EMTRICITABINE: 3,718 Adverse Event Reports & Safety Profile

TRUVADA tablets are fixed-dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. Emtricitabine is a synthetic nucleoside analog of cytidine. Tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase. Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.

Chemical Structure Tenofovir Disoproxil

Fumarate: Tenofovir disoproxil fumarate is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[( R )-2 [[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P ∙ C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted. TRUVADA tablets are for oral administration, and are available in the following strengths: Film-coated tablet containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 167 mg of emtricitabine and 250 mg of tenofovir disoproxil fumarate (which is equivalent to 204 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 133 mg of emtricitabine and 200 mg of tenofovir disoproxil fumarate (which is equivalent to 163 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 100 mg of emtricitabine and 150 mg of tenofovir disoproxil fumarate (which is equivalent to 123 mg of tenofovir disoproxil) as active ingredients All strength of TRUVADA tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free).

The

200 mg/300 mg strength tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

The

167 mg/250 mg, 133 mg/200 mg, and 100 mg/150 mg strength tablets are coated with Opadry II Blue, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.

Chemical

Structure

AND USAGE TRUVADA is a combination of EMTRIVA and VIREAD, both nucleoside analog HIV-1 reverse transcriptase inhibitors. TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg. ( 1 ) TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. ( 1 )

1.1 Treatment of HIV-1 Infection TRUVADA ® , a combination of EMTRIVA ® and VIREAD ® , is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg <span class="opacity-50 text-xs">[see Dosage and Administration (2) and Clinical Studies (14) ]</span> . The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection:The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection: It is not recommended that TRUVADA be used as a component of a triple nucleoside regimen. TRUVADA should not be coadministered with ATRIPLA ® , COMPLERA ® , EMTRIVA, GENVOYA ® , ODEFSEY ® , STRIBILD ® , VIREAD or lamivudine-containing products <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . In treatment experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history <span class="opacity-50 text-xs">[see Microbiology (12.4) ]</span> .

1.2 Pre-Exposure Prophylaxis TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples <span class="opacity-50 text-xs">[see Clinical Studies (14.2 , 14.3) ]</span> . When considering TRUVADA for pre-exposure prophylaxis the following factors may help to identify individuals at high risk: has partner(s) known to be HIV-1 infected, or engages in sexual activity within a high prevalence area or social network and one or more of the following: inconsistent or no condom use diagnosis of sexually transmitted infections exchange of sex for commodities (such as money, food, shelter, or drugs) use of illicit drugs or alcohol dependence incarceration partner(s) of unknown HIV-1 status with any of the factors listed above When prescribing TRUVADA for pre-exposure prophylaxis, healthcare providers must: prescribe TRUVADA as part of a comprehensive prevention strategy because TRUVADA is not always effective in preventing the acquisition of HIV-1 infection <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> ; counsel all uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule because the effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 was strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> ; confirm a negative HIV-1 test immediately prior to initiating TRUVADA for a PrEP indication. If clinical symptoms consistent with acute viral infection are present and recent (&lt;1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9) ]</span> ; and screen for HIV-1 infection at least once every 3 months while taking TRUVADA for PrEP.

2 DOSAGE & ADMINISTRATION

• Testing: Prior to or when initiating emtricitabine and tenofovir disoproxil fumarate tablets test for hepatitis B virus infection. Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. ( 2.1 )
• HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP and at least once every 3 months while taking Emtricitabine and tenofovir disoproxil fumarate tablets, and upon diagnosis of any other sexually transmitted infections (STIs). ( 2.2 ) Treatment of HIV-1 Infection
• Recommended dosage in adults and pediatric patients weighing at least 35 kg: One Emtricitabine and Tenofovir Disoproxil Fumarate Tablets (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.3 )
• Recommended dosage in pediatric patients weighing at least 17 kg: One emtricitabine and tenofovir disoproxil fumarate tablets low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. ( 2.4 )
• Recommended dosage in renally impaired HIV-1 infected adult patients: o Creatinine clearance (CrCl) 30 to 49 mL/min: 1 tablet every 48 hours. ( 2.6 ) o CrCl below 30 mL/min or hemodialysis: Emtricitabine and tenofovir disoproxil fumarate tablets is not recommended. ( 2.6 ) HIV-1 Pre-Exposure Prophylaxis (PrEP)
• Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One emtricitabine and tenofovir disoproxil fumarate tablets (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.5 )
• Recommended dosage in renally impaired HIV-uninfected individuals: Emtricitabine and tenofovir disoproxil fumarate tablets is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. ( 2.6 )

2.1 Testing Prior to Initiation of Emtricitabine and Tenofovir Disoproxil Fumarate Tablets for Treatment of HIV-1 Infection or for HIV-1 PrEP Prior to or when initiating emtricitabine and tenofovir disoproxil fumarate tablets, test individuals for hepatitis B virus infection [ see Warnings and Precautions ( 5.1 )]. Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus [ see Warnings and Precautions ( 5.3 ) ].

2.2 HIV-1 Screening for Individuals Receiving Emtricitabine and Tenofovir Disoproxil Fumarate Tablets for HIV-1 PrEP Screen all individuals for HIV-1 infection immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP and at least once every 3 months while taking emtricitabine and tenofovir disoproxil fumarate tablets, and upon diagnosis of any other sexually transmitted infections (STIs) <span class="opacity-50 text-xs">[see Indications and Usage ( 1.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )]</span>. If recent (&lt;1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.4 ), and Clinical Studies ( 14.3 and 14.4 )]</span>.

2.3 Recommended Dosage for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing at Least 35 kg Emtricitabine and tenofovir disoproxil fumarate tablets is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of emtricitabine and tenofovir disoproxil fumarate tablets in adults and in pediatric patients weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

2.4 Recommended Dosage for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 17 kg and Able to Swallow a Tablet The recommended oral dosage of emtricitabine and tenofovir disoproxil fumarate tablets for pediatric patients weighing at least 17 kg and who can swallow a tablet is presented in Table 1. Tablets should be taken once daily with or without food. Weight should be monitored periodically and the emtricitabine and tenofovir disoproxil fumarate tablets dose adjusted accordingly.

Table

1 Dosing for Treatment of HIV-1 Infection in Pediatric Patients Weighing 17 kg to less than 35 kg Body Weight (kg) Dosing of E mtricitabine and Tenofovir Disoproxil Fumarate Tablets (FTC/TDF) 17 to less than 22 one 100 mg /150 mg tablet once daily 22 to less than 28 one 133 mg /200 mg tablet once daily 28 to less than 35 one 167 mg /250 mg tablet once daily

2.5 Recommended Dosage for HIV-1 PrEP in Adults and Adolescents Weighing at Least 35 kg The dosage of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food in HIV-1 uninfected adults and adolescents weighing at least 35 kg <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

2.6 Dosage Adjustment in Individuals with Renal Impairment Treatment of HIV-1 Infection Table 2 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span>. No data are available to make dosage recommendations in pediatric patients with renal impairment.

Table

2 Dosage Interval Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) a Recommended Dosing Interval ≥50 30–49 <30 (Including Patients Requiring Hemodialysis)

Every

24 hours Every 48 hours Emtricitabine and Tenofovir Disoproxil Fumarate Tablets should not be recommended. a.Calculated using ideal (lean) body weight HIV-1 PrEP Emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP is not recommended in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min [ see Warnings and Precautions ( 5.3 )]. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [ see Warnings and Precautions ( 5.3 )].

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets or to the class of NNRTIs [see Warnings and Precautions (5.7) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] :

• Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• Antimycobacterials: rifampin, rifapentine
• Glucocorticoid (systemic): dexamethasone (more than a single-dose)
• Herbal Products: St John’s wort ( Hypericum perforatum )
• Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 4 )

REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [see Warnings and Precautions (5.1) ] Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ]

Depressive

Disorders [see Warnings and Precautions (5.4) ]

New

Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5) ]

Lactic Acidosis/Severe

Hepatomegaly with Steatosis [see Warnings and Precautions (5.7) ]

Immune Reconstitution

Syndrome [see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence greater than or equal to 2%, all grades) are headache and sleep disturbances. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

Adverse

Reactions in Clinical Trials of ODEFSEY in Virologically-Suppressed Adult Participants with HIV-1 The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult participants with HIV-1 who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively. A total of 754 participants received one tablet of ODEFSEY daily [see Clinical Studies (14.1) ]. The most common adverse reactions (all Grades) reported in at least 2% of participants in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1).

Over

98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity. The proportion of participants who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF.

Table

1 Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator. (All Grades) Reported in ≥1% of Virologically-Suppressed Adults with HIV-1 in Trial 1160 or Trial 1216 (Week 48 analysis)

Adverse Reaction Trial

1160 Trial 1216 ODEFSEY (N=438) EFV/FTC/TDF (N=437) Data from Trials 1160 and 1216 do not provide an adequate basis for comparison of adverse reaction incidences between ODEFSEY and the FTC/RPV/TDF and EFV/FTC/TDF groups. ODEFSEY (N=316) FTC/RPV/TDF (N=313)

Headache

2% 1% 0 1% Sleep Disturbances 2% 1% 0 <1% Flatulence 1% <1% <1% 1% Abnormal Dreams 1% 1% 0 2% Diarrhea 1% 3% 1% 2% Nausea 1% 1% 1% 1% Renal Laboratory Tests In Trial 1216, the median baseline eGFR was 104 mL per minute for participants who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48.

In Trial

1160, the median baseline eGFR was 110 mL per minute for participants who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48.

Bone Mineral Density Effects

Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160.

In Trial

1216, mean bone mineral density (BMD) increased in participants who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in participants who remained on FTC/RPV/TDF (0.08% lumbar spine, −0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY participants and 3.0% of FTC/RPV/TDF participants. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY participants and 1.2% of FTC/RPV/TDF participants.

In Trial

1160, mean BMD increased in participants who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in participantswho remained on EFV/FTC/TDF (−0.05% lumbar spine, −0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY participants and 4.9% of EFV/FTC/TDF participants. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY participants and 3.3% of EFV/FTC/TDF participants. The long-term clinical significance of these BMD changes is not known.

Serum Lipids

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2.

Table

2 Lipid Values, Mean Change from Baseline Reported in Participants Receiving ODEFSEY, FTC/RPV/TDF and EFV/FTC/TDF in Trials 1216 and 1160 at 48 Weeks Trial 1216 Trial 1160 ODEFSEY N=316 [n=235] FTC/RPV/TDF N=314 [n=245] ODEFSEY N=438 [n=295] EFV/FTC/TDF N=437 [n=308]

Baseline Week

48 Baseline Week 48 Baseline Week 48 Baseline Week 48 mg/dL Change The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values. , Participants who received lipid-lowering agents during the treatment period were excluded. mg/dL Change , mg/dL Change , mg/dL Change , Total Cholesterol (fasted) 176 +17 171 0 193 -7 192 -3 HDL-Cholesterol (fasted) 50 +3 48 0 56 -4 55 -2 LDL-Cholesterol (fasted) 111 +13 108 +1 118 [n=296] for ODEFSEY group in Study 1160 for LDL-Cholesterol (fasted) -1 119 -1 Triglycerides (fasted) 116 +12 119 -9 139 -12 133 +3 Total Cholesterol to HDL Ratio 3.7 +0.2 3.8 +0.1 3.7 +0.2 3.8 0 Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Treatment-Naïve Adult Participants with HIV-1 In pooled 96-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reactions in participantstreated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2−4) were headache, depressive disorders, and insomnia. The proportion of participants who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).

Adrenal

Function In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the RPV group and of -0.02 (-0.48, 0.44) micrograms/dL in the EFV group. In the RPV group, 43/588 (7%) of participants with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3%) in the EFV group. Of the participants who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 participants in the RPV group and 9 participants in the EFV group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the RPV group is not known.

Adverse

Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult Participants with HIV-1 In pooled 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reaction in participants treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of participants discontinued FTC+TAF with EVG+COBI due to adverse event [see Clinical Studies (14) ] . Antiretroviral treatment-naïve adult participants treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.

Renal Laboratory

Tests In two 48-week trials in antiretroviral treatment-naïve adults with HIV-1 treated with FTC+TAF with elvitegravir (EVG) plus cobicistat (COBI) (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In clinical trials of FTC+TAF with EVG+COBI in treatment-naïve participants and in virologically-suppressed participants switched to FTC+TAF with EVG+COBI with estimated creatinine clearance greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) participants.

Bone Mineral Density

Effects In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by -1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI participants. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI participants. The long-term clinical significance of these BMD changes is not known.

Adverse

Reactions in Clinical Trials in Pediatric Participants with HIV-1 In an open-label 48-week trial (TMC278-C213 Cohort 1) of 36 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%). In an open-label 48-week trial (TMC278-C213 Cohort 2) of 18 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 6 to less than 12 years (weighing at least 17 kg) treated with RPV and other antiretrovirals, the most common adverse reactions were decreased appetite (17%), vomiting (11%), ALT increased (11%), AST increased (11%), and rash (11%). In an open-label 48-week trial (TMC278HTX2002) of 26 virologically suppressed participants with HIV-1 less than 12 years of age (weighing at least 16 kg) treated with RPV and other antiretrovirals, the most commen adverse reactions were vomiting (15%), abdominal pain (12%), nausea (8%), ALT increased (12%), AST increased (8%), and decreased appetite (8%). In a 48-week, open-label trial, 50 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (Cohort 1) and 52 virologically-suppressed pediatric participants aged 6 to less than 12 years and weighing at least 25 kg (Cohort 2) received FTC+TAF with EVG+COBI. With the exception of a decrease in the mean CD4+ cell count observed in Cohort 2 of this study, the safety profile in pediatric participants who received this combination was similar to that in adults.

Bone Mineral Density Effects

Among the pediatric participants in Cohort 1 receiving FTC+TAF with EVG+COBI, mean BMD increased from baseline to Week 48, +4.2% at the lumbar spine and +1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were -0.07 for lumbar spine and -0.20 for TBLH at Week 48. In cohort 1, one participant had significant (at least 4%) lumbar spine BMD loss at Week 48. Among the pediatric participants in Cohort 2 receiving FTC+TAF with EVG+COBI, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48.

In Cohort

2, six participants had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 participants also had at least 4% TBLH BMD loss at Week 48. Change from Baseline in CD4+ Cell Counts Although all participants in Cohort 2 receiving FTC+TAF with EVG+COBI had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 are presented in Table 3. All participants maintained their CD4+ cell counts above 400 cells/mm 3 [see Use in Specific Populations (8.4) and Clinical Studies (14.3) ].

Table

3 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to FTC+TAF with EVG+COBI Mean Change from Baseline Baseline Week 2 Week 4 Week 12 Week 24 Week 32 Week 48 CD4+ Cell Count (cells/mm 3 ) 961 (275.5) Mean (SD) -117 -114 -112 -118 -62 -66 CD4% 38 (6.4) +0.3% -0.1% -0.8% -0.8% -1.0% -0.6% Adrenal Function in Clinical Trials of RPV in Pediatric Participants In trial TMC278-C213 Cohort 1, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL. Six of 30 (20%) participants with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these participants had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known. In trial TMC278-C213 Cohort 2, basal cortisol at baseline was normal (≥9 μg/dL) for 4/18 participants, low for 13/18 participants, and missing for 1/18 participants. Among the 4 participants with normal basal cortisol at baseline, 3 participants had either normal basal cortisol levels (≥9 μg/dL) or normal cortisol levels 1 hour after ACTH stimulation (≥18.1 μg/dL) throughout the trial and/or at the last available visit (Week 24 and Week 72), and 1 participant had low basal cortisol at the last available assessment (Week 48) and no ACTH stimulation test was performed. Among the 13 participants with low basal cortisol pre-dose at baseline, 2 participants had low basal and ACTH stimulated cortisol values throughout the trial, including ACTH stimulated cortisol at baseline before starting treatment with RPV. For both participants, no adverse events suggestive for adrenal insufficiency were reported. The remaining 11 participants had normal serum cortisol values after ACTH stimulation at baseline and/or during treatment. In trial TMC278HTX2002, 15/26 participants had either normal basal cortisol (≥9 μg/dL) or normal cortisol 1 hour after ACTH stimulation (≥18.1 μg/dL), 9 had low basal cortisol on Day 1, and in 2 participants the baseline value was missing. From the 19 participants with low basal cortisol at Week 48, in 15 participants, the Week 48 serum cortisol levels returned to normal (≥248 nmol/L) after repeat serum basal cortisol testing or was normal after ACTH stimulation testing (≥500 nmol/L).

In

4 participants, the serum cortisol levels remained low after repeat serum basal cortisol testing or after ACTH stimulation testing.

At Week

48, 6 participants had normal (basal) cortisol (≥9 ug/dL) and the Week 48 result was not available for 1 participant.

6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving RPV or TAF-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Rilpivirine: Metabolism and Nutrition Disorders Weight increased Skin and Subcutaneous Tissue Disorders Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Renal and Urinary Disorders Nephrotic syndrome Tenofovir alafenamide: Skin and Subcutaneous Tissue Disorders Angioedema, urticaria, and rash Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with TRUVADA. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with TRUVADA and periodically during treatment. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) Coadministration with Other Products: Do not use with drugs containing emtricitabine, tenofovir alafenamide or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. ( 5.4 ) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.5 ) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.6 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.7 ) Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. ( 5.8 ) Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. ( 5.9 ) Management to reduce the risk of acquiring HIV-1 drug resistance: Prior to initiating TRUVADA for PrEP - if clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm negative HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. While using TRUVADA for PrEP - HIV-1 screening tests should be repeated at least every 3 months. ( 5.9 )

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient or uninfected individual with known risk factors for liver disease; however, cases have also been reported in HIV-1 infected patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient or uninfected individual who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.2 HBV Infection It is recommended that all individuals be tested for the presence of chronic hepatitis B virus (HBV) before initiating TRUVADA. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients infected with HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. HBV-uninfected individuals should be offered vaccination.

5.3 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span> . It is recommended that estimated creatinine clearance be assessed in all individuals prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA ® , it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of TRUVADA, and periodically during TRUVADA therapy. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) <span class="opacity-50 text-xs">[see Drug Interactions (7.4) ]</span> . Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir disoproxil fumarate (tenofovir DF). Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Treatment of HIV-1 Infection Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30–49 mL/min <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis. Pre-exposure Prophylaxis TRUVADA for a PrEP indication should not be used if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.4 Coadministration with Other Products TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. Do not coadminister TRUVADA with other drugs containing emtricitabine or tenofovir disoproxil fumarate, or containing tenofovir alafenamide, including ATRIPLA, COMPLERA, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, or VIREAD. Due to similarities between emtricitabine and lamivudine, do not coadminister TRUVADA with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Dutrebis (lamivudine/raltegravir) , Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Triumeq (abacavir sulfate/dolutegravir/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). Do not coadminister TRUVADA with HEPSERA (adefovir dipivoxil) Do not coadminister TRUVADA with HEPSERA (adefovir dipivoxil) .

5.5 Bone Effects of Tenofovir DF Bone Mineral Density: In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, tenofovir DF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) and VIREAD prescribing information ]</span> . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, consult the VIREAD prescribing information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization

Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [see Adverse Reactions (6.3) ] . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [see Warnings and Precautions (5.3) ].

5.6 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &quot;cushingoid appearance&quot; have been observed in HIV-1 infected patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves&apos; disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.8 Early Virologic Failure Clinical trials in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virologic failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

5.9 Comprehensive Management to Reduce the Risk of Acquiring HIV-1 Use TRUVADA for pre-exposure prophylaxis only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because TRUVADA is not always effective in preventing the acquisition of HIV-1 <span class="opacity-50 text-xs">[see Clinical Studies (14.2 and 14.3) ]</span> . Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis and gonorrhea). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior. Use TRUVADA to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TRUVADA, because TRUVADA alone does not constitute a complete treatment regimen for HIV-1 treatment <span class="opacity-50 text-xs">[see Microbiology (12.4) ]</span> ; therefore, care should be taken to minimize drug exposure in HIV-infected individuals. Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA for a PrEP indication, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash, etc.) and ask about potential exposure events (e.g., unprotected, or condom broke during sex with an HIV-1 infected partner) that may have occurred within the last month. If clinical symptoms consistent with acute viral infection are present and recent (&lt;1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. While using TRUVADA for a PrEP indication, HIV-1 screening tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed using a test approved by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection. Counsel uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials <span class="opacity-50 text-xs">[see Clinical Studies (14.2 and 14.3) ]</span> .

INTERACTIONS

• Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. ( 7.1 )
• Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.7 , 7 )

7.1 Not Recommended with Other Antiretroviral Medications Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided. This section describes clinically relevant drug interactions with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Drug interaction studies were conducted with the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (FTC, RPV, and TDF as single agents) or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product <span class="opacity-50 text-xs">[see Dosage and Administration (2) , Contraindications (4) , and Clinical Pharmacology (12.3) ]</span> .

7.2 Drugs Inducing or Inhibiting CYP3A Enzymes Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV <span class="opacity-50 text-xs">[see Contraindications (4) , Warnings and Precautions (5.7) , and Clinical Pharmacology (12.3) ]</span> . Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.

7.3 Drugs Increasing Gastric pH Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration <span class="opacity-50 text-xs">[see Contraindications (4) and Clinical Pharmacology (12.3) ]</span> .

7.4 Drugs Affecting Renal Function Because FTC and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of FTC, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs <span class="opacity-50 text-xs">[see Warnings and Precautions (5.5) ]</span> .

7.5 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) have been shown to prolong the QTc interval of the electrocardiogram <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2) ]</span> . Consider alternatives to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes.

7.6 Significant Drug Interactions Important drug interaction information for emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product, or are potential drug interactions <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , Tables 9–14]</span> . For list of contraindicated drugs, <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

Table

4 Significant This table is not all inclusive.

Drug Interactions Concomitant Drug

Class: Drug Name Effect on Concentration Increase = ↑; 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 emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. 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 ↓ RPV The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets 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 emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. 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 emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir), EPCLUSA ® (sofosbuvir/velpatasvir), or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF. H 2 -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 H 2 -receptor antagonists at least 12 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.

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 emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. 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.

7.7 Drugs with No Observed Interactions with Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir, or tacrolimus in studies conducted in healthy subjects. No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. RPV did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.