Tenofovir Disoproxil Fumarate

Indications and Usage, Chronic Hepatitis B ( 1.2 ) 12/2018 Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) 12/2018 Warnings and Precautions ( 5.1 , 5.2 , 5.5 , 5.7 ) 12/2018 Early Virologic Failure Removed 12/2018

1 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)].

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): o 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: o Creatinine clearance 30 to 49 mL/min: 300 mg every 48 hours. (2.3) o Creatinine clearance 10 to 29 mL/min: 300 mg every 72 to 96 hours. (2.3) o 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. 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 tablet 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 contain dosing recommendations for tenofovir disoproxil fumarate tablets based on body weight. Weight should be monitored periodically and the tenofovir disoproxil fumarate tablets dose adjusted accordingly. Table 2 Dosing Recommendations for Pediatric Patients 2 Years of Age and Older and Weighing At Least 17 kg Using Tenofovir Disoproxil Fumarate Tablets Body Weight Kilogram (kg) Tablets Once Daily 17 to less than 22 150 mg 22 to less than 28 200 mg 28 to less than 35 250 mg 35 or greater 300 mg Chronic Hepatitis B Safety and efficacy of tenofovir disoproxil fumarate tablets 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 tablets were 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 to 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 Adj …

3 DOSAGE FORMS AND STRENGTHS Tenofovir disoproxil fumarate is available as tablets in four dose strengths. 150 mg Tablets: 150 mg of tenofovir disoproxil fumarate (TDF) (equivalent to 123 mg of tenofovir disoproxil): white to off-white, capsule shaped, biconvex, film-coated tablets debossed with ‘35’ on one side and ‘J’ on the other side. 200 mg Tablets: 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil): white to off-white, round shaped, biconvex, film-coated tablets debossed with ‘K’ on one side and ‘25’ on the other side. 250 mg Tablets: 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil): white to off-white, capsule shaped, biconvex, film-coated tablets debossed with ‘69 Y’ on one side and plain on the other side. 300 mg Tablets: 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): white to off-white, oval shaped, biconvex, film-coated tablets debossed with ‘I’ on one side and ‘36’ on the other side. Tablets: 150 mg, 200 mg, 250 mg, and 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 [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 to 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 AvKARE at 1-855-361-3993 or FDA at 1-800-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 tablets 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 tablets 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate tablets in expanded access programs. The most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 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 tablets (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 to 4) Reported in ≥5% in Any Treatment Group in Study 903 (0 to 144 Weeks) Tenofovir disoproxil fumarate Tablets +3TC+EFV d4T+3TC+EFV N=299 N=301 Body as a Whole 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 Lipodystrophy b 1% 8% Musculoskeletal Arthralgia Myalgia 5% 3% 7% 5% Nervous System Depression Insomnia Dizziness Peripheral neuropathy c Anxiety 11% 5% 3% 1% 6% 10% 8% 6% 5% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event d 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, maculopap …

7 DRUG INTERACTIONS This section describes clinically relevant drug interactions with tenofovir disoproxil fumarate tablets. Drug interactions trials are described elsewhere in the labeling [See Clinical Pharmacology ( 12.3 )]. • 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 tablets 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 tablets should not be administered in combination with HEPSERA (adefovir dipivoxil). 7.2 Established and Significant Interactions Table 11 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with tenofovir DF [see Clinical Pharmacology (12.3)]. Table 11 Established and Significanta Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials Concomitant Drug Class: Drug Name Effect on Concentration b Clinical Comment NRTI: didanosine ↑ didanosine Patients receiving tenofovir disoproxil fumarate tablets 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 tablets 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 tablets. In patients weighing less than 60 kg, reduce the didanosine dose to 200 mg when it is coadministered with tenofovir disoproxil fumarate tablets. When coadministered, tenofovir disoproxil fumarate tablets 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 tablets, atazanavir 300 mg should be given with ritonavir 100 mg. Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for tenofovir DF-associated adverse reactions. Discontinue tenofovir disoproxil fumarate tablets in patients who develop tenofovir DF-associated adverse reactions. Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ledipasvir/sofosbuvir ↑ tenofovir Monitor patients receiving tenofovir disoproxil fumarate tablets concomitantly with EPCLUSA ® (sofosbuvir/velpatasvir) or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) for adverse reactions associated with tenofovir DF. Monitor patie …

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 l …

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) which 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 following strengths: 150 mg, 200 mg, 250 mg, and 300 mg of TDF (equivalent to 123 mg, 163 mg, 204 mg, and 245 mg of tenofovir disoproxil, respectively). All strengths of tenofovir disoproxil fumarate tablets contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (maize) (gluten free). The 300 mg strength tablets are coated with Opadry II White 32K18425, which contains hypromellose 15cP, lactose monohydrate, titanium dioxide, and triacetin. The 150 mg, 200 mg, and 250 mg strength tablets are coated with Aquarius BT18242 Cool Vanilla, which contains hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin. In this insert, all dosages are expressed in terms of TDF except where otherwise noted. Tenofovir Structure

10 OVERDOSAGE Limited clinical experience at doses higher than the therapeutic dose of tenofovir disoproxil fumarate tablets 300 mg are available. In Study 901, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known. 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 tablets, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

16 HOW SUPPLIED/STORAGE AND HANDLING Tenofovir Disoproxil Fumarate Tablets, 150 mg are white to off-white, capsule shaped, biconvex, film-coated tablets debossed with ‘35’ on one side and ‘J’ on the other side. Bottles of 30 NDC 65862-818-30 3 x 10 Unit-dose Tablets NDC 65862-818-03 Tenofovir Disoproxil Fumarate Tablets, 200 mg are white to off-white, round shaped, biconvex, film-coated tablets debossed with ‘K’ on one side and ‘25’ on the other side. Bottles of 30 NDC 65862-819-30 3 x 10 Unit-dose Tablets NDC 65862-819-03 Tenofovir Disoproxil Fumarate Tablets, 250 mg are white to off-white, capsule shaped, biconvex, film-coated tablets debossed with ‘69 Y’ on one side and plain on the other side. Bottles of 30 NDC 65862-820-30 3 x 10 Unit-dose Tablets NDC 65862-820-03 Tenofovir Disoproxil Fumarate Tablets, 300 mg are white to off-white, oval shaped, biconvex, film-coated tablets debossed with ‘I’ on one side and ‘36’ on the other side. Bottles of 30 NDC 65862-421-30 Store at 20o to 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59° to 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.