TENOFOVIR DISOPROXIL FUMARATE

1 INDICATIONS AND USAGE Tenofovir disoproxil fumarate is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor and is 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 weighing at least 35 kg. ( 1.1 ) for the treatment of chronic hepatitis B in adults and pediatric patients 2 years and older weighing at least 35 kg. ( 1.2 ) 1.1 HIV-1 Infection Tenofovir disoproxil fumarate is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 2 years of age and older weighing at least 35 kg. 1.2 Chronic Hepatitis B Tenofovir disoproxil fumarate is indicated for the treatment of chronic hepatitis B virus (HBV) in adults and pediatric patients 2 years of age and older weighing at least 35 kg.

2 DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating tenofovir disoproxil fumarate test for hepatitis B virus infection and HIV-1 infection. Prior to initiation and during use of tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorous. ( 2.1 ) Recommended tablet dosage in adults and pediatric patients weighing at least 35 kg: One tenofovir disoproxil fumarate 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: For patients weighing at least 35 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 ) 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 Tenofovir Disoproxil Fumarate for Treatment of HIV-1 Infection or Chronic Hepatitis B Prior to or when initiating tenofovir disoproxil fumarate, test patients for HBV infection and HIV-1 infection. Tenofovir disoproxil fumarate alone should not be used in patients with HIV-1 infection [see Warnings and Precautions (5.3) ] . Prior to initiation and during use of tenofovir disoproxil fumarate, 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 35 kg The recommended dosage of tenofovir disoproxil fumarate in adults and pediatric patients weighing at least 35 kg is one 300 mg tablet taken orally once daily without regard to food. The dosage for tenofovir disoproxil fumarate is the same for both HIV and HBV indications. The recommended dosage of tenofovir disoproxil fumarate tablet in adults and pediatric patients 2 years and older weighing at least 35 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 at least 35 kg and able to swallow an intact tablet is provided in Table 1. Weight should be monitored periodically and the tenofovir disoproxil fumarate dose adjusted accordingly. Table 1 Recommended Dosing for Patients 2 Years and Older and Weighing at Least 35 kg Using Tenofovir Disoproxil Fumarate Tablets Body Weight (kg) Dosing of Tenofovir Disoproxil Fumarate Tablets at least 35 one 300 mg tablet once daily 2.4 Dosage Adjustment in Patients with Renal Impairment Significant increase in drug exposures occurred when tenofovir disoproxil fumarate was administered to subjects with moderate to severe renal impairment (creatinine clearance below 50 mL/min). Table 3 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment of tenofovir disoproxil fumarate tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min) [see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ] . Table 3 Dosage Interval Adjustment for Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight. 50 or greater 30-49 10-29 Hemodialysis Patients 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 approximat …

3 DOSAGE FORMS AND STRENGTHS Tenofovir disoproxil fumarate is available as tablets. • 300 mg Tablets: 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): almond-shaped, blue, film coated, debossed with “32” on one side. Tablets: 300 mg of tenofovir disoproxil fumarate. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1) ]. New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.4) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.6) ] . In HIV-infected adult subjects: Most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) were rash, diarrhea, nausea, headache, pain, depression, and asthenia. ( 6.1 ) In HBV-infected subjects with compensated liver disease: Most common adverse reaction (all grades) was nausea (9%). ( 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 ) In pediatric subjects: Adverse reactions in pediatric subjects were consistent with those observed in adults. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Quinn Pharmaceuticals at 954-755-0502 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Adults More than 12,000 subjects have been treated with tenofovir disoproxil fumarate alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs. A total of 1,544 subjects have received tenofovir disoproxil fumarate 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate in expanded access programs. The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naïve subjects received tenofovir disoproxil fumarate (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (EFV) for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 4 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 4 Selected Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Trial 903 (0–144 Weeks) Tenofovir Disoproxil Fumarate+3TC+EFV d4T+3TC+EFV N=299 N=301 Rash event Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 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 Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. 1% 8% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 1% 5% Laboratory Abnormalities: Table 5 provides a list of laboratory …

7 DRUG INTERACTIONS Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. ( 7.2 ) Coadministration decreases atazanavir concentrations. When coadministered with tenofovir disoproxil fumarate, use atazanavir given with ritonavir. ( 7.2 ) Coadministration of tenofovir disoproxil fumarate with certain HIV-1 protease inhibitors or certain drugs to treat HCV increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. ( 7.2 ) Consult Full Prescribing Information prior to and during treatment for important drug interactions. ( 7.2 ) 7.1 Drugs Affecting Renal Function Tenofovir is primarily eliminated by the kidneys [ see Clinical Pharmacology (12.3) ]. Coadministration of tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [ see Warnings and Precautions (5.2) ]. Drugs that decrease renal function may increase concentrations of tenofovir. In the treatment of chronic hepatitis B, tenofovir disoproxil fumarate should not be administered in combination with HEPSERA (adefovir dipivoxil). 7.2 Established and Significant Interactions Table 12 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with TDF [see Clinical Pharmacology (12.3)]. Table 12 Established and Significant This table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials Concomitant Drug Class: Drug Name Effect on Concentration =Increase, ↓=Decrease Clinical Comment NRTI: didanosine ↑ 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. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with tenofovir disoproxil fumarate. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with tenofovir disoproxil fumarate. When coadministered, tenofovir disoproxil fumarate and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). HIV-1 Protease Inhibitors: atazanavir lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir ↓ atazanavir ↑ tenofovir When coadministered with tenofovir disoproxil fumarate, atazanavir 300 mg should be given with ritonavir 100 mg. Monitor patients receiving tenofovir disoproxil fumarate concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir­ boosted darunavir for TDF-associated adverse reactions. Discontinue tenofovir disoproxil fumarate in patients who develop TDF-associated adverse reactions. Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ledipasvir/sofosbuvir ↑ tenofovir Monitor patients receiving tenofovir disoproxil fumarate concomitantly with EPCLUSA ® (sofosbuvir/velpatasvir) for adverse reactions associated with TDF. Monitor patients receiving tenofovir disoproxil fumarate concomitantly with HARVONI ® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, for adverse reactions associated with TDF. In patients receiving tenofovir disoproxil fumarate concomitantly with HARVONI and an H …

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding in HIV-1 infected mothers is not recommended due to the potential for HIV-1 transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to tenofovir disoproxil fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%. Published studies in HBV-infected subjects do not report an increased risk of adverse pregnancy-related outcomes with the use of tenofovir disoproxil fumarate during the third trimester of pregnancy (see Data). In animal reproduction studies, no adverse developmental effects were observed when TDF was administered at doses/exposures ≥14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of tenofovir disoproxil fumarate (see Data). Data Human Data Based on prospective reports from the APR exposures to TDF-containing regimens during pregnancy resulting in live births (including 3,342 exposed in the first trimester and 1,475 exposed in the second/third trimester), there was no increase in overall major birth defects with TDF compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.8%) with first trimester exposure to TDF-containing regimens, and 2.1% (95% CI: 1.4% to 3.0%) with the second/third trimester exposure to TDF-containing regimens. Prospective reports from the APR of overall major birth defects in pregnancies exposed to TDF are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. In published data from three controlled clinical trials, a total of 327 pregnant women with chronic HBV infection were administered tenofovir disoproxil fumarate from 28 to 32 weeks gestation through 1 to 2 months postpartum and followed for up to 12 months after delivery. There were no new safety findings in pregnant women compared with the known safety profile of tenofovir disoproxil fumarate in HBV-infected adults. An increased risk of adverse pregnancy-related outcomes was not observed; 2 stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in tenofovir disoproxil fumarate -exposed infants. Infants were followed for up to 12 months after delivery; there were no clinically relevant drug-related safety findings in infants exposed to tenofovir disoproxil fumarate during late gestation. Animal Data TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lact …

12.1 Mechanism of Action Tenofovir disoproxil fumarate is an antiviral drug [See Microbiology (12.4) ].

11 DESCRIPTION Tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase. The chemical name of TDF is 9-[( R )-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P • C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C. Tenofovir disoproxil fumarate is available as tablets. Tenofovir disoproxil fumarate tablets are for oral administration and are available in the strength of 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil). Tenofovir disoproxil fumarate tablets contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg strength tablets are coated with Opadry II 32K605004, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. In this insert, all dosages are expressed in terms of TDF except where otherwise noted. structure

10 OVERDOSAGE If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

16 HOW SUPPLIED/STORAGE AND HANDLING Tenofovir disoproxil fumarate tablets, 300 mg, are almond-shaped, blue, film-coated tablets containing 300 mg of tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil, and are debossed with “32” on one side. Each bottle contains 30 tablets and a desiccant (silica gel canister or sachet), and is closed with a child-resistant closure. NDC 71335-3155-1: 30 TABLETs in a BOTTLE NDC 71335-3155-2: 15 TABLETs in a BOTTLE Store tenofovir disoproxil fumarate tablets at 25°C (77°F), excursions permitted to 15-30°C(59-86°F) (see USP Controlled Room Temperature). Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504