Odefsey

• as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL or
• to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies/mL) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY
  [see

  12.4 Microbiology

  Mechanism of Action

  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 (RT) 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.

  Rilpivirine:

  RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.

  Tenofovir Alafenamide:

  TAF is a phosphonamidate 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 human immunodeficiency virus (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 cell culture.

  Antiviral Activity in Cell Culture

  Emtricitabine, Rilpivirine, and Tenofovir Alafenamide:

  The combinations of FTC, RPV, and TAF were not antagonistic with each other in cell culture combination antiviral activity assays. In addition, FTC, RPV, and TAF were not antagonistic with a panel of representatives from the major classes of approved anti-HIV agents (NNRTIs, NRTIs, INSTIs, and PIs).

  Emtricitabine:

  The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells (PBMCs). The EC₅₀values for FTC were in the range of 1.3–640 nM. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC₅₀values ranged from 7–75 nM) and showed strain-specific activity against HIV-2 (EC₅₀values ranged from 7–1500 nM).

  Rilpivirine:

  RPV exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC₅₀value for HIV-1_IIIBof 0.73 nM. RPV demonstrated limited activity in cell culture against HIV-2 with a median EC₅₀value of 5220 nM (range 2510–10,830 nM). RPV demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC₅₀values ranging from 0.07–1.01 nM and was less active against group O primary isolates with EC₅₀values ranging from 2.88–8.45 nM.

  Tenofovir Alafenamide:

  The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC₅₀values for TAF ranged from 2.0–14.7 nM.

  TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC₅₀values ranged from 0.10–12.0 nM) and strain specific activity against HIV-2 (EC₅₀values ranged from 0.91–2.63 nM).

  Resistance

  In Cell Culture

  Emtricitabine:

  HIV-1 isolates with reduced susceptibility to FTC were selected in cell culture. Reduced susceptibility to FTC was associated with M184V or I substitutions in HIV-1 RT.

  Rilpivirine:

  RPV-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and M230I and L.

  Tenofovir Alafenamide:

  HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.

  In Clinical Trials

  In Participants With HIV-1 and No Antiretroviral Treatment History

  Emtricitabine and Tenofovir Alafenamide:

  The resistance profile of ODEFSEY for the treatment of HIV-1 is based on studies of FTC+TAF with EVG+COBI in the treatment of HIV-1

  .

  In a pooled analysis of antiretroviral-naïve participants, genotyping was performed on plasma HIV-1 isolates from all participants with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure, at Week 48, or at time of early study drug discontinuation. Genotypic resistance developed in 7 of 14 evaluable participants. The resistance–associated substitutions that emerged were M184V/I (N=7) and K65R (N=1). Three participants had virus with emergent R, H, or E at the polymorphic Q207 residue in reverse transcriptase.

  Rilpivirine:

  In the Week 96 pooled resistance analysis for adult participants receiving RPV or efavirenz in combination with FTC/TDF, the emergence of resistance was greater among participants' viruses in the RPV+FTC/TDF arm compared to the efavirenz+FTC/TDF arm and was dependent on baseline viral load. In the Week 96 resistance analysis, 14% (77/550) of the participants in the RPV+FTC/TDF arm and 8% (43/546) of the participants in the efavirenz+FTC/TDF arm qualified for resistance analysis; 61% (47/77) of the participants who qualified for resistance analysis (resistance-analysis participants) in the RPV+FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance-analysis participants in the efavirenz+FTC/TDF arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to emtricitabine or tenofovir emerged in viruses from 57% (44/77) of the resistance-analysis participants in the RPV arm compared to 26% (11/43) in the efavirenz arm.

  Emerging NNRTI substitutions in the RPV resistance analysis of participants' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6–621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (A62V, K65R/N, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance-analysis participants than in efavirenz resistance-analysis participants

  .

  NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from participants with baseline viral loads of less than or equal to 100,000 copies/mL compared to viruses from participants with baseline viral loads of greater than 100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from participants with baseline CD4+ cell counts greater than or equal to 200 cells/mm³compared to the viruses from participants with baseline CD4+ cell counts less than 200 cells/mm³: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.

  In Virologically-Suppressed Participants

  Emtricitabine and Tenofovir Alafenamide:

  One participant was identified with emergent resistance to FTC or TAF (M184M/I) out of 4 virologic failure participants in a clinical study of virologically-suppressed participants who switched from a regimen containing FTC+TDF to FTC+TAF with EVG+COBI (N=799).

  Rilpivirine:

  Through Week 48, 4 participants who switched their protease inhibitor-based regimen to FTC/RPV/TDF (4 of 469 participants, 0.9%) and 1 participant who maintained their regimen (1 of 159 participants, 0.6%) developed genotypic and/or phenotypic resistance to a study drug. All 4 of the participants who had resistance emergence on FTC/RPV/TDF had evidence of FTC resistance and 3 of the participants had evidence of RPV resistance.

  ODEFSEY:

  Through Week 48, in participants who switched to ODEFSEY from FTC/RPV/TDF or EFV/FTC/TDF (Trials 1216 (N=316) and 1160 (N=438), respectively), of seven participants who developed virologic failure, three participants had detectable NNRTI and/or NRTI resistance substitutions at virologic failure that were pre-existing in the baseline sample by proviral DNA sequencing; one of these participants resuppressed while maintaining ODEFSEY.

  Cross-Resistance

  Emtricitabine:

  FTC-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

  Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine—thymidine analog substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution or other substitutions associated with resistance to NNRTIs was susceptible to FTC.

  Rilpivirine:

  Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.

  Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to RPV compared to 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of L100I and K103N resulted in a 7 times reduced susceptibility to RPV. In another study, the Y188L substitution resulted in a reduced susceptibility to RPV of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to RPV (fold change range of 3.7–554) in 38% and 66% of mutants, respectively.

  Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance.

  Tenofovir Alafenamide:

  Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir.

  HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R showed reduced susceptibility to TAF in cell culture.

  and

  14 CLINICAL STUDIES

  14.1 Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to ODEFSEY

  In Trial 1216, the efficacy and safety of switching from emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed adults with HIV-1. Participants were suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of FTC/RPV/TDF for at least 6 months and had no documented resistance mutations to FTC, TAF, or RPV prior to study entry. Participants were randomized in a 1:1 ratio to either switch to ODEFSEY (N=316) once daily or stay on FTC/RPV/TDF (N=314) once daily. Participants had a mean age of 45 years (range: 23–72), 90% were male, 75% were White, and 19% were Black. The mean baseline CD4+ cell count was 709 cells/mm³(range: 104–2527).

  In Trial 1160, the efficacy and safety of switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed adults with HIV-1. Participants were stably suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen of EFV/FTC/TDF for at least 6 months and had no documented resistance mutations to FTC, TAF, or RPV prior to study entry. Participants were randomized in a 1:1 ratio to either switch to ODEFSEY (N=438) once daily or stay on EFV/FTC/TDF (N=437) once daily. Participants had a mean age of 48 years (range: 19–76), 87% were male, 67% were White, and 27% were Black. The mean baseline CD4+ cell count was 700 cells/mm³(range: 140–1862).

  Treatment outcomes of Trials 1216 and 1160 are presented in Table 13.

  Table 13 Virologic Outcomes of Trials 1216 and 1160 at Week 48Week 48 window was between Day 295 and 378 (inclusive).in Virologically-Suppressed Participants who Switched to ODEFSEY

  	Study 1216		Study 1160
  	ODEFSEY (N=316)	FTC/RPV/TDF (N=313)One subject who was not on FTC/RPV/TDF prior to screening was excluded from the efficacy analysis.	ODEFSEY (N=438)	EFV/FTC/TDF (N=437)
  HIV-1 RNA <50 copies/mL	94%	94%	90%	92%
  HIV-1 RNA ≥50 copies/mLIncluded participants who had HIV-1 RNA ≥50 copies/mL in the Week 48 window; participants who discontinued early due to lack or loss of efficacy; participants who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.	1%	0%	1%	1%
  No Virologic Data at Week 48 Window	6%	6%	9%	7%
  Discontinued Study Drug Due to AE or Death and Last Available HIV-1 RNA <50 copies/mL	2%	1%	3%	1%
  Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLIncludes participants who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.	4%	4%	5%	5%
  Missing Data During Window but on Study Drug	<1%	1%	1%	1%

  14.2 Clinical Trial Results for Adult Participants with no Antiretroviral Treatment History and Adults with Renal Impairment for Components of ODEFSEY

  The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in adults as initial therapy in those with no antiretroviral treatment history

  [see Indications and Usage (1)]

  was established in trials of:

  • RPV+FTC/TDF in adults with HIV-1 as initial therapy in those with no antiretroviral treatment history (n=550). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 77% at Week 96. The virologic response rate at 96 weeks was 83% in participants with baseline HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in participants with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the virologic response rate at 96 weeks among participants with baseline CD4+ cell counts less than 200 and greater than or equal to 200 cells/mm³were 68% and 82%, respectively.
  • FTC+TAF with EVG+COBI in adults with HIV-1 as initial therapy in those with no antiretroviral treatment history (n=866). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 92% at Week 48.

  In the clinical trial of 248 adults with HIV-1 and estimated creatinine clearance greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of the combined populations of treatment-naïve (N=6) begun 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 levels less than 50 copies per mL at Week 24.

  14.3 Clinical Trial Results for Pediatric Participants Aged 6 to Less than 18 Years Old for Components of ODEFSEY

  The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients aged 6 to less than 18 years old and greater than 25 kg as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed

  [see Indications and Usage (1)]

  was established in trials of pediatric participants with HIV-1 aged 6 to less than 18 years with:

  • RPV in combination with other antiretroviral agents in 36 treatment-naïve adolescents with HIV-1 weighing at least 32 kg. The majority of participants (24/36) received RPV in combination with FTC and TDF. Of these 24 participants, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies per mL. The virologic response rate in these 20 participants (i.e., HIV-1 RNA less than 50 copies per mL) was 80% (16/20) at 48 weeks.
  • RPV in combination with other antiretroviral agents (two NRTIs) in 18 treatment-naïve pediatric participants with HIV-1 weighing at least 17 kg (median [range]: 25 kg [17–51 kg]). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 72% (13/18) at 48 weeks.
  • RPV in combination with other antiretrovirals in 26 virologically-suppressed pediatric participants with HIV-1 less than 12 years old weighing at least 16 kg (N=26) at 48-week.
  • FTC+TAF with EVG+COBI in 50 treatment-naïve adolescents with HIV-1 aged 12 to less than 18 years weighing at least 35 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 92% (46/50) at 48 weeks.
  • FTC+TAF with EVG+COBI in 52 virologically-suppressed pediatric participants with HIV-1 aged 6 to less than 12 years weighing at least 25 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 98% (51/52) at 48 weeks.

  ].

• Testing: Prior to or when initiating ODEFSEY, test for hepatitis B virus infection. Prior to or when initiating ODEFSEY, and during treatment on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus (
  2.1 Testing Prior to Initiation and During Treatment with ODEFSEY

  Prior to or when initiating ODEFSEY, test patients for hepatitis B virus infection

  [see Warnings and Precautions (5.1)]

  .

  Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus

  [see Warnings and Precautions (5.5)].
  )
• Recommended dosage: one tablet taken orally once daily with a meal. (
  2.2 Recommended Dosage in Adult and Pediatric Patients Weighing at Least 25 kg

  ODEFSEY is a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of ODEFSEY is one tablet taken orally once daily with a meal in adults and pediatric patients with body weight at least 25 kg and creatinine clearance greater than or equal to 30 mL per minute

  [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].
  )
• For pregnant patients who are already on ODEFSEY prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet taken once daily may be continued. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely. (
  2.3 Recommended Dosage During Pregnancy

  For pregnant patients who are already on ODEFSEY prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of ODEFSEY taken once daily may be continued. Lower exposures of rilpivirine, a component of ODEFSEY, were observed during pregnancy, therefore viral load should be monitored closely

  [see Use in Specific Populations (8.1)and Clinical Pharmacology (12.3)]

  .
  )
• Renal impairment: ODEFSEY is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or below 15 mL per minute who are not receiving chronic hemodialysis. (
  2.4 Not Recommended in Patients with Severe Renal Impairment

  ODEFSEY is not recommended in patients 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 (2.2), Warnings and Precautions (5.5), and Use in Specific Populations (8.6)].
  )

Each ODEFSEY tablet contains 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV) (equivalent to 27.5 mg of rilpivirine hydrochloride), and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate).

The tablets are gray, capsule-shaped, film-coated and debossed with "GSI" on one side and "255" on the other side.

• Pregnancy: Total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period. (
  2.3 Recommended Dosage During Pregnancy

  For pregnant patients who are already on ODEFSEY prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of ODEFSEY taken once daily may be continued. Lower exposures of rilpivirine, a component of ODEFSEY, were observed during pregnancy, therefore viral load should be monitored closely

  [see Use in Specific Populations (8.1)and Clinical Pharmacology (12.3)]

  .
  ,
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to ODEFSEY 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 statistically significant difference in the overall risk of major birth defects for emtricitabine (FTC), rilpivirine (RPV) or tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)

  (see Data)

  . 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%.

  Based on the experience of pregnant individuals with HIV-1 who completed a clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on a stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of RPV were observed during pregnancy compared to the postpartum period. Therefore, viral load should be monitored closely

  [see Dataand Clinical Pharmacology (12.3)]

  .

  In animal studies, no adverse developmental effects were observed when the components of ODEFSEY were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in ODEFSEY

  (see Data)

  . Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in ODEFSEY. 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 ODEFSEY.

  Data

  Human Data

  Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of ODEFSEY are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. 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 less than 20 weeks gestation.

  Emtricitabine (FTC):

  Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.

  Rilpivirine (RPV):

  RPV in combination with a background regimen was evaluated in a clinical trial of 19 pregnant participants with HIV-1 during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve participants completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six participants. The exposure (C_0hand AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period

  [see Clinical Pharmacology (12.3)]

  . One participant discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 participants who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 participants (83.3%) through the third trimester visit and in 9 participants (75%) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two participants who were withdrawn (one participant was nonadherent to the study drug and one participant withdrew consent). Among the 10 infants with HIV test results available, born to 10 pregnant participants with HIV-1, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in adults with HIV-1.

  Based on prospective reports to the APR of over 750 exposures to RPV-containing regimens during pregnancy resulting in live births (including over 550 exposed in the first trimester and over 200 exposed in the second/third trimester), the prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to RPV-containing regimens.

  Tenofovir Alafenamide (TAF):

  Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-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 (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.

  Rilpivirine:

  RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.

  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 similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of ODEFSEY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. 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 ODEFSEY.
  ,
  12.3 Pharmacokinetics

  Absorption, Distribution, Metabolism, and Excretion

  The pharmacokinetic properties of the components of ODEFSEY are provided in Table 5. The multiple dose pharmacokinetic parameters of FTC, RPV and TAF and its metabolite tenofovir are provided in Table 6.

  Table 5 Pharmacokinetic Properties of the Components of ODEFSEY

  	Rilpivirine	Emtricitabine	Tenofovir Alafenamide
  PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1.
  Absorption
  Tmax(h)	4	3	1
  Effect of moderate fat meal (relative to fasting)Values refer to geometric mean ratio [fed/ fasted] in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~800 kcal, 50% fat. Moderate-fat meal = ~600 kcal, 27% fat.	AUC Ratio = 1.13 (1.03, 1.23)	AUC Ratio = 0.91 (0.89, 0.93)	AUC Ratio = 1.45 (1.33, 1.58)
  Effect of high fat meal (relative to fasting)	AUC Ratio = 1.72 (1.49, 1.99)	AUC Ratio = 0.88 (0.85, 0.90)	AUC Ratio = 1.53 (1.39, 1.69)
  Distribution
  % Bound to human plasma proteins	~99	<4	~80
  Source of protein binding data	In vitro	In vitro	Ex vivo
  Blood-to-plasma ratio	0.7	0.6	1.0
  Metabolism
  Metabolism	CYP3A	Not significantly metabolized	Cathepsin AIn vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.(PBMCs) CES1 (hepatocytes) CYP3A (minimal)
  Elimination
  Major route of elimination	Metabolism	Glomerular filtration and active tubular secretion	Metabolism (>80% of oral dose)
  t1/2(h)t1/2values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs.	50	10	0.51
  % Of dose excreted in urineDosing in mass balance studies: FTC (single dose administration of [14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14C] tenofovir alafenamide).	6	70	<1
  % Of dose excreted in feces	85	13.7	31.7

  Table 6 Multiple Dose Pharmacokinetic Parameters of Emtricitabine, Rilpivirine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration with a Meal in Adults with HIV-1

  Parameter Mean (CV%)	EmtricitabineFrom Intensive PK analysis in a phase 2 trial in adults with HIV-1 treated with FTC+TAF with EVG+COBI (n=19).	RilpivirineFrom Population PK analysis in a trial of treatment-naïve adults with HIV-1 treated with RPV (n=679).	Tenofovir AlafenamideFrom Population PK analysis in two trials of treatment-naïve adults with HIV-1 treated within EVG+COBI+FTC+TAF (n=539).	TenofovirFrom Population PK analysis in two trials of treatment-naïve adults with HIV-1 treated with EVG+COBI+FTC+TAF (n=841).
  CV = Coefficient of Variation; NA = Not Applicable
  Cmax (microgram per mL)	2.1 (20.2)	NA	0.16 (51.1)	0.02 (26.1)
  AUCtau (microgram∙hour per mL)	11.7 (16.6)	2.2 (38.1)	0.21 (71.8)	0.29 (27.4)
  Ctrough (microgram per mL)	0.10 (46.7)	0.08 (44.3)	NA	0.01 (28.5)

  Specific Populations

  Geriatric Patients

  The pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of participants with HIV-1 in Phase 2 and Phase 3 trials of FTC+TAF with EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.

  The pharmacokinetics of RPV have not been fully evaluated in the elderly (65 years of age and older)

  [see Use in Specific Populations (8.5)].

  Pediatric Patients

  Exposures of TAF in 24 pediatric participants with HIV-1 aged 12 to less than 18 years who received FTC+TAF with EVG+COBI were decreased (23% for TAF AUC) compared to exposures achieved in treatment-naïve adults following administration of FTC+TAF with EVG+COBI. These exposure differences are not thought to be clinically significant based on exposure-response relationships. FTC exposures were similar in adolescents compared to treatment-naïve adults.

  Exposures of FTC, TAF and TFV in 23 pediatric participants with HIV-1 aged 6 to less than 12 years who received FTC+TAF with EVG+COBI were higher (50 to 80% for AUC) than exposures achieved in adults following the administration of FTC+TAF with EVG+COBI, however, the increase was not considered clinically significant as the safety profiles were similar in adult and pediatric participants.

  The PK of RPV in pediatric participants with HIV aged 6 to less than 18 years who received RPV 25 mg once daily were comparable to or slightly higher than those obtained in adults with HIV-1

  [see Use In Specific Populations (8.4)]

  .

  Race and Gender

  No clinically significant changes in the pharmacokinetics of the components of ODEFSEY have been observed based on race or gender.

  Patients with Renal Impairment

  Rilpivirine:

  Population pharmacokinetic analysis indicated that RPV exposure was similar in participants with HIV-1 and eGFR 60 to 89 mL per minute by Cockcroft-Gault method, relative to participants with HIV-1 and normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease

  [see Use in Specific Populations (8.6)]

  .

  Emtricitabine and Tenofovir Alafenamide:

  The pharmacokinetics of FTC+TAF with EVG+COBI in participants with HIV-1 and renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method), and in participants with HIV-1 and ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in subsets of virologically-suppressed participants in open-label trials. The pharmacokinetics of TAF were similar among healthy participants, participants with HIV-1 and mild or moderate renal impairment, and participants with HIV-1 and ESRD receiving chronic hemodialysis; increases in FTC and TFV exposures in participants with HIV-1 and renal impairment were not considered clinically relevant (Table 7).

  Table 7 Pharmacokinetics of FTC and a Metabolite of TAF (Tenofovir) in Adults with HIV-1 and Renal Impairment as Compared to Participants with Normal Renal Function

  	AUCtau(microgram-hour per mL) Mean (CV%)
  Estimated Creatinine ClearanceBy Cockcroft-Gault method.	≥90 mL per minute (N=18)From a phase 2 trial in adults with HIV-1 and normal renal function treated with FTC+TAF with EVG+COBI.	60–89 mL per minute (N=11)These participants had an eGFR ranging from 60 to 69 mL per minute.	30–59 mL per minute (N=18)From a phase 3 trial in adults with HIV-1 and renal impairment treated with FTC+TAF with EVG+COBI.	<15 mL per minute (N=12)From a phase 3 trial in adults with HIV-1 and ESRD receiving chronic hemodialysis treated with FTC+TAF with EVG+COBI; PK assessed prior to hemodialysis following 3 consecutive daily doses of FTC+TAF with EVG+COBI.
  Emtricitabine	11.4 (11.9)	17.6 (18.2)	23.0 (23.6)	62.9 (48.0)N=11.
  Tenofovir	0.32 (14.9)	0.46 (31.5)	0.61 (28.4)	8.72 (39.4)N=10.

  Patients with Hepatic Impairment

  Emtricitabine:

  The pharmacokinetics of FTC have not been studied in participants with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.

  Rilpivirine:

  In a study comparing 8 participants with mild hepatic impairment (Child-Pugh score A) to 8 matched controls and 8 participants with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple-dose exposure of RPV was 47% higher in participants with mild hepatic impairment and 5% higher in participants with moderate hepatic impairment

  [see Use in Specific Populations (8.7)]

  .

  Tenofovir Alafenamide:

  Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in participants with mild, moderate (Child-Pugh A and B), or severe hepatic impairment (Child-Pugh C)

  [see Use in Specific Populations (8.7)]

  .

  Hepatitis B and/or Hepatitis C Virus Coinfection

  The pharmacokinetics of FTC and TAF have not been fully evaluated in participants with hepatitis B and/or C virus. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.

  Pregnancy and Postpartum

  Rilpivirine:

  The exposure (C_0hand AUC_24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically-suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.

  Table 8 Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum

  Pharmacokinetics of total rilpivirine (mean ± SD, tmax: median [range])	Postpartum (6–12 Weeks) (n=11)	2ndTrimester of pregnancy (n=15)	3rdTrimester of pregnancy (n=13)
  C0h, ng/mL	111 ± 69.2	65.0 ± 23.9	63.5 ± 26.2
  Cmin, ng/mL	84.0 ± 58.8	54.3 ± 25.8	52.9 ± 24.4
  Cmax, ng/mL	167 ± 101	121 ± 45.9	123 ± 47.5
  tmax, h	4.00 (2.03–25.08)	4.00 (1.00–9.00)	4.00 (2.00–24.93)
  AUC24h, ng.h/mL	2714 ± 1535	1792 ± 711	1762 ± 662

  Drug Interaction Studies

  Rilpivirine:

  RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.

  RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

  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.

  The drug interaction studies described in Tables 9–12 were conducted with ODEFSEY (FTC/RPV/TAF) or the components of ODEFSEY (FTC, RPV, or TAF) administered individually.

  The effects of coadministered drugs on the exposures of RPV and TAF are shown in Tables 9 and 10, respectively. The effects of RPV and TAF on the exposure of coadministered drugs are shown in Tables 11 and 12, respectively. For information regarding clinical recommendations,

  see Drug Interactions (7).

  Table 9 Changes in Pharmacokinetic Parameters for RPV in the Presence of Coadministered Drugs in Healthy Participants

  Coadministered Drug	Dose/Schedule			Mean Ratio of RPV Pharmacokinetic Parameters With/Without Coadministered Drug (90% CI); No Effect = 1.00
  	Coadministered Drug (mg)	RPV (mg)	N	Cmax	AUC	Cmin
  CI=Confidence Interval; N=maximum number of participants with data; NA=Not Available; ↔=no change
  Acetaminophen	500 single dose	150 once daily25 mg, 75 mg, and 150 mg of RPV is 1, 3, and 6 times the recommended dose of RPV in ODEFSEY, respectively.	16	1.09 (1.01, 1.18)	1.16 (1.10, 1.22)	1.26 (1.16, 1.38)
  Atorvastatin	40 once daily	150 once daily	16	0.91 (0.79, 1.06)	0.90 (0.81, 0.99)	0.90 (0.84, 0.96)
  Chlorzoxazone	500 single dose taken 2 hours after RPV	150 once daily	16	1.17 (1.08, 1.27)	1.25 (1.16, 1.35)	1.18 (1.09, 1.28)
  Ethinylestradiol/Norethindrone	0.035 once daily /1 mg once daily	25 once dailyStudy conducted with RPV.	15	↔Comparison based on historic controls.	↔	↔
  Famotidine	40 single dose taken 12 hours before RPV	150 single dose	24	0.99 (0.84, 1.16)	0.91 (0.78, 1.07)	NA
  Famotidine	40 single dose taken 2 hours before RPV	150 single dose	23	0.15 (0.12, 0.19)	0.24 (0.20, 0.28)	NA
  Famotidine	40 single dose taken 4 hours after RPV	150 single dose	24	1.21 (1.06, 1.39)	1.13 (1.01, 1.27)	NA
  Ketoconazole	400 once daily	150 once daily	15	1.30 (1.13, 1.48)	1.49 (1.31, 1.70)	1.76 (1.57, 1.97)
  Methadone	60–100 once daily, individualized dose	25 once daily	12	↔	↔	↔
  Ledipasvir/Sofosbuvir	90/400 once daily	25 once dailyStudy conducted with ODEFSEY (FTC/RPV/TAF).	42	0.97 (0.92, 1.02)	0.95 (0.91, 0.98)	0.93 (0.89, 0.97)
  Omeprazole	20 once daily	25 single dose	15	0.30 (0.24, 0.38)	0.35 (0.28, 0.44)	NA
  Rifabutin	300 once daily	25 once daily	18	0.69 (0.62, 0.76)	0.58 (0.52, 0.65)	0.52 (0.46, 0.59)
  Rifampin	600 once daily	150 once daily	16	0.31 (0.27, 0.36)	0.20 (0.18, 0.23)	0.11 (0.10, 0.13)
  Simeprevir	25 once daily	150 once daily	23	1.04 (0.95, 1.30)	1.12 (1.05, 1.19)	1.25 (1.16, 1.35)
  Sildenafil	50 single dose	75 once daily	16	0.92 (0.85, 0.99)	0.98 (0.92, 1.05)	1.04 (0.98, 1.09)
  Sofosbuvir/velpatasvir	400/100 once daily	10 once dailyStudy conducted with FTC/RPV/TDF.	24	0.93 (0.88,0.98)	0.95 (0.90, 1.00)	0.96 (0.90,1.03)
  Sofosbuvir/velpatasvir/voxilaprevir	400/100/100 + 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV patients.once daily	25 once daily	30	0.79 (0.74, 0.84)	0.80 (0.76, 0.85)	0.82 (0.77, 0.87)

  Table 10 Changes in Pharmacokinetic Parameters for TAF in the Presence of the Coadministered Drug in Healthy Participants

  Coadministered Drug	Dose of Coadministered Drug (mg)	TAF (mg)	N	Mean Ratio of Tenofovir Alafenamide Pharmacokinetic Parameters (90% CI); No Effect = 1.00
  				Cmax	AUC	Cmin
  CI=Confidence Interval; N=maximum number of participants with data; NA=Not Available
  CobicistatIncreases TAF exposure via inhibition of intestinal P-glycoprotein.	150 once daily	8 once daily	12	2.83 (2.20, 3.65)	2.65 (2.29, 3.07)	NA
  Ledipasvir/Sofosbuvir	90/400 once daily	25 once dailyStudy conducted with ODEFSEY (FTC/RPV/TAF).	42	1.03 (0.94, 1.14)	1.32 (1.25, 1.40)	NA
  Sofosbuvir/velpatasvir/voxilaprevir	400/100/100 + 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in patients with HCV.once daily	25 once daily	30	1.32 (1.17, 1.48)	1.52 (1.43,1.61)	NA

  Table 11 Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV in Healthy Participants

  Coadministered Drug	Dose/Schedule			Mean Ratio of Coadministered Drug Pharmacokinetic Parameters With/Without RPV (90% CI); No Effect = 1.00
  	Coadministered Drug (mg)	RPV (mg)	N	Cmax	AUC	Cmin
  CI=Confidence Interval; N=maximum number of participants with data; NA=Not Available
  Acetaminophen	500 single dose	150 once daily25 mg, 75 mg, and 150 mg of RPV is 1, 3, and 6 times the recommended dose of RPV in ODEFSEY, respectively.	16	0.97 (0.86, 1.10)	0.92 (0.85, 0.99)	NA
  Atorvastatin	40 once daily	150 once daily	16	1.35 (1.08, 1.68)	1.04 (0.97, 1.12)	0.85 (0.69, 1.03)
  2-hydroxy-atorvastatin				1.58 (1.33, 1.87)	1.39 (1.29, 1.50)	1.32 (1.10, 1.58)
  4-hydroxy-atorvastatin				1.28 (1.15, 1.43)	1.23 (1.13, 1.33)	NA
  Chlorzoxazone	500 single dose taken 2 hours after RPV	150 once daily	16	0.98 (0.85, 1.13)	1.03 (0.95, 1.13)	NA
  Digoxin	0.5 single dose	25 once dailyStudy conducted with RPV.	22	1.06 (0.97, 1.17)	0.98 (0.93, 1.04)AUC(0–last).	NA
  Ethinylestradiol	0.035 once daily	25 once daily	17	1.17 (1.06, 1.30)	1.14 (1.10, 1.19)	1.09 (1.03, 1.16)
  Norethindrone	1 mg once daily			0.94 (0.83, 1.06)	0.89 (0.84, 0.94)	0.99 (0.90, 1.08)
  Ketoconazole	400 once daily	150 once daily	14	0.85 (0.80, 0.90)	0.76 (0.70, 0.82)	0.34 (0.25, 0.46)
  Ledipasvir	90 once daily	25 once dailyStudy conducted with ODEFSEY (FTC/RPV/TAF).	41	1.01 (0.97, 1.05)	1.02 (0.97, 1.06)	1.02 (0.98, 1.07)
  Sofosbuvir	400 once daily	25 once daily	41	0.96 (0.89, 1.04)	1.05 (1.01, 1.09)	NA
  GS-331007The predominant circulating nucleoside metabolite of sofosbuvir.				1.08 (1.05, 1.11)	1.08 (1.06, 1.10)	1.10 (1.07, 1.12)
  R(-) methadone	60–100 once daily, individualized dose	25 once daily	13	0.86 (0.78, 0.95)	0.84 (0.74, 0.95)	0.78 (0.67, 0.91)
  S(+) methadone				0.87 (0.78, 0.97)	0.84 (0.74, 0.96)	0.79 (0.67, 0.92)
  Metformin	850 single dose	25 once daily	20	1.02 (0.95, 1.10)	0.97 (0.90,1.06)N (maximum number of participants with data for AUC(0–∞)=15)	NA
  Rifampin	600 once daily	150 once daily	16	1.02 (0.93, 1.12)	0.99 (0.92, 1.07)	NA
  25-desacetylrifampin				1.00 (0.87, 1.15)	0.91 (0.77, 1.07)	NA
  Simeprevir	150 once daily	25 once daily	21	1.10 (0.97, 1.26)	1.06 (0.94, 1.19)	0.96 (0.83, 1.11)
  Sildenafil	50 single dose	75 once daily	16	0.93 (0.80, 1.08)	0.97 (0.87, 1.08)	NA
  N -desmethyl-sildenafil				0.90 (0.80, 1.02)	0.92 (0.85, 0.99)	NA
  Sofosbuvir GS-331007	400 once daily	25 once dailyStudy conducted with FTC/RPV/TDF.	24	1.09 (0.95, 1.25) 0.96 (0.90, 1.01)	1.16 (1.10, 1.24) 1.04 (1.00, 1.07)	NA 1.12 (1.07, 1.17)
  Velpatasvir	100 once daily	25 once daily	24	0.96 (0.85, 1.10)	0.99 (0.88, 1.11)	1.02 (0.91, 1.15)
  Sofosbuvir	400 once daily	25 once daily	30	0.95 (0.86, 1.05)	1.01 (0.97, 1.06)	NA
  GS-331007				1.02 (0.98, 1.06)	1.04 (1.01, 1.06)	NA
  Velpatasvir	100 once daily	25 once daily	30	1.05 (0.96, 1.16)	1.01 (0.94, 1.07)	1.01 (0.95, 1.09)
  Voxilaprevir	100 + 100 once daily	25 once daily	30	0.96 (0.84, 1.11)	0.94 (0.84, 1.05)	1.02 (0.92, 1.12)

  Table 12 Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TAF in Healthy Participants

  Coadministered Drug	Dose of Coadministered Drug (mg)	TAF (mg)	N	Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
  				Cmax	AUC	Cmin
  CI=Confidence Interval; N=maximum number of participants with data; NA=Not Available
  MidazolamA sensitive CYP3A4 substrate.	2.5 single dose, orally	25 once dailyStudy conducted with TAF.	18	1.02 (0.92, 1.13)	1.13 (1.04, 1.23)	NA
  	1 single dose, IV			0.99 (0.89, 1.11)	1.08 (1.04, 1.13)	NA
  LedipasvirStudy conducted with ODEFSEY (FTC/RPV/TAF).	90/400 once daily	25 once daily	41	1.01 (0.97, 1.05)	1.02 (0.97, 1.06)	1.02 (0.98,1.07)
  Sofosbuvir				0.96 (0.89, 1.04)	1.05 (1.01, 1.09)	NA
  GS-331007 ,The predominant circulating nucleoside metabolite of sofosbuvir.				1.08 (1.05, 1.11)	1.08 (1.06, 1.10)	1.10 (1.07, 1.12)
  Norelgestromin	norgestimate 0.180/0.215/0.250 once daily/ethinyl estradiol 0.025 once daily	25 once dailyStudy conducted with FTC/TAF.	29	1.17 (1.07,1.26)	1.12 (1.07, 1.17)	1.16 (1.08,1.24)
  Norgestrel				1.10 (1.02, 1.18)	1.09 (1.01, 1.18)	1.11 (1.03,1.20)
  Ethinyl estradiol				1.22 (1.15, 1.29)	1.11 (1.07, 1.16)	1.02 (0.93,1.12)
  Sofosbuvir	400 once daily	25 once daily	30	0.95 (0.86, 1.05)	1.01 (0.97, 1.06)	NA
  GS-331007				1.02 (0.98, 1.06)	1.04 (1.01, 1.06)	NA
  Velpatasvir	100 once daily			1.05 (0.96, 1.16)	1.01 (0.94, 1.07)	1.01 (0.95,1.09)
  Voxilaprevir	100 + 100 once daily			0.96 (0.84, 1.11)	0.94 (0.84, 1.05)	1.02 (0.92,1.12)
  ).
• Pediatrics: Not recommended for patients weighing less than 25 kg. (
  8.4 Pediatric Use

  The efficacy and safety of ODEFSEY as a complete regimen for the treatment of HIV-1 was established in pediatric patients 6 years of age and older with body weight greater than or equal to 25 kg

  [see Dosage and Administration (2.2)].

  No pediatric clinical trials were conducted with ODEFSEY

  .

  Use of ODEFSEY in this age group is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with EVG+COBI in adults with HIV-1, and by the following pediatric studies conducted using the components of ODEFSEY

  [see Clinical Studies (14)]:

  • 48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 32 kg (N=36) and aged 6 to less than 12 years weighing at least 17 kg (N=18) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in antiretroviral treatment-naïve adults with HIV-1 on this regimen
    [see Adverse Reactions (6.1)and Clinical Studies (14)].
  • 48-week open-label trial of 26 virologically-suppressed pediatric participants with HIV-1 aged less than 12 years old and weighing at least 16 kg (N=26) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in virologically-suppressed adults with HIV-1 on this regimen
    [see Adverse Reactions (6.1)]
  • 48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (N=50) and virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg (N=52) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI were similar to that in adults with HIV-1 on this regimen, with the exception of a decrease from baseline in CD4+ cell counts in participants 6 to less than 12 years of age weighing at least 25 kg
    [see Adverse Reactions (6.1)and Clinical Studies (14)].

  Because it is a fixed-dose combination tablet, the dose of ODEFSEY cannot be adjusted for patients of lower age and weight. The safety and efficacy of ODEFSEY have not been established in pediatric patients weighing less than 25 kg

  [see Clinical Pharmacology (12.3)and Clinical Studies (14)]

  .
  )