Emtricitabine And Tenofovir Disoproxil Fumarate

FDA Drug Information • Also known as: Emtricitabine And Tenofovir Disoproxil Fumarate, Truvada

Brand Names: Emtricitabine And Tenofovir Disoproxil Fumarate, Truvada
Drug Class: Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B and RISK OF DRUG RESISTANCE WITH USE OF TRUVADA FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED EARLY HIV-1 INFECTION Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected individuals who have discontinued TRUVADA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in individuals who are infected with HBV and discontinue TRUVADA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] . TRUVADA used for HIV-1 PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for HIV-1 PrEP following undetected acute HIV-1 infection. Do not initiate TRUVADA for HIV-1 PrEP if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed [see Warnings and Precautions (5.2) ] . WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B and RISK OF DRUG RESISTANCE WITH USE OF TRUVADA FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED EARLY HIV-1 INFECTION See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected individuals who have discontinued TRUVADA. Hepatic function should be monitored closely in these individuals who discontinue TRUVADA. If appropriate anti-hepatitis B therapy may be warranted. ( 5.1 ) TRUVADA used for HIV-1 PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with the use of TRUVADA for HIV-1 PrEP following undetected acute HIV-1 infection. Do not initiate TRUVADA for HIV-1 PrEP if signs or symptoms of acute HIV infection are present unless negative infection status is confirmed. ( 5.2 )

Description

11 DESCRIPTION TRUVADA tablets are fixed-dose combination tablets containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). FTC is a synthetic nucleoside analog of cytidine. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase. Emtricitabine: The chemical name of FTC is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: FTC is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for emtricitabine is −0.43 and the pKa is 2.65. Chemical Structure Tenofovir Disoproxil Fumarate: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF 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 water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of TDF except where otherwise noted. TRUVADA tablets are for oral administration, and are available in the following strengths: Film-coated tablet containing 200 mg of FTC and 300 mg of TDF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 167 mg of FTC and 250 mg of TDF (which is equivalent...

What Is Emtricitabine And Tenofovir Disoproxil Fumarate Used For?

1 INDICATIONS AND USAGE HIV-1 Treatment ( 1.1 ) TRUVADA is a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated: in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg. HIV-1 PrEP ( 1.2 ): TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP. 1.1 Treatment of HIV-1 Infection TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Clinical Studies (14) ] . 1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP) TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating TRUVADA test for hepatitis B virus infection. Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs). ( 2.2 ) Treatment of HIV-1 Infection Recommended dosage in adults and pediatric patients weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.3 ) Recommended dosage in pediatric patients weighing at least 17 kg: One TRUVADA low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. ( 2.4 ) Recommended dosage in renally impaired HIV-1 infected adult patients: Creatinine clearance (CrCl) 30−49 mL/min: 1 tablet every 48 hours. ( 2.6 ) CrCl below 30 mL/min or hemodialysis: TRUVADA is not recommended. ( 2.6 ) HIV-1 Pre-Exposure Prophylaxis (PrEP) Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.5 ) Recommended dosage in renally impaired HIV-uninfected individuals: TRUVADA is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. ( 2.6 ) 2.1 Testing Prior to Initiation of TRUVADA for Treatment of HIV-1 Infection or for HIV-1 PrEP Prior to or when initiating TRUVADA, test individuals for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . Prior to initiation, and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.3) ]. 2.2 HIV-1 Screening for Individuals Receiving TRUVADA for HIV-1 PrEP Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs) [see Indications and Usage (1.2) , Contraindications (4) , and Warnings and Precautions (5.2) ]. If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) , and Clinical Studies (14.3 and 14.4) ]. 2.3 Recommended Dosage for...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] . 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-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) In HIV-1 uninfected adults in PrEP trials, adverse reactions that were reported by more than 2% of TRUVADA participants and more frequently than by placebo participants were headache, abdominal pain, and weight decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-445-3235 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 Subjects Clinical Trials in Adult Subjects In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 3 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Table 3 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 Study 934 (0–144 Weeks) FTC+TDF+EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of FTC+TDF with efavirenz. 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 Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7% 9% Headache 6% 5% Insomnia 5% 7% Nasopharyngitis 5% 3% Vomiting 2% 5% Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of TDF and/or FTC (Table 4). Table 4 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of FTC+TDF with efavirenz. 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% Clinical Trials in Pediatric Subjects Emtricitabine: In addition to the adverse reactions reported in adults,...

Drug Interactions

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 TRUVADA, use atazanavir given with ritonavir. ( 7.2 ) Coadministration of TRUVADA 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 FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion [see Clinical Pharmacology (12.3) ] . No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3) ] . Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir. 7.2 Established and Significant Interactions Table 7 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either TRUVADA, the components of TRUVADA (FTC and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with TRUVADA [see Clinical Pharmacology (12.3) ]. Table 7 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 Indicates that a drug-drug interaction trial was conducted. ↑ didanosine Patients receiving TRUVADA 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 TDF with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with TRUVADA. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, TRUVADA 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 ↓...

Contraindications

4 CONTRAINDICATIONS TRUVADA for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.2) ] . TRUVADA for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRUVADA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Data on the use of TRUVADA during pregnancy from observational studies have shown no increased risk of major birth defects. Available data from the APR show no significant difference in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC) (2.3%) or 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%. In animal reproduction studies, no adverse developmental effects were observed when the components of TRUVADA were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of TRUVADA ( see Data ). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk HIV-1 PrEP: Published studies indicate an increased risk of HIV-1 infection during pregnancy and an increased risk of mother to child transmission during acute HIV-1 infection. In women at risk of acquiring HIV-1, consideration should be given to methods to prevent acquisition of HIV, including continuing or initiating TRUVADA for HIV-1 PrEP, during pregnancy. Data Human Data TRUVADA for HIV-1 PrEP: In an observational study based on prospective reports to the APR, 78 HIV-seronegative women exposed to TRUVADA during pregnancy delivered live-born infants with no major malformations. All but one were first trimester exposures, and the median...

Overdosage

10 OVERDOSAGE If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Emtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether FTC can be removed by peritoneal dialysis. Tenofovir Disoproxil Fumarate: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING TRUVADA tablets are available in bottles containing 30 tablets with child-resistant closure as follows: 100 mg of FTC and 150 mg of TDF (equivalent to 123 mg of tenofovir disoproxil) tablets are blue, oval shaped, film coated, debossed with "GSI" on one side and with "703" on the other side (NDC 61958-0703-1). 133 mg of FTC and 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil) tablets are blue, rectangular shaped, film coated, debossed with "GSI" on one side and with "704" on the other side (NDC 61958-0704-1). 167 mg of FTC and 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil) tablets are blue, modified capsule shaped, film coated, debossed with "GSI" on one side and with "705" on the other side (NDC 61958-0705-1). 200 mg of FTC and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) tablets are blue, capsule shaped, film coated, debossed with "GILEAD" on one side and with "701" on the other side (NDC 61958-0701-1). Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) (see USP Controlled Room Temperature). Keep container tightly closed. Dispense only in original container.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.