Rx Drugs Info

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use viread safely and effectively. See full prescribing information for viread.
viread (tenofovir disoproxil fumaratetablet, coated for oral use
Initial U.S. Approval: 2001

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B

See full prescribing information for complete boxed warning.

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs. ( 5.1)
  • VIREAD is not approved for the treatment of chronic Hepatitis B virus (HBV) infection. Severe acute exacerbations of Hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued VIREAD. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-Hepatitis B therapy may be warranted. ( 5.2)

INDICATIONS AND USAGE

VIREAD, a nucleoside analog HIV-1 reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. ( 1)


DOSAGE AND ADMINISTRATION

  • Recommended dose: 300 mg once daily taken orally without regard to food. ( 2.1)
  • Dose recommended in renal impairment:
    Creatinine clearance 30–49 mL/min: 300 mg every 48 hours ( 2.2)
    Creatinine clearance 10–29 mL/min: 300 mg twice a week ( 2.2)
    Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis ( 2.2)

DOSAGE FORMS AND STRENGTHS

Tablets: 300 mg. ( 3)


CONTRAINDICATIONS

VIREAD is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product. ( 4)


WARNINGS AND PRECAUTIONS

  • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with VIREAD. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs. ( 5.3)
  • Products with same active ingredient: Do not use with other tenofovir-containing products (e.g., ATRIPLA and TRUVADA). ( 5.4)
  • Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or who are at risk for osteopenia. ( 5.5)
  • Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.6)
  • Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.7)

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥10%, Grades 2 – 4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea. ( 6)



To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

  • Didanosine: Coadministration increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy). Consider dose reductions or discontinuations of didanosine if warranted. ( 7.1)
  • Atazanavir: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with VIREAD only with additional ritonavir; monitor for evidence of tenofovir toxicity. ( 7.2)
  • Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. ( 7.3)

USE IN SPECIFIC POPULATIONS

  • Nursing mothers: Women infected with HIV should be instructed not to breast feed. ( 8.3)
  • Safety and efficacy not established in patients less than 18 years of age. ( 8.4)


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 06/2008

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Adjustment for Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

5.2 Patients Coinfected with HIV-1 and HBV

5.3 New Onset or Worsening Renal Impairment

5.4 Coadministration with Related Products

5.5 Decreases in Bone Mineral Density

5.6 Fat Redistribution

5.7 Immune Reconstitution Syndrome

6 ADVERSE REACTIONS

6.1 Adverse Reactions from Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Didanosine

7.2 Atazanavir

7.3 Lopinavir/Ritonavir

7.4 Drugs Affecting Renal Function

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Impaired Renal Function

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Treatment-Naive Patients

14.2 Treatment-Experienced Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Information for Patients

17.2 FDA-Approved Patient Labeling


FULL PRESCRIBING INFORMATION

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals [See Warnings and Precautions (5.1)].

VIREAD is not approved for the treatment of chronic hepatitis B virus (HBV) infections and the safety and efficacy of Viread have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue VIREAD. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The dose of VIREAD is 300 mg once daily taken orally, without regard to food.

2.2 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 (12.3)]. 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 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 (5.3)].

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 (5.3)].

Table 1 Dosage Adjustment for Patients with Altered Creatinine Clearance
Creatinine Clearance
(mL/min)*
≥50 30–49 10–29 Hemodialysis Patients
*
Calculated using ideal (lean) body weight.
Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD should be administered following completion of dialysis.
Recommended 300 mg Dosing Interval Every 24 hours Every 48 hours Twice
a week
Every 7 days or after a total of approximately 12 hours 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.

3 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.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

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

5.2 Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic Hepatitis B virus (HBV) before initiating antiretroviral therapy. VIREAD is not approved for the treatment of chronic HBV infection and the safety and efficacy of VIREAD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of Hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued VIREAD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue VIREAD. If appropriate, initiation of anti-Hepatitis B therapy may be warranted.

5.3 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 (6.2)].

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 (2.2)]. 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.

5.4 Coadministration with Related 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.

5.5 Decreases in Bone Mineral Density

Bone mineral density monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

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

Cases of osteomalacia (associated with proximal renal tubulopathy) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].

5.6 Fat Redistribution

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

5.7 Immune Reconstitution Syndrome

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

6 ADVERSE REACTIONS

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

6.1 Adverse Reactions from Clinical Trials Experience

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.

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.

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-Naive 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* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 903 (0–144 Weeks)
VIREAD + 3TC + EFV d4T + 3TC + EFV
N=299 N=301
*
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.
Peripheral neuropathy includes peripheral neuritis and neuropathy.
§
Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
Body as a Whole
  Headache 14% 17%
  Pain 13% 12%
  Fever 8% 7%
  Abdominal pain 7% 12%
  Back pain 9% 8%
  Asthenia 6% 7%
Digestive System
  Diarrhea 11% 13%
  Nausea 8% 9%
  Dyspepsia 4% 5%
  Vomiting 5% 9%
Metabolic Disorders
  Lipodystrophy 1% 8%
Musculoskeletal
  Arthralgia 5% 7%
  Myalgia 3% 5%
Nervous System
  Depression 11% 10%
  Insomnia 5% 8%
  Dizziness 3% 6%
  Peripheral neuropathy 1% 5%
  Anxiety 6% 6%
Respiratory
  Pneumonia 5% 5%
Skin and Appendages
  Rash event§ 18% 12%

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

Table 3 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Study 903 (0–144 Weeks)
VIREAD + 3TC + EFV d4T + 3TC + EFV
N=299 N=301
Any ≥ Grade 3 Laboratory Abnormality 36% 42%
Fasting Cholesterol
(>240 mg/dL)
19% 40%
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L)
12% 12%
Serum Amylase (>175 U/L) 9% 8%
AST
(M: >180 U/L)
(F: >170 U/L)
5% 7%
ALT
(M: >215 U/L)
(F: >170 U/L)
4% 5%
Hematuria (>100 RBC/HPF) 7% 7%
Neutrophils (<750/mm3) 3% 1%
Fasting Triglycerides (>750 mg/dL) 1% 9%

Study 934 - Treatment Emergent Adverse 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* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)
VIREAD + FTC + EFV AZT/3TC + EFV
N=257 N=254
*
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
From Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.
Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.
Gastrointestinal Disorder
  Diarrhea 9% 5%
  Nausea 9% 7%
  Vomiting 2% 5%
General Disorders and Administration Site Condition
  Fatigue 9% 8%
Infections and Infestations
  Sinusitis 8% 4%
  Upper respiratory tract infections 8% 5%
  Nasopharyngitis 5% 3%
Nervous System Disorders
  Headache 6% 5%
  Dizziness 8% 7%
Psychiatric Disorders
  Depression 9% 7%
  Insomnia 5% 7%
Skin and Subcutaneous Tissue Disorders
  Rash event 7% 9%

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)
VIREAD* + FTC + EFV AZT/3TC + EFV
N=257 N=254
*
From Weeks 96 to 144 of the study, patients received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.
Any ≥ Grade 3 Laboratory Abnormality 30% 26%
Fasting Cholesterol (>240 mg/dL) 22% 24%
Creatine Kinase
(M: >990 U/L)
(F: >845 U/L)
9% 7%
Serum Amylase (>175 U/L) 8% 4%
Alkaline Phosphatase (>550 U/L) 1% 0%
AST
(M: >180 U/L)
(F: >170 U/L)
3% 3%
ALT
(M: >215 U/L)
(F: >170 U/L)
2% 3%
Hemoglobin (<8.0 mg/dL) 0% 4%
Hyperglycemia (>250 mg/dL) 2% 1%
Hematuria (>75 RBC/HPF) 3% 2%
Glycosuria (≥3+) <1% 1%
Neutrophils (<750/mm3) 3% 5%
Fasting Triglycerides (>750 mg/dL) 4% 2%

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* (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 907 (0–48 Weeks)
VIREAD
(N=368)
(Week 0–24)
Placebo
(N=182)
(Week 0–24)
VIREAD
(N=368)
(Week 0–48)
Placebo Crossover to VIREAD
(N=170)
(Week 24–48)
*
Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
Peripheral neuropathy includes peripheral neuritis and neuropathy.
Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
Body as a Whole
  Asthenia 7% 6% 11% 1%
  Pain 7% 7% 12% 4%
  Headache 5% 5% 8% 2%
  Abdominal pain 4% 3% 7% 6%
  Back pain 3% 3% 4% 2%
  Chest pain 3% 1% 3% 2%
  Fever 2% 2% 4% 2%
Digestive System
  Diarrhea 11% 10% 16% 11%
  Nausea 8% 5% 11% 7%
  Vomiting 4% 1% 7% 5%
  Anorexia 3% 2% 4% 1%
  Dyspepsia 3% 2% 4% 2%
  Flatulence 3% 1% 4% 1%
  Respiratory
  Pneumonia 2% 0% 3% 2%
Nervous System
  Depression 4% 3% 8% 4%
  Insomnia 3% 2% 4% 4%
  Peripheral neuropathy 3% 3% 5% 2%
  Dizziness 1% 3% 3% 1%
Skin and Appendage
  Rash event 5% 4% 7% 1%
  Sweating 3% 2% 3% 1%
Musculoskeletal
  Myalgia 3% 3% 4% 1%
Metabolic
  Weight loss 2% 1% 4% 2%

Laboratory Abnormalities: Laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 7.

Table 7 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-Treated Patients in Study 907 (0–48 Weeks)
VIREAD
(N=368)
(Week 0–24)
Placebo
(N=182)
(Week 0–24)
VIREAD
(N=368)
(Week 0–48)
Placebo Crossover to VIREAD
(N=170)
(Week 24–48)
(%) (%) (%) (%)
Any ≥ Grade 3 Laboratory Abnormality 25% 38% 35% 34%
Triglycerides (>750 mg/dL) 8% 13% 11% 9%
Creatine Kinase
(M: >990U/L)
(F: >845 U/L)
7% 14% 12% 12%
Serum Amylase (>175 U/L) 6% 7% 7% 6%
Urine Glucose (≥3+) 3% 3% 3% 2%
AST
(M: >180 U/L)
(F: >170 U/L)
3% 3% 4% 5%
ALT
(M: >215 U/L)
(F: >170 U/L)
2% 2% 4% 5%
Serum Glucose (>250 U/L) 2% 4% 3% 3%
Neutrophils (<750/mm3) 1% 1% 2% 1%

6.2 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
hypophosphatemia, lactic acidosis

Respiratory, Thoracic, and Mediastinal Disorders
dyspnea

Gastrointestinal Disorders
abdominal pain, increased amylase, pancreatitis

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

Skin and Subcutaneous Tissue Disorders
rash

Musculoskeletal and Connective Tissue Disorders
myopathy, osteomalacia (both associated with proximal renal tubulopathy)

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

General Disorders and Administration Site Conditions
asthenia

7 DRUG INTERACTIONS

This section describes clinically relevant drug interactions with VIREAD. Drug interactions studies are described elsewhere in the labeling [See Clinical Pharmacology (12.3)].

7.1 Didanosine

Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated 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 (12.3)]. 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.

7.2 Atazanavir

Atazanavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. 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 (12.3)]. 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.

7.3 Lopinavir/Ritonavir

Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. 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.

7.4 Drugs Affecting Renal Function

Since tenofovir is primarily eliminated by the kidneys [See Clinical Pharmacology (12.3)], coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum concentrations of tenofovir.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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

8.5 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.

8.6 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 (2.1)].

10 OVERDOSAGE

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.

11 DESCRIPTION

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

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

Chemical Structure

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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug [See Clinical Pharmacology (12.4)].

12.3 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 µg/mL and 2.29 ± 0.69 µghr/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 µg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.

Metabolism and Elimination

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

Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.

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

Effects of Food on Oral Absorption

Administration of VIREAD following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0– of approximately 40% and an increase in Cmax of approximately 14%. However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 µg/mL and 3.32 ± 1.37 µghr/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 (5.3)]. In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0– of tenofovir were increased (Table 8). 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 (2.1)].

Table 8 Pharmacokinetic Parameters (Mean ± SD) of Tenofovir* in Patients with Varying Degrees of Renal Function
Baseline Creatinine Clearance (mL/min) >80
(N=3)
50–80
(N=10)
30–49
(N=8)
12–29
(N=11)
*
300 mg, single dose of VIREAD
Cmax (µg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19
AUC0– (µg∙hr/mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22
CL/F (mL/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1
CLrenal (mL/min) 243.5 ± 33.3 168.6 ± 27.5 100.6 ± 27.5 43.0 ± 31.2

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 (12.3)].

VIREAD has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir. Tables 9 and 10 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir* in the Presence of the Coadministered Drug
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters
(90% CI)
Cmax AUC Cmin
*
Patients received VIREAD 300 mg once daily.

Increase = ↑; Decrease = ↓; No Effect = ; NC = Not Calculated

Reyataz Prescribing Information
Abacavir 300 once 8 NC
Adefovir dipivoxil 10 once 22 NC
Atazanavir 400 once daily
× 14 days
33 ↑ 14
(↑ 8 to ↑ 20)
↑ 24
(↑ 21 to ↑ 28)
↑ 22
(↑ 15 to ↑ 30)
Didanosine (enteric-coated) 400 once 25
Didanosine (buffered) 250 or 400 once daily × 7 days 14
Efavirenz 600 once daily
× 14 days
29
Emtricitabine 200 once daily
× 7 days
17
Indinavir 800 three times daily × 7 days 13 ↑ 14
(↓ 3 to ↑ 33)
Lamivudine 150 twice daily
× 7 days
15
Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 ↑ 32
(↑ 25 to ↑ 38)
↑ 51
(↑ 37 to ↑ 66)
Nelfinavir 1250 twice daily
× 14 days
29
Saquinavir/Ritonavir 1000/100 twice daily × 14 days 35 ↑ 23
(↑ 16 to ↑ 30)

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

Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIREAD
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters*
(90% CI)
Cmax AUC Cmin
*

Increase = ↑; Decrease = ↓; No Effect = ; NA = Not Applicable

Reyataz Prescribing Information
In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
§
R-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD.
Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
#
Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.
Þ
Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.
Abacavir 300 once 8 ↑ 12
(↓ 1 to ↑ 26)
NA
Adefovir dipivoxil 10 once 22 NA
Atazanavir 400 once daily
× 14 days
34 ↓ 21
(↓ 27 to ↓ 14)
↓ 25
(↓ 30 to ↓ 19)
↓ 40
(↓ 48 to ↓ 32)
Atazanavir Atazanavir/ Ritonavir
300/100 once daily
× 42 days
10 ↓ 28
(↓ 50 to ↑ 5)
↓ 25
(↓ 42 to ↓ 3)
↓ 23
(↓ 46 to ↑ 10)
Efavirenz 600 once daily
× 14 days
30
Emtricitabine 200 once daily
× 7 days
17 ↑ 20
(↑ 12 to ↑ 29)
Indinavir 800 three times daily × 7 days 12 ↓ 11
(↓ 30 to ↑ 12)
Lamivudine 150 twice daily
× 7 days
15 ↓ 24
(↓ 34 to ↓ 12)
Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24
Ritonavir
Methadone§ 40–110 once daily
× 14 days
13
Nelfinavir 1250 twice daily
× 14 days
29
M8 metabolite
Oral Contraceptives# Ethinyl Estradiol/
Norgestimate (Ortho-Tricyclen)
once daily × 7 days
20
Ribavirin 600 once 22 NA
Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22
(↑ 6 to ↑ 41)
↑ 29Þ
(↑ 12 to ↑ 48)
↑ 47Þ
(↑ 23 to ↑ 76)
Ritonavir ↑ 23
(↑ 3 to ↑ 46)

Table 11 summarizes the drug interaction between VIREAD and didanosine. Coadministration of VIREAD and didanosine should be undertaken with caution [See Drug Interactions (7.1)]. 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 11 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD
Didanosine Dose (mg)/ Method of Administration VIREAD Method of Administration* N % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted
Cmax AUC
*
Administration with food was with a light meal (~373 kcal, 20% fat).

Increase = ↑; Decrease = ↓; No Effect =

Includes 4 subjects weighing <60 kg receiving ddI 250 mg.
Buffered tablets
400 once daily × 7 days Fasted 1 hour after didanosine 14 ↑ 28
(↑ 11 to ↑ 48)
↑ 44
(↑ 31 to ↑ 59)
Enteric coated capsules
400 once, fasted With food, 2 hours after didanosine 26 ↑ 48
(↑ 25 to ↑ 76)
↑ 48
(↑ 31 to ↑ 67)
400 once, with food Simultaneously with didanosine 26 ↑ 64
(↑ 41 to ↑ 89)
↑ 60
(↑ 44 to ↑ 79)
250 once, fasted With food, 2 hours after didanosine 28 ↓ 10
(↓ 22 to ↑ 3)
250 once, fasted Simultaneously with didanosine 28 ↑ 14
(0 to ↑ 31)
250 once, with food Simultaneously with didanosine 28 ↓ 29
(↓ 39 to ↓ 18)
↓ 11
(↓ 23 to ↑ 2)

12.4 Microbiology

Mechanism of Action

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

Antiviral Activity

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

Resistance

HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 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 (14.1)], 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 (14.1)], 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 (14.2)], 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 12 summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

Table 12 HIV-1 RNA Response at Week 24 by Baseline VIREAD Susceptibility (Intent-To-Treat)*
Baseline VIREAD Susceptibility Change in HIV-1 RNA (N)
*
Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).
Fold change in susceptibility from wild-type.
Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL.
<1 -0.74 (35)
>1 and ≤3 -0.56 (49)
>3 and ≤4 -0.3 (7)
>4 -0.12 (9)

13 NONCLINICAL TOXICOLOGY

13.1 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.

13.2 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.

14 CLINICAL STUDIES

14.1 Treatment-Naive 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 and144 weeks are presented in Table 13.

Table 13 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)
At Week 48 At Week 144
Outcomes VIREAD+3TC
+EFV
(N=299)
d4T+3TC
+EFV
(N=301)
VIREAD+3TC
+EFV
(N=299)
d4T+3TC
+EFV
(N=301)
*
Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144.
Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144.
Includes lost to follow-up, patient's withdrawal, noncompliance, protocol violation and other reasons.
Responder* 79% 82% 68% 62%
Virologic failure 6% 4% 10% 8%
  Rebound 5% 3% 8% 7%
  Never suppressed 0% 1% 0% 0%
  Added an antiretroviral agent 1% 1% 2% 1%
Death <1% 1% <1% 2%
Discontinued due to adverse event 6% 6% 8% 13%
Discontinued for other reasons 8% 7% 14% 15%

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

Through 144 weeks, 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 14.

Table 14 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)
Outcomes At Week 48 At Week 144
FTC
+VIREAD
+EFV
(N=244)
AZT/3TC
+EFV
(N=243)
FTC
+VIREAD
+EFV
(N=227)*
AZT/3TC
+EFV
(N=229)*
*
Patients who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue study after Week 48 or Week 96 were excluded from analysis.
Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.
Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.
§
Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
Responder 84% 73% 71% 58%
Virologic failure 2% 4% 3% 6%
  Rebound 1% 3% 2% 5%
  Never suppressed 0% 0% 0% 0%
  Change in antiretroviral regimen 1% 1% 1% 1%
Death <1% 1% 1% 1%
Discontinued due to adverse event 4% 9% 5% 12%
Discontinued for other reasons§ 10% 14% 20% 22%

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).

14.2 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

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 15.

Table 15 Outcomes of Randomized Treatment (Study 907)
Outcomes 0–24 weeks 0–48 weeks 24–48 weeks
VIREAD
(N=368)
Placebo
(N=182)
VIREAD
(N=368)
Placebo Crossover
to VIREAD
(N=170)
*
Patients with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively.
Patients with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.
Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.
HIV-1 RNA <400 copies/mL* 40% 11% 28% 30%
Virologic failure 53% 84% 61% 64%
Discontinued due to adverse event 3% 3% 5% 5%
Discontinued for other reasons 3% 3% 5% 1%

At 24 weeks of therapy, there was a higher proportion of patients in the VIREAD arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ 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.

16 HOW SUPPLIED/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" on the other side, and are available in unit of use bottles (containing a desiccant [silica gel canister or sachet] and closed with child-resistant closure) of:

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.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (17.2)

17.1 Information for Patients

Patients should be advised that:

17.2 FDA-Approved Patient Labeling

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 provider's care when 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 an HIV-1 (human immunodeficiency virus) nucleotide analog reverse transcriptase inhibitor (NRTI). VIREAD is always used in combination with other anti-HIV-1 medicines to treat people with HIV-1 infection. VIREAD is for adults age 18 and older.

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).

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.

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

VIREAD does not reduce the risk of passing HIV-1 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

What should I tell my healthcare provider before taking VIREAD?

Tell your healthcare provider

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:

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?

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?

What are the possible side effects of VIREAD?

How do I store VIREAD?

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.

Rx Only

May 2008

VIREAD, EMTRIVA and TRUVADA are registered trademarks of Gilead Sciences, Inc. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.

21-356-GS-021 19MAY08


Viread (tenofovir disoproxil fumarate)
PRODUCT INFO
Product Code 61958-0401 Dosage Form TABLET, COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
tenofovir disoproxil fumarate (tenofovir) Active 300 MILLIGRAM  In 1 TABLET
Croscarmellose Sodium Inactive  
Lactose Monohydrate Inactive  
Magnesium Stearate Inactive  
Microcrystalline Cellulose Inactive  
Pregelatinized Starch Inactive  
Opadry II Y–30–10671–A Inactive  
FD&C Blue #2 Aluminum Lake Inactive  
Hydroxypropyl Methylcellulose 2910 Inactive  
Titanium Dioxide Inactive  
Triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color blue (Light Blue) Score 1
Shape FREEFORM (FREEFORM) Symbol false
Imprint Code GILEAD;4331;300 Coating true
Size 17mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 61958-0401-1 30 TABLET In 1 BOTTLE, PLASTIC None

Revised: 06/2008Gilead Sciences, Inc.

Data are from FDA and U.S. National Library of Medicine.