emtricitabine 200 MG / tenofovir alafenamide 25 MG Oral Tablet

Details

Generic Name: EMTRICITABINE AND TENOFOVIR ALAFENAMIDE

Brand Name: DESCOVY

Substance Name(s):
EMTRICITABINE
TENOFOVIR ALAFENAMIDE FUMARATE

DRUG INTERACTIONS

7 Consult the Full Prescribing Information prior to and during use for potential drug interactions.

( 7 , 12.3 ) 7.1 Potential for Other Drugs to Affect One or More Components of DESCOVY TAF, a component of DESCOVY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3.

Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption (see Table 5 ).

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 DESCOVY and development of resistance.

Coadministration of DESCOVY with other drugs that inhibit P-gp and BCRP 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 .

7.2 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 DESCOVY 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 [see Warnings and Precautions (5.4) ] .

7.3 Established and Other Potentially Significant Interactions Table 5 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 DESCOVY, the components of DESCOVY (emtricitabine and tenofovir alafenamide) as individual agents, or are predicted drug interactions that may occur with DESCOVY.

For magnitude of interaction, see Clinical Pharmacology (12.3) .

Table 5 Established and Other Potentially Significant This table is not all inclusive.

Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration ↓=Decrease Clinical Comment Antiretroviral Agents: Protease Inhibitors (PI) tipranavir/ritonavir ↓ TAF Coadministration with DESCOVY is not recommended.

Other Agents Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ TAF Consider alternative anticonvulsant.

Antimycobacterials: rifabutin rifampin rifapentine ↓ TAF Coadministration of DESCOVY with rifabutin, rifampin, or rifapentine is not recommended.

Herbal Products: St.

John’s wort (Hypericum perforatum) ↓ TAF Coadministration of DESCOVY with St.

John’s wort is not recommended.

7.4 Drugs without Clinically Significant Interactions with DESCOVY Based on drug interaction studies conducted with the components of DESCOVY, no clinically significant drug interactions have been either observed or are expected when DESCOVY 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 DESCOVY is combined with the following drugs: buprenorphine, itraconazole, ketoconazole, lorazepam, methadone, midazolam, naloxone, norbuprenorphine, norgestimate/ethinyl estradiol, and sertraline.

OVERDOSAGE

10 No data are available on overdose of DESCOVY in patients.

If overdose occurs, monitor the individual for evidence of toxicity.

Treatment of overdose with DESCOVY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual.

Emtricitabine (FTC): Limited clinical experience is available at doses higher than the recommended dose of FTC in DESCOVY.

In one clinical pharmacology study, single doses of FTC 1200 mg (6 times the FTC dose in DESCOVY) 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 DESCOVY) 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%.

DESCRIPTION

11 DESCOVY (emtricitabine and tenofovir alafenamide) is a fixed dose combination tablet containing emtricitabine (FTC) and tenofovir alafenamide (TAF) for oral administration.

FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).

TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Each 200/25 mg tablet contains 200 mg of FTC and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.

The tablets are film-coated with a coating material containing indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2 R -hydroxymethyl-1,3-oxathiolan-5 S -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 C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24 and has the following structural formula: FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Chemical Structure Tenofovir Alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[( S )-[[(1 R )-2-(6-amino-9 H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2 E )-2-butenedioate (2:1).

Tenofovir alafenamide fumarate has an empirical formula of C 21 H 29 O 5 N 6 P∙½(C 4 H 4 O 4 ) and a formula weight of 534.50 and has the following structural formula: Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

Chemical Structure

CLINICAL STUDIES

14 14.1 Overview of Clinical Trials The efficacy and safety of DESCOVY have been evaluated in the trials summarized in Table 13.

Table 13 Trials Conducted with FTC+TAF-Containing Products for HIV-1 Treatment and DESCOVY for HIV-1 PrEP Trial Population Study Arms (N) Timepoint Study 104 Randomized, double-blind, active-controlled study.

(NCT01780506) Study 111 (NCT01797445) HIV-1 infected treatment-naïve adults FTC+TAF with EVG+COBI Administered as GENVOYA ® .

(866) FTC+TDF with EVG+COBI Administered as STRIBILD ® .

(867) 48 Weeks Study 109 Randomized, open-label, active controlled trial.

(NCT01815736) HIV-1 infected virologically – suppressed HIV-1 RNA less than 50 copies per mL.

adults FTC+TAF with EVG+COBI (799) ATRIPLA ® or TRUVADA ® +atazanavir+cobicistat or ritonavir or FTC+TDF with EVG+COBI (397) 48 Weeks Study 112 Open label trial (NCT01818596) HIV-1 infected virologically-suppressed adults with renal impairment Estimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method.

FTC+TAF with EVG+COBI (242) 24 Weeks Study 1825 (NCT02600819) HIV-1 infected virologically-suppressed adults with ESRD End stage renal disease (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method).

receiving chronic hemodialysis FTC+TAF with EVG+COBI (55) 48 Weeks Study 106 (Cohort 1) (NCT01854775) HIV-1 infected treatment-naïve adolescents between the ages of 12 to less than 18 years (at least 35 kg) FTC+TAF with EVG+COBI (50) 48 Weeks Study 106 (Cohort 2) (NCT01854775) HIV-1 infected, virologically suppressed children between the ages of 6 to less than 12 years (at least 25 kg) FTC+TAF with EVG+COBI (23) 24 Weeks DISCOVER (NCT02842086) HIV-1 uninfected men or transgender women who have sex with men DESCOVY (2,670) TRUVADA ® (2,665) 4,370 person-years Exposure in the DESCOVY group.

14.2 Clinical Trial Results for Treatment of HIV-1 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.

An open-label, single arm trial of FTC+TAF with EVG+COBI enrolled 50 treatment-naïve HIV-1 infected adolescents aged 12 to less than 18 years weighing at least 35 kg (cohort 1) and 23 virologically suppressed children aged 6 to less than 12 years weighing at least 25 kg (cohort 2).

In cohort 1, the virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 92% (46/50) and the mean increase from baseline in CD4+ cell count was 224 cells per mm 3 at Week 48.

In cohort 2, 100% of subjects remained virologically suppressed at Week 24.

From a mean (SD) baseline CD4+ cell count of 966 (201.7), the mean change from baseline in CD4+ cell count was -150 cells/mm 3 and the mean (SD) change in CD4% was -1.5% (3.7%) at Week 24.

All subjects maintained CD4+ cell counts above 400 cells/mm 3 [see Adverse Reactions (6.1) and Use in Specific Populations (8.4) ].

In a trial in 248 HIV-1 infected adults 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 began on FTC+TAF with EVG+COBI (N=6) and those previously virologically-suppressed on other regimens and switched to FTC+TAF with EVG+COBI (N=242) had HIV-1 RNA less than 50 copies per mL at Week 24.

In a trial in 55 HIV-1 infected virologically-suppressed adults with ESRD (estimated creatinine clearance of less than 15 mL per minute) receiving chronic hemodialysis for at least 6 months who switched to FTC+TAF with EVG+COBI, 82% (45/55) maintained HIV-1 RNA less than 50 copies per mL at Week 48.

Two subjects had HIV-1 RNA ≥ 50 copies per mL by Week 48, 7 discontinued due to AE or other reasons while suppressed, and 1 did not have an HIV-1 RNA measurement at Week 48.

14.3 Clinical Trial Results for HIV-1 PrEP The efficacy and safety of DESCOVY to reduce the risk of acquiring HIV-1 infection were evaluated in a randomized, double-blind multinational trial (DISCOVER) in HIV-seronegative men (N=5,262) or transgender women (N=73) who have sex with men and are at risk of HIV-1 infection, comparing once daily DESCOVY (N=2,670) to TRUVADA (FTC/TDF 200 mg/300 mg; N=2,665).

Evidence of risk behavior at entry into the trial included at least one of the following: two or more unique condomless anal sex partners in the past 12 weeks or a diagnosis of rectal gonorrhea/chlamydia or syphilis in the past 24 weeks.

The median age of participants was 34 years (range, 18–76); 84% were White, 9% Black/Mixed Black, 4% Asian, and 24% Hispanic/Latino.

At baseline, 897 participants (17%) reported receiving TRUVADA for PrEP.

At weeks 4, 12, and every 12 weeks thereafter, all participants received local standard of care HIV-1 prevention services, including HIV-1 testing, evaluation of adherence, safety evaluations, risk-reduction counseling, condoms, management of sexually transmitted infections, and assessment of sexual behavior.

Trial participants maintained a high risk of sexual HIV-1 acquisition, with high rates of rectal gonorrhea (DESCOVY, 24%; TRUVADA, 25%), rectal chlamydia (DESCOVY, 30%; TRUVADA, 31%), and syphilis (14% in both treatment groups) during the trial.

The primary outcome was the incidence of documented HIV-1 infection per 100 person-years in participants randomized to DESCOVY and TRUVADA (with a minimum follow-up of 48 weeks and at least 50% of participants having 96 weeks of follow-up).

DESCOVY was non-inferior to TRUVADA in reducing the risk of acquiring HIV-1 infection (Table 14).

The results were similar across the subgroups of age, race, gender identity, and baseline TRUVADA for PrEP use.

Table 14 HIV-1 Infection Results in DISCOVER Trial – Full Analysis Set DESCOVY (N=2,670) TRUVADA (N=2,665) Rate Ratio (95% CI) 4,370 person-years 4,386 person-years CI = Confidence interval.

HIV-1 infections, n 7 15 Rate of HIV-1 infections per 100 person-years 0.16 0.34 0.468 (0.19, 1.15) Of the 22 participants diagnosed with HIV-1 infection in the trial, five had suspected baseline infection prior to study entry (DESCOVY, 1; TRUVADA, 4).

In a case-control substudy of intracellular drug levels and estimated number of daily doses as measured by dried blood spot testing, median intracellular tenofovir diphosphate concentrations were substantially lower in participants infected with HIV-1 at the time of diagnosis compared with uninfected matched control participants.

For both DESCOVY and TRUVADA, efficacy was therefore strongly correlated to adherence to daily dosing.

HOW SUPPLIED

16 /STORAGE AND HANDLING DESCOVY 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.

Keep container tightly closed.

Dispense only in original container.

Each blister pack contains 30 tablets (NDC 61958-2002-2).

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature).

RECENT MAJOR CHANGES

Boxed Warning 10/2019 Indications and Usage ( 1.2 ) 10/2019 Dosage and Administration ( 2.1 , 2.2 ) 10/2019 Dosage and Administration ( 2.3 , 2.4 , 2.5 ) 12/2019 Contraindications ( 4 ) 10/2019 Warnings and Precautions ( 5.2 ) 10/2019 Warnings and Precautions ( 5.4 ) 12/2019

GERIATRIC USE

8.5 Geriatric Use In clinical trials of an FTC+TAF-containing regimen for treatment of HIV-1, 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 adults between 18 and less than 65 years of age.

DOSAGE FORMS AND STRENGTHS

3 Each DESCOVY tablet contains 200 mg of emtricitabine (FTC) and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate).

The tablets are blue, rectangular-shaped, film-coated, debossed with “GSI” on one side and “225” on the other side.

Tablets: 200 mg of FTC and 25 mg of TAF ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action DESCOVY is a fixed dose combination of antiretroviral drugs emtricitabine (FTC) and tenofovir alafenamide (TAF) [see Microbiology (12.4) ] .

INDICATIONS AND USAGE

1 HIV-1 Treatment ( 1.1 ): DESCOVY is a two-drug combination of emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV nucleoside analog reverse transcriptase inhibitors (NRTIs), and is indicated: in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg.

in combination with other antiretroviral agents other than protease inhibitors that require a CYP3A inhibitor for the treatment of HIV-1 infection in pediatric patients weighing at least 25 kg and less than 35 kg.

HIV-1 PrEP ( 1.2 ): DESCOVY is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sexual acquisition, excluding individuals at risk from receptive vaginal sex.

Individuals must have a negative HIV-1 test immediately prior to initiating DESCOVY for HIV-1 PrEP.

Limitations of Use ( 1.2 ): The indication does not include use of DESCOVY in individuals at risk of HIV-1 from receptive vaginal sex because effectiveness in this population has not been evaluated.

1.1 Treatment of HIV-1 Infection DESCOVY is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg.

DESCOVY is indicated, in combination with other antiretroviral agents other than protease inhibitors that require a CYP3A inhibitor, for the treatment of HIV-1 infection in pediatric patients weighing at least 25 kg and less than 35 kg.

1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP) DESCOVY is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sexual acquisition, excluding individuals at risk from receptive vaginal sex.

Individuals must have a negative HIV-1 test immediately prior to initiating DESCOVY for HIV-1 PrEP [see Dosage and Administration (2.2) and Warnings and Precautions (5.2) ].

Limitations of Use: The indication does not include use of DESCOVY in individuals at risk of HIV-1 from receptive vaginal sex because effectiveness in this population has not been evaluated [see Clinical Studies (14.3) ].

PEDIATRIC USE

8.4 Pediatric Use Treatment of HIV-1 Infection The safety and effectiveness of DESCOVY, in combination with other antiretroviral agents, for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 25 kg [see Indication and Usage (1.1) and Dosage and Administration (2.3) ] .

Use of DESCOVY in pediatric patients between the ages of 12 to less than 18 years weighing at least 35 kg is supported by adequate and well controlled studies of FTC+TAF with EVG+COBI in adults and by an open-label trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects ages 12 to less than 18 years and weighing at least 35 kg (N=50; cohort 1).

The safety and efficacy of FTC+TAF with EVG+COBI in these pediatric subjects was similar to that of HIV-1 infected adults on this regimen [see Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] .

Use of DESCOVY in pediatric patients weighing at least 25 kg is supported by adequate and well controlled studies of FTC+TAF with EVG+COBI in adults and by an open-label trial in virologically-suppressed pediatric subjects between the ages of 6 to less than 12 years weighing at least 25 kg, in which subjects were switched from their antiretroviral regimen to FTC+TAF with EVG+COBI (N=23; cohort 2).

The safety in these subjects through 24 weeks of FTC+TAF with EVG+COBI was similar to that of HIV-1 infected adults on this regimen, with the exception of a decrease in mean change from baseline in CD4+ cell count [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] .

Safety and effectiveness of DESCOVY coadministered with an HIV-1 protease inhibitor that is administered with either ritonavir or cobicistat have not been established in pediatric subjects weighing less than 35 kg [see Dosage and Administration (2.3) ] .

Safety and effectiveness of DESCOVY for treatment of HIV-1 infection in pediatric patients less than 25 kg have not been established.

HIV-1 PrEP Safety and effectiveness of DESCOVY for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg, excluding individuals at risk from receptive vaginal sex, is supported by data from an adequate and well-controlled trial of DESCOVY for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TAF, with EVG+COBI, in HIV-1 infected adults and pediatric subjects [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3 and 12.4) , and Clinical Studies (14) ].

While using DESCOVY for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs.

Previous studies in at-risk adolescents indicated waning adherence to a daily oral PrEP regimen once visits were switched from monthly to quarterly visits.

Adolescents may therefore benefit from more frequent visits and counseling [see Warnings and Precautions (5.2) ].

Safety and effectiveness of DESCOVY for HIV-1 PrEP in pediatric patients less than 35 kg have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DESCOVY 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 risk of overall major birth defects for emtricitabine (FTC) 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).

There are insufficient tenofovir alafenamide (TAF) data from the APR to adequately assess the risk of major birth defects.

The rate of miscarriage for individual drugs 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 DESCOVY 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 DESCOVY (see Data ) .

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 DESCOVY.

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 DESCOVY.

Data Human Data Emtricitabine: Based on prospective reports to the APR through January 2019 of over 4,450 exposures to FTC-containing regimens during pregnancy (including over 3,150 exposed in the first trimester and over 1,300 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: 1.9% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.2%) with the second/third trimester exposure to FTC-containing regimens.

Tenofovir Alafenamide: Based on prospective reports to the APR of over 220 exposures to TAF-containing regimens during pregnancy (including over 160 exposed in the first trimester and over 60 exposed in the second/third trimester), there have been 6 birth defects with first trimester exposure to TAF-containing regimens.

Methodologic limitations of the APR include the use of MACDP as the external comparator group.

The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

Additionally, published observational studies on emtricitabine and tenofovir exposure in pregnancy have not shown an increased risk for major malformations.

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 DESCOVY.

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 DESCOVY.

BOXED WARNING

WARNING: POST-TREATMENT ACUTE EXACERBATION OF HEPATITIS B and RISK OF DRUG RESISTANCE WITH USE OF DESCOVY 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 products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of DESCOVY.

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 DESCOVY.

If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] .

DESCOVY 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 FTC/TDF for HIV-1 PrEP following undetected acute HIV-1 infection.

Do not initiate DESCOVY 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) ].

Severe acute exacerbations of hepatitis B (HBV) have been reported in HBV-infected individuals who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of DESCOVY.

Hepatic function should be monitored closely in these individuals.

If appropriate, anti-hepatitis B therapy may be warranted.

( 5.1 ) DESCOVY 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 FTC/TDF for HIV-1 PrEP following undetected acute HIV-1 infection.

Do not initiate DESCOVY for HIV-1 PrEP if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed.

( 5.2 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Comprehensive management to reduce the risk of sexually transmitted infections (STIs), including HIV-1, when DESCOVY is used for HIV-1 PrEP: Counsel on adherence to daily dosing and safer sex practices, including condoms, to reduce the risk of STIs.

( 5.2 ) Management to reduce the risk of acquiring HIV-1 drug resistance when DESCOVY is used for HIV-1 PrEP: refer to full prescribing information for additional detail.

( 5.2 ) Immune reconstitution syndrome during treatment of HIV-1 infection: May necessitate further evaluation and treatment.

( 5.3 ) New onset or worsening renal impairment: Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein when initiating DESCOVY and during use on a clinically appropriate schedule in all individuals.

Also assess serum phosphorus in individuals with chronic kidney disease.

( 5.4 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue DESCOVY in individuals who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

( 5.5 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Individuals with HBV Infection All individuals should be tested for the presence of hepatitis B virus (HBV) before or when initiating DESCOVY [see Dosage and Administration (2.1) ] .

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected individuals who have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of DESCOVY.

Individuals infected with HBV who discontinue DESCOVY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

If appropriate, anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

HBV-uninfected individuals should be offered vaccination.

5.2 Comprehensive Management to Reduce the Risk of Sexually Transmitted Infections, Including HIV-1, and Development of HIV-1 Resistance When DESCOVY Is Used for HIV-1 PrEP Use DESCOVY for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy, including adherence to daily administration and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs) .

The time from initiation of DESCOVY for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission).

Inform uninfected individuals about and support their efforts in reducing sexual risk behavior .

Use DESCOVY to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-1 negative.

HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only DESCOVY, because DESCOVY alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology (12.4) ]; therefore, care should be taken to minimize the risk of initiating or continuing DESCOVY before confirming the individual is HIV-1 negative.

Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection.

Prior to initiating DESCOVY for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).

While using DESCOVY for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs .

If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

Counsel HIV-1 uninfected individuals to strictly adhere to the once daily DESCOVY dosing schedule.

The effectiveness of DESCOVY in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in a clinical trial of DESCOVY for HIV-1 PrEP.

Some individuals, such as adolescents, may benefit from more frequent visits and counseling to support adherence [see Use in Specific Populations (8.4) , Microbiology (12.4) , and Clinical Studies (14.3) ].

5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including FTC, a component of DESCOVY.

During the initial phase of combination antiretroviral treatment, HIV-1 infected 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, Guillain-Barré syndrome, and autoimmune hepatitis) 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.

5.4 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) in HIV-1 infected patients 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 estimated creatinine clearance 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 estimated creatinine clearance 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 estimated creatinine clearance between 30 and 50 mL per minute [see Adverse Reactions (6.1) ] .

DESCOVY is not recommended in individuals with estimated creatinine clearance of 15 to below 30 mL per minute, or in individuals with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis.

Individuals 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.

Prior to or when initiating DESCOVY, and during treatment with DESCOVY 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.

Discontinue DESCOVY in individuals who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

5.5 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 DESCOVY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals.

Treatment with DESCOVY should be suspended in any individual 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).

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Important Information for Uninfected Individuals Taking DESCOVY for HIV-1 PrEP Advise HIV-1 uninfected individuals about the following [see Warnings and Precautions (5.2) ]: The need to confirm that they are HIV-negative before starting to take DESCOVY to reduce the risk of acquiring HIV-1.

That HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking DESCOVY, because DESCOVY alone does not constitute a complete regimen for HIV-1 treatment.

The importance of taking DESCOVY on a regular dosing schedule and strict adherence to the recommended dosing schedule to reduce the risk of acquiring HIV-1.

Uninfected individuals who miss doses are at greater risk of acquiring HIV-1 than those who do not miss doses.

That DESCOVY does not prevent other sexually acquired infections and should be used as part of a complete prevention strategy including other prevention measures.

To use condoms consistently and correctly to lower the chances of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

The importance of knowing their HIV-1 status and the HIV-1 status of their partner(s).

The importance of virologic suppression in their partner(s) with HIV-1.

The need to get tested regularly for HIV-1 (at least every 3 months, or more frequently for some individuals such as adolescents) and to ask their partner(s) to get tested as well.

To report any symptoms of acute HIV-1 infection (flu-like symptoms) to their healthcare provider immediately.

That the signs and symptoms of acute infection include fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy (cervical and inguinal).

To get tested for other sexually transmitted infections, such as syphilis, chlamydia, and gonorrhea, that may facilitate HIV-1 transmission.

To assess their sexual risk behavior and get support to help reduce sexual risk behavior.

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Infection Inform individuals that severe acute exacerbations of hepatitis B have been reported in patients who are infected with HBV and have discontinued products containing FTC and/or TDF and may likewise occur with discontinuation of DESCOVY [see Warnings and Precautions (5.1) ] .

Advise HBV-infected individuals to not discontinue DESCOVY without first informing their healthcare provider.

Immune Reconstitution Syndrome Advise HIV-1 infected patients to inform their healthcare provider immediately of any symptoms of infection.

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 [see Warnings and Precautions (5.3) ] .

New Onset or Worsening Renal Impairment Advise HIV-1 infected patients and uninfected individuals to avoid taking DESCOVY 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 [see Warnings and Precautions (5.4) ].

Lactic Acidosis and Severe Hepatomegaly Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to DESCOVY.

Advise HIV-1 infected patients and uninfected individuals that they should stop DESCOVY if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.5) ] .

Dosage Recommendations for Treatment of HIV-1 Infection Inform HIV-1 infected patients that it is important to take DESCOVY with other antiretroviral drugs for the treatment of HIV-1 on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2.3) ] .

Pregnancy Registry Inform individuals using DESCOVY that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to DESCOVY [see Use in Specific Populations (8.1) ].

Lactation Instruct mothers with HIV-1 infection not to breastfeed because of the risk of passing the HIV-1 virus to the baby [see Use in Specific Populations (8.2) ] .

DOSAGE AND ADMINISTRATION

2 Testing: Prior to or when initiating DESCOVY, test for hepatitis B virus infection.

Prior to or when initiating DESCOVY, and during use 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 DESCOVY for HIV-1 PrEP and at least once every 3 months while taking DESCOVY, and upon diagnosis of any other sexually transmitted infections (STIs).

( 2.2 ) Recommended dosage: Treatment of HIV-1 Infection: One tablet taken once daily with or without food in patients with body weight at least 25 kg.

( 2.3 ) HIV-1 PrEP: One tablet taken once daily with or without food in individuals with body weight at least 35 kg.

( 2.4 ) Renal impairment: DESCOVY is not recommended in individuals with estimated creatinine clearance of 15 to below 30 mL per minute, or below 15 mL per minute who are not receiving chronic hemodialysis.

( 2.5 ) 2.1 Testing When Initiating and During Use of DESCOVY for Treatment of HIV-1 Infection or for HIV-1 PrEP Prior to or when initiating DESCOVY, test individuals for hepatitis B virus infection [see Warnings and Precautions (5.1) ] .

Prior to or when initiating DESCOVY, and during use of DESCOVY 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 (5.4) ].

2.2 HIV-1 Screening for Individuals Receiving DESCOVY for HIV-1 PrEP Screen all individuals for HIV-1 infection immediately prior to initiating DESCOVY for HIV-1 PrEP and at least once every 3 months while taking DESCOVY, 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) ].

2.3 Recommended Dosage for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing at Least 25 kg DESCOVY 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 DESCOVY for treatment of HIV-1 is one tablet taken orally once daily with or without food in: adults and pediatric patients with body weight at least 25 kg and creatinine clearance greater than or equal to 30 mL per minute; or adults with creatinine clearance below 15 mL per minute who are receiving chronic hemodialysis.

On days of hemodialysis, administer the daily dose of DESCOVY after completion of hemodialysis treatment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .

For specific dosing recommendations for coadministered third agents, refer to their respective prescribing information [see Drug Interactions (7) ] .

The safety and effectiveness of DESCOVY coadministered with an HIV-1 protease inhibitor that is administered with either ritonavir or cobicistat have not been established in: pediatric subjects weighing less than 35 kg; or adult subjects with creatinine clearance below 15 mL per minute, with or without hemodialysis.

2.4 Recommended Dosage for HIV-1 PrEP in Adults and Adolescents Weighing at Least 35 kg The dosage of DESCOVY for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 25 mg of TAF) once daily taken orally with or without food in HIV-1 uninfected: adults and adolescents weighing at least 35 kg and with a creatinine clearance greater than or equal to 30 mL per minute; or adults with creatinine clearance below 15 mL per minute who are receiving chronic hemodialysis.

On days of hemodialysis, administer the daily dose of DESCOVY after completion of hemodialysis treatment [see Indications and Usage (1.2) and Clinical Pharmacology (12.3) ].

2.5 Not Recommended in Individuals with Severe Renal Impairment for Treatment of HIV-1 Infection or for HIV-1 PrEP DESCOVY is not recommended in individuals with: severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute); or end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are not receiving chronic hemodialysis [see Dosage and Administration (2.3 , 2.4) and Use in Specific Populations (8.6) ] .