Emtricitabine and tenofovir alafenamide fumarate

Emtricitabine and tenofovir alafenamide fumarate
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2]

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Black Box Warning

TITLE POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete Boxed Warning. Condition Name: Emtricitabine and tenofovir alafenamide fumarate is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of emtricitabine and tenofovir alafenamide fumarate have not been established in patients coinfected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of emtricitabine and tenofovir alafenamide fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue emtricitabine and tenofovir alafenamide fumarate. If appropriate, initiation of anti-hepatitis B therapy may be warranted

Overview

Emtricitabine and tenofovir alafenamide fumarate is a nucleoside analog reverse transcriptase inhibitors that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Emtricitabine and tenofovir alafenamide fumarate is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients.
• Emtricitabine and tenofovir alafenamide fumarate is not indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.
• Dosing information
  • Emtricitabine and tenofovir alafenamide fumarate is a two-drug fixed dose combination product containing 200 mg of emtricitabine (FTC) and 25 mg of tenofovir alafenamide (TAF).
  • The recommended dosage of emtricitabine and tenofovir alafenamide fumarate is one tablet taken orally once daily with or without food in adults with body weight at least 35 kg and creatinine clearance greater than or equal to 30 mL per minute.
  • For specific dosing recommendations for coadministered third agents, refer to their respective prescribing information.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Emtricitabine and tenofovir alafenamide fumarate in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Emtricitabine and tenofovir alafenamide fumarate in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• Emtricitabine and tenofovir alafenamide fumarate is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in pediatric patients 12 years of age and older.
• Emtricitabine and tenofovir alafenamide fumarate is not indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk.
• Dosing information
  • Emtricitabine and tenofovir alafenamide fumarate is a two-drug fixed dose combination product containing 200 mg of emtricitabine (FTC) and 25 mg of tenofovir alafenamide (TAF).
  • The recommended dosage of emtricitabine and tenofovir alafenamide fumarate is one tablet taken orally once daily with or without food in pediatric patients 12 years of age and older with body weight at least 35 kg and creatinine clearance greater than or equal to 30 mL per minute.
  • For specific dosing recommendations for coadministered third agents, refer to their respective prescribing information

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Emtricitabine and tenofovir alafenamide fumarate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Emtricitabine and tenofovir alafenamide fumarate in pediatric patients.

Contraindications

There is limited information regarding Emtricitabine and tenofovir alafenamide fumarate Contraindications in the drug label.

Warnings

TITLE POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete Boxed Warning. Condition Name: Emtricitabine and tenofovir alafenamide fumarate is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of emtricitabine and tenofovir alafenamide fumarate have not been established in patients coinfected with human immunodeficiency virus-1 (HIV-1) and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of emtricitabine and tenofovir alafenamide fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue emtricitabine and tenofovir alafenamide fumarate. If appropriate, initiation of anti-hepatitis B therapy may be warranted

• Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
  • Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. Emtricitabine and tenofovir alafenamide fumarate is not approved for the treatment of chronic HBV infection, and the safety and efficacy of emtricitabine and tenofovir alafenamide fumarate have not been established in patients coinfected with HIV-1 and HBV.
  • Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of emtricitabine and tenofovir alafenamide fumarate. Patients coinfected with HIV-1 and HBV who discontinue emtricitabine and tenofovir alafenamide fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
• Immune Reconstitution Syndrome
  • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC, a component of emtricitabine and tenofovir alafenamide fumarate. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
• Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
• New Onset or Worsening Renal Impairment
  • 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 prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF with cobicistat (COBI) plus elvitegravir (EVG), there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment-naïve subjects and in virally suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute. Emtricitabine and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
  • Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.
  • Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating emtricitabine and tenofovir alafenamide fumarate therapy and should be monitored during therapy in all patients. Serum phosphorus should be monitored in patients with chronic kidney disease because these patients are at greater risk of developing Fanconi syndrome on tenofovir prodrugs. Discontinue emtricitabine and tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
• 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 emtricitabine, a component of emtricitabine and tenofovir alafenamide fumarate, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with emtricitabine and tenofovir alafenamide fumarate 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).
• Bone Loss and Mineralization Defects
  • Decrease in Bone Mineral Density (BMD)
    • In animal toxicology studies and human clinical trials, TAF and tenofovir have been associated with decreases in BMD and increases in biochemical markers of bone metabolism suggestive of increased bone turnover. In clinical trials in HIV-1 infected treatment-naïve adults, a significant decline in BMD was observed in 15% of subjects treated with FTC+TAF with EVG+COBI. The long-term clinical significance of these changes has not been established.

Assessment of BMD should be considered for adults and pediatric patients treated with emtricitabine and tenofovir alafenamide fumarate who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Calcium and vitamin D 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 ubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF-containing products. Hypophosphatemia and osteomalacia secondary to PRT have occurred in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF. While not observed in clinical studies of emtricitabine and tenofovir alafenamide fumarate, the risk of osteomalacia with emtricitabine and tenofovir alafenamide fumarate is not known.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.

Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adults with HIV-1 Infection In pooled 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse events during the 48-week treatment period. The safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to FTC+TAF with EVG+COBI (N=799). Antiretroviral treatment-naïve adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.

• Renal Laboratory Tests
  • In two 48-week trials in antiretroviral treatment-naïve HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial in virologically-suppressed TDF-treated adults who switched to FTC+TAF with EVG+COBI (N=959) with a mean baseline eGFR of 112 mL per minute, mean serum creatinine was similar to baseline and median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24.

• Bone Mineral Density Effects
  • In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 −1.30% with FTC+TAF with EVG+COBI at the lumbar spine and −0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI subjects. The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 7 (0.8%) subjects in the FTC+TAF with EVG+COBI group.
  • In 799 virologically-suppressed TDF-treated adult subjects that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1.86% lumbar spine, 1.95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI subjects.

Adverse Reactions in Clinical Trials in Pediatric Subjects with HIV-1 Infection In a 24 week, open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects aged 12 to less than 18 years old (weighing at least 35 kg) who received FTC+TAF with EVG+COBI, the safety of this combination was similar to that of adults. Among these pediatric subjects, mean BMD increased from baseline to Week 24, +1.7% at the lumbar spine and +0.8% for the total body less head. Mean changes from baseline BMD Z-scores were −0.10 for lumbar spine and −0.11 for total body less head at Week 24. Two subjects had significant (greater than 4%) lumbar spine BMD loss at Week 24.

Postmarketing Experience

There is limited information regarding Emtricitabine and tenofovir alafenamide fumarate Postmarketing Experience in the drug label.

Drug Interactions

• Potential for Other Drugs to Affect One or More Components of Emtricitabine and Tenofovir Alafenamide Fumarate
  • TAF, a component of emtricitabine and tenofovir alafenamide fumarate, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption (see TABLE 1). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of emtricitabine and tenofovir alafenamide fumarate and development of resistance. Coadministration of emtricitabine and tenofovir alafenamide fumarate with other drugs that inhibit P-gp may increase the absorption and plasma concentration of TAF. TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.
• Drugs Affecting Renal Function
  • Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine and tenofovir alafenamide fumarate with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
• Established and Other Potentially Significant Interactions
  • Table 1 provides a listing of established or potentially clinically significant drug interactions with recommended steps to prevent or manage the drug interaction (the table is not all inclusive). The drug interactions described are based on studies conducted with either emtricitabine and tenofovir alafenamide fumarate, the components of emtricitabine and tenofovir alafenamide fumarate (emtricitabine and tenofovir alafenamide) as individual agents, or are predicted drug interactions that may occur with emtricitabine and tenofovir alafenamide fumarate.

This image is provided by the National Library of Medicine.

• Drugs without Clinically Significant Interactions with Emtricitabine and Tenofovir Alafenamide Fumarate
  • Based on drug interaction studies conducted with the components of emtricitabine and tenofovir alafenamide fumarate, no clinically significant drug interactions have been either observed or are expected when emtricitabine and tenofovir alafenamide fumarate is combined with the following antiretroviral agents: atazanavir with ritonavir or cobicistat, darunavir with ritonavir or cobicistat, dolutegravir, efavirenz, ledipasvir, lopinavir/ritonavir, maraviroc, nevirapine, raltegravir, rilpivirine, and sofosbuvir. No clinically significant drug interactions have been either observed or are expected when emtricitabine and tenofovir alafenamide fumarate is combined with the following drugs: buprenorphine, itraconazole, ketoconazole, lorazepam, methadone, midazolam, naloxone, norbuprenorphine, norgestimate/ethinyl estradiol, and sertraline.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Exposure Registry
  • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to emtricitabine and tenofovir alafenamide fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

• Risk Summary
  • There are insufficient human data on the use of emtricitabine and tenofovir alafenamide fumarate during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the risk of overall major birth defects for FTC (2.4%) 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). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15−20%. In animal studies, no adverse developmental effects were observed when the components of emtricitabine and tenofovir alafenamide fumarate were administered separately during the period of organogenesis at exposures 60 and 108 times (mice and rabbits, respectively) the FTC exposure and at exposure equal to or 53 times (rats and rabbits, respectively) the TAF exposure at the recommended daily dose of emtricitabine and tenofovir alafenamide fumarate. Likewise, no adverse developmental effects were seen when FTC was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily dose of emtricitabine and tenofovir alafenamide fumarate. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of emtricitabine and tenofovir alafenamide fumarate.

• Data
  • Human Data
    • Emtricitabine: Based on prospective reports to the APR through July 2015 of 2933 exposures to FTC-containing regimens during pregnancy (including 1984 exposed in the first trimester and 949 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.7% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.1% (95% CI: 1.3% to 3.2%) with the second/third trimester exposure to FTC-containing regimens.
  • Animal Data
    • Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (area under the curve [AUC]) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.
    • Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of emtricitabine and tenofovir alafenamide fumarate. TAF is rapidly converted to tenofovir; the observed tenofovir exposures in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposures in humans at the recommended daily dose of emtricitabine and tenofovir alafenamide fumarate.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emtricitabine and tenofovir alafenamide fumarate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Emtricitabine and tenofovir alafenamide fumarate during labor and delivery.

Nursing Mothers

• Risk Summary
  • The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.
  • FTC has been shown to be present in human breast milk; it is not known if TAF is present in human breast milk. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF. It is not known if TAF can be present in animal milk. While it is not known whether TAF is present in human breast milk, FTC has been shown to be present in human breast milk.
  • It is not known if emtricitabine and tenofovir alafenamide fumarate affects milk production or has effects on the breastfed child. Because of the potential for: 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving emtricitabine and tenofovir alafenamide fumarate.

• Data
  • Human Data
    • Emtricitabine: Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is present in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
  • Animal Data
    • Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use

The efficacy and safety of emtricitabine and tenofovir alafenamide fumarate, in combination with other antiretroviral agents, for the treatment of HIV-1 infection was established in pediatric patents aged 12 years old and older with body weight greater than or equal to 35 kg. Use of emtricitabine and tenofovir alafenamide fumarate in this age group is supported by adequate and well controlled studies of FTC+TAF with EVG+COBI in adults and by a 24-week open-label trial of 23 antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old (weighing at least 35 kg) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI was similar to that of antiretroviral treatment-naïve HIV-1 infected adults on this regimen. Safety and effectiveness of emtricitabine and tenofovir alafenamide fumarate in pediatric patients less than 12 years of age or less than 35 kg have not been established.

Geriatic Use

In clinical trials, 80 of the 97 subjects enrolled aged 65 years and over received FTC+TAF and EVG+COBI. No differences in safety or efficacy have been observed between elderly subjects and those between 12 and less than 65 years of age.

Gender

There is no FDA guidance on the use of Emtricitabine and tenofovir alafenamide fumarate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Emtricitabine and tenofovir alafenamide fumarate with respect to specific racial populations.

Renal Impairment

Emtricitabine and tenofovir alafenamide fumarate is not recommended in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute). No dosage adjustment of emtricitabine and tenofovir alafenamide fumarate is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute.

Hepatic Impairment

No dosage adjustment of emtricitabine and tenofovir alafenamide fumarate is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Emtricitabine and tenofovir alafenamide fumarate has not been studied in patients with severe hepatic impairment (Child-Pugh Class C)

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Emtricitabine and tenofovir alafenamide fumarate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Emtricitabine and tenofovir alafenamide fumarate in patients who are immunocompromised.

Administration and Monitoring

Administration

Testing Prior to Initiation of Emtricitabine and Tenofovir Alafenamide Fumarate

• Prior to initiation of emtricitabine and tenofovir alafenamide fumarate, patients should be tested for hepatitis B virus infection.
• Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating emtricitabine and tenofovir alafenamide fumarate therapy and should be monitored during therapy in all patients
• Not Recommended in Patients with Severe Renal Impairment
  • Emtricitabine and tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute

Monitoring

Estimated creatinine clearance, urine glucose, and urine protein should be monitored during therapy in all patients.

IV Compatibility

There is limited information regarding the compatibility of Emtricitabine and tenofovir alafenamide fumarate and IV administrations.

Overdosage

No data are available on overdose of emtricitabine and tenofovir alafenamide fumarate in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with emtricitabine and tenofovir alafenamide fumarate consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

• Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dose of FTC in emtricitabine and tenofovir alafenamide fumarate. In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the FTC dose in emtricitabine and tenofovir alafenamide fumarate) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.
• 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 per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.
• Tenofovir alafenamide (TAF): Limited clinical experience is available at doses higher than the recommended dose of TAF. A single dose of 125 mg TAF (5 times the TAF dose in 200/25 mg emtricitabine and tenofovir alafenamide fumarate) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

Pharmacology

There is limited information regarding Emtricitabine and tenofovir alafenamide fumarate Pharmacology in the drug label.

Mechanism of Action

Emtricitabine and tenofovir alafenamide fumarate is a fixed dose combination of antiretroviral drugs emtricitabine (FTC) and tenofovir alafenamide (TAF)

• Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.
• Tenofovir Alafenamide: TAF is a phosphonoamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.
• Tenofovir has activity against HIV-1. Cell culture studies have shown that both tenofovir and FTC can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

Structure

• Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. 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. FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24 and has the following structural formula:

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FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

• Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1). Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.50 and has the following structural formula:

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Pharmacodynamics

Cardiac Electrophysiology

• In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose or at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of the other component of emtricitabine and tenofovir alafenamide fumarate, FTC, or the combination of FTC and TAF on the QT interval is not known.

Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

• The pharmacokinetic (PK) properties of the components of emtricitabine and tenofovir alafenamide fumarate are provided in Table 2. The multiple dose PK parameters of FTC and TAF and its metabolite tenofovir are provided in Table 3.

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Specific Populations

• Patients with Renal Impairment
  • The pharmacokinetics of FTC+TAF combined with EVG+COBI in HIV infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method) were evaluated in a subset of virologically-suppressed subjects in an open-label trial (Table 4).

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• Patients with Hepatic Impairment
  • Emtricitabine: The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
  • Tenofovir Alafenamide: Clinically relevant changes in tenofovir pharmacokinetics in subjects with hepatic impairment were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment.
• Hepatitis B and/or Hepatitis C Virus Coinfection
  • The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
• Pediatric Patients
  • Exposures of FTC and TAF in 24 pediatric subjects aged 12 to less than 18 years who received FTC+TAF and EVG+COBI were decreased (23% for AUC) compared to exposures achieved in treatment-naïve adults following administration of this dosage regimen. These exposure differences are not thought to be clinically significant based on exposure-response relationships.
• Geriatric Patients
  • Pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF and EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.
• Race
  • Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on race.
• Gender
  • Based on population pharmacokinetic analyses, no dosage adjustment is recommended based on gender.

Drug Interaction Studies

The effects of coadministered drugs on the exposure of TAF are shown in Table 5 and the effects of emtricitabine and tenofovir alafenamide fumarate or its components on the exposure of coadministered drugs are shown in Table 6 [these studies were conducted with emtricitabine and tenofovir alafenamide fumarate or the components of emtricitabine and tenofovir alafenamide fumarate (FTC or TAF) administered alone].

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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility Emtricitabine

• In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the recommended dose of 200 mg per day in emtricitabine and tenofovir alafenamide fumarate) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the recommended dose in emtricitabine and tenofovir alafenamide fumarate).
• FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
• FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dosage in emtricitabine and tenofovir alafenamide fumarate. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dosage in emtricitabine and tenofovir alafenamide fumarate.

Tenofovir Alafenamide

• Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 167 times (mice) and 55 times (rat) those observed in humans after administration of the daily recommended dose of emtricitabine and tenofovir alafenamide fumarate. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 167 times (emtricitabine and tenofovir alafenamide fumarate) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.
• TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
• There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 62 times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

Animal Toxicology and/or Pharmacology Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three and nine month administration of TAF; reversibility was seen after a three month recovery period. No eye toxicity was observed in the dog at systemic exposures of 5 (TAF) and 15 (tenofovir) times the exposure seen in humans with the recommended daily TAF dose in emtricitabine and tenofovir alafenamide fumarate.

Clinical Studies

• In trials of FTC+TAF with EVG+COBI in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (N=866) and to replace a stable antiretroviral regimen in those who were virologically-suppressed for at least 6 months with no known resistance substitutions (N=799), 92% and 96% of patients in the two populations, respectively, had HIV-1 RNA less than 50 copies per mL at Week 48.
• In a trial of FTC+TAF with EVG+COBI in 23 treatment-naïve HIV-1 infected pediatric patients aged 12 to less than 18 years old and weighing greater than 35 kg, the virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24 weeks.
• In a trial in 248 HIV-1 infected adult patients with estimated creatinine clearance greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of the combined population of treatment-naïve subjects (N=6) began on FTC+TAF with EVG+COBI and those previously virologically-suppressed on other regimens (N=242) and switched to FTC+TAF with EVG+COBI had HIV-1 RNA less than 50 copies per mL at Week 24.

How Supplied

Emtricitabine and tenofovir alafenamide fumarate 200 mg/25 mg tablets are blue, rectangular-shaped, and film-coated with "GSI" debossed on one side and "225" on the other side. Each bottle contains 30 tablets (NDC 61958-2002-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure.

Storage

Store below 30 °C (86 °F).

• Keep container tightly closed.
• Dispense only in original container.

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Patient Counseling Information

• Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection
  • Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of emtricitabine and tenofovir alafenamide fumarate. Advise the patient to not discontinue emtricitabine and tenofovir alafenamide fumarate without first informing their healthcare provider.
• Immune Reconstitution Syndrome
  • Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.
• New Onset or Worsening Renal Impairment
  • Advise patients to avoid taking emtricitabine and tenofovir alafenamide fumarate with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs.
• Lactic Acidosis and Severe Hepatomegaly
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to emtricitabine and tenofovir alafenamide fumarate. Advise patients that they should stop emtricitabine and tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
• Decrease in Bone Mineral Density
  • Advise patients that decreases in bone mineral density have been observed with the use of emtricitabine and tenofovir alafenamide fumarate. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
• Missed Dosage
  • Inform patients that it is important to take emtricitabine and tenofovir alafenamide fumarate on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance.
• Pregnancy Registry
  • Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to emtricitabine and tenofovir alafenamide fumarate.
• Lactation
  • Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk

Precautions with Alcohol

Alcohol-Emtricitabine and tenofovir alafenamide fumarate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

DESCOVY

Look-Alike Drug Names

There is limited information regarding Emtricitabine and tenofovir alafenamide fumarate Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.