TENOFOVIR DISOPROXIL FUMARATE_- tenofovir disoproxil fumarate_tablet, film coated

Tenofovir disoproxil fumarate is an antiviral drug [see Microbiology ( 12. 4 The pharmacokinetics of TDF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations. Absorption max max 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 C max Distribution Metabolism and Elimination 0-infinity max max max Race Gender Pediatric Patients 2 Years and Older: Table 13 Mean (+/- SD) Tenofovir Pharmacokinetic Parameters by Age Groups for HIV-1-infected Pediatric Patients 2 years and older for the Tablet. Dose and Formulation 300 mg Tablet 12 Years to <18 Years (N=8) C max 0. 13 AUC tau 3. 22 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 and pediatric subjects 2 years to less than 12 years of age receiving tenofovir disoproxil fumarate 8 mg/kg of body weight (tablet or powder) up to a maximum dose of 300 mg were comparable to exposures achieved in HIV-1 infected adult subjects receiving identical doses. Geriatric Patients Patients with Renal Impairment max 0-infinity Table 14 Pharmacokinetic Parameters (Mean +/- SD) of Tenofovir a Baseline Creatinine Clearance (mL/min) >80 N=3 50-80 N=10 30-49 N=8 12-29 N=11 max 0-infinity renal a. 300 mg, single dose of tenofovir disoproxil fumarate tablets Patients with Hepatic Impairment Assessment of Drug Interactions Table 15 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir a Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters b C max AUC C min Atazanavir c 400 once daily × 14 days 33 up arrow 14 (up arrow 8 to up arrow 20) up arrow 24 (up arrow 21 to up arrow 28) up arrow 22 (up arrow 15 to up arrow 30) Atazanavir/ Ritonavir c 300/100 once daily 12 up arrow 34 (up arrow 20 to up arrow 51) up arrow 37 (up arrow 30 to up arrow 45) up arrow 29 (up arrow 21 to up arrow 36) Darunavir/ Ritonavir d 300/100 twice daily 12 up arrow 24 (up arrow 8 to up arrow 42) up arrow 22 (up arrow 10 to up arrow 35) up arrow 37 (up arrow 19 to up arrow 57) Indinavir 800 three times daily × 7 days 13 up arrow 14 (down arrow 3 to up arrow 33) left-right arrow left-right arrow Ledipasvir/ Sofosbuvir e,f 90/400 once daily × 10 days 24 up arrow 47 (up arrow 37 to up arrow 58) up arrow 35 (up arrow 29 to up arrow 42 ) up arrow 47 (up arrow 38 to up arrow 57) Ledipasvir/ Sofosbuvir e,g 23 up arrow 64 (up arrow 54 to up arrow 74) up arrow 50 (up arrow 42 to up arrow 59) up arrow 59 (up arrow 49 to up arrow 70) Ledipasvir/ Sofosbuvir h 90/400 once daily × 14 days 15 up arrow 79 (up arrow 56 to up arrow 104) up arrow 98 (up arrow 77 to up arrow 123) up arrow 163 (up arrow 132 toup arrow197) Lopinavir/ Ritonavir 400/100 twice daily × 14 days 24 left-right arrow up arrow 32 (up arrow 25 to up arrow 38) up arrow 51 (up arrow 37 to up arrow 66) Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 left-right arrow left-right arrow up arrow 23 (up arrow 16 to up arrow 30) Sofosbuvir i 400 single dose 16 up arrow 25 (up arrow 8 to up arrow 45) left-right arrow left-right arrow Sofosbuvir/ Velpatasvir j 400/100 once daily 24 up arrow 44 (up arrow 33 to up arrow 55) up arrow 40 (up arrow 34 to up arrow 46) up arrow 84 (up arrow 76 to up arrow 92) Sofosbuvir/ Velpatasvir k 400/100 once daily 30 up arrow 46 (up arrow 39 to up arrow 54) up arrow 40 (up arrow 34 to up arrow 45) up arrow 70 (up arrow 61 to up arrow 79) Sofosbuvir/ Velpatasvir/ Voxilaprevir l 400/100/100 + Voxilaprevir m 29 up arrow 48 (up arrow 36 to up arrow 61) up arrow 39 (up arrow 32 toup arrow 46) up arrow 47 (up arrow 38 to up arrow 56) Tacrolimus 0. 05 mg/kg twice daily × 7 days 21 up arrow 13 (up arrow 1 to up arrow 27) left-right arrow left-right arrow Tipranavir/ Ritonavir n 500/100 twice daily 22 down arrow 23 (down arrow 32 to down arrow 13) down arrow 2 (down arrow 9 to up arrow 5) up arrow 7 (down arrow 2 to up arrow 17) 750/200 twice daily (23 doses) 20 down arrow 38 (down arrow 46 to down arrow 29) up arrow 2 (down arrow 6 to up arrow 10) up arrow 14 (up arrow 1 to up arrow 27) a. Subjects received tenofovir disoproxil fumarate 300 mg once daily. Table 16 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil Fumarate Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parametersa (90% CI) C max AUC C min Abacavir 300 once 8 up arrow 12 ó NA Atazanavir b 400 once daily × 14 days 34 down arrow 21 down arrow 25 down arrow 40 Atazanavir b Atazanavir/ Ritonavir 300/100 once daily × 42 days 10 down arrow 28 down arrow 25c down arrow 23 c Darunavir d Darunavir/Ritonavir 300/100 once daily 12 up arrow 16 up arrow 21 up arrow 24 Didanosine e 250 once, simultaneously with tenofovir disoproxil fumarate and a light mealf 33 down arrow 20 g ó g NA Emtricitabine 200 once daily × 7 days 17 ó ó up arrow 20 Entecavir 1 mg once daily x 10 days 28 ó up arrow 13 ó Indinavir 800 three times daily × 7 days 12 down arrow 11 ó ó Lamivudine 150 twice daily × 7 days 15 down arrow 24 ó ó Lopinavir Ritonavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 ó ó ó Saquinavir Ritonavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 up arrow 22 up arrow 29h up arrow 47h Tacrolimus 0. 05 mg/kg twice daily x 7 days 21 ó ó ó Tipranavir i Tipranavir/Ritonavir 500/100 twice daily 22 down arrow 17 down arrow 18 down arrow 21 Tipranavir/Ritonavir 750/200 twice daily (23 doses) 20 down arrow 11 down arrow 9 down arrow 12 a. Increase = up arrow; Decrease = down arrow; No Effect =if and only if ; NA = Not Applicable min min Mechanism of Action Activity against HIV Antiviral Activity 50 Resistance 14. 2 Cross Resistance 14. 2 Trials 902 and 907 Phenotypic Analyses Table 17 HIV-1 RNA Response at Week 24 by Baseline Tenofovir Disoproxil Fumarate Susceptibility (Intent-To-Treat) a Baseline Tenofovir Disoproxil Fumarate Susceptibility b Change in HIV-1 RNA c <1 -0. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco). Activity against HBV Antiviral Activity The antiviral activity of tenofovir against HBV was assessed in the HepG2 2. 15 cell line. The EC50 values for tenofovir ranged 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. 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). Table 18 Amino Acid Substitutions in Viremic Subjects across HBV Trials of Tenofovir Disoproxil Fumarate. Compensated Liver Disease Decompensated Liver Disease (N=39) d Nucleotide-Naïve (N=417) a HEPSERA-Experienced (N=247) b Lamivudine-Resistant (N=136) c e f g h a. Nucleotide-naïve subjects from Trials 0102 (N=246) and 0103 (N=171) receiving up to 384 weeks of treatment with tenofovir disoproxil fumarate. Cross Resistance.

Tenofovir disoproxil fumarate tablets are a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor and is indicated: 1. 2 Tenofovir disoproxil fumarate tablets are 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.

Testing: Prior to or when initiating tenofovir disoproxil fumarate tablets test for hepatitis B virus infection and HIV-1 infection. 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 phosphorous. 4 Prior to or when initiating tenofovir disoproxil fumarate tablets, test patients for HBV infection and HIV-1 infection. Tenofovir disoproxil fumarate tablets alone should not be used in patients with HIV-1 infection [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 2 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 tablet 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 tablets dose adjusted accordingly. Body Weight (kg) Dosing of Tenofovir Disoproxil Fumarate Tablets 17 to less than 22 one 150 mg tablet once daily 22 to less than 28 one 200 mg tablet once daily 28 to less than 35 one 250 mg tablet once daily at least 35 one 300 mg tablet once daily Significant increase in drug exposures occurred when tenofovir disoproxil fumarate tablets were 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 50en dash80 mL/min) [see Warnings and Precautions ( 5. 3 Table 3 Dosage Interval Adjustment for Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) a Hemodialysis Patients 50 or greater 30en dash49 10en dash29 b Recommended 300 mg Dosing Interval Every 24 hours Every 48 hours Every 72 to 96 hours a. Calculated using ideal (lean) body weight.

The following adverse reactions are discussed in other sections of the labeling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 4 see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2en dash4) were rash, diarrhea, nausea, headache, pain, depression, and asthenia. 1 In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). 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. 1 In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults. 1 To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA,Inc. at 1-888-943-3210 or 1-855-926-3384 or www. gov/medwatch 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 Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects Table 4 Selected Adverse Reactionsa (Grades 2en dash4) Reported in >=5% in Any Treatment Group in Trial 903 (0en dash144 Weeks) Tenofovir Disoproxil Fumarate + 3TC + EFV d4T + 3TC + EFV N=299 N=301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophy c 1% 8% Peripheral neuropathy d 1% 5% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. Laboratory Abnormalities Table 5 Grades 3en dash4 Laboratory Abnormalities Reported in >=1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trial 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/mm 3 3% 1% Fasting Triglycerides (>750 mg/dL) 1% 9% [see Warnings and Precautions ( 5. 5 Table 6 Selected Adverse Reactions a Tenofovir Disoproxil Fumarate b AZT/3TC + EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash event c 7% 9% Headache 6% 5% Insomnia 5% 7% Nasopharyngitis 5% 3% Vomiting 2% 5% a. Laboratory Abnormalities Table 7 Significant Laboratory Abnormalities Reported in >=1% of Subjects in Any Treatment Group in Trial 934 (0-144 Weeks) Tenofovir disoproxil fumarate + FTC + EFV a 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/mm 3 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of tenofovir disoproxil fumarate + FTC with EFV. Clinical Trials in Treatment-Experienced HIV-1 Infected Adult Subjects Table 8 Selected Adverse Reactions a (Grades 2-4) Reported in >=3% in Any Treatment Group in Trial 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 7% 6% 11% 1% Pain 7% 7% 12% 4% Headache 5% 5% 8% 2% Abdominal pain 4% 3% 7% 6% Back pain 3% 3% 4% 2% Chest pain 3% 1% 3% 2% Fever 2% 2% 4% 2% Digestive System Diarrhea 11% 10% 16% 11% Nausea 8% 5% 11% 7% Vomiting 4% 1% 7% 5% Anorexia 3% 2% 4% 1% Dyspepsia 3% 2% 4% 2% Flatulence 3% 1% 4% 1% Respiratory 2% 0% 3% 2% Nervous System Depression 4% 3% 8% 4% Insomnia 3% 2% 4% 4% Peripheral neuropathy b 3% 3% 5% 2% Dizziness 1% 3% 3% 1% Skin and Appendage Rash event c 5% 4% 7% 1% Sweating 3% 2% 3% 1% Musculoskeletal Metabolic a. Laboratory Abnormalities Table 9 Grades 3en dash4 Laboratory Abnormalities Reported in >=1% of Tenofovir Disoproxil Fumarate Tablets-Treated Subjects in Trial 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/mm 3 1% 1% 2% 1% Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Pediatric Subjects 2 Years and Older [see Clinical Studies ( 14. 3 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 [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 Laboratory Abnormalities: Table 10 Grades 3-4 Laboratory Abnormalities Reported in >=1% of Tenofovir Disoproxil Fumarate-Treated Subjects in Trials 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 to 8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication. Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease [see Clinical Studies ( 14. 4 Adverse Reactions from Clinical Trials Experience in HBV-Infected Pediatric Subjects 2 Years and Older Assessment of adverse reactions in pediatric subjects infected with chronic HBV is based on two randomized trials: Trial GS-US- 174-0115 in 106 subjects (12 years to less than 18 years of age) receiving treatment with tenofovir disoproxil fumarate (N=52) or placebo (N=54) for 72 weeks and Trial GS-US-174- 0144 in 89 subjects (2 years to less than 12 years of age) receiving treatment with tenofovir disoproxil fumarate (N=60) or placebo (N=29) for 48 weeks [see Clinical Studies ( 14. 5 In Trial 115 (12 years to less than 18 years of age) and Trial 144 (2 years to less than 12 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 and 48 weeks, respectively, 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. In Trial 144 (2 years to less than 12 years of age), mean percentage BMD gains from baseline to Week 48 in lumbar spine and total body BMD in tenofovir disoproxil fumarate -treated subjects were less than the mean percentage BMD gains observed in placebo-treated subjects. At Week 48, the cumulative percentage of subjects with greater than or equal to 4% decreases in spine or whole body BMD was numerically higher for subjects in the TDF group compared with the placebo group (Table 11). As observed in pediatric studies of HIV-infected subjects, normal skeletal growth (height) was not affected for the duration of the clinical trial [see Warnings and Precautions ( 5. 5 Table 11 Change in Bone Mineral Density from Baseline in Pediatric Subjects 2 Years to <12 Years of Age (Trials 115 and 144) Trial 115 (Week 72) Trial 144 (Week 48) Tenofovir Disoproxil Fumarate (N=52) Placebo (N=54) Tenofovir Disoproxil Fumarate (N=60) Placebo (N=29) Mean percentage change in BMD Lumbar spine +5% +8% +4% +8% Total body +3% +5% +5% +9% Cumulative incidence of >=4% decrease in BMD Lumbar spine 6% 4% 18% 7% Total body 0% 2% 7% 0% Baseline BMD Z-score (mean) Lumbar spine -0. 29 Total body -0. 05 Mean change in BMD Z-score Lumbar spine -0. 14 Total body -0. 22 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 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 Metabolism and Nutrition Disorders Respiratory, Thoracic, and Mediastinal Disorders Gastrointestinal Disorders Hepatobiliary Disorders Skin and Subcutaneous Tissue Disorders Musculoskeletal and Connective Tissue Disorders Renal and Urinary Disorders General Disorders and Administration Site Conditions.

Lactation: Breastfeeding in HIV-1 infected mothers is not recommended due to the potential for HIV-1 transmission. 2 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. 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. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15en dash20%. see Data 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. reference population of the MACDP. The prevalence of major birth defects in live births was 2. 3% (95% CI: 1. 8%) with first trimester exposure to TDF-containing regimens, and 2. 1% (95% CI: 1. 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. 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. 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. Risk Summary see Data Treatment of HIV-1 infection: Treatment of HBV infection: Data Pediatric Patients 2 Years and Older with HIV-1 Infection [see Adverse Reactions ( 6. 3 [see Clinical Pharmacology ( 12. 3 [see Warnings and Precautions ( 5. 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 2 Years of Age and Older with Chronic Hepatitis B 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. 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. 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.

Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. 2 Tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology ( 12. 3 [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). 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 Table 12 Established and Significant a Concomitant Drug Class: Drug Name Effect on Concentration b Clinical Comment NRTI: up arrow didanosine Patients receiving tenofovir disoproxil fumarate and didanosine should be monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. 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. HIV-1 Protease Inhibitors: down arrow atazanavir When coadministered with tenofovir disoproxil fumarate, atazanavir 300 mg Hepatitis C Antiviral Agents: up arrow tenofovir Monitor patients receiving tenofovir disoproxil fumarate concomitantly with EPCLUSAregistered (sofosbuvir/velpatasvir) for adverse reactions associated with TDF. This table is not all inclusive.

OVERDOSAGE
If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
NONCLINICAL TOXICOLOGY
Carcinogenesis Mutagenesis Impairment of Fertility 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.
CLINICAL STUDIES
The efficacy and safety of tenofovir disoproxil fumarate in adults and pediatric subjects were evaluated in the trials summarized in Table 19. Table 19 Trials Conducted with Tenofovir Disoproxil Fumarate in Adults and Pediatric Subjects for HIV-1 Treatment and Chronic HBV Treatment Trial Population Study Arms (N) a Timepoint (Week) Trial 903 b HIV-1 treatment-naïve adults Tenofovir Disoproxil Fumarate +lamivudine+efavirenz (299) stavudine+lamivudine+efavirenz (301) 144 Trial 934 c emtricitabine+ Tenofovir Disoproxil Fumarate +efavirenz (257) zidovudine/lamivudine+efavirenz (254) 144 Trial 907 d HIV-1 treatment-experienced adults Tenofovir Disoproxil Fumarate (368) Placebo (182) 24 Trial 0102b (NCT00117676) HBeAg-negative adults with chronic HBV Tenofovir Disoproxil Fumarate (250) HEPSERA (125) 48 Trial 0103 b HBeAg-positive adults with chronic HBV Tenofovir Disoproxil Fumarate (176) HEPSERA (90) 48 Trial 121 b Adults with lamivudine-resistant chronic HBV Tenofovir Disoproxil Fumarate (141) 96 Trial 0108 b Adults with chronic HBV and decompensated liver disease Tenofovir Disoproxil Fumarate (45) 48 Trial 352 c HIV-1 treatment experienced pediatric subjects 2 years to <12 years Tenofovir Disoproxil Fumarate (44) stavudine or zidovudine (48) 48 Trial 321 d HIV-1 treatment-experienced pediatric subjects 12 years to <18 years Tenofovir Disoproxil Fumarate (45) Placebo (42) 48 Trial 115 d Pediatric subjects 12 years to <18 years with chronic HBV Tenofovir Disoproxil Fumarate (52) Placebo (54) 72 d a. Randomized and dosed. Treatment-Naïve Subjects: Trial 903 3 3 Table 20 Outcomes of Randomized Treatment at Week 48 and 144 (Trial 903) Outcomes At Week 48 At Week 144 Tenofovir Disoproxil Fumarate + 3TC +EFV (N=299) d4T+3TC +EFV (N=301) Tenofovir Disoproxil Fumarate +3TC +EFV (N=299) d4T+3TC +EFV (N=301) Responder a 79% 82% 68% 62% Virologic failure b 6% 4% 10% 8% Rebound 5% 3% 8% 7% Never suppressed 0% 1% 0% 0% Added an antiretroviral agent 1% 1% 2% 1% Death <1% 1% <1% 2% Discontinued due to adverse event 6% 6% 8% 13% Discontinued for other reasons c 8% 7% 14% 15% a. Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144. 3 3 3 Treatment-Naïve Subjects: Trial 934 3 3 3 Table 21 Outcomes of Randomized Treatment at Week 48 and 144 (Trial 934) Outcomes At Week 48 At Week 144 FTC +Tenofovir Disoproxil Fumarate +EFV (N=244) AZT/3TC +EFV (N=243) FTC + Tenofovir Disoproxil Fumarate +EFV (N=227)a AZT/3TC +EFV (N=229)a Responder b 84% 73% 71% 58% Virologic failure c 2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons d 10% 14% 20% 22% a. Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the trial after Week 48 or Week 96 were excluded from analysis. Through Week 48, 84% and 73% of subjects in the FTC + 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 + 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+ cell count was 190 cells/mm 3 3 3 Treatment-Experienced Subjects: Trial 907 3 Table 22 provides the percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks. Table 22 Outcomes of Randomized Treatment (Trial 907) Outcomes 0-24 weeks 0-48 weeks 24-48 weeks Tenofovir Disoproxil Fumarate (N=368 Placebo (N=182) Tenofovir Disoproxil Fumarate (N=368) Placebo Crossover to Tenofovir Disoproxil Fumarate (N=170) a b c a. Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48, respectively. 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+ cell counts by Week 24 was +11 cells/mm 3 3 3 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. 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. 3 [see Warnings and Precautions ( 5. 3 HBeAg-Negative Chronic HBV Subjects: Trial 0102 10 HBeAg-Positive Chronic HBV Subjects: Trial 0103 10 Table 23 Histological, Virological, Biochemical, and Serological Response at Week 48 (Trials 0102 and 0103) 0102 (HBeAg-) 0103 (HBeAg+) Tenofovir Disoproxil Fumarate (N=250) HEPSERA (N=125) Tenofovir Disoproxil Fumarate (N=176) HEPSERA (N=90) Complete Response 71% 49% 67% 12% Histology a 72% 69% 74% 68% HBV DNA 93% 63% 76% 13% ALT b 76% 77% 68% 54% Serology NA c NA c 20%/19% 16%/16% HBsAg Loss/ Seroconversion 0/0 0/0 3%/1% 0/0 a. Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. Treatment Beyond 48 Weeks: Trials 0102 and 0103 Lamivudine-Resistant Chronic HBV Subjects: Trial 121 10 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 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 log 10 [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. Pediatric Subjects 12 Years to less than 18 Years of Age with Chronic HBV 10 Pediatric Subjects 2 Years to less than 12 Years of Age with Chronic HBV Table 24 Outcomes of Randomized Treatment (Trial 144) in Children 2 Years to <12 Years of Age Endpoint at Week 48 Tenofovir Disoproxil Fumarate N=60 Placebo N=29 HBV DNA <400 copies/mL (69 IU/ml) 46/60 (77%) 2/29 (7%) ALT Normalization a 38/58 (66%) 4/27 (15%) HBeAg loss b 17/56 (30%) 8/29 (28%) HBeAg seroconversion b 14/56 (25%) 7/29 (24%).
PATIENT INFORMATION
Tenofovir Disoproxil Fumarate Tablets Read this Patient Information before you start taking tenofovir disoproxil fumarate tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about tenofovir disoproxil fumarate tablets? Worsening of Hepatitis B virus infection (HBV). If you have HBV infection and take tenofovir disoproxil fumarate tablets your HBV may get worse (flare-up) if you stop taking tenofovir disoproxil fumarate tablets Do not Do not For more information about side effects, see “What are the possible side effects of tenofovir disoproxil fumarate tablets?” What should I tell my healthcare provider before taking tenofovir disoproxil fumarate tablets? Pregnancy Registry Do not Tell your healthcare provider about all the medicines you take Some medicines may interact with tenofovir disoproxil fumarate tablets. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take tenofovir disoproxil fumarate tablets? Do not What are the possible side effects of tenofovir disoproxil fumarate tablets? Tenofovir disoproxil fumarate tablets may cause serious side effects, including: See “What is the most important information I should know about tenofovir disoproxil fumarate tablets?” New or worse kidney problems, including kidney failure Changes in your immune system (Immune Reconstitution Syndrome) Bone problems Too much lactic acid in your blood (lactic acidosis). Severe liver problems nausea pain rash depression diarrhea weakness headache In some people with advanced HBV-infection, other common side effects may include: fever stomach-area pain itching dizziness vomiting sleeping problems These are not all the possible side effects of tenofovir disoproxil fumarate tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store tenofovir disoproxil fumarate tablets? Do not Keep tenofovir disoproxil fumarate tablets and all medicines out of the reach of children General information about the safe and effective use of tenofovir disoproxil fumarate tablets. What are the ingredients in tenofovir disoproxil fumarate tablets? Active Ingredient Inactive Ingredients: Tablet Coating: All other trademarks referenced herein are the property of their respective owners. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for : Manufactured by: Revised: November 2022

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