Complera

COMPLERA^® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:

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

  TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

  Antiviral Activity

  Emtricitabine, Rilpivirine, and TDF:

  The triple combination of FTC, RPV, and TDF was not antagonistic in cell culture.

  Emtricitabine:

  The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC₅₀) values for FTC were in the range of 0.0013–0.64 µM. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC₅₀values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC₅₀values ranged from 0.007–1.5 µM). In drug combination studies of FTC with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, EFV, nevirapine, and RPV), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.

  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. The antiviral activity of RPV was not antagonistic when combined with the NNRTIs EFV, etravirine, or nevirapine; the N(t)RTIs abacavir, didanosine, FTC, lamivudine, stavudine, tenofovir, or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.

  Tenofovir DF:

  The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells, and peripheral blood lymphocytes. The EC₅₀values for tenofovir were in the range of 0.04–8.5 µM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC₅₀values ranged from 0.5–2.2 µM) and showed strain specific activity against HIV-2 (EC₅₀values ranged from 1.6–5.5 µM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, FTC, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, EFV, nevirapine, and RPV), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.

  Resistance

  In Cell Culture

  Emtricitabine and Tenofovir DF:

  HIV-1 isolates with reduced susceptibility to FTC or tenofovir have been selected in cell culture. Reduced susceptibility to FTC was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2–4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, FTC, lamivudine, and tenofovir.

  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.

  In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History

  In the Week 96 pooled resistance analysis for adult subjects receiving RPV or EFV in combination with FTC/TDF in the Phase 3 clinical trials C209 and C215, the emergence of resistance was greater among subjects' viruses in the RPV + FTC/TDF arm compared to the EFV + FTC/TDF arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77) of the subjects who qualified for resistance analysis (resistance analysis subjects) 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 subjects in the EFV + FTC/TDF arm who had genotypic and/or phenotypic resistance to EFV. Moreover, genotypic and/or phenotypic resistance to FTC or tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the RPV arm compared to 26% (11/43) in the EFV arm.

  Emerging NNRTI substitutions in the RPV resistance analysis of subjects' 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 FTC and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance analysis subjects than in EFV resistance analysis subjects (See Table 15).

  NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of ≤100,000 copies/mL compared to viruses from subjects with baseline viral loads of >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 FTC/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 subjects with baseline CD4+ cell counts ≥200 cells/mm³compared to the viruses from subjects with baseline CD4+ cell counts <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.

  Table 15 Proportion of Frequently Emerging Reverse Transcriptase Substitutions in the HIV-1 Virus of Resistance Analysis Adult SubjectsSubjects who qualified for resistance analysisWho Received RPV or EFV in Combination with FTC/TDF from Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis

  	C209 and C215 N=1096
  	RPV+ FTC/TDF	EFV+ FTC/TDF
  	N=550	N=546
  Subjects who Qualified for Resistance Analysis	14% (77/550)	8% (43/546)
  Subjects with Evaluable Postbaseline Resistance Data	70	31
  Emergent NNRTI SubstitutionsV90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and M230
  Any	63% (44/70)	55% (17/31)
  V90I	14% (10/70)	0
  K101E/P/T/Q	19% (13/70)	10% (3/31)
  K103N	1% (1/70)	39% (12/31)
  E138K/A/Q/G	40% (28/70)	0
  E138K+M184IThis combination of NRTI and NNRTI substitutions is a subset of those with the E138K.	30% (21/70)	0
  V179I/D	6% (4/70)	10% (3/31)
  Y181C/I/S	13% (9/70)	3% (1/31)
  V189I	9% (6/70)	0
  H221Y	10% (7/70)	0
  Emergent NRTI SubstitutionsA62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R
  Any	63% (44/70)	32% (10/31)
  M184I/V	59% (41/70)	26% (8/31)
  K65R/N	11% (8/70)	6% (2/31)
  A62V, D67N/G, K70E, Y115F, or K219E/RThese substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2), D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in RPV resistance analysis subjects.	20% (14/70)	3% (1/31)

  In Virologically Suppressed HIV-1-Infected Adult Subjects

  Study 106: Through Week 48, 4 subjects who switched to COMPLERA (4 of 469 subjects, 0.9%) and 1 subject who maintained their ritonavir-boosted protease inhibitor-based regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study drug. All 4 of the subjects who had resistance emergence on COMPLERA had evidence of FTC resistance and 3 of the subjects had evidence of RPV resistance.

  Cross Resistance

  Rilpivirine, Emtricitabine, and Tenofovir DF:

  In Cell Culture

  No significant cross-resistance has been demonstrated between RPV-resistant HIV-1 variants and FTC or tenofovir, or between FTC- or tenofovir-resistant variants and RPV.

  Rilpivirine:

  Site-Directed NNRTI Mutant Virus

  Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-fold, 15-fold, and 12-fold decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to RPV compared to 2.8-fold for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to RPV. In another study, the Y188L substitution resulted in a reduced susceptibility to RPV of 9-fold for clinical isolates and 6-fold 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.

  In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History

  Considering all 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 to EFV, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance. In a pooled 96-week analysis for adult subjects receiving RPV in combination with FTC/TDF in the Phase 3 clinical trials TMC278-C209 and TMC278-C215, 43 of the 70 (61%) RPV resistance analysis subjects with postbaseline resistance data had virus with decreased susceptibility to RPV (≥2.5 fold change). Of these, 84% (n=36/43) were resistant to EFV (≥3.3-fold change), 88% (n=38/43) were resistant to etravirine (≥3.2-fold change), and 60% (n=26/43) were resistant to nevirapine (≥6-fold change). In the EFV arm, 3 of the 15 (20%) EFV resistance analysis subjects had viruses with resistance to etravirine and RPV, and 93% (14/15) had resistance to nevirapine. Virus from subjects experiencing virologic failure on RPV in combination with FTC/TDF developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on EFV.

  Emtricitabine:

  FTC-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, EFV, nevirapine, and RPV). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V), remained sensitive to FTC. HIV-1 containing the substitutions associated with NNRTI resistance K103N or RPV-associated substitutions were susceptible to FTC.

  Tenofovir DF:

  The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to FTC and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir.

  Subjects whose virus expressed an L74V substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to TDF. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response. HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or RPV-associated substitutions, were susceptible to tenofovir.

  and

  14 CLINICAL STUDIES

  14.1 Adult Subjects

  In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History

  The efficacy of COMPLERA is based on the analyses of 48- and 96-week data from two randomized, double-blind, controlled studies (Study C209 [ECHO] and TRUVADA subset of Study C215 [THRIVE]) in treatment-naïve, HIV-1-infected subjects (N=1368). The studies are identical in design with the exception of the background regimen (BR). Subjects were randomized in a 1:1 ratio to receive either RPV 25 mg (N=686) once daily or EFV 600 mg (N=682) once daily in addition to a BR. In Study C209 (N=690), the BR was FTC/TDF. In Study C215 (N=678), the BR consisted of 2 NRTIs: FTC/TDF (60%, n=406), lamivudine/zidovudine (30%, n=204), or abacavir + lamivudine (10%, n=68).

  For subjects who received FTC/TDF (N=1096) in studies C209 and C215, the mean age was 37 years (range 18–78), 78% were male, 62% were White, 24% were Black, and 11% were Asian. The mean baseline CD4+ cell count was 265 cells/mm³(range 1–888) and 31% had CD4+ cell counts <200 cells/mm³. The median baseline plasma HIV-1 RNA was 5 log₁₀copies/mL (range 2–7). Subjects were stratified by baseline HIV-1 RNA. Fifty percent of subjects had baseline viral load ≤100,000 copies/mL, 39% of subjects had baseline viral load between 100,000 copies/mL to 500,000 copies/mL, and 11% of subjects had baseline viral load >500,000 copies/mL.

  Treatment outcomes through 96 weeks for the subset of subjects receiving FTC/TDF in studies C209 and C215 (Table 16) are generally consistent with treatment outcomes for all participating subjects (presented in the prescribing information for Edurant). The incidence of virologic failure was higher in the RPV arm than the EFV arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.

  Table 16 Pooled Virologic Outcome of Randomized Treatment of Studies C209 and C215 at Week 96 in Adult Subjects With No Antiviral Treatment History in Combination with FTC/TDF) at Week 96Analyses were based on the last observed viral load data within the Week 96 window (Week 90–103).

  	RPV+ FTC/TDF	EFV+ FTC/TDF
  	N=550	N=546
  HIV-1 RNA <50 copies/mLPredicted difference (95% CI) of response rate is 0.5% (–4.5% to 5.5%) at Week 96.	77%	77%
  HIV-1 RNA ≥50 copies/mLIncludes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral load value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol.	14%	8%
  No Virologic Data at Week 96 Window Reasons
  Discontinued study due to adverse event or deathIncludes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.	4%	9%
  Discontinued study for other reasonsIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.and the last available HIV-1 RNA <50 copies/mL (or missing)	4%	6%
  Missing data during window but on study	<1%	<1%
  HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL)
  ≤100,000	83%	80%
  >100,000	71%	74%
  HIV-1 RNA ≥50 copies/mL by Baseline HIV-1 RNA (copies/mL)
  ≤100,000	7%	5%
  >100,000	22%	12%
  HIV-1 RNA <50 copies/mL by Baseline CD4+ Cell Count (cells/mm3)
  <200	68%	72%
  ≥200	82%	79%
  HIV-1 RNA ≥50 copies/mL by Baseline CD4+ Cell Count (cells/mm3)
  <200	27%	12%
  ≥200	8%	7%

  Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from baseline at Week 96 was 226 cells/mm³for RPV + FTC/TDF-treated subjects and 223 cells/mm³for EFV + FTC/TDF-treated subjects.

  In Virologically Suppressed HIV-1-Infected Adult Subjects

  The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination with two NRTIs to COMPLERA was evaluated in Study 106, a randomized, open-label study in virologically suppressed HIV-1-infected adults. Subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of COMPLERA, and must have been suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to COMPLERA at baseline (COMPLERA arm, N=317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, N=159) and then switch to COMPLERA for an additional 24 weeks (N=52). Subjects had a mean age of 42 years (range 19–73), 88% were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino. The mean baseline CD4+ cell count was 584 cells/mm³(range 42–1484). Randomization was stratified by use of TDF and/or lopinavir/ritonavir in the baseline regimen.

  Treatment outcomes are presented in Table 17.

  Table 17 Virologic Outcomes of Study GS-US-264-0106 in Virologically Suppressed Subjects

  	COMPLERA	Stayed on Baseline Regimen (SBR)
  	Week 48Week 48 window is between Day 295 and 378 (inclusive).	Week 24For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to COMPLERA, the Week 24 window is between Day 127 and first dose day on COMPLERA.
  	N=317	N=159
  HIV-1 RNA <50 copies/mLPredicted difference (95% CI) of response rate for switching to COMPLERA at Week 48 compared to staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study design) is –0.7% (–6.4% to 5.1%).	89% (283/317)	90% (143/159)
  HIV-1 RNA ≥50 copies/mLIncludes subjects who had HIV-1 RNA ≥50 copies/mL in the time window, subjects who discontinued early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event or death and at the time of discontinuation had a viral load value of ≥50 copies/mL.	3% (8/317)	5% (8/159)
  No Virologic Data at Week 24 Window
  Discontinued study drug due to AE or deathIncludes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.	2% (7/317)	0%
  Discontinued study drug due to other reasons and last available HIV-1 RNA <50 copies/mLIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.	5% (16/317)	3% (5/159)
  Missing data during window but on study drug	1% (3/317)	2% (3/159)

  14.2 Pediatric Subjects

  The pharmacokinetics, safety, and efficacy of RPV in combination with other antiretroviral agents was evaluated in a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg (TMC-C213). Thirty-six (36) subjects were enrolled with a median age of 14.5 years (range 12 to 17 years), and were 55.6% female, 88.9% Black, and 11.1% Asian. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had baseline HIV RNA ≤100,000 copies/mL. The baseline characteristics and efficacy outcomes at Week 48 are further described below for the 20 subjects.

  The median baseline plasma HIV-1 RNA and CD4+ cell count were 49,550 (range 2060 to 92,600 copies/mL) and 437.5 cells/mm³(range 123 to 983 cells/mm³), respectively. At Week 48, 80% (16/20) of the subjects had HIV RNA <50 copies/mL, 15% (3/20) had HIV RNA ≥50 copies/mL, and one subject discontinued therapy prior to Week 48 and before reaching virologic suppression (HIV RNA <50 copies/mL). At Week 48, the mean increase in CD4+ cell count from baseline was 225 cells/mm³.

  ]
  .

• Testing: Prior to or when initiating COMPLERA, test for hepatitis B virus infection. Prior to initiation and during treatment with COMPLERA, 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 COMPLERA

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

  [see Warnings and Precautions (5.1)].

  Prior to initiation of COMPLERA, and during treatment with COMPLERA, 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 in adults and pediatric patients weighing at least 35 kg: One tablet taken orally once daily with food. (
  2.2 Recommended Dosage

  COMPLERA is a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of COMPLERA in adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with food

  [see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)].
  )
• For pregnant patients who are already on COMPLERA 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 COMPLERA prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of COMPLERA taken once daily may be continued. Lower exposures of rilpivirine, a component of COMPLERA, 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: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (
  2.4 Not Recommended in Patients with Moderate or Severe Renal Impairment

  COMPLERA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute)

  [see Warnings and Precautions (5.5)and Use in Specific Populations (8.6)]

  .
  )
• Recommended dosage with rifabutin coadministration: an additional 25 mg tablet of rilpivirine (Edurant) once per day taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration. (
  2.5 Recommended Dosage with Rifabutin Coadministration

  If COMPLERA is coadministered with rifabutin, take an additional 25 mg tablet of rilpivirine (Edurant^®) with COMPLERA once daily with a meal for the duration of the rifabutin coadministration

  [see Drug Interactions (7.6)and Clinical Pharmacology (12.3)]

  .
  ,
  7.6 Significant Drug Interactions

  Important drug interaction information for COMPLERA is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with COMPLERA as a combination product, or are potential drug interactions

  [see Clinical Pharmacology (12.3)

  ,

  Tables 9–14]

  . For list of contraindicated drugs,

  [see Contraindications (4)].

  Table 4 SignificantThis table is not all inclusive.Drug Interactions

  Concomitant Drug Class: Drug Name	Effect on ConcentrationIncrease = ↑; Decrease = ↓; No Effect = ↔	Clinical Comment
  Antacids: antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate)	↔ RPV (antacids taken at least 2 hours before or at least 4 hours after RPV) ↓ RPV (concomitant intake)	Administer antacids at least 2 hours before or at least 4 hours after COMPLERA.
  Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin	↓ RPV	Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
  Antimycobacterials: rifampin rifapentine	↓ RPV	Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
  rifabutin	↓ RPVThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted.	If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.
  Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ RPV ,This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. ↓ ketoconazole ,	No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
  Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment)	↓ RPV	Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
  Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir	↑ tenofovir	Patients receiving COMPLERA concomitantly with HARVONI®(ledipasvir/sofosbuvir), EPCLUSA®(sofosbuvir/velpatasvir), or VOSEVI®(sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF.
  H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ RPV , (famotidine taken 12 hours before RPV or 4 hours after RPV) ↓ RPV , (famotidine taken 2 hours before RPV)	Administer H2-receptor antagonists at least 12 hours before or at least 4 hours after COMPLERA.
  Herbal Products: St John's wort ( Hypericum perforatum )	↓ RPV	Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
  Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	↑ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Where possible, alternatives such as azithromycin should be considered.
  Narcotic Analgesics : methadone	↓ R(–) methadone ↓ S(+) methadone ↔ RPV ↔ methadone (when used with tenofovir)	No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
  Proton Pump Inhibitors: e.g., dexlansoprazole esomeprazole lansoprazole omeprazole pantoprazole rabeprazole	↓ RPV	Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
  ,
  12.3 Pharmacokinetics

  COMPLERA:

  Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing COMPLERA to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34).

  Single-dose administration of COMPLERA tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).

  Absorption, Distribution, Metabolism, and Excretion

  The pharmacokinetic properties of the components of COMPLERA are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6.

  Table 5 Pharmacokinetic Properties of the Components of COMPLERA

  	RPV	FTC	Tenofovir
  NC=Not Calculated
  Absorption
  Tmax(h)	4–5	1–2	1
  % Fasted oral bioavailabilityMedian	NC	93	25Oral bioavailability of tenofovir from VIREAD.
  Effect of a light meal (relative to fasting)Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. COMPLERA light meal = 390 kcal, 12 g fat; COMPLERA standard meal = 540 kcal, 21 g fat. High fat meal not evaluated. Increase = ↑; Decrease = ↓; No Effect= ↔	↑9%	↔	↑28%
  Effect of a standard meal (relative to fasting)	↑16%	↔	↑38%
  Distribution
  % Bound to human plasma proteins	~99	<4	<0.7
  Source of protein binding data	In vitro	In vitro	In vitro
  Metabolism
  Metabolism	CYP3A	Not significantly metabolized
  Elimination
  Major route of elimination	Metabolism	Glomerular filtration and active tubular secretion
  CLrenalMean ± SD(mL/min)	NC	213±89	243±33
  t1/2(h)t1/2values refer to median terminal plasma half-life.	50	10	17
  % Of dose excreted in urineDosing in mass balance studies: FTC (single dose administration of [14C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [14C] RPV); mass balance study not conducted for tenofovir.	6	86	70−80
  % Of dose excreted in feces	85	~14	NC

  Table 6 Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected Adults

  Parameter Mean ± SD	RPVPopulation PK estimates of RPV 25 mg once daily in antiretroviral treatment-naïve HIV-1-infected adult subjects (pooled data from Phase 3 trials through Week 96; n=679)	FTCMultiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n=20)	TenofovirSingle 300 mg dose of TDF to HIV-1-infected subjects in the fasted state
  NA=Not Applicable; SD=Standard Deviation
  Cmax(μg/mL)	NA	1.80±0.72Data presented as steady state values	0.30±0.09
  AUCtau(μg∙hr/mL)	2.24±0.85	10.0±3.12	2.29±0.69AUC0–24h
  C0h(μg/mL)	0.08±0.04	0.09±0.07	NA

  Specific Populations

  Geriatric Patients

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

  [see Use in Specific Populations (8.5)].

  Pediatric Patients

  Pediatric trials have not been conducted using COMPLERA tablets. Pediatric information is based on trials conducted with the individual components of COMPLERA

  [see Use in Specific Populations (8.4)]

  .

  Emtricitabine:

  The pharmacokinetics of FTC at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg FTC capsule. Mean (± SD) C_maxand AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg∙hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.

  Rilpivirine:

  The pharmacokinetics of RPV in antiretroviral treatment-naïve HIV-1- infected pediatric subjects 12 to less than 18 years of age receiving RPV 25 mg once daily were comparable to those in treatment-naïve HIV-1-infected adults receiving RPV 25 mg once daily (See Table 7). There was no clinically significant impact of body weight on RPV pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg).

  Table 7 Population Pharmacokinetic Estimates of RPV 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48)

  Parameter	RPV 25 mg once daily N=34
  AUC24h(ng∙h/mL)
  Mean ± Standard Deviation	2424 ± 1024
  Median (Range)	2269 (417−5166)
  C0h(ng/mL)
  Mean ± Standard Deviation	85 ± 40
  Median (Range)	79 (7−202)

  Tenofovir DF:

  Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1-infected pediatric subjects (12 to less than 18 years). Mean (± SD) C_maxand AUC_tauare 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg∙hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg.

  Gender

  No clinically relevant pharmacokinetic differences have been observed based on gender for FTC, RPV, and TDF.

  Race

  Emtricitabine:

  No pharmacokinetic differences due to race have been identified following the administration of FTC.

  Rilpivirine:

  Population pharmacokinetic analysis of RPV in HIV-1-infected subjects indicated that race had no clinically relevant effect on the exposure to RPV.

  Tenofovir DF:

  There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF.

  Patients with Renal Impairment

  Emtricitabine and Tenofovir DF:

  The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, C_maxand AUC of FTC and tenofovir were increased

  [see Warnings and Precautions (5.5)and Use in Specific Populations (8.6)]

  .

  Rilpivirine:

  Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with 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, and RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction

  [see Use in Specific Populations (8.6)]

  .

  Patients with Hepatic Impairment

  Emtricitabine:

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

  Rilpivirine:

  RPV is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. RPV has not been studied in subjects with severe hepatic impairment (Child-Pugh score C)

  [see Use in Specific Populations (8.7)]

  .

  Tenofovir DF:

  The pharmacokinetics of tenofovir following a 300 mg dose of TDF have been studied in non-HIV-infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.

  Hepatitis B and/or Hepatitis C Virus Coinfection

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

  Pregnancy and Postpartum

  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 RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy and Postpartum

  Pharmacokinetics of total RPV (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	2,714 ± 1,535	1,792 ± 711	1,762 ± 662

  Drug Interaction Studies

  Rilpivirine:

  RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of COMPLERA and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of COMPLERA and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of COMPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs.

  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.

  Emtricitabine and Tenofovir DF:

  In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving FTC and tenofovir with other medicinal products is low.

  FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug

  [see Drug Interactions (7.4, 7.6)]

  .

  Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

  The drug interaction studies described in Tables 9–14 were conducted with COMPLERA (RPV/FTC/TDF) or the components of COMPLERA (RPV, FTC, or TDF) administered individually.

  The effects of coadministration of other drugs on the AUC, C_max, and C_minvalues of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, C_max, and C_minvalues of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see

  Drug Interactions (7)

  .

  Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered Drugs

  Coadministered Drug	Dose of Coadministered Drug (mg)	RPV Dose (mg)	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of RPV Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Acetaminophen	500 single dose	150 once dailyThe interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug.	16	↑9 (↑1 to ↑18)	↑16 (↑10 to ↑22)	↑26 (↑16 to ↑38)
  Atorvastatin	40 once daily	150 once daily	16	↓9 (↓21 to ↑6)	↓10 (↓19 to ↓1)	↓10 (↓16 to ↓4)
  Chlorzoxazone	500 single dose taken 2 hours after RPV	150 once daily	16	↑17 (↑8 to ↑27)	↑25 (↑16 to ↑35)	↑18 (↑9 to ↑28)
  Ethinyl Estradiol/ Norethindrone	0.035 once daily/1 once daily	25 once daily	16	↔Study conducted with COMPLERA (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir).	↔	↔
  Famotidine	40 single dose taken 12 hours before RPV	150 single dose	24	↓1 (↓16 to ↑16)	↓9 (↓22 to ↑7)	NA
  	40 single dose taken 2 hours before RPV	150 single dose	23	↓85 (↓88 to ↓81)	↓76 (↓80 to ↓72)	NA
  	40 single dose taken 4 hours after RPV	150 single dose	24	↑21 (↑6 to ↑39)	↑13 (↑1 to ↑27)	NA
  Ketoconazole	400 once daily	150 once daily	15	↑30 (↑13 to ↑48)	↑49 (↑31 to ↑70)	↑76 (↑57 to ↑97)
  Ledipasvir/ Sofosbuvir	90/400 once daily	25 once daily	14	↓3 (↓12 to ↑7)	↑2 (↓6 to ↑11)	↑12 (↑3 to ↑21)
  Methadone	60–100 once daily individualized dose	25 once daily	12	↔Comparison based on historic controls.	↔	↔
  Omeprazole	20 once daily	150 once daily	16	↓40 (↓52 to ↓27)	↓40 (↓49 to ↓29)	↓33 (↓42 to ↓22)
  Rifabutin	300 once daily	25 once daily	18	↓31 (↓38 to ↓24)	↓42 (↓48 to ↓35)	↓48 (↓54 to ↓41)
  	300 once daily	50 once daily	18	↑43 (↑30 to ↑56)Reference arm for comparison was 25 mg q.d. RPV administered alone.	↑16 (↑6 to ↑26)	↓7 (↓15 to↑1)
  Rifampin	600 once daily	150 once daily	16	↓69 (↓73 to ↓64)	↓80 (↓82 to ↓77)	↓89 (↓90 to ↓87)
  Simeprevir	25 once daily	150 once daily	23	↑ 4 (↓ 5 to ↑ 13)	↑ 12 (↑ 5 to ↑ 19)	↑ 25 (↑ 16 to ↑ 35)
  Sildenafil	50 single dose	75 once daily	16	↓8 (↓15 to ↓1)	↓2 (↓8 to ↑5)	↑4 (↓2 to ↑9)
  Sofosbuvir/ Velpatasvir	400/100 once daily	25 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA (sofosbuvir/velpatasvir).	24	↓7 (↓12 to ↓2)	↓5 (↓10 to 0)	↓4 (↓10 to ↑3)
  Sofosbuvir/ Velpatasvir/ VoxilaprevirStudy conducted with ODEFSEY®(FTC/RPV/tenofovir alafenamide).	400/100/100 + 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.once daily	25 once daily	30	↓21 (↓26 to ↓16)	↓20 (↓24 to ↓15)	↓18 (↓23 to ↓13)
  TDF	300 once daily	150 once daily	16	↓4 (↓19 to ↑13)	↑1 (↓13 to ↑18)	↓1 (↓17 to ↑16)

  Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drugs

  Coadministered Drug	Dose of Coadministered Drug (mg)	FTC Dose (mg)	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of FTC Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Famciclovir	500 × 1	200 × 1	12	↔	↔	NA
  Ledipasvir/ Sofosbuvir	90/400 once daily	200 once dailyStudy conducted with COMPLERA coadministered with HARVONI.	15	↑2 (↓2 to ↑6)	↑5 (↑2 to ↑8)	↑6 (↓3 to ↑15)
  Sofosbuvir/ Velpatasvir	400/100 once daily	200 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA.	24	↓5 (↓10 to 0)	↓1 (↓3 to ↑2)	↑5 (↓1 to ↑11)
  Sofosbuvir/ Velpatasvir/ Voxilaprevir	400/100/100 + VoxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.100 once daily	200 once dailyStudy conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide).	30	↓12 (↓17 to ↓7)	↓7 (↓10 to ↓4)	↑7 (↑1 to ↑14)
  TDF	300 once daily × 7 days	200 once daily × 7 days	17	↔	↔	↑ 20 (↑ 12 to ↑ 29)

  Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drugs

  Coadministered Drug	Dose of Coadministered Drug (mg)	TDF Dose (mg)Subjects received VIREAD 300 mg daily.	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of Tenofovir Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Entecavir	1 once daily × 10 days	300 once daily		↔	↔	↔
  Emtricitabine	200 once daily × 7 days	300 once daily × 7 days	17	↔	↔	↔
  Ledipasvir/ Sofosbuvir	90/400 once daily × 10 days	300 once dailyStudy conducted with COMPLERA coadministered with HARVONI.	14	↑ 32 (↑ 25 to ↑ 39 )	↑ 40 (↑ 31 to ↑ 50 )	↑ 91 (↑ 74 to ↑ 110)
  Sofosbuvir/ Velpatasvir	400/100 once daily	300 once daily	24	↑ 44 (↑ 33 to ↑ 55)	↑ 40 (↑ 34 to ↑ 46)	↑ 84 (↑ 76 to ↑ 92)
  Tacrolimus	0.05 mg/kg twice daily × 7 days	300 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA.	21	↑ 13 (↑ 1 to ↑ 27)	↔	↔

  Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV

  Coadministered Drug	Dose of Coadministered Drug (mg)	RPV Dose (mg)	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA = not available
  Acetaminophen	500 single dose	150 once dailyThe Interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily).	16	↓ 3 (↓ 14 to ↑ 10)	↓ 8 (↓ 15 to ↓ 1)	NA
  Atorvastatin	40 once daily	150 once daily	16	↑ 35 (↑ 8 to ↑ 68)	↑ 4 (↓ 3 to ↑ 12)	↓ 15 (↓ 31 to ↑ 3)
  2-hydroxy-atorvastatin			16	↑ 58 (↑ 33 to ↑ 87)	↑ 39 (↑ 29 to ↑ 50)	↑ 32 (↑ 10 to ↑ 58)
  4-hydroxy-atorvastatin			16	↑ 28 (↑ 15 to ↑ 43)	↑ 23 (↑ 13 to ↑ 33)	NA
  Chlorzoxazone	500 single dose taken 2 hours after RPV	150 once daily	16	↓ 2 (↓ 15 to ↑ 13)	↑ 3 (↓ 5 to ↑ 13)	NA
  Digoxin	0.5 single dose	25 once daily	22	↑ 6 (↓ 3 to ↑ 17)	↓ 2 (↓ 7 to ↑ 4)	NA
  Ethinyl estradiol	0.035 once daily	25 once daily	17	↑ 17 (↑ 6 to ↑ 30)	↑ 14 (↑ 10 to ↑ 19)	↑ 9 (↑ 3 to ↑ 16)
  Norethindrone	1 mg once daily			↓ 6 (↓ 17 to ↑ 6)	↓ 11 (↓ 16 to ↓ 6)	↓ 1 (↓ 10 to ↑ 8)
  Ketoconazole	400 once daily	150 once daily	14	↓ 15 (↓ 20 to ↓ 10)	↓ 24 (↓ 30 to ↓ 18)	↓ 66 (↓ 75 to ↓ 54)
  Ledipasvir	90 once daily	25 once daily	41	↑ 1 (↓ 3 to ↑ 5)	↑ 2 (↓ 3 to ↑ 6)	↑ 2 (↓ 2 to ↑ 7)
  R(-) methadone	60−100 once daily individualized dose	25 once daily	13	↓ 14 (↓ 22 to ↓ 5)	↓ 16 (↓ 26 to ↓ 5)	↓ 22 (↓ 33 to ↓ 9)
  S(+) methadone			13	↓ 13 (↓ 22 to ↓ 3)	↓ 16 (↓ 26 to ↓ 4)	↓ 21 (↓ 33 to ↓ 8)
  Metformin	850 single dose	25 once daily	20	↑ 2 (↓ 5 to ↑ 10)	↓ 3 (↓ 10 to ↑ 6)	NA
  Omeprazole	20 once daily	150 once daily	15	↓ 14 (↓ 32 to ↑ 9)	↓ 14 (↓ 24 to ↓ 3)	NA
  Rifampin	600 once daily	150 once daily	16	↑ 2 (↓ 7 to ↑ 12)	↓ 1 (↓ 8 to ↑ 7)	NA
  25-desacetylrifampin			16	↔ (↓ 13 to ↑ 15)	↓ 9 (↓ 23 to ↑ 7)	NA
  Simeprevir	150 once daily	25 once daily	21	↑ 10 (↓ 3 to ↑ 26)	↑ 6 (↓ 6 to ↑ 19)	↓ 4 (↓ 17 to ↑ 11)
  Sildenafil	50 single dose	75 once daily	16	↓ 7 (↓ 20 to ↑ 8)	↓ 3 (↓ 13 to ↑ 8)	NA
  N -desmethyl-sildenafil				↓ 10 (↓ 20 to ↑ 2)	↓ 8 (↓ 15 to ↓ 1)	NA
  Sofosbuvir	400 once daily	25 once daily	24	↑ 9 (↓ 5 to ↑ 25)	↑ 16 (↑ 10 to ↑ 24)	NA
  GS-331007The predominant circulating nucleoside metabolite of sofosbuvir.				↓ 4 (↓ 10 to ↑ 1)	↑ 4 (0 to ↑ 7)	↑ 12 (↑ 7 to ↑ 17)
  Velpatasvir	100 once daily	25 once daily	24	↓ 4 (↓ 15 to ↑ 10)	↓ 1 (↓ 12 to ↑ 11)	↑ 2 (↓ 9 to ↑ 15)
  Sofosbuvir	400 once daily	25 once dailyStudy conducted with ODEFSEY.	30	↓ 5 (↓ 14 to ↑ 5)	↑ 1 (↓ 3 to ↑ 6)	NA
  GS-331007				↑ 2 (↓ 2 to ↑ 6)	↑ 4 (↑ 1 to ↑ 6)	NA
  Velpatasvir	100 once daily	25 once daily	30	↑ 5 (↓ 4 to ↑ 16)	↑ 1 (↓ 6 to ↑ 7)	↑ 1 (↓ 5 to ↑ 9)
  Voxilaprevir	100 + 100 once daily	25 once daily	30	↓ 4 (↓ 16 to ↑ 11)	↓ 6 (↓ 16 to ↑ 5)	↑ 2 (↓ 8 to ↑ 12)
  TDF	300 once daily	150 once daily	16	↑ 19 (↑ 6 to ↑ 34)	↑ 23 (↑ 16 to ↑ 31)	↑ 24 (↑ 10 to ↑ 38)

  Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTC

  Coadministered Drug	Dose of Coadministered Drug (mg)	FTC Dose (mg)	NAll interaction trials conducted in healthy volunteers	Mean % Change of Coadministered Drug Pharmacokinetic ParametersNo Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Famciclovir	500 × 1	200 × 1	12	↔	↔	NA
  TDF	300 once daily × 7 days	200 once daily × 7 days	17	↔	↔	↔

  No clinically significant drug interactions have been observed between FTC and indinavir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, stavudine, and zidovudine.

  Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDF

  Coadministered Drug	Dose of Coadministered Drug (mg)	TDF Dose (mg)	NAll interaction trials conducted in healthy volunteers	Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Emtricitabine	200 once daily × 7 days	300 once daily × 7 days	17	↔	↔	↑ 20 (↑ 12 to ↑ 29)
  Entecavir	1 once daily × 10 days	300 once daily	28	↔	↑ 13 (↑ 11 to ↑ 15)	↔
  Tacrolimus	0.05 mg/kg twice daily × 7 days	300 once daily	21	↔	↔	↔

  No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: methadone, oral contraceptives (ethinyl estradiol/norgestimate), or ribavirin.
  )

Each COMPLERA tablet contains 200 mg of emtricitabine (FTC), 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine [RPV]), and 300 mg of tenofovir disoproxil fumarate (TDF, equivalent to 245 mg of tenofovir disoproxil).

The tablets are purplish pink, capsule shaped, film coated, debossed with "GSI" on one side, and plain faced on the other side.

• Pregnancy: Monitor viral load closely during pregnancy as rilpivirine exposures were generally lower during pregnancy. (
  2.3 Recommended Dosage During Pregnancy

  For pregnant patients who are already on COMPLERA prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of COMPLERA taken once daily may be continued. Lower exposures of rilpivirine, a component of COMPLERA, 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 COMPLERA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

  Risk Summary

  Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)

  (see Data)

  . In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period

  [see Clinical Pharmacology (12.3)].

  The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%.

  Based on the experience of HIV-1-infected pregnant individuals 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, 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 COMPLERA were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in COMPLERA and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons

  (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 COMPLERA. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of COMPLERA.

  Data

  Human Data

  Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of COMPLERA are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

  Emtricitabine:

  Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,750 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens.

  Rilpivirine:

  RPV in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant subjects on an RPV-based regimen during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six subjects. 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 subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with available HIV test results, all were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum (all 10 infants received 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 HIV–1-infected adults.

  Based on prospective reports to the APR of exposures to RPV-containing regimens during pregnancy (including over 290 exposed during first trimester and over 160 exposed in the second/third trimester), there was no significant increase in overall risk of major birth defects with RPV compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 1.0% (95% CI: 0.2% to 2.9%) and 1.2% (95% CI: 0.2% to 4.4%) following first and second/third trimester exposure, respectively, to RPV-containing regimens.

  Tenofovir DF:

  Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 3,500 exposed in the first trimester and over 1,500 exposed in the second/third trimester), there was no increase in overall risk of major birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF-containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens.

  Animal Data

  Emtricitabine:

  FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 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 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 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 times 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 DF:

  TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of COMPLERA.
  ,
  12.3 Pharmacokinetics

  COMPLERA:

  Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing COMPLERA to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34).

  Single-dose administration of COMPLERA tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).

  Absorption, Distribution, Metabolism, and Excretion

  The pharmacokinetic properties of the components of COMPLERA are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6.

  Table 5 Pharmacokinetic Properties of the Components of COMPLERA

  	RPV	FTC	Tenofovir
  NC=Not Calculated
  Absorption
  Tmax(h)	4–5	1–2	1
  % Fasted oral bioavailabilityMedian	NC	93	25Oral bioavailability of tenofovir from VIREAD.
  Effect of a light meal (relative to fasting)Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. COMPLERA light meal = 390 kcal, 12 g fat; COMPLERA standard meal = 540 kcal, 21 g fat. High fat meal not evaluated. Increase = ↑; Decrease = ↓; No Effect= ↔	↑9%	↔	↑28%
  Effect of a standard meal (relative to fasting)	↑16%	↔	↑38%
  Distribution
  % Bound to human plasma proteins	~99	<4	<0.7
  Source of protein binding data	In vitro	In vitro	In vitro
  Metabolism
  Metabolism	CYP3A	Not significantly metabolized
  Elimination
  Major route of elimination	Metabolism	Glomerular filtration and active tubular secretion
  CLrenalMean ± SD(mL/min)	NC	213±89	243±33
  t1/2(h)t1/2values refer to median terminal plasma half-life.	50	10	17
  % Of dose excreted in urineDosing in mass balance studies: FTC (single dose administration of [14C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [14C] RPV); mass balance study not conducted for tenofovir.	6	86	70−80
  % Of dose excreted in feces	85	~14	NC

  Table 6 Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected Adults

  Parameter Mean ± SD	RPVPopulation PK estimates of RPV 25 mg once daily in antiretroviral treatment-naïve HIV-1-infected adult subjects (pooled data from Phase 3 trials through Week 96; n=679)	FTCMultiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n=20)	TenofovirSingle 300 mg dose of TDF to HIV-1-infected subjects in the fasted state
  NA=Not Applicable; SD=Standard Deviation
  Cmax(μg/mL)	NA	1.80±0.72Data presented as steady state values	0.30±0.09
  AUCtau(μg∙hr/mL)	2.24±0.85	10.0±3.12	2.29±0.69AUC0–24h
  C0h(μg/mL)	0.08±0.04	0.09±0.07	NA

  Specific Populations

  Geriatric Patients

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

  [see Use in Specific Populations (8.5)].

  Pediatric Patients

  Pediatric trials have not been conducted using COMPLERA tablets. Pediatric information is based on trials conducted with the individual components of COMPLERA

  [see Use in Specific Populations (8.4)]

  .

  Emtricitabine:

  The pharmacokinetics of FTC at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg FTC capsule. Mean (± SD) C_maxand AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg∙hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.

  Rilpivirine:

  The pharmacokinetics of RPV in antiretroviral treatment-naïve HIV-1- infected pediatric subjects 12 to less than 18 years of age receiving RPV 25 mg once daily were comparable to those in treatment-naïve HIV-1-infected adults receiving RPV 25 mg once daily (See Table 7). There was no clinically significant impact of body weight on RPV pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg).

  Table 7 Population Pharmacokinetic Estimates of RPV 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48)

  Parameter	RPV 25 mg once daily N=34
  AUC24h(ng∙h/mL)
  Mean ± Standard Deviation	2424 ± 1024
  Median (Range)	2269 (417−5166)
  C0h(ng/mL)
  Mean ± Standard Deviation	85 ± 40
  Median (Range)	79 (7−202)

  Tenofovir DF:

  Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1-infected pediatric subjects (12 to less than 18 years). Mean (± SD) C_maxand AUC_tauare 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg∙hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg.

  Gender

  No clinically relevant pharmacokinetic differences have been observed based on gender for FTC, RPV, and TDF.

  Race

  Emtricitabine:

  No pharmacokinetic differences due to race have been identified following the administration of FTC.

  Rilpivirine:

  Population pharmacokinetic analysis of RPV in HIV-1-infected subjects indicated that race had no clinically relevant effect on the exposure to RPV.

  Tenofovir DF:

  There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF.

  Patients with Renal Impairment

  Emtricitabine and Tenofovir DF:

  The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, C_maxand AUC of FTC and tenofovir were increased

  [see Warnings and Precautions (5.5)and Use in Specific Populations (8.6)]

  .

  Rilpivirine:

  Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with 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, and RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction

  [see Use in Specific Populations (8.6)]

  .

  Patients with Hepatic Impairment

  Emtricitabine:

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

  Rilpivirine:

  RPV is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. RPV has not been studied in subjects with severe hepatic impairment (Child-Pugh score C)

  [see Use in Specific Populations (8.7)]

  .

  Tenofovir DF:

  The pharmacokinetics of tenofovir following a 300 mg dose of TDF have been studied in non-HIV-infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.

  Hepatitis B and/or Hepatitis C Virus Coinfection

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

  Pregnancy and Postpartum

  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 RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2^ndTrimester of Pregnancy, the 3^rdTrimester of Pregnancy and Postpartum

  Pharmacokinetics of total RPV (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	2,714 ± 1,535	1,792 ± 711	1,762 ± 662

  Drug Interaction Studies

  Rilpivirine:

  RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of COMPLERA and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of COMPLERA and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of COMPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs.

  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.

  Emtricitabine and Tenofovir DF:

  In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving FTC and tenofovir with other medicinal products is low.

  FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug

  [see Drug Interactions (7.4, 7.6)]

  .

  Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

  The drug interaction studies described in Tables 9–14 were conducted with COMPLERA (RPV/FTC/TDF) or the components of COMPLERA (RPV, FTC, or TDF) administered individually.

  The effects of coadministration of other drugs on the AUC, C_max, and C_minvalues of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, C_max, and C_minvalues of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see

  Drug Interactions (7)

  .

  Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered Drugs

  Coadministered Drug	Dose of Coadministered Drug (mg)	RPV Dose (mg)	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of RPV Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Acetaminophen	500 single dose	150 once dailyThe interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug.	16	↑9 (↑1 to ↑18)	↑16 (↑10 to ↑22)	↑26 (↑16 to ↑38)
  Atorvastatin	40 once daily	150 once daily	16	↓9 (↓21 to ↑6)	↓10 (↓19 to ↓1)	↓10 (↓16 to ↓4)
  Chlorzoxazone	500 single dose taken 2 hours after RPV	150 once daily	16	↑17 (↑8 to ↑27)	↑25 (↑16 to ↑35)	↑18 (↑9 to ↑28)
  Ethinyl Estradiol/ Norethindrone	0.035 once daily/1 once daily	25 once daily	16	↔Study conducted with COMPLERA (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir).	↔	↔
  Famotidine	40 single dose taken 12 hours before RPV	150 single dose	24	↓1 (↓16 to ↑16)	↓9 (↓22 to ↑7)	NA
  	40 single dose taken 2 hours before RPV	150 single dose	23	↓85 (↓88 to ↓81)	↓76 (↓80 to ↓72)	NA
  	40 single dose taken 4 hours after RPV	150 single dose	24	↑21 (↑6 to ↑39)	↑13 (↑1 to ↑27)	NA
  Ketoconazole	400 once daily	150 once daily	15	↑30 (↑13 to ↑48)	↑49 (↑31 to ↑70)	↑76 (↑57 to ↑97)
  Ledipasvir/ Sofosbuvir	90/400 once daily	25 once daily	14	↓3 (↓12 to ↑7)	↑2 (↓6 to ↑11)	↑12 (↑3 to ↑21)
  Methadone	60–100 once daily individualized dose	25 once daily	12	↔Comparison based on historic controls.	↔	↔
  Omeprazole	20 once daily	150 once daily	16	↓40 (↓52 to ↓27)	↓40 (↓49 to ↓29)	↓33 (↓42 to ↓22)
  Rifabutin	300 once daily	25 once daily	18	↓31 (↓38 to ↓24)	↓42 (↓48 to ↓35)	↓48 (↓54 to ↓41)
  	300 once daily	50 once daily	18	↑43 (↑30 to ↑56)Reference arm for comparison was 25 mg q.d. RPV administered alone.	↑16 (↑6 to ↑26)	↓7 (↓15 to↑1)
  Rifampin	600 once daily	150 once daily	16	↓69 (↓73 to ↓64)	↓80 (↓82 to ↓77)	↓89 (↓90 to ↓87)
  Simeprevir	25 once daily	150 once daily	23	↑ 4 (↓ 5 to ↑ 13)	↑ 12 (↑ 5 to ↑ 19)	↑ 25 (↑ 16 to ↑ 35)
  Sildenafil	50 single dose	75 once daily	16	↓8 (↓15 to ↓1)	↓2 (↓8 to ↑5)	↑4 (↓2 to ↑9)
  Sofosbuvir/ Velpatasvir	400/100 once daily	25 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA (sofosbuvir/velpatasvir).	24	↓7 (↓12 to ↓2)	↓5 (↓10 to 0)	↓4 (↓10 to ↑3)
  Sofosbuvir/ Velpatasvir/ VoxilaprevirStudy conducted with ODEFSEY®(FTC/RPV/tenofovir alafenamide).	400/100/100 + 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.once daily	25 once daily	30	↓21 (↓26 to ↓16)	↓20 (↓24 to ↓15)	↓18 (↓23 to ↓13)
  TDF	300 once daily	150 once daily	16	↓4 (↓19 to ↑13)	↑1 (↓13 to ↑18)	↓1 (↓17 to ↑16)

  Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drugs

  Coadministered Drug	Dose of Coadministered Drug (mg)	FTC Dose (mg)	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of FTC Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Famciclovir	500 × 1	200 × 1	12	↔	↔	NA
  Ledipasvir/ Sofosbuvir	90/400 once daily	200 once dailyStudy conducted with COMPLERA coadministered with HARVONI.	15	↑2 (↓2 to ↑6)	↑5 (↑2 to ↑8)	↑6 (↓3 to ↑15)
  Sofosbuvir/ Velpatasvir	400/100 once daily	200 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA.	24	↓5 (↓10 to 0)	↓1 (↓3 to ↑2)	↑5 (↓1 to ↑11)
  Sofosbuvir/ Velpatasvir/ Voxilaprevir	400/100/100 + VoxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.100 once daily	200 once dailyStudy conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide).	30	↓12 (↓17 to ↓7)	↓7 (↓10 to ↓4)	↑7 (↑1 to ↑14)
  TDF	300 once daily × 7 days	200 once daily × 7 days	17	↔	↔	↑ 20 (↑ 12 to ↑ 29)

  Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drugs

  Coadministered Drug	Dose of Coadministered Drug (mg)	TDF Dose (mg)Subjects received VIREAD 300 mg daily.	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of Tenofovir Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Entecavir	1 once daily × 10 days	300 once daily		↔	↔	↔
  Emtricitabine	200 once daily × 7 days	300 once daily × 7 days	17	↔	↔	↔
  Ledipasvir/ Sofosbuvir	90/400 once daily × 10 days	300 once dailyStudy conducted with COMPLERA coadministered with HARVONI.	14	↑ 32 (↑ 25 to ↑ 39 )	↑ 40 (↑ 31 to ↑ 50 )	↑ 91 (↑ 74 to ↑ 110)
  Sofosbuvir/ Velpatasvir	400/100 once daily	300 once daily	24	↑ 44 (↑ 33 to ↑ 55)	↑ 40 (↑ 34 to ↑ 46)	↑ 84 (↑ 76 to ↑ 92)
  Tacrolimus	0.05 mg/kg twice daily × 7 days	300 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA.	21	↑ 13 (↑ 1 to ↑ 27)	↔	↔

  Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV

  Coadministered Drug	Dose of Coadministered Drug (mg)	RPV Dose (mg)	NN=maximum number of subjects for Cmax, AUC, or Cmin	Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA = not available
  Acetaminophen	500 single dose	150 once dailyThe Interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily).	16	↓ 3 (↓ 14 to ↑ 10)	↓ 8 (↓ 15 to ↓ 1)	NA
  Atorvastatin	40 once daily	150 once daily	16	↑ 35 (↑ 8 to ↑ 68)	↑ 4 (↓ 3 to ↑ 12)	↓ 15 (↓ 31 to ↑ 3)
  2-hydroxy-atorvastatin			16	↑ 58 (↑ 33 to ↑ 87)	↑ 39 (↑ 29 to ↑ 50)	↑ 32 (↑ 10 to ↑ 58)
  4-hydroxy-atorvastatin			16	↑ 28 (↑ 15 to ↑ 43)	↑ 23 (↑ 13 to ↑ 33)	NA
  Chlorzoxazone	500 single dose taken 2 hours after RPV	150 once daily	16	↓ 2 (↓ 15 to ↑ 13)	↑ 3 (↓ 5 to ↑ 13)	NA
  Digoxin	0.5 single dose	25 once daily	22	↑ 6 (↓ 3 to ↑ 17)	↓ 2 (↓ 7 to ↑ 4)	NA
  Ethinyl estradiol	0.035 once daily	25 once daily	17	↑ 17 (↑ 6 to ↑ 30)	↑ 14 (↑ 10 to ↑ 19)	↑ 9 (↑ 3 to ↑ 16)
  Norethindrone	1 mg once daily			↓ 6 (↓ 17 to ↑ 6)	↓ 11 (↓ 16 to ↓ 6)	↓ 1 (↓ 10 to ↑ 8)
  Ketoconazole	400 once daily	150 once daily	14	↓ 15 (↓ 20 to ↓ 10)	↓ 24 (↓ 30 to ↓ 18)	↓ 66 (↓ 75 to ↓ 54)
  Ledipasvir	90 once daily	25 once daily	41	↑ 1 (↓ 3 to ↑ 5)	↑ 2 (↓ 3 to ↑ 6)	↑ 2 (↓ 2 to ↑ 7)
  R(-) methadone	60−100 once daily individualized dose	25 once daily	13	↓ 14 (↓ 22 to ↓ 5)	↓ 16 (↓ 26 to ↓ 5)	↓ 22 (↓ 33 to ↓ 9)
  S(+) methadone			13	↓ 13 (↓ 22 to ↓ 3)	↓ 16 (↓ 26 to ↓ 4)	↓ 21 (↓ 33 to ↓ 8)
  Metformin	850 single dose	25 once daily	20	↑ 2 (↓ 5 to ↑ 10)	↓ 3 (↓ 10 to ↑ 6)	NA
  Omeprazole	20 once daily	150 once daily	15	↓ 14 (↓ 32 to ↑ 9)	↓ 14 (↓ 24 to ↓ 3)	NA
  Rifampin	600 once daily	150 once daily	16	↑ 2 (↓ 7 to ↑ 12)	↓ 1 (↓ 8 to ↑ 7)	NA
  25-desacetylrifampin			16	↔ (↓ 13 to ↑ 15)	↓ 9 (↓ 23 to ↑ 7)	NA
  Simeprevir	150 once daily	25 once daily	21	↑ 10 (↓ 3 to ↑ 26)	↑ 6 (↓ 6 to ↑ 19)	↓ 4 (↓ 17 to ↑ 11)
  Sildenafil	50 single dose	75 once daily	16	↓ 7 (↓ 20 to ↑ 8)	↓ 3 (↓ 13 to ↑ 8)	NA
  N -desmethyl-sildenafil				↓ 10 (↓ 20 to ↑ 2)	↓ 8 (↓ 15 to ↓ 1)	NA
  Sofosbuvir	400 once daily	25 once daily	24	↑ 9 (↓ 5 to ↑ 25)	↑ 16 (↑ 10 to ↑ 24)	NA
  GS-331007The predominant circulating nucleoside metabolite of sofosbuvir.				↓ 4 (↓ 10 to ↑ 1)	↑ 4 (0 to ↑ 7)	↑ 12 (↑ 7 to ↑ 17)
  Velpatasvir	100 once daily	25 once daily	24	↓ 4 (↓ 15 to ↑ 10)	↓ 1 (↓ 12 to ↑ 11)	↑ 2 (↓ 9 to ↑ 15)
  Sofosbuvir	400 once daily	25 once dailyStudy conducted with ODEFSEY.	30	↓ 5 (↓ 14 to ↑ 5)	↑ 1 (↓ 3 to ↑ 6)	NA
  GS-331007				↑ 2 (↓ 2 to ↑ 6)	↑ 4 (↑ 1 to ↑ 6)	NA
  Velpatasvir	100 once daily	25 once daily	30	↑ 5 (↓ 4 to ↑ 16)	↑ 1 (↓ 6 to ↑ 7)	↑ 1 (↓ 5 to ↑ 9)
  Voxilaprevir	100 + 100 once daily	25 once daily	30	↓ 4 (↓ 16 to ↑ 11)	↓ 6 (↓ 16 to ↑ 5)	↑ 2 (↓ 8 to ↑ 12)
  TDF	300 once daily	150 once daily	16	↑ 19 (↑ 6 to ↑ 34)	↑ 23 (↑ 16 to ↑ 31)	↑ 24 (↑ 10 to ↑ 38)

  Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTC

  Coadministered Drug	Dose of Coadministered Drug (mg)	FTC Dose (mg)	NAll interaction trials conducted in healthy volunteers	Mean % Change of Coadministered Drug Pharmacokinetic ParametersNo Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Famciclovir	500 × 1	200 × 1	12	↔	↔	NA
  TDF	300 once daily × 7 days	200 once daily × 7 days	17	↔	↔	↔

  No clinically significant drug interactions have been observed between FTC and indinavir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, stavudine, and zidovudine.

  Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDF

  Coadministered Drug	Dose of Coadministered Drug (mg)	TDF Dose (mg)	NAll interaction trials conducted in healthy volunteers	Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; No Effect = ↔ (90% CI)
  				Cmax	AUC	Cmin
  NA=not available
  Emtricitabine	200 once daily × 7 days	300 once daily × 7 days	17	↔	↔	↑ 20 (↑ 12 to ↑ 29)
  Entecavir	1 once daily × 10 days	300 once daily	28	↔	↑ 13 (↑ 11 to ↑ 15)	↔
  Tacrolimus	0.05 mg/kg twice daily × 7 days	300 once daily	21	↔	↔	↔

  No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: methadone, oral contraceptives (ethinyl estradiol/norgestimate), or ribavirin.
  )
• Lactation: Breastfeeding not recommended due to the potential for HIV-1 transmission. (
  8.2 Lactation

  Risk Summary

  The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

  Based on published data, FTC and tenofovir have been shown to be present in human milk. There are no data on the presence of RPV in human milk. RPV has been shown to be present in rat milk

  (see Data)

  .

  It is not known if the components of COMPLERA affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving COMPLERA.

  Data

  Rilpivirine:

  In animals, no studies have been conducted to assess the excretion of RPV directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).
  )
• Pediatrics: Not recommended for patients weighing less than 35 kg. (
  8.4 Pediatric Use

  The safety and effectiveness of COMPLERA as a complete regimen for the treatment of HIV-1 infection was established in pediatric subjects 12 years of age and older with body weight greater than or equal to 35 kg

  [see Dosage and Administration (2.2)]

  . Use of COMPLERA in this age group weighing at least 35 kg is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection as well as data from pediatric studies of the individual components of COMPLERA (RPV, FTC, and TDF)

  [see Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

  COMPLERA should only be administered to pediatric patients with a body weight greater than or equal to 35 kg. Because COMPLERA is a fixed-dose combination tablet, the dose of COMPLERA cannot be adjusted for patients of lower weight. Safety and effectiveness for COMPLERA have not been established in pediatric patients weighing less than 35 kg

  [see Adverse Reactions (6.1)and Clinical Pharmacology (12.3)]

  .
  )