Viread Drug Information

HIV-1 Infection VIREAD is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 2 years of age and older weighing at least 10 kg.

Chronic Hepatitis B VIREAD is indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 2 years of age and older weighing at least 10 kg.

Testing Prior to Initiation of VIREAD for Treatment of HIV-1 Infection or Chronic Hepatitis B Prior to or when initiating VIREAD, test patients for HBV infection and HIV-1 infection. VIREAD alone should not be used in patients with HIV-1 infection. Prior to initiation and during use of VIREAD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients.

In patients with chronic kidney disease, also assess serum phosphorus.

Recommended Tablet Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 17 kg The recommended dosage of VIREAD in adults and pediatric patients weighing at least 35 kg is one 300 mg tablet taken orally once daily without regard to food. The dosage for VIREAD is the same for both HIV and HBV indications. The recommended dosage of VIREAD tablet in adults and pediatric patients 2 years and older weighing at least 17 kg is 8 mg of tenofovir disoproxil fumarate (TDF) per kg of body weight (up to a maximum of 300 mg) once daily.

Weight should be monitored periodically and the VIREAD dose adjusted accordingly. Table 1 Recommended Dosing for Patients 2 Years and Older and Weighing at Least 17 kg Using VIREAD Tablets

Recommended Oral Powder Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 10 kg The recommended dosage of VIREAD oral powder in adults and pediatric patients 2 years and older weighing at least 10 kg who are unable to swallow a tablet is 8 mg of TDF per kg of body weight (up to a maximum of 300 mg) once daily administered as oral powder (see Table 2 ). 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 TDF.

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). Table 2 Dosing for Patients 2 Years and Older Weighing at least 10 kg Using VIREAD Oral Powder

Dosage Adjustment in Patients with Renal Impairment

Significant increase in drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment (creatinine clearance below 50 mL/min). Table 3 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min).

Table 3 Dosage Interval Adjustment for Adult Patients with Altered Creatinine Clearance No data are available to make dosage recommendations in patients with creatinine clearance below 10 mL/min who are not on hemodialysis. No data are available to make dosage recommendations in pediatric patients with renal impairment.

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. Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Adults 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. Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naïve subjects received VIREAD (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions 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. Table 4 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the VIREAD group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the VIREAD and d4T treatment arms.

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 d4T-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 d4T 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) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the VIREAD group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range. In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + VIREAD (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

Table 6 Selected Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Trial 934 (0–144 Weeks) Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7). Table 7 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Trial 934 (0–144 Weeks) Clinical Trials in Treatment-Experienced HIV-1 Infected Adult Subjects In Trial 907, the adverse reactions seen in HIV-1 infected 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.

Laboratory abnormalities occurred with similar frequency in the VIREAD and placebo groups. The adverse reactions observed in subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy.

Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z-score. Changes in Bone Mineral Density: In Trial 321 (12 years to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the VIREAD group compared to the placebo group. Six VIREAD-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48.

In Trial 352 (2 years to less than 12 years of age), 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 group 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.

In both trials, skeletal growth (height) appeared to be unaffected for the duration of the clinical trials. Adverse Reactions from Clinical Trials Experience in HBV-Infected Adults Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with VIREAD during the 48-week double-blind period experienced nausea: 9% with VIREAD versus 2% with HEPSERA ®. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with VIREAD included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.

No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks. Laboratory Abnormalities: Table 10 provides a list of Grade 3–4 laboratory abnormalities through Week 48. Grades 3–4 laboratory abnormalities were similar in subjects continuing VIREAD treatment for up to 384 weeks in these trials.

ALT flares generally occurred within the first 4 to 8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.

Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease In Trial 0108, a small randomized, double-blind, active-controlled trial, subjects with chronic HBV and decompensated liver disease received treatment with VIREAD or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving VIREAD, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event.

Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both VIREAD and decompensated liver disease may have an impact on renal function, the contribution of VIREAD to renal impairment in this population is difficult to ascertain. One of 45 subjects experienced an on-treatment hepatic flare during the 48-week trial.

Adverse Reactions from Clinical Trials Experience in HBV-Infected Pediatric Subjects 2 Years and Older Assessment of adverse reactions in pediatric subjects infected with chronic HBV is based on two randomized trials: Trial GS-US-174-0115 in 106 subjects (12 years to less than 18 years of age) receiving treatment with VIREAD (N=52) or placebo (N=54) for 72 weeks and Trial GS-US-174-0144 in 89 subjects (2 years to less than 12 years of age) receiving treatment with VIREAD (N=60) or placebo (N=29) for 48 weeks. In Trial 115, the mean percentage BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects (Table 11).Three subjects (6%) in the VIREAD group and two subjects (4%) in the placebo group had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 72. In Trial 144 (2 years to less than 12 years of age), mean percentage BMD gains from baseline to Week 48 in lumbar spine and total body BMD in VIREAD-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects.

At Week 48, the cumulative percentage of subjects with greater than or equal to 4% decreases in spine or whole body BMD was numerically higher for subjects in the TDF group compared with the placebo group (Table 11). As observed in pediatric studies of HIV-infected subjects, normal skeletal growth (height) was not affected for the duration of the clinical trial. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown.

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, including angioedema 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.

Drugs Affecting Renal Function Tenofovir is primarily eliminated by the kidneys. Coadministration of VIREAD with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.

Drugs that decrease renal function may increase concentrations of tenofovir. In the treatment of chronic hepatitis B, VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil).

Established and Significant Interactions Table 12 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with TDF. Table 12 Established and Significant This table is not all inclusive.

Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VIREAD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ).

The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%. Published studies in HBV-infected subjects do not report an increased risk of adverse pregnancy-related outcomes with the use of VIREAD during the third trimester of pregnancy (see Data ).

In animal reproduction studies, no adverse developmental effects were observed when TDF was administered at doses/exposures ≥ 14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of VIREAD (see Data ). Data Human Data Based on prospective reports from the APR exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. Methodological limitations of the APR include the use of MACDP as the external comparator group.

Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. There were no new safety findings in pregnant women compared with the known safety profile of VIREAD in HBV-infected adults. An increased risk of adverse pregnancy-related outcomes was not observed; 2 stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in VIREAD-exposed infants.

Infants were followed for up to 12 months after delivery; there were no clinically relevant drug-related safety findings in infants exposed to VIREAD during late gestation. No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of VIREAD.

Pediatric Use Pediatric Patients 2 Years and Older with HIV-1 Infection The safety and effectiveness of VIREAD in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials. Trial 352 was a randomized controlled trial in 92 HIV-1 treatment experienced subjects 2 years to less than 12 years of age who were virologically suppressed on a stavudine- or zidovudine-containing regimen and were randomized to either switch to a VIREAD-containing regimen (N=44) or stay on their original regimen (N=48) for 48 weeks. Overall, the trial failed to show a difference in virologic response between the VIREAD and placebo groups.

Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to VIREAD and OBR. Although changes in HIV-1 RNA in these highly treatment-experienced subjects in Trial 321 were less than anticipated, the pharmacokinetic profile of tenofovir in patients 2 years to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in HIV-1 pediatric patients 2 years and older are unknown.

The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown. Safety and effectiveness of VIREAD in pediatric patients younger than 2 years of age and weighing less than 10 kg with HIV-1 infection have not been established. Pediatric Patients 2 Years of Age and Older with Chronic Hepatitis B The safety and effectiveness of VIREAD in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials (Trial 115 and Trial 144) in which VIREAD was administered to HBV-infected treatment-experienced subjects.

Safety and effectiveness of VIREAD in chronic HBV-infected pediatric patients younger than 2 years of age and weighing less than 10 kg have not been established.

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.