EDURANT

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Do not substitute rilpivirine film-coated tablets and rilpivirine tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. A difference in bioavailability between 1 x 25 mg film-coated tablet and 10 x 2.5 mg tablets for oral suspension was observed; therefore, they are NOT substitutable.
Oral Solid Formulations
-Administer with a meal.

Oral Liquid Formulations
Tablets for Oral Suspension
-Must be dispersed in drinking water and taken immediately with a meal.
-Do not chew or swallow tablets whole.
-Place the tablets for oral suspension in a cup and add 5 mL of drinking water at room temperature. Do not crush the tablets.
-Swirl the cup carefully for 1 to 2 minutes to disperse the tablets. The oral suspension will start to look cloudy.
-Administer all the prepared oral suspension immediately or to aid in administration, the oral suspension can be further diluted with 5 mL of drinking water, milk, orange juice or applesauce. Swirl and administer all the medication immediately. A spoon can be used if needed.
-If not taken immediately, discard the oral suspension and prepare a new dose.
-Make sure the entire dose is taken and no medication is left in the cup. If required, add another 5 mL of drinking water (or alternative beverage or soft food), swirl, and administer immediately.

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood alteration, negative thoughts, suicidal ideation, and suicide attempts) were reported by 20% of rilpivirine recipients during a phase 2 trial (n = 36) in pediatric patients 12 to 17 years. The majority of these adverse events were mild to moderate in severity; the incidence of severe depression in pediatric patients was 6% with no patients requiring discontinuation of therapy. Suicidal ideation or suicidal attempt was reported in 1 pediatric patient receiving treatment with rilpivirine. Health care providers are advised to counsel patients and caregivers on the potential for severe depressive episodes during rilpivirine therapy. Instruct patients to seek immediate medical attention if depressive symptoms develop during treatment; treatment with rilpivirine may need to be discontinued. Other psychiatric adverse events reported during rilpivirine adult clinical trials include insomnia (3%), abnormal dreams (2%), and anxiety (less than 2%).

Gastrointestinal adverse reactions, including abdominal pain (8% to 12%), nausea (8% to 11%), vomiting (6% to 15%), and anorexia or decreased appetite (8% to 17%) were reported in patients receiving treatment with rilpivirine in pediatric clinical trials. Other adverse reactions reported in less than 2% of patients treated with rilpivirine during adult clinical trials include diarrhea, cholecystitis, and cholelithiasis.

In addition to psychiatric disorders, other neurologic adverse reactions reported by recipients of rilpivirine during pediatric clinical trials included headache (19%), drowsiness (14%), and dizziness (8%). Fatigue (2%) was also reported with rilpivirine in adult clinical trials.

Rilpivirine has been associated with the development of rash. In most cases, rashes are minor (Grade 1 or 2) and develop within the first 4 to 6 weeks of therapy; however, pooled data from 2 adult clinical trials found 3% of patients treated with rilpivirine-containing regimens developed a more severe rash (Grade 2 and 3; no Grade 4 rashes were reported). In pediatric trials, rash was reported in 6% to 11% of patients receiving rilpivirine. Symptoms that may accompany a severe rash include fever, blisters, conjunctivitis, angioedema, mucosal involvement, facial edema, hepatitis, and eosinophilia. Postmarketing use has been associated with the development of hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS).

Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis were reported by less than 2% of adult patients receiving treatment with rilpivirine during clinical trials. Nephrotic syndrome has been noted during the postmarketing period.

Grade 1 or 2 elevated hepatic enzymes (up to 5 x the upper limit of normal [ULN]) were reported in 8% to 12% of patients receiving treatment with rilpivirine in pediatric clinical trials. Grade 3 and 4 elevations were reported in 1% to 2% of adult patients during clinical trials. The incidence of rilpivirine-associated hepatic enzyme elevations was higher in adult patients co-infected with hepatitis B or C virus than in those patients not co-infected. Hyperbilirubinemia, defined as more than 2.5 x ULN, was observed in 1% of adult patients receiving treatment with rilpivirine during clinical trials. Less severe increases in total bilirubin were observed in 5% (1.1 to 1.5 x ULN) and 3% (more than 1.5 to 2.5 x ULN) of rilpivirine recipients.

Laboratory abnormalities in pediatric patients receiving rilpivirine were similar to those observed in adults. During adult clinical trials, rilpivirine recipients experienced hypercholesterolemia (up to 17%) and hypertriglyceridemia (up to 2%). More specifically, Grade 1 (200 to 239 mg/dL), Grade 2 (240 to 300 mg/dL), and Grade 3 (more than 300 mg/dL) increases in total fasting cholesterol were experienced by 17%, 7%, and less than 1% of patients, respectively. Increases in fasting triglycerides were experienced by 2% (500 to 750 mg/dL) and 1% (751 to 1,200 mg/dL) of patients. Other laboratory abnormalities associated with rilpivirine included adrenocortical insufficiency and elevated serum creatinine. In pediatric clinical trials, there was an overall mean increase in cortisol of 1.59 mcg/dL compared to baseline in patients 12 to 17 years receiving rilpivirine. An abnormal 250 mcg ACTH stimulation test developed in 20% of patients receiving rilpivirine. In pediatric patients 6 to 11 years, among the 13 patients with low basal cortisol pre-dose at baseline, 2 patients had low basal and ACTH stimulated cortisol values throughout the trial, including ACTH stimulated cortisol at baseline before starting treatment with rilpivirine. The remaining 11 patients had normal serum cortisol values after ACTH stimulation at baseline and/or during treatment. In another trial in pediatric patients 2 to 11 years, of the 19 patients with low basal cortisol at Week 48, in 15 patients, the Week 48 serum cortisol returned to normal (248 nanomoles/L or more) after repeat serum basal cortisol testing or was normal after ACTH stimulation testing (500 nanomoles/L or more). In 4 patients, the serum cortisol remained low after repeat serum basal cortisol testing or after ACTH stimulation testing. At Week 48, 6 patients had normal (basal) cortisol (9 mcg/dL or more) and the Week 48 result was not available for 1 patient. Despite the altered cortisol concentrations, no serious adverse reactions, deaths, or treatment discontinuations were attributed to adrenal insufficiency in clinical trials. The significance of the higher abnormal rate of 250 mcg ACTH stimulation test in patients receiving rilpivirine is not known. Elevated serum creatinine of 1.1 to 1.3 x the upper limit of normal was observed in up to 6% of adult patients receiving rilpivirine during clinical trials. The mean increases in creatinine concentrations of 0.1 mg/dL occurred within the first 4 weeks of treatment and remained stable throughout the 96-week study period. The changes did not lead to treatment discontinuation in any rilpivirine recipient.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of rilpivirine and other antiretrovirals should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine range from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to rilpivirine therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia, or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Fat redistribution and hyperlipidemia (hypertriglyceridemia or hypercholesterolemia) may occur with rilpivirine. The HIV guidelines recommend monitoring of serum cholesterol and triglycerides at initiation or modification of anti-retroviral therapy and routinely during treatment.

Patients receiving rilpivirine have experienced adverse reactions affecting the central nervous system (CNS), including depressed mood, depression and major depression, altered mood, dysphoria, negative thoughts, suicidal ideation, and suicide attempts. Most of these psychiatric adverse events were mild to moderate in severity, with only 1% of patients requiring treatment discontinuation. Prior to initiating therapy, inform patients of the potential for psychiatric adverse events. Additionally, instruct patients to seek immediate medical evaluation if severe depressive symptoms develop during therapy.

Administration of supratherapeutic rilpivirine doses (75 to 300 mg/day) to healthy subjects have resulted in prolongation of the QT interval. Use rilpivirine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or torsade de pointes or to cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when rilpivirine is used either alone or in combination with other agents. Monotherapy is not recommended. Cross-resistance between rilpivirine and other non-nucleoside reverse transcriptase inhibitors has been observed.

Hepatotoxicity has occurred in adult patients treated with rilpivirine. Individuals at increased risk for developing hepatic dysfunction include those with hepatitis and HIV coinfection or other preexisting hepatic disease. In these patients, appropriate laboratory monitoring is recommended prior to and during treatment. Liver function monitoring should also be considered for patients with no preexisting hepatic disease, as a few cases of hepatotoxicity have been reported in rilpivirine treated patients with no identifiable risk factors for hepatic disease. The HIV treatment guidelines recommend all adolescent patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in most coinfected patients regardless of CD4 count. For antiretroviral naive patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Patients presenting with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive ARV regimen with activity against both viruses (regardless of CD4 counts). The HIV treatment guidelines recommend these patients receive an ARV regimen that contains tenofovir with emtricitabine or lamivudine as a dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection; avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, adefovir, entecavir, or telbivudine as the only active agent) as this may result in HIV and HBV resistant strains. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct hepatitis and HIV coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

Patients receiving rilpivirine may be at increased risk of developing a serious rash. According to the manufacturer, severe skin and hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during the post-marketing period. In some cases, these skin reactions were accompanied by constitutional findings (i.e., fever) or organ dysfunction (i.e., elevated hepatic enzymes). Health care providers are advised to closely monitor the patients clinical status (including laboratory parameters) during treatment. Immediately discontinue rilpivirine and initiate appropriate therapy in any patient who develops signs of severe skin reactions, such as severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia.

Description: Rilpivirine is an oral, diarylpyrimidine, non-nucleoside reverse transcriptase inhibitor (NNRTI). It is indicated for use with other antiretroviral agents to treat HIV-1 infection in antiretroviral treatment-naive patients with HIV-1 RNA concentrations of 100,000 copies/mL or less at initiation of therapy. It is also indicated for short-term use in combination with cabotegravir (as a lead-in to or replacement for missed cabotegravir; rilpivirine extended-release injections) in patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and no known or suspected resistance to rilpivirine or cabotegravir. The efficacy of rilpivirine in antiretroviral treatment-naive pediatric patients has been established in clinical trials. In a single arm, open-label, Phase 2 trial (n = 54; 2 cohorts), HIV-1 RNA concentrations decreased to less than 50 copies/mL at week 48 in 79% of patients 12 to 17 years (n = 22/28) with baseline HIV-1 RNA concentrations of 100,000 copies/mL or less compared to 50% of patients (n = 4/8) with baseline HIV-1 RNA concentrations more than 100,000 copies/mL. Virologic failures occurred in 21% and 38% respectively, in these 2 groups. At week 48, there was a mean increase in CD4 count of approximately 200 cells/mm3 from baseline. In patients 6 to 11 years, the number of subjects with HIV-1 RNA less than 50 copies/mL at week 48 was 13/18 (72%), while 3/18 (17%) subjects had HIV-1 RNA of at least 50 copies/mL at week 48. Health care providers are advised of the potential for treatment emergent resistance and rilpivirine treatment failure in patients with baseline HIV-1 RNA concentrations more than 100,000 copies/mL. Rilpivirine is FDA-approved in pediatric patients as young as 2 years weighing at least 14 kg; it is approved for short-term use in combination with cabotegravir in pediatric patients 12 years and older weighing at least 35 kg.

General Dosing Information
NOTE: Prior to initiating therapy, health care providers are advised to consider the following findings from clinical trials: virologic failures occurred more frequently in patients with baseline HIV-1 RNA concentrations more than 100,000 copies/mL than in patients with concentrations of 100,000 copies/mL or less; patients with CD4 counts less than 200 cells/mm3 experienced more virologic failures than those with counts of 200 cells/mm3 or more (regardless of HIV-1 RNA concentrations); virologic failures associated with resistance and cross-resistance to the NNRTI class occurred more frequently in rilpivirine-treated patients than efavirenz-treated patients; a higher rate of tenofovir and lamivudine/emtricitabine resistance developed in rilpivirine-treated patients than in efavirenz-treated patients.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Rilpivirine plus a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option is an alternative NNRTI-based initial regimen for children and adolescents 12 years and older weighing at least 35 kg with pre-treatment HIV-1 RNA less than 100,000 copies/mL and CD4 count more than 200 cells/mm3.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
-for the treatment of HIV infection in antiretroviral treatment-naive patients with HIV-1 RNA concentrations less than or equal to 100,000 copies/mL at treatment initiation:
Oral dosage (tablets for oral suspension):
Children 2 to 12 years weighing 14 to 19 kg: 12.5 mg PO once daily with a meal.
Children 2 to 12 years weighing 20 to 24 kg: 15 mg PO once daily with a meal.
Oral dosage (film-coated tablets):
Children and Adolescents 2 to 17 years weighing 25 kg or more: 25 mg PO once daily with a meal.
-for the short-term treatment of HIV infection in combination with cabotegravir in patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and no known or suspected resistance to rilpivirine or cabotegravir:
Oral dosage (film-coated tablets):
Children and Adolescents 12 to 17 years weighing 35 kg or more receiving oral lead-in dosing to assess tolerability of rilpivirine prior to administration of cabotegravir; rilpivirine extended-release injection: 25 mg in combination with 30 mg of cabotegravir PO once daily starting at least 28 days prior to administering cabotegravir; rilpivirine extended-release injection. Administer the rilpivirine and cabotegravir tablets at approximately the same time each day with a meal. Take the last oral dose on the same day the extended-release injections are started.
Children and Adolescents 12 to 17 years weighing 35 kg or more who will miss planned dosing with cabotegravir; rilpivirine extended-release injection: If a patient plans to miss a scheduled cabotegravir; rilpivirine injection by more than 7 days, give 25 mg in combination with 30 mg of cabotegravir PO once daily as a replacement. Start the first dose of oral therapy at the same time as the planned missed injection. Administer the rilpivirine and cabotegravir tablets at approximately the same time each day with a meal. Continue the oral dose until the day the extended-release injections are restarted. Daily oral rilpivirine plus cabotegravir may be used for up to 2 months to replace missed injection(s). If a duration of longer than 2 months is expected, select an alternative oral regimen, which may include rilpivirine as a component of the regimen.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
younger than 2 years or weighing less than 14 kg: Safety and efficacy have not been established.
2 to 12 years weighing 14 to 19 kg: 12.5 mg/day PO (tablets for oral suspension); safety and efficacy of film-coated tablets have not been established.
2 to 12 years weighing 20 to 24 kg: 15 mg/day PO (tablets for oral suspension); safety and efficacy of film-coated tablets have not been established.
2 to 12 years weighing 25 kg or more: 25 mg/day PO (film-coated tablets); safety and efficacy of tablets for oral suspension have not been established.
-Adolescents
25 mg/day PO (film-coated tablets); safety and efficacy of tablets for oral suspension have not been established.

Patients with Hepatic Impairment Dosing
Mild to moderate hepatic impairment (Child-Pugh Class A and B): Dosage adjustments are not required.
Severe hepatic impairment (Child-Pugh Class C): Rilpivirine has not been studied.

Patients with Renal Impairment Dosing
Mild to moderate renal impairment: Dosage adjustments are not required.
Severe renal impairment or end-stage renal disease: Use with caution and monitor carefully for adverse effects.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Rilpivirine inhibits HIV-1 reverse transcriptase. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), it does not compete for binding nor does it require phosphorylation to be active. Rilpivirine binds directly to a site on reverse transcriptase that is distinct from where NRTIs bind. This binding causes disruption of the enzyme's active site thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. The 50% maximal inhibitory concentrations (EC50) for wild type laboratory-adapted strains of HIV-1 is 0.73 nanomolar. It has very limited activity against HIV-2 reverse transcriptase with an EC50 ranging from 2,510 to 10,830 nanomolar. Human cellular DNA polymerase alpha, beta, and gamma are not inhibited by rilpivirine.

During clinical use, treatment-emergent genotypic and phenotypic resistance occurred more frequently in patients receiving rilpivirine (58%) than in patients treated with efavirenz (45%). Resistance to background antiretrovirals (emtricitabine, lamivudine, tenofovir, abacavir, or zidovudine) developed in 52% of rilpivirine virologic failures compared to 23% in the efavirenz arm. Cross-resistance to efavirenz, etravirine, and nevirapine is likely after virologic failure and development of rilpivirine resistance.

Avoid the use of rilpivirine in patients with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.

Pharmacokinetics: Rilpivirine is administered orally. After systemic absorption, it is highly protein bound (99.7%), predominantly to albumin. It is unknown if there is distribution into compartments other than plasma, such as cerebrospinal fluid or genital tract secretions. Metabolism occurs primarily via oxidation by the hepatic cytochrome (CYP) P450 3A system. After administration of a single oral dose, an average of 85% is eliminated via the feces and 6.1% is excreted in the urine. Metabolites account for the majority of the excretion with only 25% of an administered dose excreted as unchanged rilpivirine (25% in feces, less than 1% in urine). The terminal elimination half-life is approximately 50 hours with excretion occurring predominately through the feces.

Affected cytochrome P450 isoenzymes: CYP3A
Rilpivirine is primarily metabolized via oxidation by the hepatic cytochrome (CYP) P450 3A system. Rilpivirine is neither an inducer nor an inhibitor of CYP450 isoenzymes.


-Route-Specific Pharmacokinetics
Oral Route
The absolute oral bioavailability of rilpivirine is unknown; however, the time to reach maximum plasma concentrations (Tmax) is approximately 4 to 5 hours. A difference in bioavailability between the film-coated tablet and tablets for oral suspension was observed; therefore, these products are NOT substitutable.
Effects of food
-Film-coated tablets: Compared to fasting conditions, exposure (AUC) is increased by 40% when administered with a normal caloric (533 kcal) or high fat, high caloric meal (928 kcal). Administering with only a protein-rich nutritional drink decreases exposure by 50% when compared with fed conditions.
-Tablets for oral suspension: Administration of the rilpivirine 2.5 mg tablets dispersed in drinking water in fasted conditions or after yogurt consumption resulted in a 31% and 28% lower exposure, respectively, compared to administration in fed conditions (a meal containing 533 kcal) in adults.


-Special Populations
Pediatrics
The pharmacokinetics of rilpivirine in pediatric patients (2 to 17 years weighing at least 16 kg) receiving the recommended weight-based dosing regimen were comparable or slightly higher than those obtained in adult patients.

Hepatic Impairment
During a study evaluating the effects of hepatic impairment on rilpivirine pharmacokinetics, exposure (AUC) after multiple doses was increased by 47% in patients with mild hepatic impairment (Child-Pugh Class A) and 5% in patients with moderate hepatic impairment (Child-Pugh Class B) when compared against matched controls. Pharmacokinetic parameters have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Renal Impairment
Analysis of rilpivirine pharmacokinetics indicates that exposure (AUC) in patients with mild renal impairment is comparable to the exposure observed in patients with normal renal function. There is limited information available regarding the pharmacokinetics in patients with moderate to severe renal impairment or in patients with end-stage renal disease. Caution and close monitoring are recommended for patients with severe renal impairment or end-stage renal disease. It is not likely that hemodialysis or peritoneal dialysis will remove rilpivirine from plasma, because a large percentage of circulating drug is bound to plasma proteins.

Gender Differences
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed based on gender.

Ethnic Differences
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed based on race.

Other
Hepatitis Coinfection
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed in patients with hepatitis B or C coinfection.