Dosage Form: tablet, coated
FULL PRESCRIBING INFORMATION
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 [See Warnings and Precautions (5.1)].
Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Viread. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including Viread. If appropriate, resumption of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)].
Indications and Usage for Viread
HIV-1 Infection
Viread® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.
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 ATRIPLA®, COMPLERA®, or TRUVADA® [See Warnings and Precautions (5.4)].
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 primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)].
- Viread was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease [See Adverse Reactions (6.1), Clinical Studies (14.2)].
- The numbers of subjects in clinical trials who had lamivudine- or adefovir-associated substitutions at baseline were too small to reach conclusions of efficacy [See Microbiology (12.4), Clinical Studies (14.2)].
Viread Dosage and Administration
Recommended Dose in Adults
For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg Viread tablet once daily taken orally, without regard to food.
For adults unable to swallow Viread tablets, the oral powder formulation (7.5 scoops) may be used.
In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.
Recommended Dose in Pediatric Patients (2 to Less Than 18 Years of Age)
For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of Viread is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.
Viread oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate. Viread oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer Viread oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer Viread oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).
Viread is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
Tables 1 and 2 contain dosing recommendations for Viread oral powder and tablets based on body weight. Weight should be monitored periodically and the Viread dose adjusted accordingly.
| Body Weight Kilogram (kg) | Oral Powder Once Daily Scoops of Powder |
|---|---|
| 10 to <12 | 2 |
| 12 to <14 | 2.5 |
| 14 to <17 | 3 |
| 17 to <19 | 3.5 |
| 19 to <22 | 4 |
| 22 to <24 | 4.5 |
| 24 to <27 | 5 |
| 27 to <29 | 5.5 |
| 29 to <32 | 6 |
| 32 to <34 | 6.5 |
| 34 to <35 | 7 |
| ≥35 | 7.5 |
| Body Weight Kilogram (kg) | Tablets Once Daily |
|---|---|
| 17 to <22 | 150 mg |
| 22 to <28 | 200 mg |
| 28 to <35 | 250 mg |
| ≥35 | 300 mg |
Dose Adjustment for Renal Impairment in Adults
Significantly increased drug exposures occurred when Viread was administered to subjects with moderate to severe renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval of Viread tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3. 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 (5.3)]. There are no data to recommend use of Viread tablets 150, 200 or 250 mg or Viread oral powder in patients with renal impairment.
No dose adjustment of Viread tablets 300 mg 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)].
| Creatinine Clearance (mL/min)* | ||||
|---|---|---|---|---|
| ≥50 | 30–49 | 10–29 | Hemodialysis Patients | |
| ||||
| Recommended 300 mg Dosing Interval | Every 24 hours | Every 48 hours | Every 72 to 96 hours | 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 below 10 mL/min; therefore, no dosing recommendation is available for these patients.
No data are available to make dose recommendations in pediatric patients with renal impairment.
Dosage Forms and Strengths
Viread is available as tablets or as an oral powder.
Viread tablets 150 mg contain 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil. The tablets are triangle-shaped, white, film-coated, and debossed with "GSI" on one side and "150" on the other side.
Viread tablets 200 mg contain 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil. The tablets are round-shaped, white, film-coated, and debossed with "GSI" on one side and "200" on the other side.
Viread tablets 250 mg contain 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil. The tablets are capsule-shaped, white, film-coated, and debossed with "GSI" on one side and "250" on the other side.
Viread tablets 300 mg contain 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.
The oral powder consists of white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per level scoop. Each level scoop contains 1 gram of oral powder.
Contraindications
None.
Warnings and Precautions
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 (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, including patients who have previously experienced renal events while receiving HEPSERA®.
Dosing interval adjustment of Viread and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [See Dosage and Administration (2.3)]. 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 ATRIPLA, COMPLERA, or TRUVADA since tenofovir disoproxil fumarate is a component of these products.
Viread should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.4)].
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
Assessment of bone mineral density (BMD) should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. 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-1 infected adult subjects 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 trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving Viread + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects 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 trial and this reduction was sustained through Week 144. Twenty-eight percent of Viread-treated subjects vs. 21% of the stavudine-treated subjects 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 subjects in the Viread group and 6 subjects 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.
In clinical trials evaluating Viread in HIV-1 infected pediatric subjects 2 to less than 18 years of age, bone effects were similar to those observed in adult subjects. Under normal circumstances BMD increases rapidly in pediatric patients. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the Viread and the d4T or AZT treatment groups. Total body BMD gain was less in the Viread compared to the d4T or AZT treatment group. One Viread-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with Viread for 96 weeks. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the Viread compared to the placebo treatment group. Six Viread treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with Viread for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Markers of bone turnover in Viread-treated pediatric subjects suggest increased bone turnover, consistent with the effects observed in adults.
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 (6.2)].
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 jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Early Virologic Failure
Clinical trials in HIV-infected subjects 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.
Adverse Reactions
The following adverse reactions are discussed in other sections of the labeling:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].
- Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].
- New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].
- Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].
- Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)].
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 Adult Patients with HIV-1 Infection
More than 12,000 subjects 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 programs. A total of 1,544 subjects have received Viread 300 mg once daily in clinical trials; over 11,000 subjects have received Viread in expanded access programs.
The most common adverse reactions (incidence greater than or equal to 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 trial in which 600 treatment-naïve subjects 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 4.
| Viread + 3TC + EFV | d4T + 3TC + EFV | |
|---|---|---|
| N=299 | N=301 | |
| ||
| Body as a Whole | ||
| Headache | 14% | 17% |
| Pain | 13% | 12% |
| Fever | 8% | 7% |
| Abdominal pain | 7% | 12% |
| Back pain | 9% | 8% |
| 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 trial occurred with similar frequency in the Viread and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 5.
| 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 subjects 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 trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6).
| Viread† + FTC + EFV | AZT/3TC + EFV | |
|---|---|---|
| N=257 | N=254 | |
| ||
| 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 trial were generally consistent with those seen in previous trials (Table 7).
| Viread* + FTC + EFV | AZT/3TC + EFV | |
|---|---|---|
| N=257 | N=254 | |
| ||
| 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 subjects were generally consistent with those seen in treatment naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials 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 8.
| Viread (N=368) (Week 0–24) | Placebo (N=182) (Week 0–24) | Viread (N=368) (Week 0–48) | Placebo Crossover to Viread (N=170) (Week 24–48) | |
|---|---|---|---|---|
| ||||
| Body as a Whole | ||||
| 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 | ||||
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