Rilpivirine
- Rifabutin Co-administration: For patients concomitantly receiving rifabutin, the Rilpivirine dose should be increased to 50 mg (two tablets of 25 mg each) once daily, taken with a meal. When rifabutin co-administration is stopped, the Rilpivirine dose should be decreased to 25 mg once daily, taken with a meal.
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampin, rifapentine
- proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St John's wort (Hypericum perforatum)
- Caution should be given to prescribing Rilpivirine with drugs that may reduce the exposure of rilpivirine.
- In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

## Depressive Disorders
- The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with Rilpivirine  During the Phase 3 trials (N = 1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among Rilpivirine (n = 686) or efavirenz (n = 682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both Rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among Rilpivirine or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the Rilpivirine arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Rilpivirine  and if so, to determine whether the risks of continued therapy outweigh the benefits.

## Hepatotoxicity
- Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or hepatitis C, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of Rilpivirine  A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with Rilpivirine is recommended in patients with underlying hepatic disease such as hepatitis B or hepatitis C, or in patients with marked elevations in transaminases prior to treatment initiation. *Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.

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

## Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Rilpivirine  During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution syndrome; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naive HIV-1 infected adult patients, 686 of whom received Rilpivirine (25 mg once daily). The median duration of exposure for patients in the Rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with Rilpivirine or efavirenz due to ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the Rilpivirine arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the Rilpivirine arm and 10 (1.5%) subjects in the efavirenz arm.

## Common Adverse Drug Reactions
- ADRs of at least moderate intensity ( Grade 2) reported in at least 2% of adult subjects are presented in Table 1. Selected treatment-emergent laboratory abnormalities are included in Table 2.
- No new ADR terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks.

## Less Common Adverse Drug Reactions
- Treatment-emergent ADRs of at least moderate intensity ( Grade 2) occurring in less than 2% of antiretroviral treatment-naive subjects receiving Rilpivirine are listed below by System Organ Class. Some adverse events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with Rilpivirine.
- Gastrointestinal Disorders: diarrhea, abdominal discomfort
- Hepatobiliary Disorders: cholecystitis, cholelithiasis
- Metabolism and Nutrition Disorders: decreased appetite
- Nervous System Disorders: somnolence
- Psychiatric Disorders: sleep disorders, anxiety
- Renal and Urinary Disorders: glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis

## Laboratory Abnormalities in Treatment-Naive Subjects
- The percentage of subjects treated with Rilpivirine or efavirenz in the Phase 3 trials with selected treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 2.
- In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85; -7.37) nmol/L in the Rilpivirine group and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the Rilpivirine group (+18.4  8.36 nmol/L) than in the efavirenz group (+54.1  7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.
- In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with Rilpivirine  Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed after 96 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Serum creatinine increases occurred regardless of the background N(t)RTI regimen.
- Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 3. The clinical benefit of these findings has not been demonstrated.

## Subjects Co-Infected with Hepatitis B and/or Hepatitis C Virus
- In subjects co-infected with hepatitis B or hepatitis C virus receiving Rilpivirine  the incidence of hepatic enzyme elevation was higher than in subjects receiving Rilpivirine who were not co-infected. This observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-infected subjects was comparable to that in subjects without co-infection.
- Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
- Table 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of Rilpivirine and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Rilpivirine are also included in Table 4.
In addition to the drugs included in Table 4, the interaction between Rilpivirine and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when Rilpivirine is co-administered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.
- There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram.  Rilpivirine should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Rilpivirine  an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- The effect of Rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).
- When supratherapeutic doses of 75 mg once daily and 300 mg once daily of Rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of Rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of Rilpivirine.
- The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naive HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.

## Absorption and Bioavailability
- After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 45 hours. The absolute bioavailability of Rilpivirine is unknown.

## Effects of Food on Oral Absorption
- The exposure to rilpivirine was approximately 40% lower when Rilpivirine was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When Rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.

## Distribution
- Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

## Metabolism
- In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 CYP3A system.

## Elimination
- The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.

# Special Populations

## Hepatic Impairment
- Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Rilpivirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).

## Hepatitis B and/or Hepatitis C Virus Co-infection
- Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no clinically relevant effect on the exposure to rilpivirine.

## Renal Impairment
- Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

## Gender
- No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between men and women.

## Race
- Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no clinically relevant effect on the exposure to rilpivirine.

## Pediatric Patients
- The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients have not been established.

## Drug Interactions
- Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration of Rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Co-administration of Rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration of Rilpivirine with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of NNRTIs.
- Rilpivirine at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
- Drug interaction studies were performed with Rilpivirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax, AUC, and Cmin values of rilpivirine are summarized in Table 6 (effect of other drugs on Rilpivirine). The effect of co-administration of Rilpivirine on the Cmax, AUC, and Cmin values of other drugs are summarized in Table 7 (effect of Rilpivirine on other drugs).
- The evidence of efficacy of Rilpivirine is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naive adults. Antiretroviral treatment-naive HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA  5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.
- In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the Rilpivirine arm and the efavirenz arm. Table 9 displays selected demographic and baseline disease characteristics of the subjects in the Rilpivirine and efavirenz arms.
Week 96 efficacy outcomes for subjects treated with Rilpivirine 25 mg once daily from the pooled analysis are shown in Table 10. The incidence of virologic failure was higher in the Rilpivirine arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.
At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm3 for Rilpivirine-treated subjects and 219 cells/mm3 for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials.
Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naive HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part  followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of Rilpivirine were switched to Rilpivirine 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.
Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naive adult subjects who had a plasma HIV-1 RNA  5000 copies/ml, previously received  2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs.
- At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ml receiving Rilpivirine 25 mg (N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm3 in subjects receiving Rilpivirine 25 mg and 160 cells/mm3 in subjects receiving efavirenz.
- At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA < 50 copies/mL compared to 57% (51/89) of subjects in the control group.
- Rilpivirine tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01).