VIREAD is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

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

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

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

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

Last updated on RxList: 12/29/2008

HIV-1 Infection

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

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

• VIREAD should not be used in combination with TRUVADA® or ATRIPLA® [See WARNINGS AND PRECAUTIONS].

Chronic Hepatitis B

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

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

• This indication is based on data from one year of treatment in primarily nucleoside-treatment-naïve adult patients with HBeAg-positive and HBeAg­negative chronic hepatitis B with compensated liver disease [See Clinical Efficacy in Patients with Chronic Hepatitis B].
• The numbers of patients in clinical trials who were nucleoside-experienced or who had lamivudine-associated mutations at baseline were too small to reach conclusions of efficacy [See Clinical Efficacy in Patients with Chronic Hepatitis B].
• VIREAD has not been evaluated in patients with decompensated liver disease.

Recommended Dose

For the treatment of HIV-1 or chronic hepatitis B: The dose of VIREAD 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.

Dose Adjustment for Renal Impairment

Significantly increased drug exposures occurred when VIREAD was administered to patients with moderate to severe renal impairment [See CLINICAL PHARMACOLOGY]. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance < 50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See WARNINGS AND PRECAUTIONS].

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See WARNINGS AND PRECAUTIONS].

Table 1: Dosage Adjustment for Patients with Altered Creatinine Clearance

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.

Dosage Forms And Strengths

VIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.

Storage And Handling

The almond-shaped, light blue, film-coated tablets contain 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with “GILEAD” and “4331” on one side and with “300” onthe other side, and are available in unit of use bottles (containing a desiccant [silica gel canister or sachet] and closed with a child-resistant closure) of:

30 tablets (NDC 61958–0401–1)

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

Do not use if seal over bottle opening is broken or missing.

November 2008. Gilead Sciences, Inc. FDA revision date: 11/4/2008

Last updated on RxList: 12/29/2008

The following adverse reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Severe Acute Exacerbation of Hepatitis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
• New Onset or Worsening Renal Impairment [See WARNINGS AND PRECAUTIONS].
• Decreases in Bone Mineral Density [See WARNINGS AND PRECAUTIONS].
• Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].

Adverse Reactions from Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials in Patients with HIV Infection

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

The most common adverse reactions (incidence ≥ 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

Treatment-Naïve Patients

Study 903 - Treatment-Emergent Adverse Reactions: 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 reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.

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

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

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

Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral­ naïve patients received either VIREAD + EMTRIVA® administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 4).

Table 4: Selected Treatment-Emergent Adverse Reactions^a (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in Study 934 (0–144 Weeks)

Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 5).

Table 5: Significant Laboratory Abnormalities Reported in ≥ 1% of Patients in Any Treatment Group in Study 934 (0–144 Weeks)

Treatment-Experienced Patients

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

A summary of moderate to severe, treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 6.

Table 6: Selected Treatment-Emergent Adverse Reactions^a (Grades 2–4) Reported in ≥ 3% in Any Treatment Group in Study 907 (0–48 Weeks)

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 7.

Table 7: Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Patients in Study 907 (0–48 Weeks)

Clinical Trials in Patients with Chronic Hepatitis B

Treatment-Emergent Adverse Reactions: In controlled clinical trials in patients with chronic hepatitis B, more patients treated with VIREAD experienced nausea: 9% with VIREAD versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in > 5% of patients treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.

Laboratory Abnormalities: A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 8.

Table 8: Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Patients in Studies 0102 and 0103 (0-48 Weeks)

The overall incidence of on-treatment ALT elevations (defined as serum ALT > 2 × baseline and > 10 × ULN, with or without associated symptoms) was similar between VIREAD (2.6%) and HEPSERA (2%). ALT elevations generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No patient had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders
allergic reaction

Metabolism and Nutrition Disorders
lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic , and Mediastinal Disorders
dyspnea

Gastrointestinal Disorders
pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders
rash

Musculoskeletal and Connective Tissue Disorders
rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders
acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions
asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

This section describes clinically relevant drug interactions with VIREAD. Drug interactions studies are described elsewhere in the labeling [See CLINICAL PHARMACOLOGY].

Didanosine

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

When administered with VIREAD, Cmax and AUC of didanosine (administered as either the buffered or enteric-coated formulation) increased significantly [See CLINICAL PHARMACOLOGY]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4⁺ cell counts has been observed in patients receiving tenofovir disoproxil fumarate (tenofovir DF) with didanosine 400 mg daily.

In adults weighing > 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal ( < 400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions.

Atazanavir

Atazanavir has been shown to increase tenofovir concentrations [See CLINICAL PHARMACOLOGY]. The mechanism of this interaction is unknown. Patients receiving atazanavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions. VIREAD decreases the AUC and Cmin of atazanavir [See CLINICAL PHARMACOLOGY].

When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with VIREAD.

Lopinavir/Ritonavir

Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See CLINICAL PHARMACOLOGY]. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.

Drugs Affecting Renal Function

Since tenofovir is primarily eliminated by the kidneys [See CLINICAL PHARMACOLOGY], coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir.

In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

Last updated on RxList: 12/29/2008

Included as part of the PRECAUTIONS section.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

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

Exacerbation of Hepatitis after Discontinuation of Treatment

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

New Onset or Worsening Renal Impairment

Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See ADVERSE REACTIONS].

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment.

Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance < 50 mL/min [See DOSAGE AND ADMINISTRATION].

No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.

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

Coadministration with Other Products

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

VIREAD should not be administered in combination with HEPSERA® (adefovir dipivoxil) [See DRUG INTERACTIONS].

Patients Coinfected with HIV-1 and HBV

Due to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.

HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.

Decreases in Bone Mineral Density

Bone mineral density (BMD) 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.

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

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

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

Fat Redistribution

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

Immune Reconstitution Syndrome

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

Early Virologic Failure

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 substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

Patient Counseling Information

See FDA-approved patient labeling

Patients should be advised that:

• VIREAD is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using VIREAD.
• The use of VIREAD has not been shown to reduce the risk of transmission of HIV-1 or HBV to others through sexual contact or blood contamination.
• The long term effects of VIREAD are unknown.
• VIREAD Tablets are for oral ingestion only.
• VIREAD should not be discontinued without first informing their physician.
• If you have HIV-1 infection, with or without HBV coinfection, it is important to take VIREAD with combination therapy.
• It is important to take VIREAD on a regular dosing schedule and to avoid missing doses.
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with VIREAD should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See WARNINGS AND PRECAUTIONS].
• Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy [See WARNINGS AND PRECAUTIONS].
• Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued VIREAD [See WARNINGS AND PRECAUTIONS].
• In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating VIREAD [See WARNINGS AND PRECAUTIONS].
• Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent [See WARNINGS AND PRECAUTIONS]. Dosing interval of VIREAD may need adjustment in patients with renal impairment [See DOSAGE AND ADMINISTRATION].
• VIREAD should not be coadministered with the fixed-dose combination products TRUVADA and ATRIPLA since it is a component of these products [See WARNINGS AND PRECAUTIONS].
• VIREAD should not be administered in combination with HEPSERA [See WARNINGS AND PRECAUTIONS].
• Decreases in bone mineral density have been observed with the use of VIREAD in patients with HIV. Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia [See WARNINGS AND PRECAUTIONS].
• In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

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

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

Use In Specific Populations

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, VIREAD should be used during pregnancy only if clearly needed.

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

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving VIREAD.

Pediatric Use

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

Geriatric Use

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

Patients with Impaired Renal Function

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, CLINICAL PHARMACOLOGY].

Last updated on RxList: 12/29/2008

Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In Study 901, 600 mg tenofovir disoproxil fumarate 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.

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.

None.

Last updated on RxList: 12/29/2008

Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug.

Pharmacokinetics

The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.

Absorption

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

The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing.

Distribution

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

Metabolism and Elimination

In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes. Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing.

Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ±10% of the administered dose is recovered in urine over 24 hours.

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

Effects of Food on Oral Absorption

Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ±0.12μg/mL and 3.32 ±1.37 g·hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.

Special Populations

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

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

Pediatric and Geriatric Patients: Pharmacokinetic studies have not been performed in children ( < 18 years) or in the elderly ( > 65 years).

Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in patients with renal impairment [See WARNINGS AND PRECAUTIONS]. In patients with creatinine clearance < 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC_0-∞ of tenofovir were increased (Table 9). 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 9: Pharmacokinetic Parameters (Mean ± SD) of Tenofovir^a in Patients with Varying Degrees of Renal Function

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

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

Assessment of Drug Interactions

At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving tenofovir with other medicinal products is low [See CLINICAL PHARMACOLOGY].

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. Tables 10 and 11 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.

Table 10: Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir^a in the Presence of the Coadministered Drug

Following multiple dosing to HIV- and HBV-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 11: Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIREAD

Table 12 summarizes the drug interaction between VIREAD and didanosine. Coadministration of VIREAD and didanosine should be undertaken with caution [See DRUG INTERACTIONS]. 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 12: Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD

Microbiology

Mechanism of Action

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

Activity against HIV

Antiviral Activity

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC₅₀ (50% effective concentration) values for tenofovir were in the range of 0.04 M to 8.5μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC₅₀ values ranged from 0.5 M to 2.2μM) and strain specific activity against HIV-2 (EC₅₀ values ranged from 1.6 M to 5.5μM).

Resistance

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

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

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

Cross Resistance

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

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

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced patients participating in Studies 902 and 907.

In these clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation. These included resistance substitutions associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), the abacavir/emtricitabine/lamivudine resistance-associated substitution (M184V), and others. In addition the majority of participants evaluated had substitutions 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 substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated substitutions were observed and appeared to depend on the number of specific substitutions. VIREAD-treated patients whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to VIREAD therapy.

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

Studies 902 and 907 Phenotypic Analyses

The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment-experienced patients participating in two controlled trials. Phenotypic analysis of baseline HIV-1 from patients in these studies demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 13 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

Table 13: HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (Intent­To-Treat)^a

Activity against HBV

Antiviral Activity

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

Resistance

Out of 426 HBeAg negative and HBeAg positive patients, 39 patients had serum HBV DNA > 400 copies/mL at Week 48. Genotypic data from paired baseline and on treatment isolates were available for 28 of the 39 patients. No specific amino acid substitutions occurred in these subjects' ates at sufficient frequency to establish an association with tenofovir resistance.

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 substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7 to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.

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

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

Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9 to 1.5-fold that of wild type virus.

Animal Toxicology and/or Pharmacology

Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Clinical Studies

Clinical Efficacy in Patients with HIV-1 Infection

Treatment-Naïve Patients

Study 903

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing VIREAD (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve patients. Patients had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4⁺ cell count was 279 cells/mm³ (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4⁺ cell count. Forty-three percent of patients had baseline viral loads > 100,000 copies/mL and 39% had CD4⁺ cell counts < 200 cells/mm³. Treatment outcomes through 48 and 144 weeks are presented in Table 14.

Table 14: Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)

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, 11 patients in the VIREAD group and 9 patients in the stavudine group experienced a new CDC Class C event.

Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing emtricitabine + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve patients. From Weeks 96 to 144 of the study, patients received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + VIREAD with efavirenz. 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⁺ cell count ( < or ≥ 200 cells/mm³); 41% had CD4⁺ cell counts < 200 cells/mm³ and 51% of patients had baseline viral loads > 100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 15.

Table 15: Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)

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

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

Treatment-Experienced Patients

Study 907

Study 907 was a 24-week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label VIREAD for an additional 24 weeks. Patients had a mean baseline CD4⁺ cell count of 427 cells/mm³(range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic. Changes from baseline in log₁₀ copies/mL plasma HIV-1 RNA levels over time up to Week 48 are presented below in Figure 1.

Figure 1: Mean Change from Baseline in Plasma HIV-1 RNA (log₁₀ copies/mL) Through Week 48 (Study 907; All Available Data)^†

The percent of patients with HIV-1 RNA < 400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 16.

Table 16: Outcomes of Randomized Treatment (Study 907)

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

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

Clinical Efficacy In Patients with Chronic Hepatitis B

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 with compensated liver function, the majority of whom were nucleoside-naïve. 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-naïve patients with compensated liver function. The mean age of patients was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and < 5% were nucleoside experienced. At baseline, 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 and results are summarized below.

The primary efficacy endpoint in both studies was complete response to treatment defined as HBV DNA < 400 copies/mL and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 17).

Table 17: Histological, Virological, Biochemical, and Serological Response at Week 48

A small proportion of nucleoside-experienced patients received VIREAD in the clinical trials: 43 patients in Study 0102 and 8 patients in Study 0103. Across both studies, 5 patients had HBV containing lamivudine-resistance associated substitutions at baseline. The numbers of patients in these subgroups were too small to establish efficacy.

Last updated on RxList: 12/29/2008

VIREAD®
(VEER ee ad) Tablets

Generic Name: tenofovir disoproxil fumarate (te NOE' fo veer dye soe PROX il FYOU-mar-ate)

Read this leaflet carefully before you start taking VIREAD. Also, read it each time you get your VIREAD prescription refilled, in case something has changed. This information does not take the place of talking with your healthcare provider when you start this medicine and at check ups. You should stay under a healthcare taking VIREAD. Do not change or stop your medicine without first talking with your healthcare provider. Talk to your healthcare provider if you have any questions about VIREAD.

What is VIREAD and how does it work?

VIREAD is a type of medicine called a nucleotide analog reverse transcriptase and HBV polymerase inhibitor (NRTI).

Use in the Treatment of HIV-1 Infection:

VIREAD is a treatment for Human Immunodeficiency Virus (HIV) infection in adults age 18 years and older. VIREAD is always used in combination with other anti-HIV-1 medicines to treat people with HIV-1 infection.

HIV infection destroys CD4⁺ T cells, which are important to the immune system. After a large number of T cells are destroyed, acquired immune deficiency syndrome (AIDS) develops.

VIREAD helps to block HIV-1 reverse transcriptase, a chemical in your body (enzyme) that is needed for HIV-1 to multiply. VIREAD lowers the amount of HIV-1 in the blood (called viral load) and may help to increase the number of T cells (called CD4⁺ cells). Lowering the amount of HIV-1 in the blood lowers the chance of death or infections that happen when your immune system is weak (opportunistic infections).

Use in the Treatment of Chronic Hepatitis B:

VIREAD is also used to treat chronic hepatitis B (an infection with hepatitis B virus [HBV]) in adults age 18 years and older. VIREAD works by interfering with the normal working of an enzyme (HBV DNA polymerase) that is essential for the HBV virus to reproduce itself. VIREAD may help lower the amount of hepatitis B virus in your body by lowering the ability of the virus to multiply and infect new liver cells.

Does VIREAD cure HIV-1 or AIDS?

VIREAD does not cure HIV-1 infection or AIDS. The long-term effects of VIREAD are not known at this time. People taking VIREAD may still get opportunistic infections or other conditions that happen with HIV-1 infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

We do not know how long VIREAD may help your hepatitis. Sometimes viruses change in your body and medicines no longer work. This is called drug resistance.

We do not know if VIREAD will reduce your chances of getting liver cancer from chronic hepatitis B.

Does VIREAD reduce the risk of passing HIV-1 or HBV to others?

VIREAD does not reduce the risk of passing HIV-1 or HBV to others through sexual contact or blood contamination. Continue to practice safe sex and do not use or share dirty needles.

Who should not take VIREAD?

Together with your healthcare provider, you need to decide whether VIREAD is right for you. Do not take VIREAD if

• you are allergic to VIREAD or any of its ingredients
• you are already taking TRUVADA® or ATRIPLA® because VIREAD is one of the active ingredients in TRUVADA and ATRIPLA
• you have not already discontinued treatment with HEPSERA®

What should I tell my healthcare provider before taking VIREAD?

Tell your healthcare provider

• If you are pregnant or planning to become pregnant: The effects of VIREAD on pregnant women or their unborn babies are not known.
• If you are breast-feeding: Do not breast-feed if you are taking VIREAD. Do not breast-feed if you have HIV. If you are a woman who has or will have a baby, talk with your healthcare provider about the best way to feed your baby. If your baby does not already have HIV, there is a chance that the baby can get HIV through breast-feeding.
• If you have kidney or bone problems
• If you have liver problems including Hepatitis B Virus infection
• If you have HIV-1 Infection
• Tell your healthcare provider about all your medical conditions

TELL YOUR HEALTHCARE PROVIDER ABOUT ALL THE MEDICINES YOU TAKE, INCLUDING PRESCRIPTION AND NON-PRESCRIPTION MEDICINES AND DIETARY SUPPLEMENTS. ESPECIALLY TELL YOUR HEALTHCARE PROVIDER IF YOU TAKE:

• VIDEX, VIDEX EC (DIDANOSINE). VIREAD MAY INCREASE THE AMOUNT OF VIDEX IN YOUR BLOOD. YOU MAY NEED TO BE FOLLOWED MORE CAREFULLY IF YOU ARE TAKING VIDEX AND VIREAD TOGETHER. IF YOU ARE TAKING VIDEX AND VIREAD TOGETHER YOUR HEALTHCARE PROVIDER MAY NEED TO REDUCE YOUR DOSE OF VIDEX.
• REYATAZ (ATAZANAVIR SULFATE) OR KALETRA (LOPINAVIR/RITONAVIR). THESE MEDICINES MAY INCREASE THE AMOUNT OF VIREAD IN YOUR BLOOD, WHICH COULD RESULT IN MORE SIDE EFFECTS. YOU MAY NEED TO BE FOLLOWED MORE CAREFULLY IF YOU ARE TAKING VIREAD AND REYATAZ OR KALETRA TOGETHER. VIREAD MAY DECREASE THE AMOUNT OF REYATAZ IN YOUR BLOOD. IF YOU ARE TAKING VIREAD AND REYATAZ TOGETHER YOU SHOULD ALSO BE TAKING NORVIR (RITONAVIR).

IT IS A GOOD IDEA TO KEEP A COMPLETE LIST OF ALL THE MEDICINES THAT YOU TAKE. MAKE A NEW LIST WHEN MEDICINES ARE ADDED OR STOPPED. GIVE COPIES OF THIS LIST TO ALL OF YOUR HEALTHCARE PROVIDERS EVERY TIME YOU VISIT YOUR HEALTHCARE PROVIDER OR FILL A PRESCRIPTION.

How should I take VIREAD?

• Stay under a healthcare provider's care treatment or stop treatment without first talking with your healthcare provider.
• Take VIREAD exactly as your healthcare provider prescribed it. Follow the directions from your healthcare provider, exactly as written on the label. Set up a dosing schedule and follow it carefully.
• If you are taking VIREAD to treat your HIV or if you have HIV and HBV co-infection and are taking VIREAD, always take VIREAD in combination with other anti-HIV medicines. VIREAD and other products like VIREAD may be less likely to work in the future if you are not taking VIREAD with other anti-HIV medicines because you may develop resistance to those medicines.
• Talk to your doctor about taking an HIV test before you start treatment with VIREAD for chronic hepatitis B.
• The usual dose of VIREAD is 1 tablet once a day. If you have kidney problems, your healthcare provider may recommend that you take VIREAD less frequently.
• VIREAD may be taken with or without a meal.
• When your VIREAD supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to VIREAD and become harder to treat.
• Only take medicine that has been prescribed specifically for you. Do not give VIREAD to others or take medicine prescribed for someone else.

What should I do if I miss a dose of VIREAD?

It is important that you do not miss any doses. If you miss a dose of VIREAD, take it as soon as possible and then take your next scheduled dose at its regular time. If it is almost time for your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not double the next dose.

What happens if I take too much VIREAD?

If you suspect that you took more than the prescribed dose of VIREAD, contact your local poison control center or emergency room right away.

As with all medicines, VIREAD should be kept out of reach of children.

What should I avoid while taking VIREAD?

• Do not breast-feed. See “What should Itell my healthcare provider before taking VIREAD?”

What are the possible side effects of VIREAD?

• Clinical studies in patients with HIV-1: The most common side effects of VIREAD are: rash, headache, pain, diarrhea, depression, weakness, and nausea. Less common side effects include vomiting, dizziness, and intestinal gas.
  Clinical studies in patients with chronic hepatitis B: The most common side effect of VIREAD is nausea. Less common side effects include abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.
• Marketing experience: Other side effects reported since VIREAD has been marketed include: lactic acidosis, kidney problems (including decline or failure of kidney function), inflammation of the pancreas, inflammation of the liver, allergic reaction, shortness of breath, stomach pain, and high volume of urine and thirst caused by kidney problems. Muscle pain and muscle weakness, bone pain, and softening of the bone (which may contribute to fractures) as a consequence of kidney problems have been reported.
• Some patients treated with VIREAD have had kidney problems. If you have had kidney problems in the past or need to take another drug that can cause kidney problems, your healthcare provider may need to perform additional blood tests.
• Laboratory tests show changes in the bones of patients treated with VIREAD. If you have had bone problems in the past, your healthcare provider may need to perform additional tests or may suggest additional medication. Additionally, bone pain and softening of the bone (which may contribute to fractures) may occur as a consequence of kidney problems.
• Some patients taking antiviral drugs like VIREAD have developed a condition called lactic acidosis (a buildup in the blood of lactic acid, the same substance that causes your muscles to burn during heavy exercise). Symptoms of lactic acidosis include nausea, vomiting, unusual or unexpected stomach discomfort, and weakness. If you notice these symptoms or if your medical condition changes suddenly, call your healthcare provider right away.
• Changes in body fat have been seen in some patients taking anti-HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the mainpart of your body (trunk). Loss of fat from the legs, arms and face may also happen. The cause and long term health effects of these conditions are not known at this time.
• In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your doctor immediately.
• If you have HBV infection or HIV and HBV infection together, you may have a “flare­up” of Hepatitis B, in which the diseasesuddenly returns in a worse way than before if you stop taking VIREAD. Do not stop taking VIREAD without your After stopping VIREAD, tell your doctor immediately about any new, unusual, or worsening symptoms that you notice after stopping treatment. After you stop taking VIREAD, your doctor will still need to check your health and take blood tests to check your liver for several months.
• There have been other side effects in patients taking VIREAD. However, these side effects may have been due to other medicines that patients were taking or to the illness itself. Some of these side effects can be serious.
• This list of side effects is not complete. If you have questions about side effects, ask your healthcare provider. You should report any new or continuing symptoms to your healthcare provider right away. Your healthcare provider may be able to help you manage these side effects.

How do I store VIREAD?

• Keep VIREAD and all other medications out of reach of children.
• Store VIREAD at room temperature 77°F (25 °C). It should remain stable until the expiration date printed on the label.
• Do not keep your medicine in places that are too hot or cold.
• Do not keep medicine that is out of date or that you no longer need. If you throw any medicines away make sure that children will not find them.

General advice about prescription medicines:

TALK TO YOUR HEALTHCARE PROVIDER IF YOU HAVE ANY QUESTIONS ABOUT THIS MEDICINE OR YOUR CONDITION. MEDICINES ARE SOMETIMES PRESCRIBED FOR PURPOSES OTHER THAN THOSE LISTED IN A PATIENT INFORMATION LEAFLET. IF YOU HAVE ANY CONCERNS ABOUT THIS MEDICINE, ASK YOUR HEALTHCARE PROVIDER. YOUR HEALTHCARE PROVIDER OR PHARMACIST CAN GIVE YOU INFORMATION ABOUT THIS MEDICINE THAT WAS WRITTEN FOR HEALTH CARE PROFESSIONALS. DO NOT USE THIS MEDICINE FOR A CONDITION FOR WHICH IT WAS NOT PRESCRIBED. DO NOT SHARE THIS MEDICINE WITH OTHER PEOPLE.

DO NOT USE IF SEAL OVER BOTTLE OPENING IS BROKEN OR MISSING.

What are the ingredients of VIREAD?

Active Ingredient: tenofovir disoproxil fumarate

Inactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II Y–30–10671–A, which contains FD&C blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.

Last updated on RxList: 12/29/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

TENOFOVIR - ORAL

(te-NOE-fo-veer)

COMMON BRAND NAME(S): Viread

WARNING: Rarely, tenofovir has caused a severe (sometimes fatal) liver and blood problem (lactic acidosis). Immediately tell your doctor if you develop symptoms of liver problems (persistent nausea, stomach/abdominal pain, dark urine, yellowing eyes/skin), or of lactic acidosis (rapid breathing, drowsiness, muscle aches).

If you have hepatitis B infection along with HIV, your hepatitis symptoms may get worse or become very serious if you stop taking tenofovir. Talk with your doctor before stopping this medication. Your doctor will perform liver function tests for several months after you stop tenofovir. Tell your doctor immediately if you develop symptoms of worsening liver problems.

USES: This drug, used in combination with other medications, helps to control your HIV infection, thereby improving your quality of life. It also lowers your risk of getting HIV complications (e.g., new infections, cancer). Tenofovir belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors.

Tenofovir is not a cure for HIV and it does not prevent the spread of HIV to others through sexual contact or blood contamination (e.g., sharing used needles).

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used in a person who is not infected with HIV. When used properly with other medications as directed by a doctor, tenofovir might prevent HIV infection after possible contact with the virus (e.g., accidental needle stick).

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start taking tenofovir and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily or as directed by your doctor.

Dosage is based on your weight, kidney function, medical condition, and response to therapy.

It is very important to continue taking this medication (and other HIV medications) exactly as prescribed by your doctor.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it at the same time each day.

Do not take more or less of this drug than prescribed or stop taking it (or other HIV medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of virus to increase, make the infection more difficult to treat (resistant), or worsen side effects.

SIDE EFFECTS: See also Warning section.

Dizziness, nausea, diarrhea, stomach pain, gas, headache, trouble sleeping, loss of appetite, or weakness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., depression, anxiety), tingling/numbness of hands or feet.

Tell your doctor immediately if any of these rare but very serious side effects occur: bone pain, stomach/back pain with or without nausea/vomiting, muscle tenderness/pain/weakness, new fever, chills, cough, breathing problems, weight loss, new diarrhea, sore throat, pink/bloody urine, change in the amount of urine.

Changes in body fat may occur while you are taking this medication (e.g., increased fat in the upper back and stomach areas, decreased fat in the arms and legs). The cause and long-term effects of these changes are unknown. Discuss the risks and benefits of therapy with your doctor, as well as the possible role of exercise to reduce this side effect.

If you are taking HIV medications for the first time, you may experience symptoms of an old infection. This may happen as your immune system begins to work better. Contact your doctor immediately if you notice any of the following symptoms: new cough, trouble breathing, fever, new vision problems, new headaches, new skin problems.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking tenofovir, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: pancreatitis with other HIV medicines, kidney problems, liver problems (hepatitis B, hepatitis C, cirrhosis), alcohol use, bone problems (e.g., osteopenia, osteoporosis, pathologic bone fracture).

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

Caution is advised when using this drug in children because they may be more sensitive to the effects of the drug, especially the increased risk of pancreatitis.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug.

This medication should be used only when clearly needed during pregnancy. However, it is now normal to prescribe HIV medicines for pregnant women with HIV. This has been shown to decrease the risk of giving HIV to the baby. Tenofovir may be part of that treatment. Discuss the risks and benefits with your doctor.

It is not known if tenofovir passes into breast milk. Because breast milk can transmit HIV, do not breast-feed.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: lopinavir/ritonavir, atazanavir, didanosine.

Some drugs may also change the way your body gets rid of tenofovir (e.g., adefovir, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir). If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting tenofovir.

Some HIV medications contain 2 different drugs in 1 product. Tenofovir is often used in such combinations. Check the labels of all your medications to see if they contain tenofovir. Do not take 2 medications that both contain tenofovir without checking with your doctor first.

If you are taking medications that can cause kidney problems (e.g., amphotericin B, vancomycin, cyclosporine, nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen), you may be at higher risk for having kidney problems (including kidney failure) from tenofovir. Consult your doctor or pharmacist for other drugs that can cause kidney problems. You may also need to have kidney tests done more often to monitor for problems.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: To reduce the risk of spreading HIV to others, always use effective barrier protections (e.g., latex or polyurethane condoms, dental dams) during all sexual activity. Consult your doctor or pharmacist for more details.

Do not share this medication with others.

Laboratory and/or medical tests (e.g., kidney tests, liver tests, viral load, t-cell counts) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Keep all medical and laboratory appointments.

MISSED DOSE: If you miss a dose, take it as soon as you remember unless it is less than 2 hours before the time for your next dose. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.