity

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported with the use of VIREAD during clinical practice (see WARNINGS AND PRECAUTIONS).

General

VIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since it is a component of these products. VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil). For the effect of co-administered drugs, see DRUG INTERACTIONS section. Clinical studies in HIV-infected patients have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance mutations have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

Bone Effects

In HIV-infected patients treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both VIREAD and stavudine treatment arms of the study and significantly greater decreases were seen in the lumbar spine measurement in the Viread group relative to the stavudine group. Clinically relevant fractures were reported in both treatment groups. Increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) were observed, suggesting increased bone turnover. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range (see ADVERSE REACTIONS, Study 903). The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Cases of osteomalacia (associated with proximal renal tubulopathy and infrequently contributing to fractures) have been reported in association with the use of VIREAD (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). Bone monitoring should be considered for 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tenofovir DF did not show any carcinogenic potential in a long-term oral carcinogenicity study in rats. A long-term oral carcinogenicity study in mice showed a low incidence of duodenal tumors, considered likely related to high local concentrations in the gastrointestinal tract at the high dose of 600 mg/kg/day. The mechanism of tumor formation in mice and potential relevance for humans are uncertain. 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 at doses up to 2000 mg/kg when administered orally to male mice. There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered at 600 mg/kg/day to male rats 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. A dose of 600 mg/kg/day is equivalent to 19 times the human dose based on body surface area comparisons.

Endocrine and Metabolism

Fat Redistribution

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

Hepatic/Biliary/Pancreatic

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues, including tenofovir disoproxil fumarate, alone or in combination with other antiretrovirals in the treatment of HIV infection. A majority of these cases have been reported in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering nucleoside analogs to any patient, and particularly to those 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 levels).

Pancreatitis

Pancreatitis has occurred during therapy with combination regimens that included VIREAD. Caution should be used when administering nucleoside analogues (including VIREAD) to patients with a history of pancreatitis or risk factors for the development of pancreatitis. Therapy should be suspended in patients with suspected pancreatitis.

Hepatic Impairment

Tenofovir and tenofovir disoproxil are not metabolized by liver enzymes. Clinically relevant pharmacokinetic changes in patients with hepatic impairment are not observed. Therefore, no dose adjustment is required in patients with hepatic impairment. The safety and efficacy of tenofovir DF has not been established or specifically studied in patients with underlying liver disorders. Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products

Exacerbation of Hepatitis After Discontinuation of Treatment

Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Therefore, in these patients, discontinuation of treatment without initiation of alternative anti-hepatitis B therapy is not recommended.

Immune

Immune Reconstitution Syndrome

During the initial phase of treatment, HIV-infected patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Renal

Nephrotoxicity

Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported with the use of VIREAD in clinical practice (see ADVERSE REACTIONS, Post Market Adverse Reactions and DRUG INTERACTIONS). The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors. 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. Particular caution should be exercised when administering VIREAD to patients with known risk factors for renal disease and a history of renal dysfunction; however, cases of renal failure have also been reported in patients with no known risk factors. VIREAD should be avoided with concurrent use of a nephrotoxic agent. Dosing interval adjustment is required in all patients with creatinine clearance <50 mL/min (see DOSAGE and ADMINISTRATION). The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated, therefore, clinical response to treatment and renal function should be closely monitored in these patients. The potential benefit of VIREAD therapy should be assessed against the potential risk for renal toxicity.

Special Populations

Patients with HIV and Hepatitis B Virus Coinfection

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

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. 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. Reduced pup body weights, survival, and delay in sexual maturation was observed in a peri- and postnatal toxicity study in rats at the maternally toxic doses of 450 and 600 mg/kg (approximately 14 and 19 times the human dose based on body surface area comparisons). Because animal reproduction studies are not always predictive of human response, tenofovir disoproxil fumarate should be used in pregnant women only if the potential benefits outweigh the potential risks to the fetus.

Antiretroviral Pregnancy Registry

To monitor fetal outcomes of pregnant women exposed to ART including VIREAD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling (800)-258-4263.

Nursing Women

It is currently recommended that HIV and HBV infected women should not breast-feed to avoid postnatal transmission of HIV-1 and HBV. Studies in rats and rhesus monkeys have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving VIREAD.

Pediatrics

Safety and effectiveness in pediatric patients have not been established.

Geriatrics

Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than 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.

DRUG INTERACTIONS

Serious Drug Interactions

Atazanavir and lopinavir/ritonavir increase tenofovir disoproxil fumarate concentrations which may lead to tenofovir-associated adverse events (see WARNINGS and PRECAUTIONS)

Tenofovir disoproxil fumarate decreases atazanavir concentrations - administer atazanavir with ritonavir (see below)

Tenofovir disoproxil fumarate increases didanosine (ddI) concentrations - the dose of ddI may be reduced but use with caution and monitor for ddI-related adverse events and clinical response (see below)

Drug-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. Co-administration 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. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir. VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil). VIREAD has been evaluated in healthy volunteers in combination with abacavir, atazanavir, didanosine, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir and tacrolimus (see below). No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir and tacrolimus. Tables 10 and 11 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of tenofovir on the pharmacokinetics of coadministered drug.

Didanosine

Pharmacokinetic studies have shown that coadministration of didanosine and tenofovir DF results in 40-60% increase in Cmax and AUC of didanosine (see Table 13). The mechanism of this interaction is unknown. Increases in didanosine concentrations of this magnitude could potentiate didanosine-associated adverse events, including pancreatitis, lactic acidosis, and neuropathy. In addition, suppression of CD4 counts has been observed in patients receiving tenofovir DF with didanosine at a dose of 400 mg daily. A reduced dose of Videx EC(r) (ddI-EC) is recommended when coadministered with VIREAD. When coadminstered with VIREAD, the Videx EC(r) Product Monograph recommends a reduced dose of 250 mg ddI-EC for HIV-infected adults with body weight

>=60 kg and creatinine clearance >=60 mL/min. For patients with body weight <60 kg, and creatinine clearance >=60 mL/min, the recommended dose of ddI-EC is 200 mg. Data are not available to recommend a dose adjustment for patients with creatinine clearance <60mL/min or for the buffered tablet formulation of didanosine (Videx(r)). Caution should be used when coadministering reduced-dose didanosine, tenofovir, and an NNRTI in treatment-naive patients with high viral loads at baseline since such use has been associated with reports of a high rate of virologic failure and emergence of resistance at an early stage. All patients receiving tenofovir disoproxil fumarate and didanosine concomitantly should be closely monitored for didanosine-related adverse events and clinical response.

Atazanavir and Lopinavir/Ritonavir

Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations (see Table 11). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving atazanavir, lopinavir/ritonavir and tenofovir disoproxil fumarate should be monitored for tenofovir-associated adverse events. Tenofovir decreases atazanavir concentrations (see Table 12). Although safety and efficacy data are limited, it is recommended that atazanavir, without ritonavir, should not be coadministered with tenofovir disoproxil fumarate. The recommended regimen is atazanavir 300 mg given with ritonavir 100 mg when used in combination with tenofovir disoproxil fumarate 300 mg (all as a single daily dose with food).

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir1 in the Presence of the Coadministered Drug

1. Patients received VIREAD 300 mg once daily.

2. Increase = |; Decrease = |; No Effect = U; NC = Not Calculated

3. REYATAZ(r) Prescribing Information (Bristol-Myers Squibb)

4. Includes 4 subjects weighing <60 kg receiving ddI 250 mg.

Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIREAD

1. Increase = |; Decrease = |; No Effect = U; NA = Not Applicable

2. REYATAZ(r) Prescribing Information (Bristol-Myers Squibb).

3. 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.

4. R-(active), S-and total methadone exposures were equivalent when dosed alone or with VIREAD

5. Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.

6. Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.

7. Increase 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.

Table 13 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD

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 = |; No Difference = U

Includes 4 subjects weighing <60 kg receiving ddI 250 mg.

Drug-Food Interactions

Interactions of VIREAD with food have not been established (see ACTIONS AND CLINICAL PHARMACOLOGY, Effect of Food on Absorption).

Drug-Herb Interactions

Interactions of VIREAD with herbs have not been established.

Drug-Laboratory Interactions

Interactions of VIREAD with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

For the treatment of HIV or chronic hepatitis B: The dose of VIREAD (tenofovir disoproxil fumarate) is 300 mg once daily taken orally without regard to food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. VIREAD may be discontinued if there is HBsAg loss or HBsAg seroconversion.

Dose Adjustment for Renal Impairment

Significantly increased drug exposures occurred when VIREAD was administered to patients with moderate to severe renal impairment (see ACTIONS AND CLINICAL PHARMACOLOGY, Renal Insufficiency). Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 14. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in moderate to severe renal impairment, therefore, clinical response to treatment and renal function should be closely monitored in these patients. Routine monitoring of creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment (creatinine clearance 50-80 mL/min). (see WARNINGS and PRECAUTIONS).

Table 14 Dosage Adjustment for Patients with Altered Creatinine Clearance

1. Calculated using ideal (lean) body weight.

2. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.

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

Missed Dose

If a patient misses a dose at the regularly scheduled time, but then remembers it that same day, the patient should take the missed dose immediately. The next dose should be taken at the regularly scheduled time the following day. The patient should not take two doses of VIREAD at once to make up for missing a dose.

OVERDOSAGE

For management of a suspected drug overdose, please contact your regional Poison Control Centre. Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In Study 901 tenofovir disoproxil fumarate 600 mg was administered to 8 patients orally for 28 days. No severe adverse reactions were reported. 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. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. 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.

ACTION AND CLINICAL PHARMACOLOGY

VIREAD (tenofovir disoproxil fumarate) is an acyclic nucleotide diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis (by non-specific esterases in blood and tissues) 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 reverse transcriptase and HBV polymerase 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, b, and mitochondrial DNA polymerase g. VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. Following oral administration of a single dose of VIREAD 300 mg to HIV-infected patients in the fasted state, maximum serum concentrations (Cmax) of tenofovir are achieved in 1.0 +- 0.4 hours. The oral bioavailability of tenofovir from VIREAD in fasted patients is approximately 25%. Administration of VIREAD following a high-fat meal increases the oral bioavailability, with an increase in tenofovir AUC[?] of approximately 40% and an increase in Cmax of approximately 14% (see DOSAGE AND ADMINISTRATION). Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition with other compounds that are also renally eliminated.

Pharmacodynamics

Activity in HIV-1

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 values for tenofovir were in the range of 0.04-8.5 mM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, and zidovudine), non- nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir), additive to synergistic effects were observed. Most of these drug combinations have not been studied in humans. Tenofovir displayed antiviral activity in vitro against HIV-1 clades A, B, C, D, E, F, G, and O (IC50 values ranged from 0.5-2.2 mM). The antiviral effects of tenofovir disoproxil fumarate monotherapy in reducing HIV-1 viral load and the relationship with dose were assessed in clinical phase 1 studies in treatment- naive and treatment-experienced HIV-infected patients. Doses of tenofovir disoproxil fumarate ranging from 75 mg to 600 mg once daily resulted in statistically significant decreases in plasma HIV-1 RNA levels compared with placebo. In a mixed population of treatment-naive and treatment-experienced patients who received 28 days of repeat daily dosing with tenofovir disoproxil fumarate 300 mg QD (Study GS-97-901) the median decrease in plasma log10 HIV-1 RNA level was 1.22 log10 copies/mL.

Activity in HBV

The in vitro antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir were in the range of 0.14 to 1.5 mM, with CC50 (50% cytotoxicity concentration) values >100 mM. Tenofovir diphosphate inhibits recombinant HBV polymerase with a Ki (inhibition constant) of 0.18 mM. In in vitro drug combination studies of tenofovir with nucleoside anti-HBV reverse transcriptase inhibitors lamivudine, telbivudine, and entecavir, additive anti-HBV activity was observed. Additive to slightly synergistic effects were observed with the combination of tenofovir and emtricitabine.

Pharmacokinetics

Pharmacokinetics of intravenous tenofovir were evaluated in Study GS-96-701 (N=16). Following intravenous administration of tenofovir 1.0 and 3.0 mg/kg, pharmacokinetics were dose-proportional with the exception of the estimated terminal half-life (5.3 and 7.8 hours, respectively). The pharmacokinetics of tenofovir were not affected by repeated dosing in the 1.0 mg/kg/day group, with the exception of half-life (5.3 on Day 1 vs. 7.7 on Day 14) and volume of distribution (763 vs. 1320 mL/kg). At the 3.0 mg/kg/day, there was an approximate 27% decrease in serum clearance of tenofovir following 7 days of once daily administration; renal clearance and estimated terminal half-life were also significantly different. The pharmacokinetics of tenofovir following administration of tenofovir disoproxil fumarate were evaluated in the fasted state in Study GS-97-901 (HIV-infected patients) and Study GS-00-914 (healthy volunteers). The pharmacokinetics in HIV-infected patients and healthy volunteers were similar. The estimated terminal half-life in HIV-infected patients measured over 24 hours was ~12-13 hr. The terminal elimination half-life in healthy subjects assessed over 48 hours was ~17 hours. There were no significant differences in the dose-normalized steady-state pharmacokinetics of tenofovir over the dose range of 75 to 600 mg. Tenofovir exposure following 8 and 28 days was slightly higher than those observed following the first dose.

Absorption

VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted patients is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 +- 0.4 hours. Cmax and AUC values are 296 +- 90 ng/mL and 2287 +- 685 ng *hr/mL, respectively.

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 0.01-25 mg/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

In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes. Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 +- 10% of the administered dose is recovered in urine over 24 hours.

Excretion

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Effects of Food on Oral Absorption

Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40-50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-[?] of approximately 40% and an increase in Cmax of approximately 14%. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 326 +- 119 ng/mL and 3324 +- 1370 ng *hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Special Populations and Conditions

Pediatrics and Geriatrics

Pharmacokinetic studies have not been performed in children or in the elderly.

Race

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

Gender

Limited data on the pharmacokinetics of tenofovir in women indicate no major gender effect.

Hepatic Insufficiency

The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD have been studied in 8 non-HIV, non-HBV infected subjects with moderate hepatic impairment and 8 non-HIV infected subjects with 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.

Renal Insufficiency

The pharmacokinetics of tenofovir are altered in subjects with renal impairment (see WARNINGS, Nephrotoxicity). In non-HIV, non-HBV infected subjects with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-[?] of tenofovir were increased (Table 15). 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 15 Pharmacokinetic Parameters (Mean +- SD) of Tenofovir * in Patients with varying Degrees of Renal Function

* 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.

STORAGE AND STABILITY

Store at 25 degC (77 degF), excursions permitted to 15-30 degC (59-86 degF).

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

VIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with a blue colored film (Opadry II Y-30-10671-A) that is made of FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin. 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. Available in bottles containing 30 tablets with a desiccant (silica gel canister or sachet) and closed with child-resistant closure.

PART II. SCIENTIFIC INFORMATION

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

CLINICAL TRIALS

Clinical Efficacy in Patients with HIV Treatment-Experienced Patients

Study Demographics and Trial Design

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 RNA of 2340 (range 50-75,000) copies/mL, and mean duration of prior HIV treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

Table 16 Study 907: VIREAD + Standard Background Therapy (SBD) Compared to Placebo + SBD

Treatment-Naive 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, lamivudine, and efavirenz in 600 antiretroviral- naive 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/mL.

Table 17 Study 903: VIREAD + Lamivudine + Efavirenz Compared with Stavudine + Lamivudine + Efavirenz

1. Stavudine/placebo capsules 20/15 mg BID as need for dose reduction.

Study 934 VIREAD + Emtricitabine+ Efavirenz Compared with Lamivudine/Zidovudine + Efavirenz

Data through 144 weeks are reported for Study 934, a randomized, open-label, active controlled multicenter study comparing VIREAD (300 mg QD) + emtricitabine (200 mg QD) administered in combination with efavirenz (600 mg QD) versus lamivudine 150 mg/ zidovudine 300 mg bid administered in combination with efavirenz (600 mg QD) in 511 antiretroviral-naive patients. From weeks 96 to 144 of the study, patients randomized to VIREAD + emtricitabine received TRUVADA with efavirenz in place of emtricitabine + VIREAD. 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

Table 18 Study 934 EMTRIVA+ VIREAD + Efavirenz Compared with Lamivudine/Zidovudine +Efavirenz

From weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of emtricitabine + VIREAD

Study Results

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

Changes from baseline in log10 copies/mL plasma HIV-1 RNA levels through Week 48 are presented in Table 19.

Table 19 Mean Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL): Study 907 (48 Weeks)

For Placebo Crossover to VIREAD, baseline HIV-1 RNA was reset at Week 24

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 20.

Table 20 Outcomes of Randomized Treatment (Study 907)

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 VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (22% and 1%, respectively). Mean change in absolute CD4 counts by Week 24 was +12 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.

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

+ Efavirenz

Treatment outcomes through 144 weeks are presented in Table 21.

Table 21 Outcomes of Randomized Treatment (Study 903)

1. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 144.

2. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 144.

3. Includes lost to follow-up, patient'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 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, twelve patients in the VIREAD group and nine patients in the stavudine group experienced a new CDC Class C event. The proportion of patients who achieved and maintained confirmed HIV RNA <400 using intent-to-treat analysis at Weeks 24, 48, 96 and 144 in Study 903 are presented in Table 22.

Table 22 Virologic Response Through Week 144, Study 903 *+

*Roche Amplicor HIV-1 Monitor Test

+

Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit

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

Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 23.

Table 23 Outcomes of Randomized Treatment at Weeks 48 and 144 (Study 934)

1. Patients who were responders at Week 48 or Week 96 but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.

2. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48.

3. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48.

4. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons.

In this study, VIREAD + emtricitabine in combination with efavirenz showed statistically significant superiority over lamivudine/zidovudine in combination with efavirenz in achieving and maintaining HIV-1 RNA <400 copies/mL through 48 weeks and 144 weeks (Table 23). The difference in the percentages of responders, stratified by baseline CD4 cell count (< or >=200 cells/mm3), between the VIREAD + emtricitabine group and the lamivudine/zidovudine group was 11.4%, and the 95% CI was 4.3% to 18.6% (p=0.002) at Week 48 and was 13% at Week 144, 95% CI = 4% to 22% (p=0.004). Through 48 weeks of therapy, 80% and 70% of patients in the VIREAD + emtricitabine and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA <50 copies/mL (64% and 56%, respectively, through Week 144). The difference in the percentages of responders, stratified by baseline CD4 cell count (< or >=200 cells/mm3), between the VIREAD + emtricitabine group and the lamivudine/zidovudine group was 9.1%, and the 95% CI was 1.6% to 16.6% (p=0.021) at Week 48 and was 8% at Week 144, 95% CI = -1% to 17% (p=0.082). The mean increase from baseline in CD4 cell count was 190 cells/mm3 for the VIREAD + emtricitabine + efavirenz arm, and 158 cells/mm3 for the lamivudine/zidovudine + efavirenz arm (p=0.002) at Week 48 (312 and 271 cells/mm3, respectively, at Week 144, p=0.089). Through 48 weeks, 7 patients in the VIREAD + emtricitabine group and 5 patients in the lamivudine/zidovudine group experienced a new CDC Class C event (10 and 6 patients, respectively, through 144 weeks). 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.

Genotypic Analyses of VIREAD in Patients with Previous Antiretroviral Therapy (Studies 902 and 907)

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment experienced patients participating in trials 902 and 907. In both of these studies, 94% of the participants evaluated had baseline HIV isolates expressing at least one NRTI mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), the lamivudine/abacavir- associated mutation (M184V), and others. In addition the majority of participants evaluated had mutations associated with either protease inhibitor or non-nucleotide reverse transcriptase inhibitor use. Virologic responses for patients in the genotype sub-study were similar to the overall results in Studies 902 and 907. Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational patterns on virologic outcome. Reduced responses to VIREAD were observed in patients with pre-existing zidovudine- associated mutations and appeared to depend on the number of specific mutations. VIREAD-treated patients whose HIV expressed 3 or more zidovudine-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N mutation did not appear to affect responses to VIREAD therapy. In the protocol defined analyses, virologic response to VIREAD was not reduced in patients with HIV that expressed the lamivudine/abacavir-associated M184V mutation. In the absence of zidovudine-associated mutations, patients with the M184V mutation receiving VIREAD showed a -0.84 log10 copies/mL decrease in their HIV-1 RNA relative to placebo. In the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV RNA responses to VIREAD treatment. HIV-1 RNA responses among these patients were durable through Week 48. There were limited data on patients expressing some primary nucleoside reverse transcriptase inhibitor mutations and multi-drug resistant mutations at baseline. However, patients expressing mutations at K65R (N=6), or L74V without zidovudine-associated mutations (N=6) appeared to have reduced virologic responses to VIREAD. The presence of at least one HIV protease inhibitor or non-nucleoside reverse transcriptase inhibitor mutation at baseline did not appear to affect the virologic response to VIREAD. Cross-resistance between VIREAD and HIV-1 protease inhibitors is unlikely because of the different enzyme targets involved. In treatment-experienced patients, 14/304 (4.6%, studies 902 and 907) isolates from patients failing VIREAD at 96 weeks showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid substitution.

Phenotypic Analyses of VIREAD in Patients with Previous Antiretroviral Therapy (Studies 902 and 907)

The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment experienced patients participating in trials 902 and 907. Phenotypic analysis of baseline HIV from patients in Studies 902 and 907 demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 24 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

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

1. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram(tm) 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.

Genotypic Analyses of VIREAD in Antiretroviral-Naive 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 (Study 903). The K65R mutation occurred in 8 patients on the VIREAD arm and in 2 patients on the stavudine arm. Of the 8 patients who developed K65R in the VIREAD arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and the last one at Week 96. Among these patients, 5/8 patients subsequently gained full virologic control (<50 copies/mL) upon switching to new regimens that included a protease inhibitor in combination with nucleoside reverse transcriptase inhibitors through a median of 155 weeks of follow-up. From both genotypic and phenotypic analyses there was no evidence for other pathways of resistance to VIREAD. In Study 934 (VIREAD + emtricitabine + efavirenz compared with lamivudine/zidovudine + efavirenz), resistance analysis was performed on HIV isolates from all patients with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Genotypic resistance to efavirenz, predominantly the K103N mutation, was the most common form of resistance that developed. Resistance to efavirenz occurred in 13/19 (68%) analyzed patients in the VIREAD + emtricitabine group and in 21/29 (72%) analyzed patients in the lamivudine/zidovudine group. The M184V mutation, associated with resistance to emtricitabine and lamivudine, was observed in 2/19(11%) analyzed patients in the VIREAD + emtricitabine group and in 10/29 (34%) analyzed patients in the lamivudine/zidovudine group. In treatment-naive patients treated with VIREAD + emtricitabine + efavirenz, none of the HIV isolates from 19 patients analyzed for resistance showed reduced susceptibility to tenofovir or the presence of the K65R mutation.

Clinical Efficacy in Patient with HBV

Study Demographics and Trial Design

HBeAg-Negative Chronic Hepatitis B: Study 0102 was a Phase 3, randomized, double- blind, active-controlled study of VIREAD 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) patients, the majority of whom were nucleoside-naive. The mean age of patients was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, patients 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 study of VIREAD 300 mg compared to HEPSERA 10 mg in 266 (HBeAg+) nucleoside-naive patients. The mean age of patients was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, and 16% had previously received alpha-

interferon therapy. At baseline, patients 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 patients reached 48 weeks of treatment.

Table 25 Studies 0102 and 0103: VIREAD Compared to HEPSERA

Study Results

In HBeAg- and HBeAg + patients VIREAD was shown to be statistically superior with respect to the primary efficacy endpoint (complete response to treatment). VIREAD was associated with significantly greater proportions of patients with HBV DNA < 400 copies/mL when compared to HEPSERA as shown in Table 26. In study 0103, a significantly greater proportion of patients in the VIREAD group had normalized ALT and achieved HBsAg loss, when compared to HEPSERA.

Table 26 Histological, Virological, Biochemical and Serological Response at Week 48 (Studies 0102 and 0103)

*p value vs adefovir dipivoxil < 0.001, * *p value vs adefovir dipivoxil <0.05, a Complete response defined as HBV DNA levels < 400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis, b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis, cThe population used for analysis of ALT normalization included only patients with ALT above ULN at baseline. VIREAD was associated with significantly greater proportions of patients with undetectable HBV DNA (< 169 copies/mL[< 29 IU/mL]; the limit of quantification of the Roche Cobas Taqman HBV assay), when compared to HEPSERA (study 0102; 91%, 56%, p<0.001 and study 0103; 69%, 9%, p<0.001), respectively. Response to treatment with VIREAD was comparable in nucleoside-experienced (n=51) and nucleoside-naive (n=375) patients and in patients with normal ALT (n=21) and abnormal ALT (n=405) at baseline when studies 0102 and 0103 were combined. Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naive patients achieved complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naive patients achieved HBV DNA suppression < 400 copies/mL. All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression < 400 copies/mL. VIREAD has demonstrated anti-HBV activity in patients with HBV-containing lamivudine- resistance-associated mutations. In Study ACTG 5127, a randomized, 48 week double-blind, controlled trial of VIREAD 300 mg in patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (90% of patients were lamivudine resistant), the mean serum HBV DNA level at baseline in patients randomized to the VIREAD arm was 9.45 log10 copies/mL (n=27). Treatment with VIREAD was associated with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48 week data, of -5.74 log10 copies/mL (n=18). In addition, 61% of patients had normal ALT at Week 48.

Genotypic Analyses of VIREAD in Patients with HBV (Studies 0102 and 0103)

Four hundred and twenty six HBeAg negative and HBeAg positive patients were evaluated for genotypic changes in HBV polymerase. Genotypic evaluations were performed on all patients with HBV DNA >400 copies/mL at week 48. No nucleoside-naive or nucleoside- experienced patient treated with tenofovir DF for 48 weeks in studies 0102 (N=250) or 0103 (N=176) developed mutations associated with VIREAD resistance.

DETAILED PHARMACOLOGY VIROLOGY (MICROBIOLOGY)

Activity in HIV-1

Tenofovir diphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases a, b, and mitochondrial DNA polymerase g.

Anti-HIV Activity In Vitro

The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC50 (50% inhibitory concentrations) for tenofovir was in the range of 0.04 mM to 8.5 mM. In drug combination studies of tenofovir with nucleoside and non- nucleoside analog inhibitors of HIV reverse transcriptase, and protease inhibitors, additive to synergistic effects were observed. In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1.

In Vitro Resistance

HIV isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 3-4-fold reduction in susceptibility to tenofovir.

In Vitro Cross-Resistance

Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The in vitro activity of tenofovir against HIV-1 strains with zidovudine-associated reverse transcriptase mutations (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) was evaluated. Zidovudine-associated mutations may also confer reductions in susceptibility to other nucleoside reverse transcriptase inhibitors (NRTIs) and these mutations have been reported to emerge during combination therapy with stavudine and didanosine. In 20 samples that had multiple zidovudine-associated mutations (mean 3.3), a mean 3.1-fold increase of the IC50 of tenofovir was observed (range 0.8-8.4). Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir. Tenofovir showed slightly increased activity against HIV-1 expressing the M184V resistance mutation.

Activity in HBV

Anti-Hepatitis B Virus Activity In Vitro

The in vitro antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir were in the range of 0.14 to 1.5 mM, with CC50 (50% cytotoxicity concentration) values >100 mM. Tenofovir diphosphate inhibits recombinant HBV polymerase with a Ki (inhibition constant) of 0.18 mM. In in vitro drug combination studies of tenofovir with nucleoside anti-HBV reverse transcriptase inhibitors lamivudine, telbivudine, and entecavir, additive anti-HBV activity was observed. Additive to slightly synergistic effects were observed with the combination of tenofovir and emtricitabine.

In Vitro Cross-Resistance

Cross-resistance has been observed among HBV reverse transcriptase inhibitors. In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V mutations 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. HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations 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-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9 to 10-fold that of wild type virus. Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC50 values 1.5-fold that of wild type virus.

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name:

tenofovir disoproxil fumarate (USAN)

Chemical Name:

9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]- methoxy]propyl]adenine fumarate (1:1)

Empirical Formula: C19H30N5O10P * C4H4O4

Molecular Weight:

635.52

Structural Formula:

NH2

N N

NO

N O

O P O O O O O

H

• C C

CO2H

O

HO2C H

O

TOXICOLOGY

The nonclinical safety profile of tenofovir disoproxil fumarate has been studied in mice, rats, guinea pigs, rabbits, dogs, and monkeys. In all species, tenofovir disoproxil fumarate was hydrolyzed to tenofovir following absorption. Tenofovir was cleared exclusively by renal elimination, without further metabolic changes, by a combination of glomerular filtration and tubular secretion.

Single Dose Toxicity

Following single doses, the no-effect-level (NOEL) in rats was 1500 mg/kg. Following single doses in dogs (270 mg/kg), mild renal tubular karyomegaly and/or basophilia were the only effects observed. Single oral doses of tenofovir disoproxil fumarate had no adverse effects on the central nervous system (male rats, 50 or 500 mg/kg) or on cardiovascular and respiratory function (conscious male dogs, 30 mg/kg). An assessment of effects on renal function demonstrated increased urinary electrolyte excretion and urine volume in rats administered tenofovir disoproxil fumarate 500 mg/kg; no effect was observed at 50 mg/kg. When rats were administered tenofovir disoproxil fumarate (0, 50, or 500 mg/kg) to evaluate effects on the gastrointestinal transit of a charcoal meal, there was reduced gastric emptying at 500 mg/kg/day, but no effect at 50 mg/kg/day.

Subacute and Chronic Toxicity

The target organs of toxicity identified in the preclinical program were the gastrointestinal tract, renal tubular epithelium, and bone.

Gastrointestinal Tract

Gastrointestinal (GI) toxicity, observed primarily in rats, was dose related, reversible, and characterized by inflammation of the stomach and intestines, epithelial cytomegaly in the duodenum and jejunum, and villous atrophy of the ileum in rodents.

Kidney

Renal tubular epithelial karyomegaly, a morphologic change without pathologic consequence, was the most sensitive histological indicator of an effect on the kidney and was observed in rats, dogs, and monkeys. In dogs, the species most sensitive to effects on the kidney, additional microscopic alterations reported following chronic administration of tenofovir disoproxil fumarate (>=10 mg/kg/day for 42 weeks) included individual cell necrosis, tubular dilatation, degeneration/regeneration, pigment accumulation, and interstitial nephritis. Associated biochemical changes in dogs administered tenofovir disoproxil fumarate 30 mg/kg/day were a slight elevation in serum creatinine, glucosuria, proteinuria, and increased urine volume. The incidence and severity of nephrotoxicity was dose related.

Bone

Chronic administration of high doses of tenofovir or tenofovir disoproxil fumarate in laboratory animals resulted in bone alterations. Minimal decreases in bone mineral density and content were observed in rats and dogs following oral administration of tenofovir DF at the doses of 300 and 30 mg/kg/day, respectively (6 and 10x human exposure, respectively). In juvenile monkeys pathologic osteomalacia and hypophosphatemia was observed following subcutaneous administration of tenofovir at the dose of 30 mg/kg/day (25x human exposure). Monkeys treated chronically with tenofovir 10 mg/kg/day, sc, (AUC = 4x humans), had no clinical or radiographic evidence of bone toxicity. Bone changes in rats and dogs did not appear to consistently reverse during the recovery period; osteomalacia in juvenile monkeys was reversible. Studies designed to evaluate the mechanism underlying effects on bone suggest that tenofovir may not have direct toxicity to bone. The mechanism is as yet unclear, however data suggest bone effects may be secondary to negative phosphate balance resulting from tenofovir-related reductions in intestinal phosphate absorption and/or renal reabsorption of phosphate.

Mutagenicity

Tenofovir disoproxil fumarate was equivocal in the in vitro bacterial mutation (Ames) assay (Salmonella-Eschericia coli/ Mammalian-Microsome Reverse Mutation Assay) but positive in the in vitro mouse lymphoma assay (L5178Y TK +/- Forward Mutation Assay), with and without metabolic activation. Tenofovir disoproxil fumarate was negative in the in vivo mouse micronucleus assay at plasma exposure levels of more than 10x the human exposure.

Reproductive Toxicity

Reproductive toxicity was evaluated in rats and rabbits. Tenofovir disoproxil fumarate had no adverse effects on fertility or general reproductive performance in rats at doses up to 600 mg/kg/day. Tenofovir disoproxil fumarate had no adverse effects on embryo-fetal development in rats at doses 450 mg/kg/day and in rabbits at doses up to 300 mg/kg/day. In a study of effects on peri- and postnatal development in rats, effects considered due to maternal toxicity (450-600 mg/kg/day) were reduced survival and a slight delay in sexual maturation in the F1 generation. There were no adverse effects on growth, development, behavior, or reproductive parameters at non-maternally toxic doses (150 mg/kg/day).

Carcinogenicity

Long-term oral carcinogenicity studies were conducted in mice and rats receiving tenofovir disoproxil fumarate. In the mouse study, (60/sex/group), one male and two female mice in the 600 mg/kg/day group (15 times the human systemic exposure at the recommended human dose of 300 mg/day) had duodenal tumors. The mechanism underlying this effect is uncertain but may relate to high local drug concentrations in the gastrointestinal tract. No treatment-related tumors were seen in mice in the 100 or 300 mg/kg/day groups. In the rat study (60/sex/group) at doses of 30, 100 and 300 mg/kg/day (approximately 5 times human exposure), no treatment-related increase in tumor incidence was observed.

REFERENCES

1. Deeks, S. G., et al, Safety, Pharmacokinetics, and Antiretroviral Activity of Intravenous 9-{2-(R)-(Phosphonomethoxy)propyl}adenine, a Novel Anti-Human Immunodeficiency Virus (NIV) Therapy, in HIV-Infected Adults. Antimicrobial Agents and Chemotherapy, Sept. 1998, p. 2380-2384.

2. Patricia Barditch-Crovo, Steven G. Deeks, Ann Collier, Sharon Safrin, Dion F. Coakley, Michael Miller, Brian P. Kearney, Rebecca L. Coleman, Patrick D. Lamy, James O. Kahn, Ian McGowan, Paul S. Lietman Phase I/II Trial of the Pharmacokinetics, Safety, and Antiretroviral Activity of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Adults, AAC, Oct 2001, Vol 45, No 10, p 2733-2739

3. Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, Chen SS, Miller MD, Isaacson E, and Cheng AK (2002) Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS. (16:9) pp 1257-1263

4. Margot NA, Isaacson E, McGowan I, Cheng AK, Schooley RT, and Miller MD (2002) Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF. AIDS. (16:9) pp 1227-1235

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6. Study 907: Squires K, Pozniak AL, Pierone G, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF and Cheng AK. (2003) Tenofovir DF in antiretroviral-experienced, nucleoside-resistant HIV-1 infected patients with incomplete viral suppression. Annals of Internal Medicine 139 (5): pp 313-320

7. Gallant, J.E., DeJesus, E., Arribas, J.R., Pozniak, A.L., Gazzard, B., Campo, R.E. et al. Tenofovir DF, Emtricitabine and Efavirenz versus Zidovudine, Lamivudine and Efavirenz for HIV. New Engl. J. Med. 2006 (354): 251-26

8. EMEA Public Statement, Efficacy and safety concerns regarding the co- administration of tenofovir disoproxil fumarate (TDF, Viread) and didanosine (ddI, Videx), 2005. http://www.emea.eu.int/pdfs/human/press/pus/6233105en.pdf

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