1.1 HIV-1 Infection

Tenofovir disoproxil fumarate 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.

1.2 Chronic Hepatitis B

Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 12 years of age and older.

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information

2.1 Testing Prior to Initiation of Tenofovir Disoproxil Fumarate for Treatment of HIV-1 Infection or Chronic Hepatitis B

Prior to or when initiating tenofovir disoproxil fumarate tablets, test patients for HBV infection and HIV-1 infection. Tenofovir disoproxil fumarate alone should not be used in patients with HIV-1 infection [see Warnings and Precautions (5.3)].

Prior to initiation and during use of tenofovir disoproxil fumarate tablets, 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 [see Warnings and Precautions (5.2)].

2.2 Recommended Tablet Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 17 kg

The recommended dosage of tenofovir disoproxil fumarate tablets 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 tenofovir disoproxil fumarate is the same for both HIV and HBV indications.

The recommended dosage of tenofovir disoproxil fumarate 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. Dosage for pediatric patients 2 years and older weighing between 17 kg and 35 kg and able to swallow an intact tablet is provided in Table 1. Weight should be monitored periodically and the tenofovir disoproxil fumarate dose adjusted accordingly.

2.4 Dosage Adjustment in Patients with Renal Impairment

Significant increase in drug exposures occurred when tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min) [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

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.

5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection

All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating tenofovir disoproxil fumarate [see Dosage and Administration (2.1)].

Discontinuation of anti-HBV therapy, including tenofovir disoproxil fumarate, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue tenofovir disoproxil fumarate 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, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 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 tenofovir disoproxil fumarate [see Adverse Reactions (6.2)].

Prior to initiation and during use of tenofovir disoproxil fumarate, 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.

Dosing interval adjustment of tenofovir disoproxil fumarate and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [see Dosage and Administration (2.4)]. No safety or efficacy data are available in patients with renal impairment who received tenofovir disoproxil fumarate using these dosing guidelines, so the potential benefit of tenofovir disoproxil fumarate therapy should be assessed against the potential risk of renal toxicity.

Tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

5.3 Patients Coinfected with HIV-1 and HBV

Due to the risk of development of HIV-1 resistance, tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir disoproxil fumarate.

5.4 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including tenofovir disoproxil fumarate. During the initial phase of combination antiretroviral treatment, HIV-1 infected 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- Barre 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.

5.5 Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults, tenofovir disoproxil fumarate was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions (6.1)]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil fumarate.

Clinical trials evaluating tenofovir disoproxil fumarate in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir disoproxil fumarate-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects 12 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials [see Adverse Reactions (6.1)].

The effects of tenofovir disoproxil fumarate-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected, appropriate consultation should be obtained.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with tenofovir disoproxil fumarate use [see Adverse Reactions (6.2)]. Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions (5.2)].

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

5.6 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 TDF, alone or in combination with other antiretrovirals. Treatment with tenofovir disoproxil fumarate 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).

5.7 Risk of Adverse Reactions Due to Drug Interactions

The concomitant use of tenofovir disoproxil fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2)].

See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with tenofovir disoproxil fumarate; review concomitant medications during therapy with tenofovir disoproxil fumarate; and monitor for adverse reactions associated with the concomitant drugs.

6.1 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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate (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.

Laboratory Abnormalities: Table 5 provides a list of laboratory abnormalities (Grades 3−4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the tenofovir disoproxil fumarate group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and d4T treatment arms.

Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate+ 3TC + EFV (−2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (−1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (−2.8% ± 3.5 in the tenofovir disoproxil fumarate group vs. −2.4% ± 4.5 in the d4T 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 tenofovir disoproxil fumarate -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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.5)].

In Trial 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either emtricitabine (FTC) + tenofovir disoproxil fumarate (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 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).

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. Table 8 provides the treatment-emergent adverse reactions (Grades 2−4) occurring in greater than or equal to 3% of subjects treated in any treatment group.

Laboratory Abnormalities: Table 9 provides a list of Grade 3−4 laboratory abnormalities observed in Trial 907. Laboratory abnormalities occurred with similar frequency in the tenofovir disoproxil fumarate and placebo groups.

Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Pediatric Subjects 2 Years and Older

Assessment of adverse reactions is based on two randomized trials (Trials 352 and 321) in 184 HIV-1 infected pediatric subjects (2 years to less than 18 years of age) who received treatment with tenofovir disoproxil fumarate (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks [see Clinical Studies (14.3)]. The adverse reactions observed in subjects who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical trials in adults.

In Trial 352, 89 pediatric subjects (2 years to less than 12 years of age) received tenofovir disoproxil fumarate for a median exposure of 104 weeks. 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 [see Warnings and Precautions (5.5)].

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 tenofovir disoproxil fumarate group compared to the placebo group. Six tenofovir disoproxil fumarate-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 tenofovir disoproxil fumarate for 96 weeks. 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 tenofovir disoproxil fumarate and the d4T or AZT treatment groups. Total body BMD gain was less in the tenofovir disoproxil fumarate group compared to the d4T or AZT treatment group. One tenofovir disoproxil fumarate-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 tenofovir disoproxil fumarate for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected for the duration of the clinical trials [see Warnings and Precautions (5.5)].

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 tenofovir disoproxil fumarate during the 48-week double-blind period experienced nausea: 9% with tenofovir disoproxil fumarate versus 2% with HEPSERA®. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with tenofovir disoproxil fumarate included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash.

In Trials 0102 and 0103, during the open-label phase of treatment with tenofovir disoproxil fumarate (weeks 48–384), 2% of subjects (13/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. 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 tenofovir disoproxil fumarate treatment for up to 384 weeks in these trials.

The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between tenofovir disoproxil fumarate (2.6%) and HEPSERA (2%). 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.

The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with tenofovir disoproxil fumarate were consistent with those observed in other HBV clinical trials in adults.

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 tenofovir disoproxil fumarate or other antiviral drugs for up to 48 weeks [see Clinical Studies (14.4)]. Among the 45 subjects receiving tenofovir disoproxil fumarate, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) 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. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). 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 tenofovir disoproxil fumarate and decompensated liver disease may have an impact on renal function, the contribution of tenofovir disoproxil fumarate 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 12 Years and Older

Assessment of adverse reactions in pediatric subjects infected with chronic HBV is based on one randomized trial: Trial GS-US-174-0115 in 106 subjects (12 years to less than 18 years of age) receiving treatment with tenofovir disoproxil fumarate (N=52) or placebo (N=54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical trials of tenofovir disoproxil fumarate in adults.

In Trial 115 (12 years to less than 18 years of age), both the tenofovir disoproxil fumarate and placebo treatment arms experienced an overall increase in mean lumbar spine and total body BMD over 72 weeks, as expected for a pediatric population (Table 11). In Trial 115, the mean percentage BMD gains from baseline to Week 72 in lumbar spine and total body BMD in tenofovir disoproxil fumarate-treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects (Table 11). Three subjects (6%) in the tenofovir disoproxil fumarate group and two subjects (4%) in the placebo group had significant (greater than or equal to 4%) lumbar spine BMD loss at Week 72.

The effects of tenofovir disoproxil fumarate-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in 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 [see Warnings and Precautions (5.5)].

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tenofovir disoproxil fumarate. 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.

7.1 Drugs Affecting Renal Function

Tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)]. Coadministration of tenofovir disoproxil fumarate 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 [see Warnings and Precautions (5.2)]. Drugs that decrease renal function may increase concentrations of tenofovir.

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

7.2 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 [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate (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. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF-containing regimens.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to TDF are compared with a U.S. background major birth defect rate. 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.

In published data from three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil fumarate from 28 to 32 weeks gestation through 1 to 2 months postpartum and followed for up to 12 months after delivery. There were no new safety findings in pregnant women compared with the known safety profile of tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate -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 tenofovir disoproxil fumarate during late gestation.

Animal Data

TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). 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 tenofovir disoproxil fumarate.

8.2 Lactation

Risk Summary

Based on published data, tenofovir has been shown to be present in human breast milk (see Data). It is not known if tenofovir affects milk production or has effects on the breastfed child.

Treatment of HIV-1 infection:

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking tenofovir disoproxil fumarate for the treatment of HIV-1.

Treatment of HBV infection:

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tenofovir disoproxil fumarate and any potential adverse effects on the breastfed infant from tenofovir disoproxil fumarate or from the underlying maternal condition.

Data

In a study of 50 HIV-uninfected, breastfeeding women on a tenofovir-containing regimen initiated between 1 and 24 weeks postpartum (median 13 weeks), tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. There were no serious adverse events in mothers or infants.

8.4 Pediatric Use

Pediatric Patients 2 Years and Older with HIV-1 Infection 

The safety and effectiveness of tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate-containing regimen (N=44) or stay on their original regimen (N=48) for 48 weeks. At Week 48, 89% of subjects in the tenofovir disoproxil fumarate treatment group and 90% of subjects in the d4T or AZT treatment group had HIV-1 RNA concentrations <400 copies/mL. Trial 321 was a placebo-controlled trial in 87 HIV-1 treatment experienced subjects 12 years to less than 18 years of age who were treated with tenofovir disoproxil fumarate (N=45) or placebo (N=42) in combination with an optimized background regimen for 48 weeks. Overall, the trial failed to show a difference in virologic response between the tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate and OBR [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

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 [see Clinical Pharmacology (12.3)].

The effects of tenofovir disoproxil fumarate-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 [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Safety and effectiveness of tenofovir disoproxil fumarate 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 12 Years of Age and Older with Chronic Hepatitis B

The safety and effectiveness of tenofovir disoproxil fumarate in pediatric patients 12 years to less than 18 years of age is supported by data from one randomized trial (Trial 115) in which tenofovir disoproxil fumarate was administered to HBV-infected treatment-experienced subjects.

In Trial 115, 106 HBeAg negative (9%) and positive (91%) subjects 12 years to less than 18 years of age with chronic HBV infection were randomized to receive blinded treatment with tenofovir disoproxil fumarate or placebo for 72 weeks. At Week 72, 88% of subjects in the tenofovir disoproxil fumarate group and 0% of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). The effects of tenofovir disoproxil fumarate-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in chronic HBV-infected 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 [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

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

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

Clinical trials of tenofovir disoproxil fumarate 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 Renal Impairment

The dosing interval for tenofovir disoproxil fumarate should be modified in adult patients with estimated creatinine clearance below 50 mL/min or in patients with end stage renal disease requiring dialysis [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

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

Absorption

Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted subjects is approximately 25%. Following oral administration of a single dose of tenofovir disoproxil fumarate 300 mg to HIV-1 infected subjects 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 μg•hr/mL, respectively.

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

In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.

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 tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate 300 mg tablets following a high-fat meal (~700 to 1,000 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 tenofovir disoproxil fumarate 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 μg·hr/mL following multiple doses of tenofovir disoproxil fumarate 300 mg once daily in the fed state, when meal content was not controlled.

Specific 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 subjects.

Pediatric Patients 

Steady-state pharmacokinetics of tenofovir were evaluated in HIV-1 infected pediatric subjects 12 years to less than 18 years of age (Table 13). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of tenofovir disoproxil fumarate 300 mg (tablet) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil fumarate 300 mg.

Tenofovir exposures in HBV-infected pediatric subjects (12 years to less than 18 years of age) receiving oral once-daily doses of tenofovir disoproxil fumarate 300 mg tablet were comparable to exposures achieved in HIV-1 infected adult subjects receiving identical doses.

Geriatric Patients

Pharmacokinetic trials have not been performed in the elderly (65 years and older).

Patients with Renal Impairment

The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.2)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0-∞ of tenofovir were increased (Table 14).

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir disoproxil fumarate have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in tenofovir disoproxil fumarate 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.

Tenofovir disoproxil fumarate has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 15 and 16 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of tenofovir disoproxil fumarate on the pharmacokinetics of coadministered drug.

TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.

No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with tenofovir disoproxil fumarate: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 (TFV-DP), an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV RT 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.

Activity against HIV

Antiviral Activity

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies, tenofovir was not antagonistic with HIV-1 NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine), NNRTIs (efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). 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 RT and showed a 2- to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.

In Trial 903 of treatment-naïve subjects (tenofovir disoproxil fumarate &#43; 3TC &#43; EFV versus d4T &#43; 3TC &#43; EFV) [see Clinical Studies (14.2)], genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of EFV and 3TC resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) of analyzed patient isolates in the tenofovir disoproxil fumarate arm and in 2/49 (4%) of analyzed patient isolates in the d4T arm. Of the 8 subjects whose virus developed K65R in the tenofovir disoproxil fumarate arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the tenofovir disoproxil fumarate arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to tenofovir disoproxil fumarate were not identified in this trial.

In Trial 934 of treatment-naïve subjects (tenofovir disoproxil fumarate &#43; FTC &#43; EFV versus AZT/3TC &#43; EFV) [see Clinical Studies (14.2)], genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of EFV resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to FTC and 3TC, was observed in 2/19 of analyzed subject isolates in the tenofovir disoproxil fumarate &#43; FTC group and in 10/29 of analyzed subject isolates in the AZT/3TC group. Through 144 weeks of Trial 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.

Cross Resistance

Cross-resistance among certain HIV-1 NRTIs has been recognized. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to FTC and 3TC. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three AZT-associated RT substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.

In Trials 902 and 907 conducted in treatment-experienced subjects (tenofovir disoproxil fumarate &#43; Standard Background Therapy (SBT) compared to placebo &#43; SBT) [see Clinical Studies (14.2)], 14/304 (5%) of the tenofovir disoproxil fumarate-treated subjects 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 RT gene.

The virologic response to tenofovir disoproxil fumarate therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Trials 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial 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 tenofovir disoproxil fumarate to pre-existing AZT resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. Tenofovir disoproxil fumarate-treated subjects whose HIV-1 expressed 3 or more AZT resistance-associated substitutions that included either the M41L or L210W RT substitution showed reduced responses to tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate therapy. Subjects whose virus expressed an L74V substitution without AZT resistance-associated substitutions (N=8) had reduced response to tenofovir disoproxil fumarate. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

In the protocol defined analyses, virologic response to tenofovir disoproxil fumarate was not reduced in subjects with HIV-1 that expressed the abacavir/FTC/3TC resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.

Trials 902 and 907 Phenotypic Analyses

Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to tenofovir disoproxil fumarate and response to tenofovir disoproxil fumarate therapy. Table 17 summarizes the HIV-1 RNA response by baseline tenofovir disoproxil fumarate susceptibility.

Activity against HBV

Antiviral Activity

The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 µM, with CC50 (50% cytotoxicity concentration) values >100 µM. In cell culture combination antiviral activity studies of tenofovir with HBV NRTIs entecavir, lamivudine, and telbivudine, and with the HIV-1 NRTI emtricitabine, no antagonistic activity was observed.

Resistance

Cumulative tenofovir disoproxil fumarate genotypic resistance has been evaluated annually for up to 384 weeks in Trials 0102, 0103, 0106, 0108, and 0121 [see Clinical Studies (14.4)] with the paired HBV RT amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of tenofovir disoproxil fumarate monotherapy and remained viremic with HBV DNA ≥400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of tenofovir disoproxil fumarate monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Trials 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on tenofovir disoproxil fumarate monotherapy (15% versus 5%, respectively).

HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 18); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to tenofovir disoproxil fumarate (genotypic and phenotypic analyses).

Cross Resistance

Cross resistance has been observed between HBV NRTIs.

In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine (3TC) and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.

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

HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.

One hundred fifty-two subjects initiating tenofovir disoproxil fumarate therapy in Trials 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV NRTIs: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with 3TC resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and 3TC resistance-associated substitutions. Following up to 384 weeks of tenofovir disoproxil fumarate treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with 3TC-resistant HBV, and 2 of the 3 subjects with both adefovir- and 3TC-resistant HBV achieved and maintained virologic suppression (HBV DNA <400 copies/mL [69 IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term oral carcinogenicity studies of TDF 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.

Mutagenesis

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, TDF was negative when administered to male mice.

Impairment of Fertility

There were no effects on fertility, mating performance or early embryonic development when TDF 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 TDF 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.

14.1 Overview of Clinical Trials

The efficacy and safety of tenofovir disoproxil fumarate in adults and pediatric subjects were evaluated in the trials summarized in Table 19.

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

14.2 Clinical Trial Results in Adults with HIV-1 Infection

Treatment-Naïve Subjects: Trial 903

Data through 144 weeks are reported for Trial 903, a double-blind, active-controlled multicenter trial comparing tenofovir disoproxil fumarate (300 mg once daily) administered in combination with lamivudine (3TC) and efavirenz (EFV) versus stavudine (d4T), 3TC, and EFV in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18–64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4&#43; 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). Subjects were stratified by baseline HIV-1 RNA and CD4&#43; cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4&#43; cell counts <200 cells/mm3. Table 20 provides treatment outcomes through 48 and 144 weeks.

Achievement of plasma HIV-1 RNA concentrations of <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&#43; cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the tenofovir disoproxil fumarate and d4T arms, respectively, achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4&#43; cell count was 263 cells/mm3 for the tenofovir disoproxil fumarate arm and 283 cells/mm3 for the d4T arm.

Through 144 weeks, 11 subjects in the tenofovir disoproxil fumarate group and 9 subjects in the d4T group experienced a new CDC Class C event.

Treatment-Naïve Subjects: Trial 934

Data through 144 weeks are reported for Trial 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine (FTC) &#43; tenofovir disoproxil fumarate administered in combination with efavirenz (EFV) versus zidovudine (AZT)/lamivudine (3TC) fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of FTC and TDF with EFV in place of FTC &#43; tenofovir disoproxil fumarate with EFV. Subjects had a mean age of 38 years (range 18–80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4&#43; 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). Subjects were stratified by baseline CD4&#43; cell count (< or ≥200 cells/mm3); 41% had CD4&#43; cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Table 21 provides treatment outcomes through 48 and 144 weeks for those subjects who did not have EFV resistance at baseline.

Through Week 48, 84% and 73% of subjects in the FTC &#43; tenofovir disoproxil fumarate group and the AZT/3TC group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects 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 AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the FTC &#43; tenofovir disoproxil fumarate group and the AZT/3TC 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&#43; cell count was 190 cells/mm3 in the FTC &#43; tenofovir disoproxil fumarate group and 158 cells/mm3 in the AZT/3TC group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the FTC &#43; tenofovir disoproxil fumarate group and 5 subjects in the AZT/3TC group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Treatment-Experienced Subjects: Trial 907

Trial 907 was a 24-week, double-blind, placebo-controlled multicenter trial of tenofovir disoproxil fumarate added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label tenofovir disoproxil fumarate for an additional 24 weeks. Subjects had a mean baseline CD4&#43; cell count of 427 cells/mm3 (range 23–1,385), median baseline plasma HIV-1 RNA of 2,340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years; 85% were male, 69% Caucasian, 17% Black, and 12% Hispanic.

Table 22 provides the percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks.

At 24 weeks of therapy, there was a higher proportion of subjects in the tenofovir disoproxil fumarate arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4&#43; cell counts by Week 24 was &#43;11 cells/mm3 for the tenofovir disoproxil fumarate group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4&#43; cell counts by Week 48 was &#43;4 cells/mm3 for the tenofovir disoproxil fumarate group.

Through Week 24, one subject in the tenofovir disoproxil fumarate group and no subjects in the placebo group experienced a new CDC Class C event.

14.3 Clinical Trial Results in Pediatric Subjects with HIV-1 Infection

In Trial 352, 92 treatment-experienced subjects 2 years to less than 12 years of age with stable, virologic suppression on a stavudine (d4T)- or zidovudine (AZT)-containing regimen were randomized to either replace d4T or AZT with tenofovir disoproxil fumarate (N=44) or continue their original regimen (N=48) for 48 weeks. Five additional subjects over the age of 12 years were enrolled and randomized (tenofovir disoproxil fumarate N=4, original regimen N=1) but are not included in the efficacy analysis. After 48 weeks, all eligible subjects were allowed to continue in the trial receiving open-label tenofovir disoproxil fumarate. At Week 48, 89% of subjects in the tenofovir disoproxil fumarate treatment group and 90% of subjects in the d4T or AZT treatment group had HIV-1 RNA concentrations <400 copies/mL. During the 48-week randomized phase of the trial, 1 subject in the tenofovir disoproxil fumarate group discontinued the trial prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the tenofovir disoproxil fumarate group and 1 subject in the d4T or AZT group) discontinued for other reasons.

In Trial 321, 87 treatment-experienced subjects 12 years to less than 18 years of age were treated with tenofovir disoproxil fumarate (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate and OBR.

Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of tenofovir disoproxil fumarate in pediatric patients 12 years and older who weigh at least 35 kg and whose HIV-1 isolate is expected to be sensitive to tenofovir disoproxil fumarate [see Warnings and Precautions (5.5), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

14.4 Clinical Trial Results in Adults with Chronic Hepatitis B

HBeAg-Negative Chronic HBV Subjects: Trial 0102

Trial 0102 was a Phase 3, randomized, double-blind, active-controlled trial of tenofovir disoproxil fumarate 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe&#43;) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years; 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy, and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.

HBeAg-Positive Chronic HBV Subjects: Trial 0103

Trial 0103 was a Phase 3, randomized, double-blind, active-controlled trial of tenofovir disoproxil fumarate 300 mg compared to HEPSERA 10 mg in 266 HBeAg&#43; nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years; 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.

The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.

The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (see Table 23).

Treatment Beyond 48 Weeks: Trials 0102 and 0103

In Trials 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to tenofovir disoproxil fumarate and HEPSERA, respectively) were eligible to roll over to open-label tenofovir disoproxil fumarate with no interruption in treatment.

In Trial 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the trial through Week 384. Among subjects randomized to tenofovir disoproxil fumarate followed by open-label treatment with tenofovir disoproxil fumarate, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with tenofovir disoproxil fumarate, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384. At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.

In Trial 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the trial through Week 384. Among subjects randomized to tenofovir disoproxil fumarate, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with tenofovir disoproxil fumarate, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384. At Week 384, HBsAg loss and seroconversion were 11% and 8%, respectively, in subjects initially randomized to tenofovir disoproxil fumarate and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two trials, liver biopsy data from 328 subjects who received continuing open-label treatment with tenofovir disoproxil fumarate monotherapy were available for analysis at baseline, Week 48, and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label tenofovir disoproxil fumarate without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Lamivudine-Resistant Chronic HBV Subjects: Trial 121

Trial 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of tenofovir disoproxil fumarate compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V &#43;/- rtL180M). One hundred forty-one adult subjects were randomized to the tenofovir disoproxil fumarate treatment arm. The mean age of subjects randomized to tenofovir disoproxil fumarate was 47 years (range 18&#8722;73); 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.

After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to tenofovir disoproxil fumarate had HBV DNA <400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to tenofovir disoproxil fumarate, 10 of 65 subjects (15%) experienced HBeAg loss and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the tenofovir disoproxil fumarate monotherapy and the comparator arms.

Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

Chronic HBV and Decompensated Liver Disease Subjects: Trial 0108

Trial 0108 was a small randomized, double-blind, active-controlled trial evaluating the safety of tenofovir disoproxil fumarate compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks.

Forty-five adult subjects (37 males and 8 females) were randomized to the tenofovir disoproxil fumarate treatment arm. At baseline, 69% of subjects were HBeAg-negative and 31% were HBeAg-positive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL, and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥0.5 mg/dL or confirmed serum phosphorus of <2 mg/dL [see Adverse Reactions (6.1)].

At 48 weeks, 31/44 (70%) and 12/26 (46%) tenofovir disoproxil fumarate-treated subjects achieved an HBV DNA <400 copies/mL (69 IU/mL), and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.

14.5 Clinical Trial Results in Pediatric Subjects with Chronic Hepatitis B

Pediatric Subjects 12 Years to less than 18 Years of Age with Chronic HBV

In Trial 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with tenofovir disoproxil fumarate 300 mg (N=52) or placebo (N=54) for 72 weeks. At trial entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with tenofovir disoproxil fumarate, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the tenofovir disoproxil fumarate group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving tenofovir disoproxil fumarate had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One tenofovir disoproxil fumarate-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of trial participation.

In Trial 115, sequencing data from paired baseline and on treatment HBV isolates from subjects who received tenofovir disoproxil fumarate were available for 14 of 15 subjects who had plasma HBV DNA ≥400 copies/mL.

No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were identified in these isolates by Week 72 (Trial 115). 

Pediatric use information is approved for Gilead Sciences, Inc.'s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.