tenofovir disoproxil fumarate 0.04 MG/MG Oral Powder

INDICATIONS & USAGE Tenofovir disoproxil fumarate tablets are a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor. • 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 ® , BIKTARVY ® , 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 chronic hepatitis B 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)].

DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating VIREAD test for hepatitis B virus infection and HIV-1 infection. Prior to initiation and during use of VIREAD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorous. ( 2.1 ) Recommended tablet dosage in adults and pediatric patients weighing at least 35 kg: One VIREAD 300 mg tablet once daily taken orally without regard to food. ( 2.2 ) Recommended dosage in pediatric patients at least 2 years of age and adults: Tablets: For patients weighing at least 17 kg who can swallow an intact tablet, one VIREAD tablet (150 mg, 200 mg, 250 mg, or 300 mg based on body weight) once daily taken orally without regard to food. ( 2.2 ) Oral powder: For patients weighing at least 10 kg and unable to swallow a tablet, 8 mg per kg VIREAD oral powder (up to a maximum of 300 mg) taken once daily with food. ( 2.3 ) Recommended dosage in renally impaired adult patients: Creatinine clearance (CrCl) 30–49 mL/min: 300 mg every 48 hours. ( 2.4 ) CrCl 10–29 mL/min: 300 mg every 72 to 96 hours. ( 2.4 ) Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis. ( 2.4 ) 2.1 Testing Prior to Initiation of VIREAD for Treatment of HIV-1 Infection or Chronic Hepatitis B Prior to or when initiating VIREAD, test patients for HBV infection and HIV-1 infection. VIREAD alone should not be used in patients with HIV-1 infection [see Warnings and Precautions (5.3) ] . Prior to initiation and during use of VIREAD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [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 VIREAD in adults and pediatric patients weighing at least 35 kg is one 300 mg tablet taken orally once daily without regard to food . The dosage for VIREAD is the same for both HIV and HBV indications. The recommended dosage of VIREAD tablet in adults and pediatric patients 2 years and older weighing at least 17 kg is 8 mg of tenofovir disoproxil fumarate (TDF) per kg of body weight (up to a maximum of 300 mg) once daily. 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 VIREAD dose adjusted accordingly. Table 1 Recommended Dosing for Patients 2 Years and Older and Weighing at Least 17 kg Using VIREAD Tablets Body Weight (kg) Dosing of VIREAD 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 2.3 Recommended Oral Powder Dosage in Adults and Pediatric Patients 2 Years and Older Weighing at Least 10 kg The recommended dosage of VIREAD oral powder in adults and pediatric patients 2 years and older weighing at least 10 kg who are unable to swallow a tablet is 8 mg of TDF per kg of body weight (up to a maximum of 300 mg) once daily administered as oral powder (see Table 2 ). Weight should be monitored periodically and the VIREAD dose adjusted accordingly. VIREAD oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder, which contains 40 mg of TDF. VIREAD oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer VIREAD oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer VIREAD oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information). Table 2 Dosing for Patients 2 Years and Older Weighing at least 10 kg Using VIREAD Oral Powder Body Weight (kg) Dosing of VIREAD Oral Powder Total Daily Dosage (40 mg per scoop) 10 to less than 12 2 scoops once daily 80 mg 12 to less than 14 2.5 scoops once daily 100 mg 14 to less than 17 3 scoops once daily 120 mg 17 to less than 19 3.5 scoops once daily 140 mg 19 to less than 22 4 scoops once daily 160 mg 22 to less than 24 4.5 scoops once daily 180 mg 24 to less than 27 5 scoops once daily 200 mg 27 to less than 29 5.5 scoops once daily 220 mg 29 to less than 32 6 scoops once daily 240 mg 32 to less than 34 6.5 scoops once daily 260 mg 34 to less than 35 7 scoops once daily 280 mg at least 35 7.5 scoops once daily 300 mg 2.4 Dosage Adjustment in Patients with Renal Impairment Significant increase in drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment (creatinine clearance below 50 mL/min). Table 3 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment of VIREAD tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min) [see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . Table 3 Dosage Interval Adjustment for Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight. Hemodialysis Patients 50 or greater 30–49 10–29 Recommended 300 mg Dosing Interval Every 24 hours Every 48 hours Every 72 to 96 hours Every 7 days or after a total of approximately 12 hours of dialysis Generally once weekly assuming 3 hemodialysis sessions a week of approximately 4 hours' duration. VIREAD should be administered following completion of dialysis. 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.

WARNINGS AND PRECAUTIONS • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with tenofovir disoproxil fumarate tablets. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein before initiating treatment with tenofovir disoproxil fumarate tablets and periodically during treatment. Avoid administering tenofovir disoproxil fumarate tablets with concurrentor recent use of nephrotoxic drugs. (5.2) • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.3) • Coadministration with other products: Do not use with other tenofovir-containing products (e.g., ATRIPLA, BIKTARVY, COMPLERA, DESCOVY, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, or VEMLIDY). Do not administer in combination with HEPSERA. (5.4) • HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with tenofovir disoproxil fumarate tablets. Tenofovir disoproxil fumarate tablets should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection. (5.5) • Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6) • Immune reconstitution syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. (5.7) • Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.8) 5.1 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including tenofovir disoproxil fumarate tablets, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue tenofovir disoproxil fumarate tablets 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. 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 tablets [See Adverse Reactions (6.2)]. It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with tenofovir disoproxil fumarate tablets. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA ®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of tenofovir disoproxil fumarate tablets, and periodically during tenofovir disoproxil fumarate tablets therapy. Dosing interval adjustment of tenofovir disoproxil fumarate tablets and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [See Dosage and Administration (2.3)]. No safety or efficacy data are available in patients with renal impairment who received tenofovir disoproxil fumarate tablets using these dosing guidelines, so the potential benefit of tenofovir disoproxil fumarate tablets therapy should be assessed against the potential risk of renal toxicity. Tenofovir disoproxil fumarate tablets 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 tenofovir DF. 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 at-risk patients. 5.3 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 tenofovir DF, alone or in combination with other antiretrovirals. Treatment with tenofovir disoproxil fumarate tablets 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). 5.4 Coadministration with Other Products Tenofovirdisoproxil fumarate tablets should not be used in combination with other drugs containing tenofovir DF or tenofovir alafenamide, including ATRIPLA, BIKTARVY, COMPLERA, DESCOVY,GENVOYA,ODEFSEY, STRIBILD, TRUVADA, or VEMLIDY. Tenofovir disoproxil fumarate tablets should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.2)]. 5.5 Patients Coinfected with HIV-1 and HBV Due to the risk of development of HIV-1 resistance, tenofovir disoproxil fumarate tablets 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 tablets. 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 tablets. 5.6 Bone Effects Bone Mineral Density: In clinical trials in HIV-1 infected adults, tenofovir disoproxil fumarate tablets were 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. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil fumarate tablets [See Adverse Reactions (6.1)]. Clinical trials evaluating tenofovir disoproxil fumarate tablets in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, 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 hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected [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 are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities

CONTRAINDICATIONS None. None. ( 4 )

CLINICAL PHARMACOLOGY 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. Ab sorption Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate tablets in fasted subjects is approximately 25%. Following oral administration of a single dose of tenofovir disoproxil fumarate tablets 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C max ) are achieved in 1.0 ± 0.4 hrs. C max and AUC values are 0.30 ± 0.09 mcg/mL and 2.29 ± 0.69 mcg • hr/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over a tenofovir disoproxil fumarate dose range of 75 mg 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 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 mcg/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 to 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 tablet, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate tablets 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. E ffects 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 AUC 0-∞ of approximately 40% and an increase in C max 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 C max by approximately 1 hour. C max and AUC of tenofovir are 0.33 ± 0.12 mcg/mL and 3.32 ± 1.37 mcg • hr/mL following multiple doses of tenofovir disoproxil fumarate tablets 300 mg once daily in the fed state, when meal content was not controlled. Specific Po p u lations 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. Ped iatric Patients Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 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. Table 13 Mean (± SD) Tenofovir Pharmacokinetic Parameters 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 (mcg/mL) 0.38 ± 0.13 AUC tau (mcg • hr/mL) 3.39 ± 1.22 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 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, C max , and AUC 0-∞ of tenofovir were increased (Table 14). Table 14 Pharmacokinetic Parameters (Mean ± SD) of Tenofovir a in Subjects with Varying Degrees of Renal Function Baseline Creatinine Clearance (mL/min) > 80 N=3 50-80 N=10 30-49 N=8 12-29 N=11 C max (mcg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19 AUC 0-∞ (mcg • hr/mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22 CL/F (mL/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1 CL renal (mL/min) 243.5 ± 33.3 168.6 ± 27.5 100.6 ± 27.5 43.0 ± 31.2 a. 300 mg, single dose of tenofovir disoproxil fumarate Pa tients with Hepatic Impairment The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir disoproxil fumarate tablet 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. A ssessment 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. Table 15 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir a in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters b (90% CI) C max AUC C min Atazanavir c 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30) Atazanavir/ Ritonavir c 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36) Darunavir/ Ritonavir d 300/100 twice daily 12 ↑ 24 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57) Indinavir 800 three times daily × 7 days