Data from FDA - Curated by EPG Health - Last updated 02 February 2018

Indication(s)

1 INDICATIONS & USAGE Tenofovir disoproxil fumarate tablets are a nucleotide analog HIV-1 reverse transcriptase inhibitors and an HBV reverse transcriptase inhibitors. •Tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.(1) • Tenofovir disoproxil fumarate tablets are indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older. (1) 1.1 HIV-1 Infection Tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older. The following points should be considered when initiating therapy with tenofovir disoproxil fumarate tablets for the treatment of HIV-1 infection: •Tenofovir disoproxil fumarate tablets should not be used in combination with ATRIPLA®, COMPLERA®, DESCOVY®, GENVOYA®,ODEFSEY®, STRIBILD®, TRUVADA®, or VEMLIDY® [See Warnings and Precautions (5.4)]. 1.2 Chronic Hepatitis B Tenofovir disoproxil fumarate tablets are indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older. The following points should be considered when initiating therapy with tenofovir disoproxil fumarate tablets for the treatment of HBV infection: •The indication in adults is based on safety and efficacy data from treatment of subjects who were nucleoside-treatment-naïve and subjects who were treatment-experienced with documented resistance to lamivudine. Subjects were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)]. •Tenofovir disoproxil fumarate tablets were evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease [See Adverse Reactions (6.1), Clinical Studies (14.2)]. •The numbers of subjects in clinical trials who had adefovir resistance-associated substitutions at baseline were too small to reach conclusions of efficacy [See Microbiology (12.4), Clinical Studies (14.2)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.1)]. • New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.2)]. • Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions (5.3)]. • Bone Effects [See Warnings and Precautions (5.6)]. • Immune Reconstitution Syndrome [See Warnings and Precautions (5.7)]. • In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea. (6.1) • In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). (6.1) • In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults. (6.1) • In HBV-infected subjects with decompensated liver disease: Most common adverse reactions (incidence greater than or equal to 10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA,Inc. at 1-888-943-3210 or FDA at1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions from Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Patients with HIV-1 Infection More than 12,000 subjects have been treated with 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 1544 subjects have received tenofovir disoproxil fumarate tablets 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. Treatment-Naïve Patients Study 903 -Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received tenofovir disoproxil fumarate (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 4. Table 4 Selected Treatment-Emergent Adverse Reactionsa (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 903 (0–144 Weeks) Tenofovir Disoproxil Fumarate + 3TC + EFV d4T + 3TC + EFV N=299 N=301 Body as a W hole Headache Pain Fever Abdominal pain Back pain Asthenia 14% 13% 8% 7% 9% 6% 17% 12% 7% 12% 8% 7% Digestive System Diarrhea Nausea Dyspepsia Vomiting 11% 8% 4% 5% 13% 9% 5% 9% Metabolic Disorders Lipodystrophyb 1% 8% Musculoskeletal Arthralgia Myalgia 5% 3% 7% 5% Nervous System Depression Insomnia Dizziness Peripheral neuropathyc Anxiety 11% 5% 3% 1% 6% 10% 8% 6% 5% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash eventd 18% 12% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. c. Peripheral neuropathy includes peripheral neuritis and neuropathy. d. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir disoproxil fumarate (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grades 3–4 laboratory abnormalities is provided in Table 5. Table 5 Grades 3–4 Laboratory Abnormalities Reported in ≥1% of tenofovir disoproxil fumarate-Treated Subjects in Study 903 (0-144 Weeks) Tenofovir Disoproxil Fumarate + 3TC + EFV d4T + 3TC + EFV N=299 N=301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (>240 mg/dL) 19% 40% Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12% Serum Amylase (>175 U/L) 9% 8% AST (M: >180 U/L; F: >170 U/L) 5% 7% ALT (M: >215 U/L; F: >170 U/L) 4% 5% Hematuria (>100 RBC/HPF) 7% 7% Neutrophils (<750/mm3) 3% 1% Fasting Triglycerides (>750 mg/dL) 1% 9 Study 934 – Treatment-Emergent Adverse Reactions: In Study 934, 511 antiretroviralnaïve subjects received either tenofovir disoproxil fumarate + EMTRIVA® administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6). Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-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 stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir disoproxil fumarate-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir disoproxil fumarate group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir disoproxil fumarate group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [See Warnings and Precautions (5.6)]. Table 6 Selected Treatment-Emergent Adverse Reactions a (Grades 2-4) Reported in ≥5% in Any Treatment Group in Study 934 (0-144 Weeks) Tenofovir Disoproxil Fumarateb + FTC + EFV AZT/3TC + EFV N=257 N=254 Gastrointestinal Disorder Diarrhea Nausea Vomiting 9% 9% 2% 5% 7% 5% General Disorders and Administration Site Condition Fatigue 9% 8% Infections and Infestations Sinusitis Upper respiratory tract infections Nasopharyngitis 8% 8% 5% 4% 5% 3% Nervous System Disorders Headache Dizziness 6% 8% 5% 7% Psychiatric Disorders Depression Insomnia 9% 5% 7% 7% Skin and Subcutaneous Tissue Disorders Rash eventc 7% 9% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of tenofovir disoproxil fumarate+ EMTRIVA with efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. 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 Study 934 (0-144 Weeks) Tenofovir disoproxil fumaratea + FTC + EFV AZT/3TC + EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L; F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L; F: >170 U/L) 3% 3% ALT (M: >215 U/L; F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm3) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a. From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of tenofovir disoproxil fumarate + EMTRIVA with efavirenz. Treatment-Experienced Patients Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment-experienced subjects were generally consistent with those seen in treatment-naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907). A summary of moderate to severe treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 8. Table 8 Selected Treatment-Emergent Adverse Reactions a (Grades 2-4) Reported in ≥3% in Any Treatment Group in Study 907 (0-48 Weeks) Tenofovir Disoproxil Fumarate (N=368) (Week 0-24) Placebo (N=182) (Week 0-24) Tenofovir Disoproxil Fumarate (N=368) (Week 0-48) Placebo Crossover to Tenofovir Disoproxil Fumarate (N=170) (Week 24-48 Body as a Whole Asthenia Pain Headache Abdominal pain Back pain Chest pain Fever 7% 7% 5% 4% 3% 3% 2% 6% 7% 5% 3% 3% 1% 2% 11% 12% 8% 7% 4% 3% 4% 1% 4% 2% 6% 2% 2% 2% Digestive System Diarrhea Nausea Vomiting Anorexia Dyspepsia Flatulence 11% 8% 4% 3% 3% 3% 10% 5% 1% 2% 2% 1% 16% 11% 7% 4% 4% 4% 11% 7% 5% 1% 2% 1% Respiratory Pneumonia 2% 0% 3% 2% Nervous System Depression Insomnia Peripheral neuropathyb Dizziness 4% 3% 3% 1% 3% 2% 3% 3% 8% 4% 5% 3% 4% 4% 2% 1% Skin and Appendage Rash eventc Sweating 5% 3% 4% 2% 7% 3% 1% 1% Musculoskeletal Myalgia 3% 3% 4% 1% Metabolic Weight loss 2% 1% 4% 2% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. Peripheral neuropathy includes peripheral neuritis and neuropathy. c. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and placebo-treated groups. A summary of Grades 3–4 laboratory abnormalities is provided in Table 9. Table 9 Grades 3–4 Laboratory Abnormalities Reported in ≥1% of tenofovir disoproxil fumarate tablets-Treated Subjects in Study 907 (0-48 Weeks) Tenofovir Disoproxil Fumarate (N=368) (Week 0-24) Placebo (N=182) (Week 0-24) Tenofovir Disoproxil Fumarate (N=368) (Week 0-48) Placebo Crossover to Tenofovir Disoproxil Fumarate (N=170) (Week 24-48) Any ≥ Grade 3 Laboratory Abnormality 25% 38% 35% 34% Triglycerides (>750 mg/dL) 8% 13% 11% 9% Creatine Kinase (M: >990 U/L; F: >845 U/L) 7% 14% 12% 12% Serum Amylase (>175 U/L) 6% 7% 7% 6% Glycosuria (≥3+) 3% 3% 3% 2% AST (M: >180 U/L; F: >170 U/L) 3% 3% 4% 5% ALT (M: >215 U/L; F: >170 U/L) 2% 2% 4% 5% Serum Glucose (>250 U/L) 2% 4% 3% 3% Neutrophils (<750/mm3) 1% 1% 2% 1% Clinical Trials in Pediatric Subjects 2 Years of Age and Older with HIV-1 Infection Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 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. The adverse reactions observed in subjects who received treatment with tenofovir disoproxil fumarate were consistent with those observed in clinical trials in adults. Eighty-nine pediatric subjects (2 to less than 12 years of age) received tenofovir disoproxil fumarate in Study 352 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 (5.6)]. Changes in Bone Mineral Density: Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the tenofovir disoproxil fumarate compared to the placebo treatment 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 Study 352 (2 to less than 12 years), 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 compared to the d4T or AZT treatment groups. 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 [See Warnings and Precautions (5.6)]. Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with tenofovir disoproxil fumarate during the 48week 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. During the open-label phase of treatment with tenofovir disoproxil fumarate (weeks 48–384) in Studies 0102 and 0103, 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: A summary of Grades 3–4 laboratory abnormalities through Week 48 is provided in Table 10. Grades 3–4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate treatment for up to 384 weeks in these trials. Table 10 Grades 3-4 Laboratory Abnormalities Reported in ≥1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Studies 0102 and 0103 (0-48 Weeks) Tenofovir Disoproxil Fumarate (N=426) HEPSERA (N=215) Any ≥ Grade 3 Laboratory Abnormality 19% 13% Creatine Kinase (M: >990 U/L; F: >845 U/L) 2% 3% Serum Amylase (>175 U/L) 4% 1% Glycosuria (≥3+) 3% <1% AST (M: >180 U/L; F: >170 U/L) 4% 4% ALT (M: >215 U/L; F: >170 U/L) 10% 6% 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 4-8 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 hepatitis B clinical trials in adults. Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with tenofovir disoproxil fumarate or other antiviral drugs for up to 48 weeks [See Clinical Studies (14.2)]. 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. Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B 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 this study, both the tenofovir disoproxil fumarate and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in tenofovir disoproxil fumarate -treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the tenofovir disoproxil fumarate group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to tenofovir disoproxil fumarate were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving tenofovir disoproxil fumarate for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected [See Warnings and Precautions (5.6)]. 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.

Usage information

Dosing and administration
2 DOSAGE & ADMINISTRATION •Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults and pediatric patients 12 years of age and older (35 kg or more): 300 mg once daily taken orally without regard to food. (2.1) • Recommended dose for the treatment of HIV-1 in pediatric patients (2 to less than 12 years of age): • Tablets: for pediatric patients weighing greater than or equal to 17 kg who can swallow an intact tablet, one tenofovir disoproxil fumarate tablet (300 mg based on body weight) once daily taken orally without regard to food. (2.2) • Dose recommended in renal impairment in adults: • Creatinine clearance 30-49 mL/min: 300 mg every 48 hours. (2.3) • Creatinine clearance 10-29 mL/min: 300 mg every 72 to 96 hours. (2.3) • Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis. (2.3) 2.1 Recommended Dose in Adults and Pediatric Patients 12 Years of Age and Older (35 kg or more) For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg tenofovir disoproxil fumarate tablet once daily taken orally, without regard to food. For patients unable to swallow tenofovir disoproxil fumarate tablets, the oral powder formulation may be used. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established. 2.2 Recommended Dose in Pediatric Patients 2 Years to Less than 12 Years of Age HIV-1 Infection For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of tenofovir disoproxil fumarate tablets is 8 mg of tenofovir disoproxil fumarate(tenofovir DF) per kilogram of body weight (up to a maximum of 300 mg) once daily administered as tablets. Tenofovir disoproxil fumarate is available as tablets in 300 mg strength for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food. Table 2 contains dosing recommendations for tenofovir disoproxil fumarate tablets based on body weight. Weight should be monitored periodically and the tenofovir disoproxil fumarate dose adjusted accordingly. Table 2 Dosing Recommendations for Pediatric Patients ≥2 Years of Age and Weighing ≥17 kg Using Tenofovir Disoproxil Fumarate Tablets Body Weight Kilogram (kg) Tablets Once Daily 17 to <22 150 mg 22 to <28 200 mg 28 to <35 250 mg ≥35 300 mg Chronic Hepatitis B Safety and efficacy of tenofovir disoproxil fumarate in patients younger than 12 years of age have not been established 2.3 Dose Adjustment for Renal Impairment in Adults Significantly increased drug exposures occurred when tenofovir disoproxil fumarate was administered to subjects with moderate to severe renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval of tenofovir disoproxil fumarate tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.2)]. No dose adjustment of tenofovir disoproxil fumarate tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment [See Warnings and Precautions (5.2)]. Table 3 Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min)a Hemodialysis Patients ≥50 30–49 10–29 Every 7 days or after a total of approximately 12 hours of dialysisb Recommended 300 mg Dosing Interval Every 24 hours Every 48 hours Every 72 to 96 hours a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. tenofovir disoproxil fumarate should be administered following completion of dialysis. The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment. The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment.
Use in special populations
8 USE IN SPECIFIC POPULATIONS • Nursing mothers: Women infected with HIV should be instructed not to breastfeed. (8.3) 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, tenofovir disoproxil fumarate should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to tenofovir disoproxil fumarate, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Risk Summary Animal Data Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. 8.3 Nursing Mothers Nursing Mothers: 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. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving tenofovir disoproxil fumarate. 8.4 Pediatric Use Pediatric Patients 2 Years of Age and Older with HIV-1 infection The safety of tenofovir disoproxil fumarate in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which tenofovir disoproxil fumarate was administered to HIV-1 infected treatment-experienced subjects. In addition, the pharmacokinetic profile of tenofovir in patients 2 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)]. In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine-or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with tenofovir disoproxil fumarate (N=44) or continue their original regimen (N=48) for 48 weeks. Five additional subjects over the age of 12 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 study 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 stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL. During the 48 week randomized phase of the study, 1 subject in the tenofovir disoproxil fumarate group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the tenofovir disoproxil fumarate group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons. In Study 321, 87 treatment-experienced subjects 12 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/mm3 and 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 treatment 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 of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to tenofovir disoproxil fumarate. [See Warnings and Precautions (5.6), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. Safety and effectiveness of tenofovir disoproxil fumarate in pediatric patients younger than 2 years of age with HIV-1 infection have not been established. Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B In Study 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 tablets 300 mg (N=52) or placebo (N=54) for 72 weeks. At study 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)ideexperienced. 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 study participation. Safety and effectiveness of tenofovir disoproxil fumarate in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established. 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 Patients with Impaired Renal Function It is recommended that the dosing interval for tenofovir disoproxil fumarate be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis [See Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers Nursing Mothers: 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. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving tenofovir disoproxil fumarate.

Interactions

7 DRUG INTERACTIONS This section describes clinically relevant drug interactions with tenofovir disoproxil fumarate. Drug interactions trials are described elsewhere in the labeling [See Clinical Pharmacology (12.3)]. • Didanosine: Coadministration increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy). Consider dose reductions or discontinuations of didanosine if warranted. (7.1) • HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. When coadministered with tenofovir disoproxil fumarate, use atazanavir given with ritonavir. Coadministration of tenofovir disoproxil fumarate with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2) 7.1 Didanosine Coadministration of tenofovir disoproxil fumarate and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with tenofovir disoproxil fumarate, Cmax and AUC of didanosine increased significantly [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir disoproxil fumarate with didanosine 400 mg daily. In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with tenofovir disoproxil fumarate. In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with tenofovir disoproxil fumarate. When coadministered, tenofovir disoproxil fumarate and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). For additional information on coadministration of tenofovir disoproxil fumarate and didanosine, please refer to the full prescribing information for didanosine. 7.2 HIV-1 Protease Inhibitors Tenofovir disoproxil fumarate decreases the AUC and Cmin of atazanavir [See Clinical Pharmacology (12.3)]. When coadministered with tenofovir disoproxil fumarate, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Tenofovir disoproxil fumarate should not be coadministered with atazanavir without ritonavir. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. Tenofovir DF is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir DF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving tenofovir disoproxil fumarate concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for tenofovir disoproxil fumarate -associated adverse reactions. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir disoproxil fumarate -associated adverse reactions. 7.3 Hepatitis C Antiviral Agents Coadministration of Tenofovir disoproxil fumarate and EPCLUSA® (sofosbuvir/velpatasvir) or HARVONI® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure [See Clinical Pharmacology (12.3)]. In patients receiving tenofovir disoproxil fumarate concomitantly with EPCLUSA, monitor for adverse reactions associated with tenofovir DF. In patients receiving tenofovir disoproxil fumarate concomitantly with HARVONI without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir DF. In patients receiving tenofovir disoproxil fumarate concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with tenofovir DF. 7.4 Drugs Affecting Renal Function Since tenofovir is primarily eliminated by the kidneys [See Clinical Pharmacology (12.3)], coadministration of tenofovir disoproxil fumarate with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [See Warnings and Precautions (5.2)]. In the treatment of chronic hepatitis B, tenofovir disoproxil fumarate should not be administered in combination with HEPSERA (adefovir dipivoxil).

More information

Category Value
Authorisation number ANDA203232
Agency product number OTT9J7900I
Orphan designation No
Product NDC 33342-096
Date Last Revised 18-01-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Macleods Pharmaceuticals Limited
Warnings WARNING:POST TREATMENT EXACERBATION OF HEPATITIS WARNING: POST TREATMENT EXACERBATION OF HEPATITIS Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including tenofovir disoproxilfumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including tenofovir disoproxil fumarate. If appropriate, resumption of anti-hepatitis B therapy may be warranted [See Warnings and Precautions ( 5.1 )]. WARNING: POST TREATMENT EXACERBATION OF HEPATITIS See full prescribing information for complete boxed warning. • Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including tenofovir disoproxil fumarate. Hepatic function should be monitored closely in these patients. If appropriate, resumption of anti-hepatitis B therapy may be warranted. (5.1)