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Uses

Treatment of HIV Infection

Rilpivirine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents 12 years of age or older.

Rilpivirine usually is used in HIV nonnucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimens that include rilpivirine and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

Single-entity rilpivirine is labeled by FDA for use in conjunction with other antiretrovirals for the treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) adults and adolescents 12 years of age or older with plasma HIV-1 RNA levels of 100,000 copies/mL or less. Rilpivirine also is commercially available in fixed-combination preparations that contain emtricitabine and a tenofovir prodrug (either tenofovir alafenamide or tenofovir disoproxil fumarate [tenofovir DF]). These fixed combinations can be used in specific patient groups to decrease pill burden and improve compliance.

If an HIV NNRTI-based regimen of rilpivirine, emtricitabine, and tenofovir alafenamide is used for the treatment of HIV-1 infection, a fixed-combination preparation containing all 3 drugs (emtricitabine/rilpivirine/tenofovir alafenamide; Odefsey) is commercially available and can be used in antiretroviral-naive adults and adolescents 12 years of age or older weighing at least 35 kg with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less. Emtricitabine/rilpivirine/tenofovir alafenamide also can be used to replace a stable antiretroviral regimen in certain antiretroviral-experienced (previously treated) patients who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL). Emtricitabine/rilpivirine/tenofovir alafenamide is used alone as a complete regimen for the treatment of HIV-1 infection.

If an HIV NNRTI-based regimen of rilpivirine, emtricitabine, and tenofovir DF is used for the treatment of HIV-1 infection, a fixed-combination preparation containing all 3 drugs (emtricitabine/rilpivirine/tenofovir DF; Complera) is commercially available and can be used in antiretroviral-naive adults and adolescents 12 years of age or older weighing at least 35 kg with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less. Emtricitabine/rilpivirine/tenofovir DF also can be used to replace a stable antiretroviral regimen in certain antiretroviral-experienced patients who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL). Emtricitabine/rilpivirine/tenofovir DF is used alone as a complete regimen for the treatment of HIV-1 infection.

The manufacturer states that the following factors should be considered when initiating rilpivirine or emtricitabine/rilpivirine/tenofovir DF in antiretroviral-naive patients. In clinical studies evaluating rilpivirine, patients with baseline plasma HIV-1 RNA levels exceeding 100,000 copies/mL had greater rates of virologic failure than those with lower baseline HIV-1 RNA levels and patients with baseline CD4 T-cell counts less than 200 cells/mm (regardless of HIV-1 RNA levels) had greater rates of virologic failure than those with higher baseline CD4 T-cell counts. Patients experiencing virologic failure while receiving a rilpivirine regimen had higher rates of overall treatment-emergent resistance and NNRTI-class cross-resistance than those receiving an efavirenz regimen. In addition, resistance to the HIV nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir, lamivudine, and emtricitabine developed more frequently in patients receiving a rilpivirine regimen than in those receiving an efavirenz regimen.

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

For initial treatment in HIV-infected adults and adolescents who are antiretroviral-naive, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that rilpivirine in conjunction with tenofovir alafenamide and emtricitabine or rilpivirine in conjunction with tenofovir DF and emtricitabine (or lamivudine) are alternative NNRTI-based regimens, but should be used only in patients with baseline plasma HIV-1 RNA levels less than 100,000 copies/mL and baseline CD4 T-cell count greater than 200 cells/mm.

Clinical Experience

Rilpivirine has been evaluated in 2 phase 3, randomized, double-blind, multicenter, noninferiority studies (studies TMC278-C209 [ECHO], TMC278-C215 [THRIVE]) in antiretroviral-naive adults with baseline plasma HIV-1 RNA levels of at least 5000 copies/mL. Patients enrolled in these studies were screened to ensure they had HIV-1 that did not have specific NNRTI resistance-associated mutations and were susceptible to NRTIs. Over 1300 patients (median age 36 years [range 18-78], 76% male, 60-61% white, 23-24% black, 11-14% Asian, median baseline plasma HIV-1 RNA level 5.0 log10 copies/mL, median baseline CD4 T-cell count 249-260 cells/mm) were randomized to receive rilpivirine 25 mg once daily or efavirenz 600 mg once daily. All patients received a background regimen of 2 NRTIs (dual NRTIs); patients enrolled in the ECHO study received a fixed combination of emtricitabine and tenofovir DF (emtricitabine/tenofovir DF) and patients enrolled in the THRIVE study received an investigator-selected dual NRTI option of emtricitabine and tenofovir DF, zidovudine and lamivudine, or abacavir and lamivudine. At 48 weeks, rilpivirine was noninferior to efavirenz in both studies. Based on pooled results at 48 weeks, 84% of those receiving rilpivirine and 2 NRTIs and 82% of those receiving efavirenz and 2 NRTIs had plasma HIV-1 RNA levels below 50 copies/mL. In addition, the mean increase in CD4 T-cell count from baseline at week 48 was 192 cells/mm in patients receiving a rilpivirine regimen and 176 cells/mm in those receiving an efavirenz regimen. Pooled results at week 96 showed that 76% of those receiving rilpivirine and 2 NRTIs and 77% of those receiving efavirenz and 2 NRTIs had plasma HIV-1 RNA levels below 50 copies/mL. The mean increase in CD4 T-cell count from baseline at week 96 was 228 cells/mm in patients receiving a rilpivirine regimen and 219 cells/mm in those receiving an efavirenz regimen.

Pooled data from the ECHO and THRIVE studies indicated that the virologic failure rate at week 96 (plasma HIV-1 RNA levels 50 copies/mL or greater) was 16 or 10% in those randomized to rilpivirine or efavirenz, respectively, and 2 NRTIs; most virologic failures occurred in the first 48 weeks. When results were stratified by baseline plasma HIV-1 RNA levels among patients randomized to receive rilpivirine, virologic failure occurred in 9% of patients with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less and in 24% of those with baseline levels exceeding 100,000 copies/mL.

Rilpivirine also has been evaluated in a randomized, active-controlled, phase 2b, dose-comparison study (TMC278-C204) in 368 antiretroviral-naive HIV-infected adults (median age 35 years, 67% male, 45% white, 24% black, 18% Asian) with baseline plasma HIV-1 RNA levels of at least 5000 copies/mL. Patients enrolled in this study had previously received no more than 2 weeks of treatment with NRTIs or HIV protease inhibitors (PIs), had not previously received any NNRTIs, and were screened to ensure they had HIV-1 that did not have specific NNRTI resistance-associated mutations and were susceptible to NRTIs. Patients received an investigator-selected background regimen of 2 NRTIs (lamivudine and zidovudine or emtricitabine and tenofovir DF; administered as fixed-combination preparations whenever possible) and were randomized (1:1:1:1) to receive open-label efavirenz (600 mg once daily) or 1 of 3 blinded rilpivirine dosage regimens (25, 75, or 150 mg once daily) for 96 weeks. At 96 weeks, 76% of patients receiving a regimen of rilpivirine 25 mg and 2 NRTIs and 71% of patients receiving a regimen of efavirenz and 2 NRTIs had plasma HIV-1 RNA levels below 50 copies/mL. The mean increase in CD4 T-cell count from baseline was 146 cells/mm in those receiving rilpivirine 25 mg and 160 cells/mm in those receiving efavirenz. At 96 weeks, patients originally randomized to any dose of rilpivirine were switched to an open label rilpivirine regimen of 25 mg once daily and 2 NRTIs for long-term follow-up. At 240 weeks, virologic suppression (plasma HIV-1 RNA levels below 50 copies/mL) was achieved in 60% of patients originally randomized to rilpivirine 25 mg and 57% of those randomized to efavirenz.

Efficacy of the fixed combination emtricitabine/rilpivirine/tenofovir alafenamide for the treatment of HIV-1 infection in antiretroviral-naive HIV-infected adults is based on results of clinical trials evaluating a regimen of rilpivirine and emtricitabine/tenofovir DF and clinical trials evaluating a regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.

Antiretroviral-experienced Adults and Adolescents

Emtricitabine, Rilpivirine, and Tenofovir Alafenamide

The fixed combination emtricitabine/rilpivirine/tenofovir alafenamide can be used to replace a stable antiretroviral regimen for the treatment of HIV-1 infection in antiretroviral-experienced adults and adolescents 12 years of age or older weighing at least 35 kg who have been virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) on their current regimen for at least 6 months, have no history of treatment failure, and are infected with HIV-1 with no known substitutions associated with resistance to the antiretroviral components of the fixed combination (i.e., emtricitabine, rilpivirine, tenofovir).

Efficacy of emtricitabine/rilpivirine/tenofovir alafenamide for the treatment of HIV-1 infection in antiretroviral experienced adults is based on results of clinical trials evaluating a regimen of rilpivirine and emtricitabine/tenofovir DF and clinical trials evaluating a regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.

Emtricitabine, Rilpivirine, and Tenofovir DF

The fixed combination emtricitabine/rilpivirine/tenofovir DF can be used to replace a stable antiretroviral regimen for treatment of HIV-1 infection in antiretroviral-experienced adults and adolescents 12 years of age or older weighing at least 35 kg who have been virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) on their current regimen for at least 6 months, are currently receiving only their first or second antiretroviral regimen, have no history of virologic failure, and have no current evidence or history of resistance to emtricitabine, rilpivirine, or tenofovir DF.

The efficacy and safety of emtricitabine/rilpivirine/tenofovir DF have been evaluated in a randomized, open-label study (study 106) in 476 virologically suppressed HIV-infected adults (mean age 42 years, 88% male, 77% white, 17% black, 17% Hispanic, mean baseline CD4 T-cell count 584 cells/mm). Patients were receiving their first or second antiretroviral regimen with no history of virologic failure; had no history of resistance to emtricitabine, rilpivirine, or tenofovir DF; and were virologically suppressed (plasma HIV-1 RNA levels less than 50 copies/mL) for at least 6 months. Patients were randomized in a 2:1 ratio to switch to emtricitabine/rilpivirine/tenofovir DF for 48 weeks or to continue receiving their baseline antiretroviral regimen containing a ritonavir-boosted HIV protease inhibitor (PI) for 24 weeks and then switch to emtricitabine/rilpivirine/tenofovir DF for an additional 24 weeks. In patients initially switched to emtricitabine/rilpivirine/tenofovir DF, 89% maintained plasma HIV-1 RNA levels less than 50 copies/mL at 48 weeks; 90% of those who continued to receive their baseline regimen maintained plasma HIV-1 RNA levels less than 50 copies/mL at 24 weeks.

Pediatric Patients

Rilpivirine is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg.

The fixed combination emtricitabine/rilpivirine/tenofovir alafenamide or the fixed combination emtricitabine/rilpivirine/tenofovir DF can be used alone as a complete regimen for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg.

For initial treatment in pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children states that rilpivirine and 2 NRTIs is an alternative HIV NNRTI-based regimen in antiretroviral-naive adolescents 12 years of age or older weighing 35 kg or more, but should be used only in those with baseline plasma HIV-1 RNA levels less than 100,000 copies/mL.

Clinical Experience

The efficacy and safety of rilpivirine in conjunction with 2 NRTIs were evaluated in a single-arm, open-label, phase 2 study (TMC278-C213) in 36 treatment-naive pediatric patients 12 to less than 18 years of age weighing at least 32 kg (median age 14.5 years, 56% female, 89% black, 11% Asian, median baseline plasma HIV-1 RNA level 49,550 copies/mL, median baseline CD4 T-cell count 438 cells/mm). Of the 36 patients, 24 received rilpivirine in conjunction with emtricitabine and tenofovir DF. At week 48, virologic response (plasma HIV-1 RNA levels less than 50 copies/mL) was achieved in 79% of patients with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less compared with 50% of those with baseline HIV-1 RNA levels greater than 100,000 copies/mL. The mean increase in CD4 T-cell count from baseline was 201 cells/mm. In a subgroup of patients receiving rilpivirine in conjunction with emtricitabine and tenofovir DF who had baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less, virologic response (plasma HIV-1 RNA levels less than 50 copies/mL) was achieved by 80% at 48 weeks and the mean increase in CD4 T-cell count from baseline was 225 cells/mm at 48 weeks.

Postexposure Prophylaxis following Occupational Exposure to HIV

Rilpivirine is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada). Rilpivirine and 2 NRTIs is one of several alternative regimens recommended when the preferred regimen cannot be used. The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Rilpivirine is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when that exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada) and the alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada). CDC states that a regimen of rilpivirine and 2 NRTIs (may be administered as the fixed combination emtricitabine/rilpivirine/tenofovir DF; Complera) is one of several other alternative regimens for nPEP.

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

Rilpivirine hydrochloride is administered orally once daily with a meal.

Food enhances rilpivirine bioavailability. Systemic exposure is 40 or 50% lower if rilpivirine is administered under fasting conditions or with only a protein-rich nutritional drink (300 kcal, 8 grams of fat), respectively, compared with following a standard meal (533 kcal, 21 grams of fat) or high-fat meal (928 kcal, 56 grams of fat).

Single-entity rilpivirine hydrochloride is commercially available as tablets. Rilpivirine hydrochloride also is commercially available in fixed-combination tablets containing emtricitabine, rilpivirine hydrochloride, and tenofovir alafenamide (emtricitabine/rilpivirine/tenofovir alafenamide; Odefsey) and in fixed-combination tablets containing emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate (emtricitabine/rilpivirine/tenofovir DF; Complera).(See Fixed Combinations Containing Rilpivirine under Dosage and Administration: Administration.)

Rilpivirine is used in conjunction with other antiretrovirals. Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir alafenamide. Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir DF, unless needed for adjustment of rilpivirine dosage (e.g., when the fixed combination is used concomitantly with rifabutin).

Fixed Combinations Containing Rilpivirine

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) tablets are administered orally once daily with a meal. Each fixed-combination tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine, and 25 mg of tenofovir alafenamide. The fixed combination is used alone as a complete treatment regimen.

Emtricitabine/rilpivirine/tenofovir DF (Complera) tablets are administered orally once daily with a meal. A fixed-combination tablet containing 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF taken with a meal is bioequivalent to a 200-mg emtricitabine capsule, 25-mg rilpivirine tablet, and 300-mg tenofovir DF tablet taken simultaneously with a meal. The fixed combination is used alone as a complete treatment regimen. Emtricitabine/rilpivirine/tenofovir DF should not be used concomitantly with single-entity rilpivirine, unless needed for adjustment of the rilpivirine dosage (e.g., when the fixed combination is used concomitantly with rifabutin).

Estimated creatinine clearance, urine glucose, and urine protein should be determined prior to initiation of emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF and routinely monitored during treatment in all patients. In addition, serum phosphorous should be monitored in those with chronic kidney disease or at risk for renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Because the antiretrovirals contained in emtricitabine/rilpivirine/tenofovir alafenamide and emtricitabine/rilpivirine/tenofovir DF also may be available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Cautions: Warnings/Precautions.)

Dosage

Rilpivirine is commercially available as rilpivirine hydrochloride; dosage is expressed in terms of rilpivirine.

Adult Dosage

Treatment of HIV Infection in Antiretroviral-naive Adults

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive adults, the usual dosage of rilpivirine (Edurant) is 25 mg once daily.

When emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is used for the treatment of HIV-1 infection in antiretroviral-naive adults, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 25 mg of tenofovir alafenamide) once daily.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in antiretroviral-naive adults, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

Treatment of HIV Infection in Antiretroviral-experienced Adults

When emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is used for the treatment of HIV-1 infection in previously treated adults, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 25 mg of tenofovir alafenamide) once daily.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in previously treated adults, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

Treatment of HIV Infection in Adults Receiving Rifabutin

If single-entity rilpivirine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adults receiving rifabutin, an increased rilpivirine dosage of 50 mg daily should be used.(See Rifabutin under Drugs Interactions: Antimycobacterial Agents.)

Concomitant use of emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) and rifabutin is not recommended.

If emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in adults receiving rifabutin, patients should receive 1 tablet of the fixed combination (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily and a 25-mg tablet of single-entity rilpivirine once daily to provide a total rilpivirine dosage of 50 mg daily.

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel or other individuals, rilpivirine is administered in a dosage of 25 mg once daily in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.) Alternatively, if emtricitabine/rilpivirine/tenofovir DF (Complera) is used for PEP, the recommended dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used as a complete regimen for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP), adults should receive 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days. If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.

Pediatric Dosage

Treatment of HIV Infection in Antiretroviral-naive Pediatric Patients

For the treatment of HIV-1 infection in antiretroviral-naive adolescents 12 years of age or older weighing at least 35 kg, the usual dosage of rilpivirine (Edurant) is 25 mg once daily.

When emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is used for the treatment of HIV-1 infection in antiretroviral-naive adolescents 12 years of age or older weighing at least 35 kg, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 25 mg of tenofovir alafenamide) once daily.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in antiretroviral-naive adolescents 12 years of age or older weighing at least 35 kg, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients

When emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is used for the treatment of HIV-1 infection in previously treated adolescents 12 years of age or older weighing at least 35 kg, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 25 mg of tenofovir alafenamide) once daily.

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in previously treated adolescents 12 years of age or older weighing at least 35 kg, the usual dosage is 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.

Treatment of HIV Infection in Pediatric Patients Receiving Rifabutin

If single-entity rilpivirine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg receiving rifabutin, an increased rilpivirine dosage of 50 mg daily should be used.(See Rifabutin under Drugs Interactions: Antimycobacterial Agents.)

Concomitant use of emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) and rifabutin is not recommended.

If emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in adolescents 12 years of age or older weighing at least 35 kg receiving rifabutin, patients should receive 1 tablet of the fixed combination (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily and a 25-mg tablet of single-entity rilpivirine once daily to provide a total rilpivirine dosage of 50 mg daily.

Special Populations

Hepatic Impairment

Dosage adjustment of rilpivirine (Edurant) is not necessary for the treatment of HIV-1 infection in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Rilpivirine has not been studied in those with severe hepatic impairment (Child-Pugh class C).

When emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is used for the treatment of HIV-1 infection in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), usual dosage can be used; the fixed combination has not been studied in those with severe hepatic impairment (Child-Pugh class C).

When emtricitabine/rilpivirine/tenofovir DF (Complera) is used for the treatment of HIV-1 infection in patients with mild or moderate hepatic impairment (Child-Pugh class A or B), usual dosage can be used; the fixed combination has not been studied in those with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Dosage adjustment of rilpivirine (Edurant) is not necessary for the treatment of HIV-1 infection in patients with mild or moderate renal impairment. The manufacturer makes no specific dosage recommendations for those with severe renal impairment or end-stage renal disease; rilpivirine should be used with caution in such individuals.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

When emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is used for the treatment of HIV-1 infection, usual dosage can be used in patients with estimated creatinine clearance of 30 mL/minute or greater; the fixed combination is not recommended in those with severe renal impairment (estimated creatinine clearance less than 30 mL/minute).

Emtricitabine/rilpivirine/tenofovir DF (Complera) should not be used in patients with renal impairment that is moderate, severe, or end-stage (estimated creatinine clearance less than 50 mL/minute) or requires dialysis.

Cautions

Contraindications

Concomitant use of rilpivirine with drugs that induce cytochrome P-450 isoenzyme 3A (CYP3A) or drugs that elevate gastric pH is contraindicated since substantially decreased plasma rilpivirine concentrations may occur and may result in loss of virologic response and development of resistance to rilpivirine and/or class resistance to human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitors (NNRTIs). Concomitant use with certain anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), certain antimycobacterials (rifampin, rifapentine), systemic dexamethasone (given in multiple doses), proton-pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), or certain herbal supplements (St. John's wort [Hypericum perforatum]) is contraindicated.(See Drug Interactions.)

When the fixed combination containing emtricitabine, rilpivirine, and tenofovir alafenamide (emtricitabine/rilpivirine/tenofovir alafenamide; Odefsey) or the fixed combination containing emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (emtricitabine/rilpivirine/tenofovir DF; Complera) is used, the contraindications associated with each drug in the fixed combination should be considered.(See Precautions Related to Use of Fixed Combinations under Cautions: Warnings/Precautions.)

Warnings/Precautions

Dermatologic and Sensitivity Reactions

Severe skin and hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during postmarketing experience in patients receiving rilpivirine-containing antiretroviral regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunction, including elevated serum concentrations of hepatic enzymes. During phase 3 studies of rilpivirine-containing antiretroviral regimens, treatment-associated rash with at least grade 2 severity was reported in 1-3% of patients. Most rashes were grade 1 or 2 and occurred in the first 4-6 weeks of therapy.

Rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine tenofovir DF should be discontinued immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (e.g., severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia). Clinical status, including laboratory parameters, should be monitored and appropriate therapy initiated.

Interactions

Concomitant use with certain drugs (e.g., drugs that may reduce rilpivirine concentrations, drugs known to increase the risk of torsades de pointes) is contraindicated or requires particular caution. (See Cautions: Contraindications and see Drug Interactions.)

Depressive Disorders

Depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been reported in patients receiving rilpivirine. During phase 3 studies (ECHO and THRIVE studies), 9% of adults receiving rilpivirine reported depressive disorders compared with 8% of patients receiving efavirenz. While most depressive events were reported to be mild or moderate in severity, 1% of adults in each treatment group reported a grade 3 or 4 depressive disorder and 1% in each treatment group discontinued therapy as a result of a depressive disorder. Suicidal ideation was reported in 4 adults in each treatment group and suicide attempt was reported in 2 adults receiving rilpivirine.

During a phase 2 study evaluating rilpivirine in pediatric patients 12 to less than 18 years of age, the incidence of depressive disorders was 19.4%. While most depressive events were reported to be mild or moderate in severity, 5.6% of pediatric patients reported a grade 3 or 4 depressive disorder. Suicidal ideation and suicide attempt were reported in a pediatric patient.

Patients experiencing severe depressive symptoms should seek immediate medical evaluation to determine the likelihood that symptoms are related to rilpivirine and to determine if the benefits of continued rilpivirine therapy outweigh the risks.

Hepatotoxicity

Adverse hepatic effects have been reported in patients receiving rilpivirine in conjunction with other antiretrovirals. Hepatotoxicity has been reported in patients receiving rilpivirine who had no preexisting hepatic disease or other risk factors.

HIV-infected patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection or markedly elevated serum aminotransferase concentrations prior to initiation of rilpivirine may be at increased risk for development or worsening of aminotransferase elevations.

If rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is used in patients with underlying hepatic disease (e.g., HBV or HCV infection, markedly elevated aminotransferase concentrations), laboratory tests should be performed to evaluate hepatic function prior to and during rilpivirine treatment. Liver enzyme monitoring also should be considered in patients without preexisting hepatic disease or other risk factors.

Precautions Related to Use of Fixed Combinations

When emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF is used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug. For cautionary information related to and , see Cautions in the individual drug monographs.

Because the antiretrovirals contained in emtricitabine/rilpivirine/tenofovir alafenamide and emtricitabine/rilpivirine/tenofovir DF also may be available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if one of these fixed combinations is used in conjunction with other antiretrovirals.

Emtricitabine/rilpivirine/tenofovir DF should not be used concomitantly with single-entity rilpivirine, unless needed for adjustment of rilpivirine dosage (e.g., when the fixed combination is used concomitantly with rifabutin).(See Drug Interactions: Antimycobacterial Agents.)

Because of similarities between emtricitabine and lamivudine, fixed combinations containing emtricitabine should not be used concomitantly with any preparation containing lamivudine. In addition, fixed combinations containing tenofovir DF should not be used concomitantly with adefovir dipivoxil.

If emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF is used, clinicians should consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.

If emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF is used, clinicians should consider that severe, acute exacerbations of HBV infection have been reported following discontinuance of emtricitabine and/or tenofovir DF in HIV-infected patients coinfected with HBV. The fixed combinations are not labeled for treatment of chronic HBV infection, and safety and efficacy have not been established in HIV-infected patients coinfected with HBV. Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several months after the fixed combination is discontinued in coinfected patients. If appropriate, initiation of HBV treatment may be warranted.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral therapy. The mechanisms and long-term consequences of adipogenic effects are unknown; a causal relationship has not been established.

Immune Reconstitution Syndrome

During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium, M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); such responses may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre 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 antiretroviral therapy.

Specific Populations

Pregnancy

Rilpivirine (Edurant): Category B.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Insufficient human data to assess the risk of birth defects and miscarriage if used during pregnancy.

Emtricitabine/rilpivirine/tenofovir DF (Complera): Category B.

Antiretroviral Pregnancy Registry at 800-258-4263 or http://www.APRegistry.com.

For initial treatment in antiretroviral-naive pregnant women, the US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that rilpivirine in conjunction with tenofovir DF and emtricitabine (or rilpivirine in conjunction with a preferred 2-NRTI backbone) is an alternative NNRTI-based regimen, but should be used only in patients with baseline plasma HIV-1 RNA levels less than 100,000 copies/mL and baseline CD4 T-cell count greater than 200 cells/mm.

Lactation

It is not known whether rilpivirine is distributed into human milk; however, the drug is distributed into milk in rats.

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.

Pediatric Use

Safety and efficacy of single-entity rilpivirine (Edurant) have not been established in pediatric patients younger than 12 years of age.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Safety and efficacy have not been established in pediatric patients younger than 12 years of age or weighing less than 35 kg.

Emtricitabine/rilpivirine/tenofovir DF (Complera): Safety and efficacy have not been established in pediatric patients younger than 12 years of age or weighing less than 35 kg.

Depressive disorders have been reported in pediatric patients 12 to less than 18 years of age receiving rilpivirine-containing regimens.(See Depressive Disorders under Cautions: Warnings/Precautions.)

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently to rilpivirine than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Rilpivirine (Edurant), emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey), and emtricitabine/rilpivirine/tenofovir DF (Complera) have not been studied in patients with severe hepatic impairment (Child-Pugh class C).

During phase 3 clinical trials evaluating rilpivirine, HIV-infected patients coinfected with HBV and/or HCV had a higher incidence of increased serum aminotransferase concentrations compared with those without coinfection.(See Hepatotoxicity under Cautions: Warnings/Precautions.)

Renal Impairment

Rilpivirine (Edurant) should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease since concentrations of the drug may be increased due to alterations in absorption, distribution, or metabolism.(See Renal Impairment under Dosage and Administration: Special Populations.)

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) is not recommended in patients with severe renal impairment (estimated creatinine clearance less than 30 mL/minute).

Emtricitabine/rilpivirine/tenofovir DF (Complera) should not be used in patients with renal impairment that is moderate, severe, or end-stage (estimated creatinine clearance less than 50 mL/minute) or requires dialysis.

Common Adverse Effects

Adverse effects of moderate or severe intensity and reported in 2% or more of patients receiving rilpivirine include depressive disorders (see Depressive Disorders under Cautions: Warnings/Precautions), insomnia, headache, and rash. Increased serum AST and/or ALT concentrations (more than 2.5 times the upper limit of normal [ULN] were reported in 4-5% of patients receiving rilpivirine.

Drug Interactions

Most rilpivirine drug interaction studies reported to date used rilpivirine dosages of 75 or 150 mg once daily; these dosages are considerably higher than the usually recommended rilpivirine dosage (25 mg once daily).

The following drug interactions are based on studies using rilpivirine, the fixed combination of emtricitabine, rilpivirine, and tenofovir alafenamide (emtricitabine/rilpivirine/tenofovir alafenamide), the fixed combination of emtricitabine, rilpivirine, and tenofovir DF (emtricitabine/rilpivirine/tenofovir DF), or the individual components of the fixed combinations, or are predicted to occur. When emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF is used, interactions associated with each drug in the fixed combination should be considered.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Rilpivirine is metabolized by the cytochrome P-450 (CYP) isoenzyme 3A. Concomitant use with drugs that induce CYP3A may result in decreased plasma rilpivirine concentrations and may result in possible loss of virologic response and development of resistance to rilpivirine or the human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI) class. Concomitant use with drugs that inhibit CYP3A may result in increased plasma rilpivirine concentrations.

When the recommended rilpivirine dosage (25 mg once daily) is used, it is unlikely to have clinically important effects on the pharmacokinetics of drugs that are metabolized by CYP isoenzymes.

Drugs Affected by P-glycoprotein Transport

Tenofovir alafenamide, a component of emtricitabine/rilpivirine/tenofovir alafenamide, is a substrate of P-glycoprotein (P-gp) transport.

Concomitant use of emtricitabine/rilpivirine/tenofovir alafenamide and P-gp inhibitors may result in increased absorption of tenofovir alafenamide and may result in increased plasma concentrations of tenofovir alafenamide and increased adverse effects.

Concomitant use of emtricitabine/rilpivirine/tenofovir alafenamide and P-gp inducers is expected to decrease absorption of tenofovir alafenamide and may result in decreased plasma concentrations of tenofovir alafenamide leading to loss of therapeutic effect and development of resistance.

Drugs that Increase Gastric pH

Concomitant use of rilpivirine and drugs that increase gastric pH may result in decreased plasma rilpivirine concentrations and may result in loss of virologic response and development of resistance to rilpivirine or the NNRTI class.

Antacids

Potential pharmacokinetic interaction if antacids such as aluminum hydroxide, calcium carbonate, or magnesium hydroxide are used concomitantly with rilpivirine (decreased plasma rilpivirine concentrations).

Antacids and rilpivirine should be used concomitantly with caution; antacids should be administered at least 2 hours before or at least 4 hours after rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF.

Histamine H2-receptor Antagonists

Concomitant use of famotidine and rilpivirine has resulted in decreased rilpivirine plasma concentrations and area under the concentration-time curve (AUC). Concomitant use of other histamine H2-receptor antagonists (e.g., cimetidine, nizatidine, ranitidine) also may result in decreased rilpivirine plasma concentrations.

Histamine H2-receptor antagonists and rilpivirine should be used concomitantly with caution; histamine H2-receptor antagonists should be administered at least 12 hours before or at least 4 hours after rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF.

Proton-pump Inhibitors

Concomitant use of omeprazole and rilpivirine has resulted in decreased rilpivirine plasma concentrations and AUC. Concomitant use of other proton-pump inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may result in decreased rilpivirine plasma concentrations.

Concomitant use of proton-pump inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) and rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is contraindicated.

Drugs that Prolong the QT Interval

Only limited data are available to date regarding the potential for pharmacodynamic interactions if rilpivirine is used concomitantly with drugs known to prolong the QT interval and increase the risk of torsades de pointes. Data from healthy individuals indicate that the recommended rilpivirine dosage (25 mg once daily) can result in increases in the corrected QT (QTc) interval that are not considered clinically important; however, higher rilpivirine dosage (75 or 300 mg once daily) results in clinically important prolongation of the QTc interval.

Caution is advised if rilpivirine or emtricitabine/rilpivirine/tenofovir DF is used concomitantly with drugs known to increase the risk of torsades de pointes. An alternative to emtricitabine/rilpivirine/tenofovir alafenamide should be considered in patients receiving drugs known to increase the risk of torsades de pointes.

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

The emtricitabine and tenofovir components of emtricitabine/rilpivirine/tenofovir alafenamide and emtricitabine/rilpivirine/tenofovir DF are primarily excreted renally by a combination of glomerular filtration and active tubular secretion.

Potential pharmacokinetic interactions if emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF is used concomitantly with drugs that reduce renal function or compete for active tubular secretion (e.g., acyclovir, aminoglycosides [gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]); increased plasma concentrations of emtricitabine, tenofovir, and/or the concomitant drug may occur and increase the risk of adverse effects.

Acetaminophen

Clinically important pharmacokinetic interactions between rilpivirine and acetaminophen have not been observed; dosage adjustments are not needed.

Anticonvulsants

Potential pharmacokinetic interactions when rilpivirine is used concomitantly with carbamazepine, oxcarbazepine, phenobarbital, or phenytoin (decreased plasma rilpivirine concentrations).

Concomitant use of anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin) and rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is contraindicated.

Antifungal Agents

Concomitant use of ketoconazole and rilpivirine has resulted in increased rilpivirine plasma concentrations and AUC and decreased ketoconazole plasma concentrations and AUC. Concomitant use of other azole antifungals (e.g., fluconazole, isavuconazonium, itraconazole, posaconazole, voriconazole) and rilpivirine also may result in increased rilpivirine plasma concentrations and decreased antifungal plasma concentrations. Concomitant use of an azole antifungal with emtricitabine/rilpivirine/tenofovir alafenamide may also result in increased tenofovir alafenamide concentrations.

When rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is used concomitantly with an azole antifungal (e.g., fluconazole, isavuconazonium, itraconazole, ketoconazole, posaconazole, voriconazole), dosage adjustments are not needed; however, patients should be monitored for breakthrough fungal infections.

Antimycobacterial Agents

Rifampin and Rifapentine

Concomitant use of rilpivirine and rifampin or rifapentine results in decreased rilpivirine plasma concentrations and AUC.

Concomitant use of rifampin or rifapentine with rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is contraindicated.

Rifabutin

Concomitant use of rifabutin and rilpivirine results in decreased rilpivirine plasma concentrations and AUC.

If single-entity rilpivirine is used concomitantly with rifabutin, rilpivirine dosage should be increased to 50 mg once daily; if rifabutin is discontinued, the usual dosage of single-entity rilpivirine (25 mg once daily) should be resumed.

Concomitant use of rifabutin and emtricitabine/rilpivirine/tenofovir alafenamide results in decreased rilpivirine concentrations and may also result in decreased tenofovir alafenamide concentrations. Concomitant use of emtricitabine/rilpivirine/tenofovir alafenamide and rifabutin is not recommended.

If emtricitabine/rilpivirine/tenofovir DF is used concomitantly with rifabutin, the manufacturer recommends that patients receive 1 tablet of the fixed combination (25 mg of rilpivirine, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily and a 25-mg tablet of single-entity rilpivirine once daily to provide a total rilpivirine dosage of 50 mg daily.(See Dosage and Administration: Dosage.)

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and enfuvirtide.

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and maraviroc.

Clinically important pharmacokinetic interactions are not expected.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of dolutegravir and rilpivirine does not have a clinically important effect on the pharmacokinetics of either drug. Dosage adjustments are not needed if rilpivirine and dolutegravir are used concomitantly.

Elvitegravir

Concomitant use of rilpivirine and cobicistat-boosted elvitegravir may result in altered concentrations of elvitegravir, cobicistat, and/or rilpivirine. Rilpivirine and cobicistat-boosted elvitegravir should not be used concomitantly.

Concomitant use of rilpivirine and elvitegravir used in conjunction with a ritonavir-boosted HIV protease inhibitor (PI) is expected to increase rilpivirine plasma concentrations. Dosage adjustments are not needed if rilpivirine is used concomitantly with elvitegravir used in conjunction with a ritonavir-boosted HIV PI; however, the recommended dosage of elvitegravir depends on which ritonavir-boosted HIV PI is used.

Raltegravir

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and raltegravir.

Concomitant use of raltegravir and rilpivirine does not have a clinically important effect on plasma concentrations or AUC of raltegravir or rilpivirine. Dosage adjustments are not needed for either drug.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and NNRTIs (efavirenz, etravirine, nevirapine).

Concomitant use of delavirdine and rilpivirine may result in increased rilpivirine plasma concentrations; concomitant use of efavirenz, etravirine, or nevirapine may result in decreased rilpivirine plasma concentrations.

Concomitant use of rilpivirine and other NNRTIs (delavirdine, efavirenz, etravirine, nevirapine) is not recommended.

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and HIV nucleoside reverse transcriptase inhibitors (NRTIs) (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine).

Although not specifically studied, clinically important pharmacokinetic interactions are not expected if rilpivirine is used concomitantly with abacavir, emtricitabine, lamivudine, stavudine, or zidovudine.

Didanosine

Pharmacokinetic interactions were not observed when didanosine delayed-release capsules were administered 2 hours before rilpivirine. Although dosage adjustments are not needed if rilpivirine and didanosine are used concomitantly, didanosine should be administered (without food) at least 2 hours before or 4 hours after rilpivirine (with food).

Tenofovir

Concomitant use of tenofovir DF and rilpivirine has resulted in increased tenofovir plasma concentrations and AUC, but did not have a clinically important effect on rilpivirine plasma concentrations or AUC.

Dosage adjustments are not needed if tenofovir DF and rilpivirine are used concomitantly.

HIV Protease Inhibitors (PIs)

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and HIV PIs (amprenavir [commercially available as fosamprenavir], atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir).

Atazanavir

Concomitant use of rilpivirine and ritonavir-boosted atazanavir, cobicistat-boosted atazanavir, or unboosted atazanavir may result in increased rilpivirine plasma concentrations, but is not expected to affect atazanavir concentrations.

Dosage adjustments are not needed if rilpivirine is used concomitantly with ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.

Darunavir

Concomitant use of rilpivirine and ritonavir-boosted darunavir resulted in increased rilpivirine plasma concentrations and AUC, but did not have a clinically important effect on darunavir concentrations or AUC. Concomitant use of cobicistat-boosted darunavir and rilpivirine may increase rilpivirine plasma concentrations, but is not expected to affect darunavir concentrations.

Dosage adjustments are not needed if rilpivirine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Fosamprenavir

Concomitant use of rilpivirine and fosamprenavir or ritonavir-boosted fosamprenavir may result in increased rilpivirine plasma concentrations, but is not expected to affect amprenavir concentrations (active metabolite of fosamprenavir).

Dosage adjustments are not needed if fosamprenavir (with or without low-dose ritonavir) and rilpivirine are used concomitantly.

Indinavir

Concomitant use of rilpivirine and indinavir may result in increased rilpivirine plasma concentrations, but is not expected to affect indinavir concentrations.

Lopinavir

Concomitant use of rilpivirine and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) increased rilpivirine plasma concentrations and AUC, but did not have a clinically important effect on lopinavir plasma concentrations or AUC.

Dosage adjustments are not needed if lopinavir/ritonavir and rilpivirine are used concomitantly.

Nelfinavir

Concomitant use of nelfinavir may result in increased rilpivirine plasma concentrations, but is not expected to affect nelfinavir concentrations.

Saquinavir

Concomitant use of rilpivirine and ritonavir-boosted saquinavir may result in increased rilpivirine plasma concentrations, but is not expected to affect saquinavir concentrations.

Dosage adjustments are not needed if ritonavir-boosted saquinavir and rilpivirine are used concomitantly.

Tipranavir

Concomitant use of rilpivirine and ritonavir-boosted tipranavir may result in increased rilpivirine plasma concentrations, but is not expected to affect tipranavir concentrations.

Dosage adjustments are not needed if ritonavir-boosted tipranavir and rilpivirine are used concomitantly.

Benzodiazepines

Data are not available regarding concomitant use of rilpivirine and alprazolam; if the drugs are used concomitantly, patients should be monitored for alprazolam therapeutic effects.

Clinically important pharmacokinetic interactions are not expected if emtricitabine/rilpivirine/tenofovir alafenamide is used concomitantly with lorazepam or midazolam.

Chlorzoxazone

Clinically important pharmacokinetic interactions between rilpivirine and chlorzoxazone have not been observed; dosage adjustments are not needed.

Corticosteroids

Potential pharmacokinetic interaction if multiple doses of systemic dexamethasone are used concomitantly with rilpivirine (decreased plasma rilpivirine concentrations). Concomitant use of more than a single dose of dexamethasone with rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is contraindicated.

Digoxin

Rilpivirine does not have a clinically important effect on digoxin pharmacokinetics.

Estrogens and Progestins

Clinically important pharmacokinetic interactions have not been observed when usual rilpivirine dosage was used concomitantly with hormonal contraceptives containing ethinyl estradiol and norethindrone; dosage adjustments are not needed.

Clinically important pharmacokinetic interactions are not expected if emtricitabine/rilpivirine/tenofovir alafenamide is used concomitantly with the fixed combination of ethinyl estradiol and norgestimate.

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir

Concomitant use of sofosbuvir and rilpivirine does not have a clinically important effect on sofosbuvir or rilpivirine pharmacokinetics. Dosage adjustments are not needed for either drug.

Sofosbuvir and Velpatasvir

Concomitant use of the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) and rilpivirine did not result in clinically important pharmacokinetic interactions.

HCV Protease Inhibitors

Simeprevir

Concomitant use of simeprevir and rilpivirine does not have a clinically important effect on simeprevir or rilpivirine pharmacokinetics. Dosage adjustments are not needed for either drug.

Clinically important pharmacokinetic interactions are not expected if emtricitabine/rilpivirine/tenofovir alafenamide is used concomitantly with simeprevir.

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir and rilpivirine is not expected to result in clinically important pharmacokinetic interactions.

Dosage adjustments are not needed if daclatasvir is used concomitantly with rilpivirine.

Elbasvir and Grazoprevir

Concomitant use of the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) and rilpivirine does not have a clinically important effect on elbasvir, grazoprevir, or rilpivirine pharmacokinetics.

Dosage adjustments are not needed if elbasvir/grazoprevir is used concomitantly with rilpivirine.

Ledipasvir and Sofosbuvir

Concomitant use of rilpivirine and the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) does not have clinically important effects on the pharmacokinetics of rilpivirine, ledipasvir, or sofosbuvir. Dosage adjustments are not necessary if rilpivirine and ledipasvir/sofosbuvir are used concomitantly.

Clinically important pharmacokinetic interactions are not expected if emtricitabine/rilpivirine/tenofovir alafenamide is used concomitantly with ledipasvir or sofosbuvir.

Concomitant use of emtricitabine/rilpivirine/tenofovir DF and ledipasvir/sofosbuvir does not have clinically important effects on the pharmacokinetics of rilpivirine, ledipasvir, or sofosbuvir, but results in increased tenofovir plasma concentrations and AUC. If emtricitabine/rilpivirine/tenofovir DF is used concomitantly with ledipasvir/sofosbuvir, the patient should be monitored for tenofovir-associated adverse effects.

Ombitasvir, Paritaprevir, and Ritonavir

Concomitant use of rilpivirine and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with or without dasabuvir results in substantially increased plasma concentrations and AUC of rilpivirine and may increase the potential for QT interval prolongation.

Concomitant use of rilpivirine and ombitasvir/paritaprevir/ritonavir with or without dasabuvir is not recommended.

HMG-CoA Reductase Inhibitors

Clinically important pharmacokinetic interactions have not been observed when atorvastatin and rilpivirine were used concomitantly; dosage adjustments are not needed.

Data are not available regarding concomitant use of pitavastatin and rilpivirine, but clinically important interactions are not expected and dosage adjustments are not needed.

Macrolides

Concomitant use of rilpivirine and clarithromycin, erythromycin, or telithromycin may result in increased rilpivirine plasma concentrations, but is not expected to affect plasma concentrations of the macrolide. An alternative to these macrolides (e.g., azithromycin) should be considered whenever possible in patients receiving rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF.

Metformin

Rilpivirine does not have a clinically important effect on metformin pharmacokinetics.

Opiates, Opiate Partial Agonists, and Opiate Antagonists

Clinically important pharmacokinetic interactions are not expected if emtricitabine/rilpivirine/tenofovir alafenamide is used concomitantly with buprenorphine or naloxone.

Methadone

Concomitant use of methadone and usual rilpivirine dosage resulted in decreased methadone concentrations, but did not have a clinically important effect on rilpivirine concentrations or AUC.

Although adjustment of initial methadone dosage is not needed when methadone and rilpivirine are used concomitantly, close monitoring is recommended and methadone maintenance dosage may need to be adjusted in some patients.

Phosphodiesterase Type 5 Inhibitors

Avanafil

Data are not available regarding concomitant use of avanafil and rilpivirine; concomitant use is not recommended.

Sildenafil

Clinically important pharmacokinetic interactions have not been observed when sildenafil and rilpivirine were used concomitantly; dosage adjustments are not needed.

Ribavirin

Clinically important pharmacokinetic interactions between rilpivirine and ribavirin are not expected.

St. John's Wort

Potential pharmacokinetic interaction if St. John's wort (Hypericum perforatum) is used concomitantly with rilpivirine (decreased plasma rilpivirine concentrations); may result in loss of therapeutic effect and development of resistance. Concomitant use of St. John's wort and rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF is contraindicated.

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