EDURANT and EDURANT PED, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 2 years of age and older and weighing at least 14 kg with plasma HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.

Limitations of Use

EDURANT is indicated in combination with VOCABRIA (cabotegravir) for short-term treatment of HIV-1 infection in adults and adolescents 12 years and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as [see Dosage and Administration (2.6)] :

EDURANT is available in two dosage forms:

Do not substitute EDURANT tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. A difference in bioavailability between 1 × 25 mg film-coated tablet and 10 × 2.5 mg tablets for oral suspension was observed; therefore, they are NOT substitutable [see Warnings and Precautions (5.6)and Clinical Pharmacology (12.3)].

Take EDURANT and EDURANT PED once daily with a meal in combination with other antiretrovirals [see Clinical Pharmacology (12.3)].

The recommended dosage of EDURANT in adult patients is one 25 mg tablet taken orally once daily with a meal [see Use in Specific Populations (8.1)and Clinical Pharmacology (12.3)] .

The recommended dosage of EDURANT and EDURANT PED in pediatric patients 2 years of age and older and weighing at least 14 kg is based on body weight (see Table 1). Both EDURANT and EDURANT PED should be taken orally once daily with a meal [see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)] .

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1: Recommended Dosage of EDURANT and EDURANT PED for Pediatric Patients</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule" valign="bottom">Body Weight (kg)</th><th align="left" class="Rrule" valign="bottom">EDURANT 25 mg Tablets</th><th align="left" class="Rrule" valign="bottom">EDURANT PED 2.5 mg Tablets for Oral Suspension</th><th align="left" class="Rrule" valign="bottom">Total Daily Dose</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">14 kg to less than 20 kg</td><td align="left" class="Rrule">Not recommended</td><td align="left" class="Rrule">5 tablets once daily</td><td align="left" class="Rrule">12.5 mg EDURANT PED once daily</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">20 kg to less than 25 kg</td><td align="left" class="Rrule">Not recommended</td><td align="left" class="Rrule">6 tablets once daily</td><td align="left" class="Rrule">15 mg EDURANT PED once daily</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Greater than or equal to 25 kg</td><td align="left" class="Rrule">1 tablet once daily</td><td align="left" class="Rrule">Not recommended</td><td align="left" class="Rrule">25 mg EDURANT once daily</td> </tr> </tbody> </table></div>

Advise patients or caregivers of patients taking EDURANT PED to refer to the Instructions for Use to properly prepare and take the medication.

EDURANT PED must be dispersed in drinking water and taken immediately with a meal. If not taken immediately, then the oral suspension should be discarded, and a new dose of medicine should be prepared. The patient should not chew or swallow EDURANT PED whole. The following instructions should be followed:

For pregnant patients who are already on a stable EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) the recommended dosage in adults and pediatric patients weighing at least 25 kg is one 25 mg tablet once daily taken orally with a meal. Refer to Table 1 for dosing recommendations for pediatric patients [see Dosage and Administration (2.2, 2.3)]. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1)and Clinical Pharmacology (12.3)] .

Consult the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) before initiating EDURANT to ensure therapy with CABENUVA is appropriate.

Oral Lead-In Dosing to Assess Tolerability of Rilpivirine

Oral lead-in should be used for approximately 1 month (at least 28 days) to assess the tolerability of rilpivirine prior to the initiation of CABENUVA. The recommended oral daily dose is one 25 mg tablet of EDURANT (rilpivirine) in combination with one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) orally once daily at approximately the same time each day with a meal [see Clinical Pharmacology (12.3)].

Because EDURANT is indicated in combination with VOCABRIA (cabotegravir), the prescribing information for VOCABRIA (cabotegravir) tablets should also be consulted.

The last oral dose should be taken on the same day injections with CABENUVA are started.

Oral Dosing to Replace Planned Missed Injections of CABENUVA

Planned Missed Injections for Patients on Monthly Dosing Schedule

If a patient plans to miss a scheduled monthly injection of CABENUVA by more than 7 days, take daily oral therapy for up to 2 months to replace missed injection visits. The recommended oral daily dose is one 25 mg tablet of EDURANT and one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) at approximately the same time each day with a meal. The first dose of oral therapy should be initiated at approximately the same time as the planned missed injection and continued until the day injection dosing is restarted. For oral therapy with EDURANT and VOCABRIA of durations greater than 2 months, an alternative oral regimen is recommended, which may include EDURANT. See full prescribing information for CABENUVA to resume monthly injection dosing.

Planned Missed Injections for Patients on Every-2-Month Dosing Schedule

If a patient plans to miss a scheduled every-2-month injection of CABENUVA by more than 7 days, take daily oral therapy for a duration of up to 2 months to replace 1 missed scheduled every-2-month injection. The recommended oral daily dose is one 25 mg tablet of EDURANT and one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) at approximately the same time each day with a meal. The first dose of oral therapy should be initiated at approximately the same time as the planned missed injection and continued until the day injection dosing is restarted. For oral therapy with EDURANT and VOCABRIA of durations greater than 2 months, an alternative oral regimen is recommended, which may include EDURANT. See full prescribing information for CABENUVA to resume every-2-month injection dosing.

If EDURANT is coadministered with rifabutin, the EDURANT dose should be increased to 50 mg (two 25 mg tablets) once daily, taken with a meal. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal [see Drug Interactions (7)and Clinical Pharmacology (12.3)].

Note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. Refer to CABENUVA labeling for additional detail.

EDURANT 25 mg Film-Coated Tablets

25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with "TMC" on one side and "25" on the other side. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

EDURANT PED 2.5 mg Tablets for Oral Suspension

2.5 mg white to almost white, round 6.5 mm tablet, debossed with "TMC" on one side and "PED" on the other side. Each tablet for oral suspension contains 2.75 mg of rilpivirine hydrochloride equivalent to 2.5 mg rilpivirine.

EDURANT and EDURANT PED are contraindicated for coadministration with the drugs in Table 2 for which significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to EDURANT or EDURANT PED or to the class of NNRTIs [see Drug Interactions (7)and Clinical Pharmacology (12.3)] .

{ "type": "p", "children": [], "text": "EDURANT and EDURANT PED are contraindicated for coadministration with the drugs in Table 2 for which significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to EDURANT or EDURANT PED or to the class of NNRTIs\n \n [see\n \n Drug Interactions (7)and\n \n Clinical Pharmacology (12.3)]\n \n .\n\n " }

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: Drugs That are Contraindicated with EDURANT and EDURANT PED</span> </caption> <col align="left" valign="top" width="23%"/> <col align="left" valign="top" width="23%"/> <col align="left" valign="top" width="54%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="bottom">Drug Class</th><th align="center" class="Rrule" valign="bottom">Contraindicated Drugs in Class</th><th align="center" class="Rrule" valign="bottom">Clinical Comment</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Anticonvulsants</td><td align="left" class="Rrule">Carbamazepine <br/> Oxcarbazepine <br/> Phenobarbital <br/> Phenytoin </td><td align="left" class="Rrule" rowspan="4">Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" valign="middle">Antimycobacterials</td><td align="left" class="Rrule">Rifampin <br/> Rifapentine </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" valign="middle">Glucocorticoid <br/> (systemic) </td><td align="left" class="Rrule">Dexamethasone <br/> (more than a single-dose treatment) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Herbal Products</td><td align="left" class="Rrule">St. John's wort <br/> ( <span class="Italics">Hypericum perforatum</span>) </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Proton Pump Inhibitors</td><td align="left" class="Rrule">e.g., Esomeprazole <br/> Lansoprazole <br/> Omeprazole <br/> Pantoprazole <br/> Rabeprazole </td><td align="left" class="Rrule">Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"85%\">\n<caption>\n<span>Table 2: Drugs That are Contraindicated with EDURANT and EDURANT PED</span>\n</caption>\n<col align=\"left\" valign=\"top\" width=\"23%\"/>\n<col align=\"left\" valign=\"top\" width=\"23%\"/>\n<col align=\"left\" valign=\"top\" width=\"54%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" valign=\"bottom\">Drug Class</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">Contraindicated Drugs in Class</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">Clinical Comment</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\">Anticonvulsants</td><td align=\"left\" class=\"Rrule\">Carbamazepine \n <br/> Oxcarbazepine \n <br/> Phenobarbital \n <br/> Phenytoin\n </td><td align=\"left\" class=\"Rrule\" rowspan=\"4\">Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" valign=\"middle\">Antimycobacterials</td><td align=\"left\" class=\"Rrule\">Rifampin \n <br/> Rifapentine\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" valign=\"middle\">Glucocorticoid \n <br/> (systemic)\n </td><td align=\"left\" class=\"Rrule\">Dexamethasone \n <br/> (more than a single-dose treatment)\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Herbal Products</td><td align=\"left\" class=\"Rrule\">St. John's wort \n <br/> (\n \n <span class=\"Italics\">Hypericum perforatum</span>)\n \n </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\">Proton Pump Inhibitors</td><td align=\"left\" class=\"Rrule\">e.g., Esomeprazole \n <br/> Lansoprazole \n <br/> Omeprazole \n <br/> Pantoprazole \n <br/> Rabeprazole\n </td><td align=\"left\" class=\"Rrule\">Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response.</td>\n</tr>\n</tbody>\n</table></div>" }

Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving EDURANT. No Grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1and 6.2)] . Discontinue EDURANT or EDURANT PED immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, 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 should be initiated.

Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT or EDURANT PED. A few cases of hepatic toxicity have been reported in adult 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 EDURANT or EDURANT PED is recommended in patients with underlying hepatic disease such as hepatitis B or C virus infection, 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.

The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with EDURANT. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to EDURANT or EDURANT PED, and if so, to determine whether the risks of continued therapy outweigh the benefits.

During the Phase 3 trials in adults (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among EDURANT (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 EDURANT and efavirenz. The incidence of discontinuation due to depressive disorders among EDURANT 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 EDURANT arm.

During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving EDURANT through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.

The concomitant use of EDURANT or EDURANT PED and other drugs may result in potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.7), Contraindications (4), and Drug Interactions (7)] :

In healthy subjects, 75 mg once daily and 300 mg once daily (3 times and 12 times the dose in EDURANT) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to EDURANT or EDURANT PED when coadministered with a drug that is known to have a risk of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.2)] .

See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during EDURANT or EDURANT PED therapy and review concomitant medications during therapy.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EDURANT. 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 jirovecii pneumonia or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

EDURANT and EDURANT PED have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis. A difference in bioavailability between 1 × 25 mg film-coated tablet and 10 × 2.5 mg tablets for oral suspension was observed; therefore, they are not substitutable [see Clinical Pharmacology (12.3)]. When a pediatric patient weighs 25 kg or greater, they must switch from EDURANT PED tablets for oral suspension to one 25 mg EDURANT tablet daily [see Dosage and Administration (2.3)]. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to rilpivirine.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience in Adults

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-naïve HIV-1 infected adult patients, 686 of whom received EDURANT (25 mg once daily) [see Clinical Studies (14.1)] . The median duration of exposure for patients in the EDURANT arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most adverse reactions occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with EDURANT or efavirenz due to adverse reaction, regardless of severity, was 2% and 4%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the EDURANT arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (<1%) subject in the EDURANT arm and 10 (2%) subjects in the efavirenz arm.

Common Adverse Reactions

Adverse reactions of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are presented in Table 3. Selected laboratory abnormalities are included in Table 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3: Selected Adverse Reactions of at Least Moderate Intensity <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a>(Grades 2–4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects (Week 96 Analysis) </span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2">System Organ Class, <br/> Preferred Term, <br/> % </th><th align="center" class="Rrule" colspan="2">Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials</th> </tr> <tr class="Last"> <th align="center" class="Rrule">EDURANT + BR <br/> N=686 </th><th align="center" class="Rrule">Efavirenz + BR <br/> N=682 </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">N=total number of subjects per treatment group; BR=background regimen</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule"><span class="Bold">Gastrointestinal Disorders</span></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Abdominal pain</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">General Disorders and Administration Site Conditions</span></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fatigue</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">Nervous System Disorders</span></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">4%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">7%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">Psychiatric Disorders</span></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Depressive disorders <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">4%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Insomnia</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">4%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Abnormal dreams</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">4%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">Skin and Subcutaneous Tissue Disorders</span></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Rash</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">11%</td> </tr> </tbody> </table></div>

No new adverse reaction 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 Reactions

Adverse reactions of at least moderate intensity (≥Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving EDURANT 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 EDURANT.

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-Naïve Subjects

The percentage of subjects treated with EDURANT or efavirenz in the Phase 3 trials with selected laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity are shown in Table 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4: Selected Changes in Laboratory Parameters (Grades 1 to 4) Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Week 96 Analysis)</span> </caption> <col align="left" valign="top" width="32%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="top" width="24%"/> <col align="center" valign="top" width="24%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="top">Laboratory Parameter Abnormality, (%)</th><th align="center" class="Rrule" rowspan="2" valign="top">DAIDS Toxicity Range</th><th align="center" class="Rrule" colspan="2">Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials</th> </tr> <tr class="Botrule"> <th align="center" class="Rrule">EDURANT + BR <br/> N=686 </th><th align="center" class="Rrule">Efavirenz + BR <br/> N=682 </th> </tr> <tr class="Last"> <th align="left" class="Lrule"><span class="Italics">BIOCHEMISTRY</span></th><th align="center" class="Rrule" colspan="3"></th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="4" valign="top">BR=background regimen; ULN=upper limit of normal</td> </tr> <tr> <td align="left" colspan="4" valign="top">N=number of subjects per treatment group</td> </tr> <tr class="Last"> <td align="left" colspan="4" valign="top">Note: Percentages were calculated versus the number of subjects in ITT.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Increased Creatinine</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 1</td><td align="center" class="Rrule">≥1.1–≤1.3 × ULN</td><td align="center" class="Rrule">6%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">&gt;1.3–≤1.8 × ULN</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">&gt;1.8–≤3.4 × ULN</td><td align="center" class="Rrule">&lt;1%</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 4</td><td align="center" class="Rrule">&gt;3.4 × ULN</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">&lt;1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Increased AST</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 1</td><td align="center" class="Rrule">≥1.25–≤2.5 × ULN</td><td align="center" class="Rrule">16%</td><td align="center" class="Rrule">19%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">&gt;2.5–≤5.0 × ULN</td><td align="center" class="Rrule">4%</td><td align="center" class="Rrule">7%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">&gt;5.0–≤10.0 × ULN</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 4</td><td align="center" class="Rrule">&gt;10.0 × ULN</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Increased ALT</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 1</td><td align="center" class="Rrule">≥1.25–≤2.5 × ULN</td><td align="center" class="Rrule">18%</td><td align="center" class="Rrule">20%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">&gt;2.5–≤5.0 × ULN</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">7%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">&gt;5.0–≤10.0 × ULN</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 4</td><td align="center" class="Rrule">&gt;10.0 × ULN</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Increased Total Bilirubin</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 1</td><td align="center" class="Rrule">≥1.1–≤1.5 × ULN</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">&lt;1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">&gt;1.5–≤2.5 × ULN</td><td align="center" class="Rrule">3%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">&gt;2.5–≤5.0 × ULN</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">&lt;1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 4</td><td align="center" class="Rrule">&gt;5.0 × ULN</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Increased Total Cholesterol (fasted)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 1</td><td align="center" class="Rrule">5.18–6.19 mmol/L <br/> 200–239 mg/dL </td><td align="center" class="Rrule">17%</td><td align="center" class="Rrule">31%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">6.20–7.77 mmol/L <br/> 240–300 mg/dL </td><td align="center" class="Rrule">7%</td><td align="center" class="Rrule">19%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">&gt;7.77 mmol/L <br/> &gt;300 mg/dL </td><td align="center" class="Rrule">&lt;1%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Increased LDL Cholesterol (fasted)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 1</td><td align="center" class="Rrule">3.37–4.12 mmol/L <br/> 130–159 mg/dL </td><td align="center" class="Rrule">14%</td><td align="center" class="Rrule">26%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">4.13–4.90 mmol/L <br/> 160–190 mg/dL </td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">13%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">≥4.91 mmol/L <br/> ≥191 mg/dL </td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">5%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Increased Triglycerides (fasted)</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 2</td><td align="center" class="Rrule">5.65–8.48 mmol/L <br/> 500–750 mg/dL </td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Grade 3</td><td align="center" class="Rrule">8.49–13.56 mmol/L <br/> 751–1,200 mg/dL </td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">3%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Grade 4</td><td align="center" class="Rrule">&gt;13.56 mmol/L <br/> &gt;1,200 mg/dL </td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1%</td> </tr> </tbody> </table></div>

Adrenal Function

In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the EDURANT group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group.

In the EDURANT group, 43/588 (7%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3%) in the efavirenz group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, fourteen subjects in the EDURANT group and nine subjects in the efavirenz group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the EDURANT group is not known.

Serum Creatinine

In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with EDURANT. 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.

Serum Lipids

Changes from baseline in total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides are presented in Table 5. The clinical benefit of these findings has not been demonstrated.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5: Lipid Values, Mean Change from Baseline <a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></span> </caption> <col align="left" valign="middle" width="16%"/> <col align="center" valign="top" width="6%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="6%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="3"></th><th align="center" class="Rrule" colspan="8">Pooled Data from the Week 96 Analysis of the Phase 3 TMC278-C209 and TMC278-C215 Trials</th> </tr> <tr class="Botrule"> <th align="center" class="Rrule" colspan="4">EDURANT + BR</th><th align="center" class="Rrule" colspan="4">Efavirenz + BR</th> </tr> <tr class="Botrule"> <th align="center" class="Rrule">N</th><th align="center" class="Rrule">Baseline</th><th align="center" class="Rrule" colspan="2">Week 96</th><th align="center" class="Rrule">N</th><th align="center" class="Rrule">Baseline</th><th align="center" class="Rrule" colspan="2">Week 96</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">Mean <br/> (95% CI) </th><th align="center" class="Rrule"></th><th align="center" class="Rrule" valign="bottom">Mean <br/> (mg/dL) </th><th align="center" class="Rrule" valign="bottom">Mean <br/> (mg/dL) </th><th align="center" class="Rrule">Mean Change <a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a> <br/> (mg/dL) </th><th align="center" class="Rrule"></th><th align="center" class="Rrule" valign="bottom">Mean <br/> (mg/dL) </th><th align="center" class="Rrule" valign="bottom">Mean <br/> (mg/dL) </th><th align="center" class="Rrule">Mean Change <a class="Sup" href="#footnote-4">†</a> <br/> (mg/dL) </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="9" valign="top">N=number of subjects per treatment group; BR=background regimen</td> </tr> <tr> <td align="left" colspan="9"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Excludes subjects who received lipid lowering agents during the treatment period</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Total Cholesterol <br/> (fasted) </td><td align="center" class="Rrule">546</td><td align="center" class="Rrule">161 <br/> </td><td align="center" class="Rrule">166 <br/> </td><td align="center" class="Rrule">5 <br/> </td><td align="center" class="Rrule">507</td><td align="center" class="Rrule">160 <br/> </td><td align="center" class="Rrule">187 <br/> </td><td align="center" class="Rrule">28 <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">HDL-cholesterol <br/> (fasted) </td><td align="center" class="Rrule">545</td><td align="center" class="Rrule">41 <br/> </td><td align="center" class="Rrule">46 <br/> </td><td align="center" class="Rrule">4 <br/> </td><td align="center" class="Rrule">505</td><td align="center" class="Rrule">40 <br/> </td><td align="center" class="Rrule">51 <br/> </td><td align="center" class="Rrule">11 <br/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">LDL-cholesterol <br/> (fasted) </td><td align="center" class="Rrule">543</td><td align="center" class="Rrule">96 <br/> </td><td align="center" class="Rrule">98 <br/> </td><td align="center" class="Rrule">1 <br/> </td><td align="center" class="Rrule">503</td><td align="center" class="Rrule">95 <br/> </td><td align="center" class="Rrule">109 <br/> </td><td align="center" class="Rrule">14 <br/> </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Triglycerides <br/> (fasted) </td><td align="center" class="Rrule">546</td><td align="center" class="Rrule">122 <br/> </td><td align="center" class="Rrule">116 <br/> </td><td align="center" class="Rrule">-6 <br/> </td><td align="center" class="Rrule">507</td><td align="center" class="Rrule">130 <br/> </td><td align="center" class="Rrule">141 <br/> </td><td align="center" class="Rrule">11 <br/> </td> </tr> </tbody> </table></div>

Subjects Co-infected with Hepatitis B and/or Hepatitis C Virus

In subjects co-infected with hepatitis B or C virus receiving EDURANT, the incidence of hepatic enzyme elevation was higher than in subjects receiving EDURANT 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.

Use in Combination with Cabotegravir

Safety findings from Phase 3/3b trials in adults were similar when EDURANT was administered in combination with VOCABRIA (cabotegravir) or other antiretrovirals. See full prescribing information for VOCABRIA and CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) for additional information.

Clinical Trials Experience in Pediatric Patients

Pediatric Population (≥12 to less than 18 years of age)

Trial TMC278-C213 Cohort 1

The safety assessment is based on the Week 48 analysis of the single-arm, open-label, Phase 2 trial, TMC278-C213 Cohort 1, in which 36 antiretroviral treatment-naïve HIV-1 infected patients 12 to less than 18 years of age and weighing at least 32 kg received EDURANT (25 mg once daily) in combination with other antiretroviral agents [see Clinical Studies (14.3)] . The median duration of exposure was 63.5 weeks. There were no patients who discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.

Adverse reactions were reported in nineteen pediatric subjects (53%). Most adverse reactions were Grade 1 or 2. The most common adverse reactions reported in at least 2 subjects (regardless of severity) include headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%).

Observed laboratory abnormalities were comparable to those in adults.

Adrenal Function

In trial TMC278-C213 Cohort 1, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL.

Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known.

Trial 208580 [MOCHA]

Based on data from the Week 16 analysis of the MOCHA trial in 15 adolescents (12 to less than 18 years of age and weighing ≥35 kg) receiving EDURANT (25 mg once daily) in addition to continuing background antiretroviral therapy, the safety profile during the oral lead-in period in adolescents was consistent with the safety profile established with EDURANT in adults.

Pediatric Population (≥2 to less than 12 years of age)

Two clinical trials were conducted in pediatric subjects weighing at least 16 kg (5 to less than 12 years of age). A total of 18 and 26 pediatric subjects were enrolled in Trial TMC278-C213 and Trial TMC278HTX2002, respectively. Overall, the safety data in these pediatric studies were similar to those observed in adults. Safety results from the two trials are summarized below.

Trial TMC278-C213 Cohort 2

Cohort 2 of the single-arm, open-label Phase 2 trial, TMC278-C213 evaluated the safety of the EDURANT and EDURANT PED weight adjusted doses 25, 15 and 12.5 mg once daily in antiretroviral treatment-naïve HIV-1 infected patients (≥6 to <12 years of age and weighing at least 17 kg) [see Clinical Studies (14.4)] . The median duration of exposure for patients in the Week 48 analysis (including post-Week 48 extension) was 69.5 (range 35 to 218) weeks.

All adverse reactions were Grade 1 or 2. Adverse reactions reported in at least 2 subjects, regardless of grading, in Trial TMC278-C213 Cohort 2 were: decreased appetite (3/18, 17%), vomiting (2/18, 11%), ALT increased (2/18, 11%), AST increased (2/18, 11%), and rash (2/18, 11%). No adverse reactions led to discontinuation.

Adrenal Function

In trial TMC278-C213 Cohort 2, basal cortisol at baseline was normal (≥9 μg/dL) for 4/18 subjects, low for 13/18 subjects, and missing for 1/18 subjects.

Among the 4 subjects with normal basal cortisol at baseline, 3 subjects had either normal basal cortisol levels (≥9 μg/dL) or normal cortisol levels 1 hour after ACTH stimulation (≥18.1 μg/dL) throughout the trial and/or at the last available visit (Week 24 and Week 72), and 1 subject had low basal cortisol at the last available assessment (Week 48) and no ACTH stimulation test was performed. Among the 13 subjects with low basal cortisol pre-dose at baseline, 2 subjects had low basal and ACTH stimulated cortisol values throughout the trial, including ACTH stimulated cortisol at baseline before starting treatment with rilpivirine. For both subjects, no adverse events suggestive for adrenal insufficiency were reported. The remaining 11 subjects had normal serum cortisol values after ACTH stimulation at baseline and/or during treatment.

Trial TMC278HTX2002

The single arm, open-label Phase 2 trial, TMC278HTX2002, evaluated the safety of EDURANT and EDURANT PED weight-adjusted doses 25, 15 and 12.5 mg once daily in virologically suppressed HIV-1 infected patients (≥2 to <12 years of age and weighing at least 16 kg). The median duration of exposure for patients in the Week 48 analysis was 48.4 (range 47 to 52) weeks.

All adverse reactions were Grade 1 or 2. Adverse reactions reported in at least 2 subjects, regardless of grading, in Trial TMC278HTX2002 were: vomiting (4/26, 15%), abdominal pain (3/26, 12%), nausea (2/26, 8%), ALT increased (3/26, 12%), AST increased (2/26, 8%), and decreased appetite (2/26, 8%). No adverse reactions led to discontinuation.

Adrenal Function

In trial TMC278HTX2002, 15/26 subjects had either normal basal cortisol (≥9 μg/dL) or normal cortisol 1 hour after ACTH stimulation (≥18.1 μg/dL), 9 had low basal cortisol on Day 1, and in 2 subjects the baseline value was missing.

From the 19 subjects with low basal cortisol at Week 48, in 15 subjects, the Week 48 serum cortisol levels returned to normal (≥248 nmol/L) after repeat serum basal cortisol testing or was normal after ACTH stimulation testing (≥500 nmol/L). In 4 subjects, the serum cortisol levels remained low after repeat serum basal cortisol testing or after ACTH stimulation testing. At Week 48, 6 subjects had normal (basal) cortisol (≥9 ug/dL) and the Week 48 result was not available for 1 subject.

Adverse reactions have been identified during postmarketing experience in patients receiving a rilpivirine containing regimen. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Renal and Genitourinary Disorders: nephrotic syndrome

Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

QT Prolonging Drugs

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, 75 mg once daily and 300 mg once daily (3 times and 12 times the dose in EDURANT) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology (12.2)] . Consider alternatives to EDURANT when coadministered with a drug with a known risk of torsade de pointes.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period (see Data) .

In animal reproduction studies, no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures up to 15 (rats) and 70 (rabbits) times the exposure in humans (≥12 years of age and weighing at least 32 kg) at the recommended dose of 25 mg once daily (see Data) .

Clinical Considerations

Dosing During Pregnancy and the Postpartum Period

Based on the experience of HIV-1-infected pregnant women who completed a clinical trial through the postpartum period with a rilpivirine-based regimen, no dose adjustments are required for pregnant patients who are already on a stable EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.5)]. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Clinical Pharmacology (12.3)] .

Data

Human Data

Based on prospective reports to the APR of over 550 exposures to rilpivirine during the first trimester of pregnancy resulting in live births, there was no significant difference between the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens.

Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant women during the second and third trimesters and postpartum. Each of the women were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C 0hand AUC) of total rilpivirine was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of rilpivirine was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following spontaneous termination of the pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant women, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV–1-infected adults.

Animal Data

Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg once daily. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg daily.

Risk Summary

Based on limited data after oral administration, rilpivirine is present in human breast milk. The data do not allow determination of the amount of rilpivirine that is transferred to milk. There are no data on the effects on a breastfed infant, or the effects on milk production. Rilpivirine is present in rat milk (see Data) . Potential risks of breastfeeding include: (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

Data

Animal Data

Animal lactation studies with rilpivirine have not been conducted. However, rilpivirine was detected in the plasma of nursing pups on lactation day 7 in the rat pre- and postnatal development study.

The safety and effectiveness of EDURANT and EDURANT PED has been established for the treatment of HIV-1 infection in treatment-naïve pediatric patients 2 years of age and older and weighing at least 14 kg. Use of EDURANT or EDURANT PED in this population is supported by three trials: TMC278-C213, TMC278HTX2002 and MOCHA.

Trial TMC278-C213

TMC278-C213 was a single arm, open-label, Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects, and was divided into two Cohorts.

Trial TMC278HTX2002

The safety, tolerability, antiviral activity and pharmacokinetics of EDURANT and EDURANT PED weight-adjusted doses 25, 15 and 12.5 mg daily was evaluated in a single-arm, open-label Phase 2 trial in 26 HIV-1 infected pediatric subjects 2 to less than 12 years of age and weighing at least 16 kg. Trial TMC278HTX2002 supports the safety and effectiveness of EDURANT and EDURANT PED in treatment-naïve HIV-1 infected pediatric patients 2 to less than 6 years of age [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

MOCHA Trial (NCT03497676)

The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label, non- comparative study, MOCHA (IMPAACT 2017) [see Adverse Reactions (6.1)] . Refer to the VOCABRIA and CABENUVA prescribing information for additional information when EDURANT is used in combination with cabotegravir.

The safety and effectivness of EDURANT in these pediatric subjects were similar to that seen in adults, and there were no significant changes on rilpivirine exposures [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness in pediatric patients less than 2 years of age or weighing less than 14 kg have not been established. Treatment with EDURANT PED is not recommended in pediatric patients less than 2 years of age or weighing below 14 kg [see Warnings and Precautions (5.6)] .

Clinical studies of EDURANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of EDURANT in elderly patients reflecting the greater frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy.

No dose adjustment of EDURANT or EDURANT PED is required in patients with mild or moderate renal impairment. However, in patients with severe renal impairment or end-stage renal disease, EDURANT or EDURANT PED should be used with caution and with increased monitoring for adverse effects, as rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)] .

No dosage adjustment of EDURANT or EDURANT PED is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. EDURANT and EDURANT PED have not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)] .

There is no specific antidote for overdose with EDURANT or EDURANT PED. Human experience of overdose with EDURANT or EDURANT PED is limited. Treatment of overdose with EDURANT or EDURANT PED consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

{ "type": "p", "children": [], "text": "There is no specific antidote for overdose with EDURANT or EDURANT PED. Human experience of overdose with EDURANT or EDURANT PED is limited. Treatment of overdose with EDURANT or EDURANT PED consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance." }

EDURANT ® (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).

{ "type": "p", "children": [], "text": "EDURANT \n ® (rilpivirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).\n " }

The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C 22H 18N 6∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:

{ "type": "p", "children": [], "text": "The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C \n 22H\n 18N\n 6∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:\n " }

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

{ "type": "p", "children": [], "text": "Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range." }

EDURANT 25 mg tablets are available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each EDURANT 25 mg tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.

{ "type": "p", "children": [], "text": "EDURANT 25 mg tablets are available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each EDURANT 25 mg tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin." }

EDURANT PED 2.5 mg tablets for oral suspension are available as white to almost white, round 6.5 mm tablet, debossed with "TMC" on one side and "PED" on the other side. Each tablet for oral suspension contains 2.75 mg of rilpivirine hydrochloride equivalent to 2.5 mg rilpivirine. Each tablet for oral suspension also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, mannitol, microcrystalline cellulose, polysorbate 20, povidone K30, sodium lauryl sulfate and sodium stearyl fumarate.

{ "type": "p", "children": [], "text": "EDURANT PED 2.5 mg tablets for oral suspension are available as white to almost white, round 6.5 mm tablet, debossed with \"TMC\" on one side and \"PED\" on the other side. Each tablet for oral suspension contains 2.75 mg of rilpivirine hydrochloride equivalent to 2.5 mg rilpivirine. Each tablet for oral suspension also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, mannitol, microcrystalline cellulose, polysorbate 20, povidone K30, sodium lauryl sulfate and sodium stearyl fumarate." }

Rilpivirine is an antiviral drug [see Microbiology (12.4)] .

Effects on Electrocardiogram

The effect of EDURANT 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 doses of 75 mg once daily and 300 mg once daily of EDURANT (3 times and 12 times the dose in EDURANT) 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 EDURANT 75 mg once daily and 300 mg once daily resulted in a mean steady-state C maxapproximately 2.6-fold and 6.7-fold, respectively, higher than the mean C maxobserved with the recommended 25 mg once daily dose of EDURANT [see Warnings and Precautions (5.4)] .

Pharmacokinetics in Adults

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 7: Pharmacokinetic Estimates of Rilpivirine 25 mg Once Daily in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Pooled Data from Phase 3 Trials through Week 96)</span> </caption> <col align="left" valign="top" width="65%"/> <col align="center" valign="top" width="35%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Parameter</th><th align="center" class="Rrule">Rilpivirine 25 mg once daily <br/> N=679 </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">AUC <span class="Sub">24h</span>(ng∙h/mL) </td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Mean±Standard Deviation</td><td align="center" class="Rrule">2235±851</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Median (Range)</td><td align="center" class="Rrule">2096 (198 – 7307)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">C <span class="Sub">0h</span>(ng/mL) </td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Mean±Standard Deviation</td><td align="center" class="Rrule">79±35</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Median (Range)</td><td align="center" class="Rrule">73 (2 – 288)</td> </tr> </tbody> </table></div>

Absorption and Bioavailability

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT and EDURANT PED is unknown.

Effects of Food on Oral Absorption

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

Administration of the EDURANT PED 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.

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 (CYP) 3A 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.

Specific Populations

Pregnancy and Postpartum

The exposure (C 0hand AUC 24h) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 8: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 <span class="Sup">nd </span>Trimester of Pregnancy, the 3 <span class="Sup">rd </span>Trimester of Pregnancy and Postpartum </span> </caption> <colgroup> <col align="left" valign="bottom" width="28%"/> <col align="center" valign="bottom" width="24%"/> <col align="center" valign="bottom" width="24%"/> <col align="center" valign="bottom" width="24%"/> </colgroup> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Pharmacokinetics of total rilpivirine <br/> (mean ± SD, t <span class="Sub">max</span>: median [range]) </th><th align="center" class="Rrule">Postpartum <br/> (6–12 Weeks) <br/> (n=11) </th><th align="center" class="Rrule">2 <span class="Sup">nd </span>Trimester of pregnancy <br/> (n=15) </th><th align="center" class="Rrule">3 <span class="Sup">rd </span>Trimester of pregnancy <br/> (n=13) </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">C <span class="Sub">0h</span>, ng/mL </td><td align="center" class="Rrule">111±69.2</td><td align="center" class="Rrule">65.0±23.9</td><td align="center" class="Rrule">63.5±26.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">C <span class="Sub">min</span>, ng/mL </td><td align="center" class="Rrule">84.0±58.8</td><td align="center" class="Rrule">54.3±25.8</td><td align="center" class="Rrule">52.9±24.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">C <span class="Sub">max</span>, ng/mL </td><td align="center" class="Rrule">167±101</td><td align="center" class="Rrule">121±45.9</td><td align="center" class="Rrule">123±47.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">t <span class="Sub">max</span>, h </td><td align="center" class="Rrule">4.00 (2.03–25.08)</td><td align="center" class="Rrule">4.00 (1.00–9.00)</td><td align="center" class="Rrule">4.00 (2.00–24.93)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">AUC <span class="Sub">24h</span>, ng.h/mL </td><td align="center" class="Rrule">2714±1535</td><td align="center" class="Rrule">1792±711</td><td align="center" class="Rrule">1762±662</td> </tr> </tbody> </table></div>

Pediatric Patients

The pharmacokinetics of rilpivirine in HIV-1 infected pediatric patients 2 to less than 18 years of age and weighing at least 16 kg receiving the recommended weight-based dosing regimen of EDURANT and EDURANT PED were comparable or slightly higher than those obtained in treatment-naïve HIV-1 infected adult patients (see Table 9 and Table 10).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 9: Pharmacokinetic Estimates of Rilpivirine After Administration of the Recommended Daily Oral Dosing Regimen in Pediatric Patients ≥6 to &lt;18 Years (Trial TMC278-C213) <a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></span> </caption> <colgroup> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> </colgroup> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule" valign="bottom">Pharmacokinetics of rilpivirine <a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a> <br/> Mean±SD <br/> Median (range) </th><th align="center" class="Rrule" valign="bottom">12.5 mg once daily <br/> &lt;20 kg </th><th align="center" class="Rrule" valign="bottom">15 mg once daily <br/> ≥20 to &lt;25 kg </th><th align="center" class="Rrule" valign="bottom">25 mg once daily <br/> ≥25 kg </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top">NA = not applicable</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>The 12.5 mg and 15 mg doses were administered as 5 and 6 dispersed 2.5 mg tablets, respectively. The 25 mg dose was administered as one 25 mg tablet. Mean rilpivirine exposure was approximately 40% higher in TMC278HTX2002 compared to TMC278-C213</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>Individual data when N=2</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">N</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">44</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC <span class="Sub">24h</span>(ng.h/mL) </td><td align="center" class="Rrule">1974, 2707 <br/> NA (1974 – 2707) </td><td align="center" class="Rrule">1912, 2477 <br/> NA (1912 – 2477) </td><td align="center" class="Rrule">2536±979 <br/> 2413 (973 – 4848) </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">C <span class="Sub">0h</span>(ng/mL) </td><td align="center" class="Rrule">68.1, 86.7 <br/> NA (68.1 – 86.7) </td><td align="center" class="Rrule">48.3, 80.0 <br/> NA (48.3 – 80.0) </td><td align="center" class="Rrule">87.0±34.5 <br/> 82.7 (27.8 – 171) </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 10: Pharmacokinetic Estimates of Rilpivirine After Administration of the Recommended Daily Oral Dosing Regimen in Pediatric Patients ≥2 to &lt;18 Years (Trial TMC278HTX2002) <a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a></span> </caption> <colgroup> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> </colgroup> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule" valign="bottom">Pharmacokinetics of rilpivirine <a class="Sup" href="#footnote-10" name="footnote-reference-10">†</a> <br/> Mean±SD <br/> Median (range) </th><th align="center" class="Rrule" valign="bottom">12.5 mg once daily <br/> ≥10 to &lt;20 kg </th><th align="center" class="Rrule" valign="bottom">15 mg once daily <br/> ≥20 to &lt;25 kg </th><th align="center" class="Rrule" valign="bottom">25 mg once daily <br/> ≥25 kg </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top">NA = not applicable</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>The 12.5 mg and 15 mg doses were administered as 5 and 6 dispersed 2.5 mg tablets, respectively. The 25 mg dose was administered as one 25 mg tablet. Mean rilpivirine exposure was approximately 40% higher in TMC278HTX2002 compared to TMC278-C213</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">†</a> </dt> <dd>Individual data when N=2</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">N</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">18</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC <span class="Sub">24h</span>(ng.h/mL) </td><td align="center" class="Rrule">4375, 5057 <br/> NA (4375 – 5057) </td><td align="center" class="Rrule">3541±949 <br/> 3112 (2689 – 4947) </td><td align="center" class="Rrule">4195±1056 <br/> 4016 (2732 – 6260) </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">C <span class="Sub">0h</span>(ng/mL) </td><td align="center" class="Rrule">151, 163 <br/> NA (151 – 163) </td><td align="center" class="Rrule">112±39.8 <br/> 91.8 (73.7 – 172) </td><td align="center" class="Rrule">134±38.7 <br/> 121 (78.9 – 220) </td> </tr> </tbody> </table></div>

Renal Impairment

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 [see Use in Specific Populations (8.6)] .

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. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7)] .

Sex, Race, Hepatitis B and/or Hepatitis C Virus Co-infection

No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between sex, race and patients with hepatitis B and/or C-virus co-infection.

Drug Interactions

[see Contraindications (4)and Drug Interactions (7)].

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT or EDURANT PED and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance. Coadministration of EDURANT and EDURANT PED and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT and EDURANT PED 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.

EDURANT and EDURANT PED at the recommended doses are not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the C max, AUC, and C minvalues of rilpivirine are summarized in Table 11 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the C max, AUC, and C minvalues of other drugs are summarized in Table 12 (effect of EDURANT on other drugs). [For information regarding clinical recommendations, see Drug Interactions (7)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 11: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Coadministered Drugs</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="7%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="bottom">Coadministered Drug</th><th align="center" class="Botrule Rrule" colspan="2" valign="bottom">Dose/Schedule</th><th align="center" class="Rrule" rowspan="2" valign="bottom">N</th><th align="center" class="Botrule Rrule" colspan="3" valign="bottom">Mean Ratio of <span class="Underline">Rilpivirine</span> <br/> Pharmacokinetic Parameters With/Without Coadministered Drug <br/> (90% CI); No Effect=1.00 </th> </tr> <tr class="Last"> <th align="center" class="Rrule" valign="bottom">Coadministered Drug</th><th align="center" class="Rrule" valign="bottom">Rilpivirine</th><th align="center" class="Rrule" valign="bottom">C <span class="Sub">max</span></th><th align="center" class="Rrule" valign="bottom">AUC</th><th align="center" class="Rrule" valign="bottom">C <span class="Sub">min</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="7">CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily</td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug.</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">†</a> </dt> <dd>Comparison based on historic controls</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With HIV Protease Inhibitors (PIs)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Darunavir/ritonavir</td><td align="center" class="Rrule">800/100 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a></td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">1.79 <br/> (1.56–2.06) </td><td align="center" class="Rrule">2.30 <br/> (1.98–2.67) </td><td align="center" class="Rrule">2.78 <br/> (2.39–3.24) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Lopinavir/ritonavir <br/> (soft gel capsule) </td><td align="center" class="Rrule">400/100 mg b.i.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">1.29 <br/> (1.18–1.40) </td><td align="center" class="Rrule">1.52 <br/> (1.36–1.70) </td><td align="center" class="Rrule">1.74 <br/> (1.46–2.08) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Didanosine</td><td align="center" class="Rrule">400 mg q.d. <br/> delayed release capsules taken 2 hours before rilpivirine </td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">1.00 <br/> (0.90–1.10) </td><td align="center" class="Rrule">1.00 <br/> (0.95–1.06) </td><td align="center" class="Rrule">1.00 <br/> (0.92–1.09) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Tenofovir disoproxil fumarate</td><td align="center" class="Rrule">300 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.96 <br/> (0.81–1.13) </td><td align="center" class="Rrule">1.01 <br/> (0.87–1.18) </td><td align="center" class="Rrule">0.99 <br/> (0.83–1.16) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With HIV Integrase Strand Transfer Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cabotegravir</td><td align="center" class="Rrule">30 mg q.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">0.96 <br/> (0.85–1.09) </td><td align="center" class="Rrule">0.99 <br/> (0.89–1.09) </td><td align="center" class="Rrule">0.92 <br/> (0.79–1.07) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Raltegravir</td><td align="center" class="Rrule">400 mg b.i.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">1.12 <br/> (1.04–1.20) </td><td align="center" class="Rrule">1.12 <br/> (1.05–1.19) </td><td align="center" class="Rrule">1.03 <br/> (0.96–1.12) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With other Antivirals</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Simeprevir</td><td align="center" class="Rrule">150 mg q.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">1.04 <br/> (0.95–1.13) </td><td align="center" class="Rrule">1.12 <br/> (1.05–1.19) </td><td align="center" class="Rrule">1.25 <br/> (1.16–1.35) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With Drugs other than Antiretrovirals</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Acetaminophen</td><td align="center" class="Rrule">500 mg single dose</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.09 <br/> (1.01–1.18) </td><td align="center" class="Rrule">1.16 <br/> (1.10–1.22) </td><td align="center" class="Rrule">1.26 <br/> (1.16–1.38) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Atorvastatin</td><td align="center" class="Rrule">40 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.91 <br/> (0.79–1.06) </td><td align="center" class="Rrule">0.90 <br/> (0.81–0.99) </td><td align="center" class="Rrule">0.90 <br/> (0.84–0.96) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Chlorzoxazone</td><td align="center" class="Rrule">500 mg single dose taken 2 hours after rilpivirine</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.17 <br/> (1.08–1.27) </td><td align="center" class="Rrule">1.25 <br/> (1.16–1.35) </td><td align="center" class="Rrule">1.18 <br/> (1.09–1.28) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Ethinylestradiol/Norethindrone</td><td align="center" class="Rrule">0.035 mg q.d./ <br/> 1 mg q.d. </td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">↔ <a class="Sup" href="#footnote-12" name="footnote-reference-12">†</a></td><td align="center" class="Rrule">↔ <a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Rrule">↔ <a class="Sup" href="#footnote-12">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Famotidine</td><td align="center" class="Rrule">40 mg single dose taken 12 hours before rilpivirine</td><td align="center" class="Rrule">150 mg single dose <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">24</td><td align="center" class="Rrule">0.99 <br/> (0.84–1.16) </td><td align="center" class="Rrule">0.91 <br/> (0.78–1.07) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Famotidine</td><td align="center" class="Rrule">40 mg single dose taken 2 hours before rilpivirine</td><td align="center" class="Rrule">150 mg single dose <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">0.15 <br/> (0.12–0.19) </td><td align="center" class="Rrule">0.24 <br/> (0.20–0.28) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Famotidine</td><td align="center" class="Rrule">40 mg single dose taken 4 hours after rilpivirine</td><td align="center" class="Rrule">150 mg single dose <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">24</td><td align="center" class="Rrule">1.21 <br/> (1.06–1.39) </td><td align="center" class="Rrule">1.13 <br/> (1.01–1.27) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Ketoconazole</td><td align="center" class="Rrule">400 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">1.30 <br/> (1.13–1.48) </td><td align="center" class="Rrule">1.49 <br/> (1.31–1.70) </td><td align="center" class="Rrule">1.76 <br/> (1.57–1.97) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Methadone</td><td align="center" class="Rrule">60–100 mg q.d., individualized dose</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">↔ <a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Rrule">↔ <a class="Sup" href="#footnote-12">†</a></td><td align="center" class="Rrule">↔ <a class="Sup" href="#footnote-12">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Omeprazole</td><td align="center" class="Rrule">20 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.60 <br/> (0.48–0.73) </td><td align="center" class="Rrule">0.60 <br/> (0.51–0.71) </td><td align="center" class="Rrule">0.67 <br/> (0.58–0.78) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Rifabutin</td><td align="center" class="Rrule">300 mg q.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">0.69 <br/> (0.62–0.76) </td><td align="center" class="Rrule">0.58 <br/> (0.52–0.65) </td><td align="center" class="Rrule">0.52 <br/> (0.46–0.59) </td> </tr> <tr> <td align="left" class="Lrule Rrule">Rifabutin</td><td align="center" class="Rrule">300 mg q.d.</td><td align="center" class="Rrule">50 mg q.d.</td><td align="center" class="Rrule">18</td><td align="center" class="Rrule">1.43 <br/> (1.30–1.56) </td><td align="center" class="Rrule">1.16 <br/> (1.06–1.26) </td><td align="center" class="Rrule">0.93 <br/> (0.85–1.01) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule Toprule" colspan="3">(reference arm for comparison was 25 mg q.d. rilpivirine administered alone)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Rifampin</td><td align="center" class="Rrule">600 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.31 <br/> (0.27–0.36) </td><td align="center" class="Rrule">0.20 <br/> (0.18–0.23) </td><td align="center" class="Rrule">0.11 <br/> (0.10–0.13) </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Sildenafil</td><td align="center" class="Rrule">50 mg single dose</td><td align="center" class="Rrule">75 mg q.d. <a class="Sup" href="#footnote-11">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.92 <br/> (0.85–0.99) </td><td align="center" class="Rrule">0.98 <br/> (0.92–1.05) </td><td align="center" class="Rrule">1.04 <br/> (0.98–1.09) </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 12: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of EDURANT</span> </caption> <col align="left" valign="top" width="22%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="6%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="14%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="bottom">Coadministered Drug</th><th align="center" class="Botrule Rrule" colspan="2" valign="bottom">Dose/Schedule</th><th align="center" class="Rrule" rowspan="2" valign="bottom">N</th><th align="center" class="Botrule Rrule" colspan="3" valign="bottom">Mean Ratio of <span class="Underline">Coadministered Drug</span> <br/> Pharmacokinetic Parameters With/Without EDURANT <br/> (90% CI); No Effect=1.00 </th> </tr> <tr class="Last"> <th align="center" class="Rrule" valign="bottom">Coadministered Drug</th><th align="center" class="Rrule" valign="bottom">Rilpivirine</th><th align="center" class="Rrule" valign="bottom">C <span class="Sub">max</span></th><th align="center" class="Rrule" valign="bottom">AUC</th><th align="center" class="Rrule" valign="bottom">C <span class="Sub">min</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="7">CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily</td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-13" name="footnote-13">*</a> </dt> <dd>This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">†</a> </dt> <dd>AUC (0–last)</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">‡</a> </dt> <dd>N (maximum number of subjects with data) for AUC (0–∞)=15 </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With HIV Protease Inhibitors (PIs)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Darunavir/ritonavir</td><td align="center" class="Rrule">800/100 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13" name="footnote-reference-13">*</a></td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">0.90 <br/> (0.81–1.00) </td><td align="center" class="Rrule">0.89 <br/> (0.81–0.99) </td><td align="center" class="Rrule">0.89 <br/> (0.68–1.16) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Lopinavir/ritonavir <br/> (soft gel capsule) </td><td align="center" class="Rrule">400/100 mg b.i.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">0.96 <br/> (0.88–1.05) </td><td align="center" class="Rrule">0.99 <br/> (0.89–1.10) </td><td align="center" class="Rrule">0.89 <br/> (0.73–1.08) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Didanosine</td><td align="center" class="Rrule">400 mg q.d. <br/> delayed release capsules taken 2 hours before rilpivirine </td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">0.96 <br/> (0.80–1.14) </td><td align="center" class="Rrule">1.12 <br/> (0.99–1.27) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Tenofovir disoproxil fumarate</td><td align="center" class="Rrule">300 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.19 <br/> (1.06–1.34) </td><td align="center" class="Rrule">1.23 <br/> (1.16–1.31) </td><td align="center" class="Rrule">1.24 <br/> (1.10–1.38) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With HIV Integrase Strand Transfer Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cabotegravir</td><td align="center" class="Rrule">30 mg q.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">1.05 <br/> (0.96–1.15) </td><td align="center" class="Rrule">1.12 <br/> (1.05–1.19) </td><td align="center" class="Rrule">1.14 <br/> (1.04–1.24) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Raltegravir</td><td align="center" class="Rrule">400 mg b.i.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">1.10 <br/> (0.77–1.58) </td><td align="center" class="Rrule">1.09 <br/> (0.81–1.47) </td><td align="center" class="Rrule">1.27 <br/> (1.01–1.60) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With other Antivirals</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Simeprevir</td><td align="center" class="Rrule">150 mg q.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">21</td><td align="center" class="Rrule">1.10 <br/> (0.97–1.26) </td><td align="center" class="Rrule">1.06 <br/> (0.94–1.19) </td><td align="center" class="Rrule">0.96 <br/> (0.83–1.11) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Coadministration With Drugs other than Antiretrovirals</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Acetaminophen</td><td align="center" class="Rrule">500 mg single dose</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.97 <br/> (0.86–1.10) </td><td align="center" class="Rrule">0.91 <br/> (0.86–0.97) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr> <td align="left" class="Lrule Rrule">Atorvastatin</td><td align="center" class="Rrule">40 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.35 <br/> (1.08–1.68) </td><td align="center" class="Rrule">1.04 <br/> (0.97–1.12) </td><td align="center" class="Rrule">0.85 <br/> (0.69–1.03) </td> </tr> <tr> <td align="left" class="Lrule Rrule">2-hydroxy-atorvastatin</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.58 <br/> (1.33–1.87) </td><td align="center" class="Rrule">1.39 <br/> (1.29–1.50) </td><td align="center" class="Rrule">1.32 <br/> (1.10–1.58) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" valign="bottom">4-hydroxy-atorvastatin</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.28 <br/> (1.15–1.43) </td><td align="center" class="Rrule">1.23 <br/> (1.13–1.33) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Chlorzoxazone</td><td align="center" class="Rrule">500 mg single dose taken 2 hours after rilpivirine</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.98 <br/> (0.85–1.13) </td><td align="center" class="Rrule">1.03 <br/> (0.95–1.13) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Digoxin</td><td align="center" class="Rrule">0.5 mg single dose</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">1.06 <br/> (0.97–1.17) </td><td align="center" class="Rrule">0.98 <br/> (0.93–1.04) <a class="Sup" href="#footnote-14" name="footnote-reference-14">†</a></td><td align="center" class="Rrule">N.A.</td> </tr> <tr> <td align="left" class="Lrule Rrule">Ethinylestradiol</td><td align="center" class="Rrule">0.035 mg q.d.</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">1.17 <br/> (1.06–1.30) </td><td align="center" class="Rrule">1.14 <br/> (1.10–1.19) </td><td align="center" class="Rrule">1.09 <br/> (1.03–1.16) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Norethindrone</td><td align="center" class="Rrule">1 mg q.d.</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">17</td><td align="center" class="Rrule">0.94 <br/> (0.83–1.06) </td><td align="center" class="Rrule">0.89 <br/> (0.84–0.94) </td><td align="center" class="Rrule">0.99 <br/> (0.90–1.08) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Ketoconazole</td><td align="center" class="Rrule">400 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">14</td><td align="center" class="Rrule">0.85 <br/> (0.80–0.90) </td><td align="center" class="Rrule">0.76 <br/> (0.70–0.82) </td><td align="center" class="Rrule">0.34 <br/> (0.25–0.46) </td> </tr> <tr> <td align="left" class="Lrule Rrule">R(-) methadone</td><td align="center" class="Rrule">60–100 mg q.d., individualized dose</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">0.86 <br/> (0.78–0.95) </td><td align="center" class="Rrule">0.84 <br/> (0.74–0.95) </td><td align="center" class="Rrule">0.78 <br/> (0.67–0.91) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">S(+) methadone</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">0.87 <br/> (0.78–0.97) </td><td align="center" class="Rrule">0.84 <br/> (0.74–0.96) </td><td align="center" class="Rrule">0.79 <br/> (0.67–0.92) </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Metformin</td><td align="center" class="Rrule">850 mg single dose</td><td align="center" class="Rrule">25 mg q.d.</td><td align="center" class="Rrule">20</td><td align="center" class="Rrule">1.02 <br/> (0.95–1.10) </td><td align="center" class="Rrule">0.97 <br/> (0.90–1.06) <a class="Sup" href="#footnote-15" name="footnote-reference-15">‡</a></td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Omeprazole</td><td align="center" class="Rrule">20 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">0.86 <br/> (0.68–1.09) </td><td align="center" class="Rrule">0.86 <br/> (0.76–0.97) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr> <td align="left" class="Lrule Rrule">Rifampin</td><td align="center" class="Rrule">600 mg q.d.</td><td align="center" class="Rrule">150 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.02 <br/> (0.93–1.12) </td><td align="center" class="Rrule">0.99 <br/> (0.92–1.07) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">25-desacetylrifampin</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">1.00 <br/> (0.87–1.15) </td><td align="center" class="Rrule">0.91 <br/> (0.77–1.07) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr> <td align="left" class="Lrule Rrule">Sildenafil</td><td align="center" class="Rrule">50 mg single dose</td><td align="center" class="Rrule">75 mg q.d. <a class="Sup" href="#footnote-13">*</a></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.93 <br/> (0.80–1.08) </td><td align="center" class="Rrule">0.97 <br/> (0.87–1.08) </td><td align="center" class="Rrule">N.A.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">N</span>-desmethyl-sildenafil </td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">0.90 <br/> (0.80–1.02) </td><td align="center" class="Rrule">0.92 <br/> (0.85–0.99) <a class="Sup" href="#footnote-14">†</a></td><td align="center" class="Rrule">N.A.</td> </tr> </tbody> </table></div>

Mechanism of Action

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

Antiviral Activity in Cell Culture

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC 50value for HIV-1 IIIBof 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited activity in cell culture against HIV-2 with a median EC 50value of 5220 nM (range 2510 to 10830 nM) (920 to 3970 ng/mL).

Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC 50values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC 50values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).

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

Resistance

In Cell Culture

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L.

In Treatment-Naïve Adult Subjects

In the Week 96 pooled resistance analysis of the Phase 3 trials TMC278-C209 and TMC278-C215, the emergence of resistance was greater among subjects' viruses in the EDURANT arm compared to the efavirenz arm, and was dependent on baseline viral load. In the pooled resistance analysis, 58% (57/98) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the EDURANT arm had virus with genotypic and/or phenotypic resistance to rilpivirine compared to 45% (25/56) of the resistance analysis subjects in the efavirenz arm who had genotypic and/or phenotypic resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to a background drug (emtricitabine, lamivudine, tenofovir, abacavir or zidovudine) emerged in viruses from 52% (51/98) of the resistance analysis subjects in the rilpivirine arm compared to 23% (13/56) in the efavirenz arm.

Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 – 621. The E138K substitution emerged most frequently during rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, T215S/T, or K219E/R) emerged more frequently in rilpivirine resistance analysis subjects compared to efavirenz resistance analysis subjects (see Table 13).

NNRTI- and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses from subjects with baseline viral load of ≤100,000 copies/mL compared to viruses from subjects with baseline viral load of >100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm 3compared to viruses from subjects with baseline CD4+ cell counts <200 cells/mm 3: 37% (20/54) compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72% (36/50) of NRTI-resistance substitutions.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 13: Proportion of Resistance Analysis Subjects <a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a>with Frequently Emerging Reverse Transcriptase Substitutions from the Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis </span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Botrule Rrule" colspan="2">TMC278-C209 and TMC278-C215 <br/> N=1368 </th> </tr> <tr class="Botrule Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">EDURANT + BR <br/> N=686 </th><th align="center" class="Rrule">Efavirenz + BR <br/> N=682 </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">BR=background regimen</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>Subjects who qualified for resistance analysis.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227 or M230</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">‡</a> </dt> <dd> This combination of NNRTI and NRTI substitutions is a subset of those with the E138K.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">§</a> </dt> <dd>A62V, K65R/N, D67N/G, K70E, L74I, V75I, Y115F, M184I/V, L210F, T215S/T, K219E/R</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">¶</a> </dt> <dd>These substitutions emerged in addition to the primary substitutions M184V/I or K65R/N; A62V (n=3), D67N/G (n=3), K70E (n=4), Y115F (n=2), T215S/T (n=1), K219E/R (n=8) in rilpivirine resistance analysis subjects.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Subjects who Qualified for Resistance Analysis</span></td><td align="center" class="Rrule">15% (98/652)</td><td align="center" class="Rrule">9% (56/604)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Subjects with Evaluable Post-Baseline Resistance Data</span></td><td align="center" class="Rrule">87</td><td align="center" class="Rrule">43</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Emerging NNRTI Substitutions</span><a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Any</td><td align="center" class="Rrule">62% (54/87)</td><td align="center" class="Rrule">53% (23/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">V90I</td><td align="center" class="Rrule">13% (11/87)</td><td align="center" class="Rrule">2% (1/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">K101E/P/T/Q</td><td align="center" class="Rrule">20% (17/87)</td><td align="center" class="Rrule">9% (4/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">K103N</td><td align="center" class="Rrule">1% (1/87)</td><td align="center" class="Rrule">40% (17/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">E138K/A/Q/G</td><td align="center" class="Rrule">40% (35/87)</td><td align="center" class="Rrule">2% (1/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  E138K+ M184I <a class="Sup" href="#footnote-18" name="footnote-reference-18">‡</a></td><td align="center" class="Rrule">25% (22/87)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">V179I/L/D</td><td align="center" class="Rrule">6% (5/87)</td><td align="center" class="Rrule">7% (3/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Y181C/I/S</td><td align="center" class="Rrule">10% (9/87)</td><td align="center" class="Rrule">2% (1/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">V189I</td><td align="center" class="Rrule">8% (7/87)</td><td align="center" class="Rrule">2% (1/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">H221Y</td><td align="center" class="Rrule">9% (8/87)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Emerging NRTI Substitutions <a class="Sup" href="#footnote-19" name="footnote-reference-19">§</a></span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Any</td><td align="center" class="Rrule">57% (50/87)</td><td align="center" class="Rrule">30% (13/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">M184I/V</td><td align="center" class="Rrule">54% (47/87)</td><td align="center" class="Rrule">26% (11/43)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">K65R/N</td><td align="center" class="Rrule">9% (8/87)</td><td align="center" class="Rrule">5% (2/43)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">A62V, D67N/G, K70E, Y115F, T215S/T or K219E/R <a class="Sup" href="#footnote-20" name="footnote-reference-20">¶</a></td><td align="center" class="Rrule">21% (18/87)</td><td align="center" class="Rrule">2% (1/43)</td> </tr> </tbody> </table></div>

Treatment--Naïve HIV-1-Infected Pediatric Subjects

In trial TMC278-C213 Cohort 1, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1-infected pediatric subjects ≥12 to less than 18 years [see Clinical Studies (14.3)] , rilpivirine resistance-associated substitutions were observed in 62.5% (5/8) of subjects with virologic failure and post-baseline genotypic data at 48 weeks with 4 of 5 having ≥2.5-fold decrease in susceptibility to rilpivirine. In addition, 4 of the 5 subjects with rilpivirine resistance substitutions also had at least 1 treatment-emergent resistance substitution to nucleos(t)ide reverse transcriptase inhibitors.

In trial TMC278-C213 Cohort 2, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1-infected pediatric subjects 6 to less than 12 years of age [see Clinical Studies (14.4)] , 83% (5/6) of subjects with virologic failure (3 subjects failed ≤48 weeks and 3 subjects failed after 48 weeks) had treatment-emergent rilpivirine resistance-associated substitutions with 4 showing reduced rilpivirine susceptibility. Additionally, 4 of the virologic failures also had treatment-emergent resistance substitutions to nucleos(t)ide reverse transcriptase inhibitors.

The emergent rilpivirine resistance-associated substitutions in pediatric patients are consistent with those seen in adults failing on a rilpivirine-containing regimen (see Table 13).

Cross-Resistance

Site-Directed NNRTI Mutant Virus

Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions had decreased susceptibility to rilpivirine (fold change range of 3.7 – 554) in 38% and 66% of mutants analyzed, respectively.

Treatment-Naïve HIV-1-Infected Adult Subjects

Considering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L.

Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the Week 96 pooled analyses of the Phase 3 TMC278-C209 and TMC278-C215 clinical trials, 50 of the 87 (57%) rilpivirine resistance analysis subjects with post-baseline resistance data had virus with decreased susceptibility to rilpivirine (≥2.5-fold change). Of these, 86% (n=43/50) were resistant to efavirenz (≥3.3-fold change), 90% (n=45/50) were resistant to etravirine (≥3.2-fold change) and 62% (n=31/50) were resistant to nevirapine (≥6-fold change). In the efavirenz arm, 3 of the 21 (14%) efavirenz resistance analysis subjects' viruses were resistant to etravirine and rilpivirine, and 95% (n=20/21) were resistant to nevirapine. Virus from subjects experiencing virologic failure on EDURANT developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class compared to virus from subjects who failed on efavirenz.

Carcinogenesis and Mutagenesis

Two-year carcinogenicity studies in mice and rats were conducted with rilpivirine. In rats, there were no drug related neoplasms at exposures 3 times those observed in humans (12 years of age and older and weighing greater than 32 kg) and ≥1.4 times relative to the predicted exposures in children (2 to less than 12 years of age, weighing at least 14 kg) at the recommended daily dose. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested dose in the mouse carcinogenicity study, the systemic exposure to rilpivirine was 21 times that observed in humans (12 years of age and older and weighing greater than 32 kg) and ≥12 times relative to the predicted exposures in children (2 to less than 12 years of age, weighing at least 14 kg) at the recommended daily dose.

Rilpivirine was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivorodent micronucleus assay.

Impairment of Fertility

In rat fertility and early embryonic development studies with rilpivirine, no effects on fertility were observed at rilpivirine exposures (AUC) greater than 36 times (male) and 40 times (female) the exposure in humans (12 years of age and older and weighing at least 32 kg) at the recommended daily dose of 25 mg.

The evidence of efficacy of EDURANT 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-naïve adults. Antiretroviral treatment-naïve 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 resistance-associated substitutions (RASs). The Phase 3 trials were identical in design, apart from 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 EDURANT arm and the efavirenz arm. Table 14 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 14: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis)</span> </caption> <colgroup> <col align="left" valign="top" width="44%"/> <col align="center" valign="top" width="28%"/> <col align="center" valign="top" width="28%"/> </colgroup> <thead> <tr class="First"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Botrule Rrule" colspan="2">Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">EDURANT + BR <br/> N=686 </th><th align="center" class="Rrule">Efavirenz + BR <br/> N=682 </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3">BR=background regimen</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Demographic Characteristics</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Median Age, years (range)</td><td align="center" class="Rrule">36 (18–78)</td><td align="center" class="Rrule">36 (19–69)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Sex</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Male</td><td align="center" class="Rrule">76%</td><td align="center" class="Rrule">76%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Female</td><td align="center" class="Rrule">24%</td><td align="center" class="Rrule">24%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Race</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">White</td><td align="center" class="Rrule">61%</td><td align="center" class="Rrule">60%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Black/African American</td><td align="center" class="Rrule">24%</td><td align="center" class="Rrule">23%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Asian</td><td align="center" class="Rrule">11%</td><td align="center" class="Rrule">14%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="center" class="Rrule">2%</td><td align="center" class="Rrule">2%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Not allowed to ask per local regulations</td><td align="center" class="Rrule">1%</td><td align="center" class="Rrule">1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Baseline Disease Characteristics</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Median Baseline Plasma HIV-1 RNA (range), log <span class="Sub">10</span>copies/mL </td><td align="center" class="Rrule">5.0 (2–7)</td><td align="center" class="Rrule">5.0 (3–7)</td> </tr> <tr> <td align="left" class="Lrule Rrule">Percentage of Patients with Baseline Plasma Viral Load:</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">≤100,000</td><td align="center" class="Rrule">54%</td><td align="center" class="Rrule">48%</td> </tr> <tr> <td align="left" class="Lrule Rrule">&gt;100,000 to ≤500,000</td><td align="center" class="Rrule">36%</td><td align="center" class="Rrule">40%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">&gt;500,000</td><td align="center" class="Rrule">10%</td><td align="center" class="Rrule">12%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Median Baseline CD4+ Cell Count (range), cells/mm <span class="Sup">3</span></td><td align="center" class="Rrule">249 (1–888)</td><td align="center" class="Rrule">260 (1–1137)</td> </tr> <tr> <td align="left" class="Lrule Rrule">Percentage of Subjects with:</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hepatitis B/C Virus Co-infection</td><td align="center" class="Rrule">7%</td><td align="center" class="Rrule">10%</td> </tr> <tr> <td align="left" class="Lrule Rrule">Percentage of Patients with the Following Background Regimens:</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">tenofovir disoproxil fumarate plus emtricitabine</td><td align="center" class="Rrule">80%</td><td align="center" class="Rrule">80%</td> </tr> <tr> <td align="left" class="Lrule Rrule">zidovudine plus lamivudine</td><td align="center" class="Rrule">15%</td><td align="center" class="Rrule">15%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">abacavir plus lamivudine</td><td align="center" class="Rrule">5%</td><td align="center" class="Rrule">5%</td> </tr> </tbody> </table></div>

Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 15. The incidence of virologic failure was higher in the EDURANT 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. Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm 3 experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm 3.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 15: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96</span> </caption> <colgroup> <col align="left" valign="top" width="56%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> </colgroup> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">EDURANT + BR <br/> N=686 </th><th align="center" class="Rrule">Efavirenz + BR <br/> N=682 </th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="3" valign="top">N=total number of subjects per treatment group; BR=background regimen.</td> </tr> <tr class="Last"> <td align="left" colspan="3" valign="top">Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-21" name="footnote-21">*</a> </dt> <dd>CI=Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96.</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">†</a> </dt> <dd>Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">‡</a> </dt> <dd>Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">§</a> </dt> <dd>Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">HIV-1 RNA &lt;50 copies/mL <a class="Sup" href="#footnote-21" name="footnote-reference-21">*</a></span></td><td align="center" class="Rrule">76%</td><td align="center" class="Rrule">77%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">HIV-1 RNA ≥50 copies/mL <a class="Sup" href="#footnote-22" name="footnote-reference-22">†</a></span></td><td align="center" class="Rrule">16%</td><td align="center" class="Rrule">10%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">No virologic data at Week 96 window</span> <br/> <span class="Underline">Reasons</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Discontinued study due to adverse event or death <a class="Sup" href="#footnote-23" name="footnote-reference-23">‡</a></td><td align="center" class="Rrule">4%</td><td align="center" class="Rrule">8%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Discontinued study for other reasons and last available HIV-1 RNA &lt;50 copies/mL (or missing) <a class="Sup" href="#footnote-24" name="footnote-reference-24">§</a></td><td align="center" class="Rrule">4%</td><td align="center" class="Rrule">5%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Missing data during window but on study</td><td align="center" class="Rrule">&lt;1%</td><td align="center" class="Rrule">&lt;1%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">HIV-1 RNA &lt;50 copies/mL by Baseline HIV-1 RNA (copies/mL)</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">≤100,000</td><td align="center" class="Rrule">82%</td><td align="center" class="Rrule">78%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">&gt;100,000</td><td align="center" class="Rrule">70%</td><td align="center" class="Rrule">75%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">HIV-1 RNA ≥50 copies/mL <a class="Sup" href="#footnote-22">†</a>by Baseline HIV-1 RNA (copies/mL) </span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">≤100,000</td><td align="center" class="Rrule">9%</td><td align="center" class="Rrule">8%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">&gt;100,000</td><td align="center" class="Rrule">24%</td><td align="center" class="Rrule">11%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">HIV-1 RNA &lt;50 copies/mL by CD4+ cell count (cells/mm <span class="Sup">3</span>) </span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">&lt;200</td><td align="center" class="Rrule">68%</td><td align="center" class="Rrule">74%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">≥200</td><td align="center" class="Rrule">81%</td><td align="center" class="Rrule">77%</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">HIV-1 RNA ≥50 copies/mL <a class="Sup" href="#footnote-22">†</a>by CD4+ cell count (cells/mm <span class="Sup">3</span>) </span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">&lt;200</td><td align="center" class="Rrule">27%</td><td align="center" class="Rrule">10%</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">≥200</td><td align="center" class="Rrule">10%</td><td align="center" class="Rrule">9%</td> </tr> </tbody> </table></div>

At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm 3 for EDURANT-treated subjects and 219 cells/mm 3 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-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 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-naïve 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 RASs.

At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/mL receiving EDURANT 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/mm 3in subjects receiving EDURANT 25 mg and 160 cells/mm 3in 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.

The use of EDURANT in combination with VOCABRIA (cabotegravir) as an oral lead-in and in patients who miss planned injections with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) was evaluated in two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (Trial 201584: FLAIR [NCT02938520], Trial 201585: ATLAS [NCT2951052]), and one Phase 3b randomized, multicenter, parallel-group, open-label, non-inferiority trial (Trial 207966: ATLAS-2M [NCT03299049]) in subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL). See full prescribing information for VOCABRIA and CABENUVA for additional information.

The pharmacokinetics, safety, tolerability and efficacy of EDURANT 25 mg once daily, in combination with an investigator-selected background regimen (BR) containing two NRTIs, was evaluated in trial TMC278-C213 Cohort 1, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg. Thirty six (36) subjects were enrolled in the trial to complete at least 48 weeks of treatment. The 36 subjects had a median age of 14.5 years (range: 12 to 17 years), and were 56% female, 89% Black and 11% Asian.

In the efficacy analysis, most subjects (75%; 28/36) had baseline HIV RNA <100,000 copies/mL. For these 28 subjects the median baseline plasma HIV-1 RNA was 44,250 (range: 2,060–92,600 copies/mL) and the median baseline CD4+ cell count was 445.5 cells/mm 3(range: 123 to 983 cells/mm 3).

Among the subjects who had baseline HIV RNA ≤100,000, the proportion with HIV-1 RNA <50 copies/mL at Week 48 was 79% (22/28), versus 50% (4/8) in those with >100,000 copies/mL. The proportion of virologic failures among subjects with a baseline viral load ≤100,000 copies/mL was 21% (6/28), versus 38% (3/8) in those with >100,000 copies/mL. At Week 48, the mean increase in CD4+ cell count from baseline was 201.2 cells/mm 3.

The pharmacokinetics, safety, tolerability and efficacy of EDURANT and EDURANT PED weight-adjusted doses 25, 15 and 12.5 mg once daily in combination with an investigator-selected BR containing two NRTIs, was evaluated in trial TMC278-C213 Cohort 2, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 6 to less than 12 years of age and weighing at least 17 kg. The Week 48 analysis included 18 subjects, 17 (94%) subjects completed the 48-week treatment period, and 1 (6%) subject discontinued the study early due to reaching a virologic endpoint. The 18 subjects had a median age of 9 years (range 6 to 11 years) and the median weight at baseline was 25 kg (range 17 to 51 kg). 89% were Black and 39% were female. The median baseline plasma viral load was 55,400 (range 567–149,000) copies/mL, and the median absolute baseline CD4+ cell count was 432.5 (range 12–2,068) cells/µL.

The number of subjects with HIV-1 RNA <50 copies/mL at Week 48 was 13/18 (72%), while 3/18 (17%) subjects had HIV-1 RNA ≥50 copies/mL at Week 48 [see Microbiology (12.4)] . Two out of 18 (11%) participants in the 15 mg once daily (20 to ≤25 kg) dose-weight group had missing viral load data at Week 48 but remained on study. The viral load for these 2 subjects was <50 copies/mL, post-Week 48. The mean increase (SE) in CD4+ from baseline was 215.9 (62.42) cells/µL at Week 48.

The safety and efficacy of EDURANT and EDURANT PED in treatment naïve pediatric subjects 2 to less than 6 years of age is supported by evidence from adequate and well-controlled studies of EDURANT in adults with additional population pharmacokinetic data from adults and pediatric subjects 6 years and older [see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)] .

EDURANT Tablets

EDURANT ® (rilpivirine) 25 mg tablets are supplied as white to off-white, film-coated, round, biconvex, 6.4 mm tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each tablet is debossed with "TMC" on one side and "25" on the other side.

EDURANT 25 mg tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01).

Store EDURANT tablets in the original bottle in order to protect from light. Store EDURANT tablets at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature].

EDURANT PED Tablets for Oral Suspension

EDURANT ® PED (rilpivirine) 2.5 mg tablets for oral suspension are supplied as white to almost white, round 6.5 mm tablets, debossed with "TMC" on one side and "PED" on the other side. Each tablet for oral suspension contains 2.75 mg rilpivirine hydrochloride equivalent to 2.5 mg rilpivirine.

EDURANT PED 2.5 mg tablets for oral suspension are packaged in aluminum cold form film blister with integrated desiccant and an aluminum peelable lidding foil. Each blister contains 10 tablets with 9 blisters per carton (NDC 59676-280-90).

Store EDURANT PED tablets for oral suspension in the original package in order to protect from light and moisture. Store at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature].

Severe Skin and Hypersensitivity Reactions

Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking EDURANT or EDURANT PED and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of more serious reactions such as DRESS severe hypersensitivity: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing a swelling of the face, eyes, lips, mouth, tongue or throat, which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems as it may be a sign of a more serious reaction. Advise patients that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.1)] .

Hepatotoxicity

Inform patients that hepatotoxicity has been reported with EDURANT. Inform patients that laboratory monitoring for hepatotoxicity during therapy with EDURANT or EDURANT PED is recommended, especially for patients with underlying liver disease such as hepatitis B or C virus infection [see Warnings and Precautions (5.2)].

Depressive Disorders

Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with EDURANT. Advise patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.3)] .

Drug Interactions

EDURANT or EDURANT PED may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7)] .

For patients concomitantly receiving rifabutin, the EDURANT dose should be increased to 50 mg once daily, taken with a meal. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal [see Dosage and Administration (2.7)] .

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when EDURANT or EDURANT PED is started [see Warnings and Precautions (5.5)].

EDURANT Tablets and EDURANT PED Tablets for Oral Suspension Are Not Substitutable

Advise patients that EDURANT and EDURANT PED have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis. Advise patients or their care providers that patients switching from EDURANT PED tablets for oral suspension to EDURANT tablets must adjust the dose [see Dosage and Administration (2.1, 2.3)and Warnings and Precautions (5.6)].

To avoid a dosing error from using the wrong formulation of EDURANT, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled [see Dosage and Administration (2), Warnings and Precautions (5.6), and How Supplied/Storage and Handling (16)].

Administration Instructions

Advise patients to take EDURANT or EDURANT PED with a meal once a day as prescribed. A protein drink or yogurt alone does not replace a meal [see Clinical Pharmacology (12.3)] . EDURANT and EDURANT PED must always be used in combination with other antiretroviral drugs. Advise patients not to alter the dose of EDURANT or EDURANT PED or discontinue therapy without consulting their physician.

Inform patients and caregivers that EDURANT PED tablets for oral suspension should be dispersed in drinking water and should not be crushed, chewed, or swallowed whole [see Dosage and Administration (2.4)].

If the patient misses a dose of EDURANT or EDURANT PED within 12 hours of the time it is usually taken, advise the patient to take EDURANT or EDURANT PED with a meal as soon as possible and then take the next dose of EDURANT or EDURANT PED at the regularly scheduled time. If a patient misses a dose of EDURANT or EDURANT PED by more than 12 hours, advise the patient to not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of EDURANT or EDURANT PED at any one time.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)] .

Manufactured for: Janssen Products, LP Horsham, PA 19044, USA

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For patent information: www.janssenpatents.com

{ "type": "p", "children": [], "text": "For patent information: www.janssenpatents.com" }

© Johnson & Johnson and its affiliates 2011, 2024

{ "type": "p", "children": [], "text": "© Johnson & Johnson and its affiliates 2011, 2024" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="45%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="20%"/> </colgroup> <thead> <tr class="First"> <th align="center" class="Lrule Rrule" colspan="5">PATIENT INFORMATION</th> </tr> <tr class="Last"> <th align="left" class="Lrule"></th><th align="center" colspan="2">EDURANT <span class="Sup">® </span>(ee dur ant) <br/> (rilpivirine) <br/> tablets, for oral use </th><th align="center" class="Rrule" colspan="2">EDURANT <span class="Sup">® </span>PED (ee dur ant ped) <br/> (rilpivirine) <br/> tablets, for oral suspension </th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="4">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 11/2024</td> </tr> <tr class="Last"> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are EDURANT and EDURANT PED?</span> <ul class="Disc"> <li>EDURANT and EDURANT PED are prescription medicines that are used with other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in people 2 years of age and older and who weigh at least 31 pounds (lbs) or 14 kilograms (kg) who: <ul class="Circle"> <li>have <span class="Bold">never </span>taken HIV-1 medicines before, <span class="Bold">and</span> </li> <li>have an amount of HIV-1 in their blood (this is called 'viral load') that is no more than 100,000 copies/mL.</li> </ul> </li> <li>EDURANT is also used with oral VOCABRIA (cabotegravir) for short term treatment of HIV-1 infection in people 12 years of age and older and who weigh at least 77 lbs (35 kg) when their healthcare provider determines that they meet certain requirements.</li> </ul> HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). <br/> If you take EDURANT in combination with oral VOCABRIA (cabotegravir), you should also read the Patient Information that comes with oral VOCABRIA (cabotegravir). <br/> It is not known if EDURANT or EDURANT PED is safe and effective in children less than 2 years of age or who weigh less than 31 Ibs (14 kg). </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Do not take EDURANT or EDURANT PED if you are taking any of the following medicines:</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule" colspan="2"></td><td align="left"> <ul> <li>carbamazepine</li> <li>phenobarbital</li> <li>rifampin</li> <li>dexamethasone (more than a single dose treatment)</li> <li>esomeprazole</li> <li>omeprazole</li> <li>rabeprazole</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul> <li>oxcarbazepine</li> <li>phenytoin</li> <li>rifapentine</li> <li>St. John's wort ( <span class="Italics">Hypericum perforatum</span>) </li> <li>lansoprazole</li> <li>pantoprazole</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Before taking EDURANT or EDURANT PED, tell your healthcare provider about all your medical conditions, including if you:</span> <ul> <li>have ever had a severe skin rash or an allergic reaction to medicines that contain rilpivirine</li> <li>have or had liver problems, including hepatitis B or C virus infection</li> <li>have kidney problems</li> <li>have ever had a mental health problem</li> <li>are pregnant or plan to become pregnant. It is not known if EDURANT or EDURANT PED will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with EDURANT or EDURANT PED. <ul class="Circle"> <li> <span class="Bold">Pregnancy Registry: </span>There is a pregnancy registry for women who take EDURANT during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry. </li> </ul> </li> <li>are breastfeeding or plan to breastfeed. EDURANT or EDURANT PED can pass into your breast milk. Talk with your healthcare provider about the following risks of breastfeeding during treatment with EDURANT or EDURANT PED: <ul class="Circle"> <li>The HIV-1 virus may pass to your baby if your baby does not have the HIV-1 infection.</li> <li>The HIV-1 virus may become harder to treat if your baby has HIV-1 infection.</li> <li>Your baby may get side effects from EDURANT or EDURANT PED.</li> </ul> </li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with EDURANT or EDURANT PED. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. <ul class="Disc"> <li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with EDURANT or EDURANT PED.</li> <li> <span class="Bold">Do not start taking a new medicine without telling your healthcare provider</span>. Your healthcare provider can tell you if it is safe to take EDURANT or EDURANT PED with other medicines. </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I take EDURANT or EDURANT PED? <br/> See the " <a href="#IFU">Instructions for Use</a>" for detailed instructions on how to prepare and give a dose of EDURANT PED tablets for oral suspension. </span> <ul> <li>Take EDURANT or EDURANT PED exactly as your healthcare provider tells you to.</li> <li> <span class="Bold">Take EDURANT or EDURANT PED 1 time each day with a meal. </span>A protein drink or yogurt alone does not replace a meal. </li> <li>EDURANT and EDURANT PED must be used with other HIV-1 medicines.</li> <li>Do not change your dose or stop taking EDURANT or EDURANT PED without first talking with your healthcare provider.</li> <li>Stay under the care of your healthcare provider during treatment with EDURANT or EDURANT PED.</li> <li> <span class="Bold">EDURANT PED tablets for oral suspension provided in a blister package are not the same as EDURANT tablets provided in a bottle and cannot be substituted for each other. </span>Contact your pharmacist or healthcare provider if you did not receive the correct dosage form. Your child's healthcare provider will prescribe EDURANT or EDURANT PED based on your child's weight. </li> <li>EDURANT PED tablets for oral suspension must be dispersed in drinking water. <span class="Bold">Do not</span>crush, chew, or swallow whole EDURANT PED tablets for oral suspension. </li> <li>If you take an H <span class="Sub">2</span>-receptor antagonist (such as famotidine, cimetidine, nizatidine, or ranitidine), you should take these medicines at least 12 hours before or at least 4 hours after you take EDURANT or EDURANT PED. </li> <li>If you take antacids, or other products that contain aluminum, calcium carbonate, or magnesium hydroxide, you should take these medicines at least 2 hours before or at least 4 hours after you take EDURANT or EDURANT PED.</li> <li> <span class="Bold">Do not </span>miss a dose of EDURANT or EDURANT PED. </li> <li>If you miss a dose of EDURANT or EDURANT PED within 12 hours of the time you usually take it, take your dose of EDURANT or EDURANT PED with a meal as soon as possible. Then, take your next dose of EDURANT or EDURANT PED at the regularly scheduled time. If you miss a dose of EDURANT or EDURANT PED by more than 12 hours of the time you usually take it, wait and then take the next dose of EDURANT or EDURANT PED at the regularly scheduled time.</li> <li> <span class="Bold">Do not </span>take more than your prescribed dose to make up for a missed dose or take less than your prescribed dose. </li> <li>If you take too much EDURANT or EDURANT PED, call your healthcare provider or go to the nearest hospital emergency room right away.</li> <li>When your supply of EDURANT or EDURANT PED starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of EDURANT or EDURANT PED. The amount of HIV in your blood may increase if the medicine is stopped even for a short time.</li> <li>When your healthcare provider prescribes use of EDURANT with oral VOCABRIA (cabotegravir): <ul class="Circle"> <li>Take EDURANT and oral VOCABRIA (cabotegravir) 1 time a day at about the same time each day with a meal.</li> <li>You will receive treatment with EDURANT tablets in combination with VOCABRIA tablets for one month (at least 28 days) before you receive the long-acting medicine called CABENUVA (cabotegravir; rilpivirine extended-release injectable suspensions) for the first time. This will allow your healthcare provider to assess how well you tolerate these medicines.</li> <li>Your final dose of EDURANT and VOCABRIA tablets should be taken on the same day you receive your first CABENUVA injections.</li> <li>If you miss or plan to miss a scheduled monthly or every 2 months injection of CABENUVA by more than 7 days, call your healthcare provider right away to discuss your treatment options.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the possible side effects of EDURANT and EDURANT PED? <br/> EDURANT and EDURANT PED can cause serious side effects including: </span> <ul class="Disc"> <li> <span class="Bold">Severe skin rash and allergic reactions. </span>Call your healthcare provider right away if you develop a rash with EDURANT or EDURANT PED. In some cases, rash and allergic reaction may need to be treated in a hospital. <br/> <span class="Bold">Stop taking EDURANT or EDURANT PED and get medical help right away if you develop a rash with any of the following signs or symptoms</span>: </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul> <li>fever</li> <li>tiredness</li> <li>difficulty breathing or swallowing</li> <li>skin blisters</li> <li>swelling of the face, lips, mouth, tongue, or throat</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul> <li>generally ill feeling</li> <li>muscle or joint aches</li> <li>blisters or mouth sores</li> <li>redness or swelling of the eyes (conjunctivitis)</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul> <li> <span class="Bold">Liver problems. </span>People with a history of hepatitis B or C virus infection or who have certain liver function test changes may have an increased risk of developing new or worsening changes in certain liver tests during treatment with EDURANT or EDURANT PED. Liver problems have also happened in people without a history of problems or other risk factors. Your healthcare provider may need to do tests to check your liver function before and during treatment with EDURANT or EDURANT PED. <span class="Bold">Call your healthcare provider right away if you develop any of the following signs or symptoms of liver problems:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>light colored stools (bowel movements)</li> <li>pain, aching, or tenderness on the right side of the stomach area</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul> <li>loss of appetite</li> <li>dark or "tea colored" urine</li> <li>nausea or vomiting</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul> <li> <span class="Bold">Depression or mood changes. Call your healthcare provider right away if you have any of the following symptoms:</span> <ul class="Circle"> <li>feeling sad or hopeless</li> <li>feeling anxious or restless</li> <li>have thoughts of hurting yourself (suicide) or have tried to hurt yourself</li> </ul> </li> <li> <span class="Bold">Changes in your immune system (Immune Reconstitution Syndrome) </span>can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">The most common side effects of EDURANT or EDURANT PED include </span>depression, headache, trouble sleeping (insomnia) and rash. <br/> These are not all the possible side effects of EDURANT or EDURANT PED. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I store EDURANT or EDURANT PED?</span> <ul> <li>Store EDURANT or EDURANT PED at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep EDURANT tablets in the original bottle to protect from light.</li> <li>Keep EDURANT PED tablets in the original package to protect from light and moisture.</li> </ul> <span class="Bold">Keep EDURANT or EDURANT PED and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">General information about the safe and effective use of EDURANT and EDURANT PED.</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EDURANT or EDURANT PED for a condition for which it was not prescribed. Do not give EDURANT or EDURANT PED to other people even if they have the same condition you have. It may harm them. <br/> You can ask your healthcare provider or pharmacist for information about EDURANT or EDURANT PED that is written for health professionals. </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the ingredients in EDURANT and EDURANT PED? <br/> Active ingredient: </span>rilpivirine. <br/> <span class="Bold">Inactive ingredients: <br/> EDURANT 25 mg tablets: </span>croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin. <br/> <span class="Bold">EDURANT PED 2.5 mg tablets for oral suspension: </span>croscarmellose sodium, lactose monohydrate, mannitol, microcrystalline cellulose, povidone K30, polysorbate 20, sodium lauryl sulfate and sodium stearyl fumarate. <br/> Manufactured for: Janssen Products, LP, Horsham PA 19044, USA <br/> For patent information: www.janssenpatents.com <br/> © Johnson &amp; Johnson and its affiliates 2011, 2024 <br/> For more information go to www.EDURANT.com or call 1-800-526-7736 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"45%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n</colgroup>\n<thead>\n<tr class=\"First\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"5\">PATIENT INFORMATION</th>\n</tr>\n<tr class=\"Last\">\n<th align=\"left\" class=\"Lrule\"></th><th align=\"center\" colspan=\"2\">EDURANT\n <span class=\"Sup\">® </span>(ee dur ant)\n <br/>\n\t\t\t(rilpivirine)\n <br/>\n\t\t\ttablets, for oral use\n </th><th align=\"center\" class=\"Rrule\" colspan=\"2\">EDURANT\n <span class=\"Sup\">® </span>PED (ee dur ant ped)\n <br/>\n\t\t\t(rilpivirine)\n <br/>\n\t\t\ttablets, for oral suspension\n </th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" colspan=\"4\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: 11/2024</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are EDURANT and EDURANT PED?</span>\n<ul class=\"Disc\">\n<li>EDURANT and EDURANT PED are prescription medicines that are used with other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in people 2 years of age and older and who weigh at least 31 pounds (lbs) or 14 kilograms (kg) who:\n\t\t\t\t\n <ul class=\"Circle\">\n<li>have \n <span class=\"Bold\">never </span>taken HIV-1 medicines before, \n <span class=\"Bold\">and</span>\n</li>\n<li>have an amount of HIV-1 in their blood (this is called 'viral load') that is no more than 100,000 copies/mL.</li>\n</ul>\n</li>\n<li>EDURANT is also used with oral VOCABRIA (cabotegravir) for short term treatment of HIV-1 infection in people 12 years of age and older and who weigh at least 77 lbs (35 kg) when their healthcare provider determines that they meet certain requirements.</li>\n</ul>\n\t\t\tHIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).\n <br/>\n\t\t\tIf you take EDURANT in combination with oral VOCABRIA (cabotegravir), you should also read the Patient Information that comes with oral VOCABRIA (cabotegravir).\n <br/>\n\t\t\tIt is not known if EDURANT or EDURANT PED is safe and effective in children less than 2 years of age or who weigh less than 31 Ibs (14 kg).\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Do not take EDURANT or EDURANT PED if you are taking any of the following medicines:</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule\" colspan=\"2\"></td><td align=\"left\">\n<ul>\n<li>carbamazepine</li>\n<li>phenobarbital</li>\n<li>rifampin</li>\n<li>dexamethasone (more than a single dose treatment)</li>\n<li>esomeprazole</li>\n<li>omeprazole</li>\n<li>rabeprazole</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul>\n<li>oxcarbazepine</li>\n<li>phenytoin</li>\n<li>rifapentine</li>\n<li>St. John's wort ( \n <span class=\"Italics\">Hypericum perforatum</span>)\n </li>\n<li>lansoprazole</li>\n<li>pantoprazole</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Before taking EDURANT or EDURANT PED, tell your healthcare provider about all your medical conditions, including if you:</span>\n<ul>\n<li>have ever had a severe skin rash or an allergic reaction to medicines that contain rilpivirine</li>\n<li>have or had liver problems, including hepatitis B or C virus infection</li>\n<li>have kidney problems</li>\n<li>have ever had a mental health problem</li>\n<li>are pregnant or plan to become pregnant. It is not known if EDURANT or EDURANT PED will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with EDURANT or EDURANT PED.\n\t\t\t\t\n <ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Pregnancy Registry: </span>There is a pregnancy registry for women who take EDURANT during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.\n </li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. EDURANT or EDURANT PED can pass into your breast milk. Talk with your healthcare provider about the following risks of breastfeeding during treatment with EDURANT or EDURANT PED:\n\t\t\t\t\n <ul class=\"Circle\">\n<li>The HIV-1 virus may pass to your baby if your baby does not have the HIV-1 infection.</li>\n<li>The HIV-1 virus may become harder to treat if your baby has HIV-1 infection.</li>\n<li>Your baby may get side effects from EDURANT or EDURANT PED.</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with EDURANT or EDURANT PED. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.\n\n\t\t\t\n <ul class=\"Disc\">\n<li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with EDURANT or EDURANT PED.</li>\n<li>\n<span class=\"Bold\">Do not start taking a new medicine without telling your healthcare provider</span>. Your healthcare provider can tell you if it is safe to take EDURANT or EDURANT PED with other medicines.\n </li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I take EDURANT or EDURANT PED?\n <br/>\n\t\t\tSee the \" \n <a href=\"#IFU\">Instructions for Use</a>\" for detailed instructions on how to prepare and give a dose of EDURANT PED tablets for oral suspension. \n </span>\n<ul>\n<li>Take EDURANT or EDURANT PED exactly as your healthcare provider tells you to.</li>\n<li>\n<span class=\"Bold\">Take EDURANT or EDURANT PED 1 time each day with a meal. </span>A protein drink or yogurt alone does not replace a meal.\n </li>\n<li>EDURANT and EDURANT PED must be used with other HIV-1 medicines.</li>\n<li>Do not change your dose or stop taking EDURANT or EDURANT PED without first talking with your healthcare provider.</li>\n<li>Stay under the care of your healthcare provider during treatment with EDURANT or EDURANT PED.</li>\n<li>\n<span class=\"Bold\">EDURANT PED tablets for oral suspension provided in a blister package are not the same as EDURANT tablets provided in a bottle and cannot be substituted for each other. </span>Contact your pharmacist or healthcare provider if you did not receive the correct dosage form. Your child's healthcare provider will prescribe EDURANT or EDURANT PED based on your child's weight.\n </li>\n<li>EDURANT PED tablets for oral suspension must be dispersed in drinking water. \n <span class=\"Bold\">Do not</span>crush, chew, or swallow whole EDURANT PED tablets for oral suspension.\n </li>\n<li>If you take an H \n <span class=\"Sub\">2</span>-receptor antagonist (such as famotidine, cimetidine, nizatidine, or ranitidine), you should take these medicines at least 12 hours before or at least 4 hours after you take EDURANT or EDURANT PED.\n </li>\n<li>If you take antacids, or other products that contain aluminum, calcium carbonate, or magnesium hydroxide, you should take these medicines at least 2 hours before or at least 4 hours after you take EDURANT or EDURANT PED.</li>\n<li>\n<span class=\"Bold\">Do not </span>miss a dose of EDURANT or EDURANT PED.\n </li>\n<li>If you miss a dose of EDURANT or EDURANT PED within 12 hours of the time you usually take it, take your dose of EDURANT or EDURANT PED with a meal as soon as possible. Then, take your next dose of EDURANT or EDURANT PED at the regularly scheduled time. If you miss a dose of EDURANT or EDURANT PED by more than 12 hours of the time you usually take it, wait and then take the next dose of EDURANT or EDURANT PED at the regularly scheduled time.</li>\n<li>\n<span class=\"Bold\">Do not </span>take more than your prescribed dose to make up for a missed dose or take less than your prescribed dose.\n </li>\n<li>If you take too much EDURANT or EDURANT PED, call your healthcare provider or go to the nearest hospital emergency room right away.</li>\n<li>When your supply of EDURANT or EDURANT PED starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of EDURANT or EDURANT PED. The amount of HIV in your blood may increase if the medicine is stopped even for a short time.</li>\n<li>When your healthcare provider prescribes use of EDURANT with oral VOCABRIA (cabotegravir):\n\t\t\t\t\n <ul class=\"Circle\">\n<li>Take EDURANT and oral VOCABRIA (cabotegravir) 1 time a day at about the same time each day with a meal.</li>\n<li>You will receive treatment with EDURANT tablets in combination with VOCABRIA tablets for one month (at least 28 days) before you receive the long-acting medicine called CABENUVA (cabotegravir; rilpivirine extended-release injectable suspensions) for the first time. This will allow your healthcare provider to assess how well you tolerate these medicines.</li>\n<li>Your final dose of EDURANT and VOCABRIA tablets should be taken on the same day you receive your first CABENUVA injections.</li>\n<li>If you miss or plan to miss a scheduled monthly or every 2 months injection of CABENUVA by more than 7 days, call your healthcare provider right away to discuss your treatment options.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the possible side effects of EDURANT and EDURANT PED?\n <br/>\n\t\t\tEDURANT and EDURANT PED can cause serious side effects including:\n </span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Severe skin rash and allergic reactions. </span>Call your healthcare provider right away if you develop a rash with EDURANT or EDURANT PED. In some cases, rash and allergic reaction may need to be treated in a hospital.\n <br/>\n<span class=\"Bold\">Stop taking EDURANT or EDURANT PED and get medical help right away if you develop a rash with any of the following signs or symptoms</span>:\n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul>\n<li>fever</li>\n<li>tiredness</li>\n<li>difficulty breathing or swallowing</li>\n<li>skin blisters</li>\n<li>swelling of the face, lips, mouth, tongue, or throat</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul>\n<li>generally ill feeling</li>\n<li>muscle or joint aches</li>\n<li>blisters or mouth sores</li>\n<li>redness or swelling of the eyes (conjunctivitis)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul>\n<li>\n<span class=\"Bold\">Liver problems. </span>People with a history of hepatitis B or C virus infection or who have certain liver function test changes may have an increased risk of developing new or worsening changes in certain liver tests during treatment with EDURANT or EDURANT PED. Liver problems have also happened in people without a history of problems or other risk factors. Your healthcare provider may need to do tests to check your liver function before and during treatment with EDURANT or EDURANT PED. \n <span class=\"Bold\">Call your healthcare provider right away if you develop any of the following signs or symptoms of liver problems:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul>\n<li>your skin or the white part of your eyes turns yellow (jaundice)</li>\n<li>light colored stools (bowel movements)</li>\n<li>pain, aching, or tenderness on the right side of the stomach area</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul>\n<li>loss of appetite</li>\n<li>dark or \"tea colored\" urine</li>\n<li>nausea or vomiting</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul>\n<li>\n<span class=\"Bold\">Depression or mood changes. Call your healthcare provider right away if you have any of the following symptoms:</span>\n<ul class=\"Circle\">\n<li>feeling sad or hopeless</li>\n<li>feeling anxious or restless</li>\n<li>have thoughts of hurting yourself (suicide) or have tried to hurt yourself</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Changes in your immune system (Immune Reconstitution Syndrome) </span>can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.\n </li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">The most common side effects of EDURANT or EDURANT PED include </span>depression, headache, trouble sleeping (insomnia) and rash.\n <br/>\n\t\t\tThese are not all the possible side effects of EDURANT or EDURANT PED.\n <br/>\n\t\t\tCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I store EDURANT or EDURANT PED?</span>\n<ul>\n<li>Store EDURANT or EDURANT PED at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Keep EDURANT tablets in the original bottle to protect from light.</li>\n<li>Keep EDURANT PED tablets in the original package to protect from light and moisture.</li>\n</ul>\n<span class=\"Bold\">Keep EDURANT or EDURANT PED and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">General information about the safe and effective use of EDURANT and EDURANT PED.</span>\n<br/>\n\t\t\tMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use EDURANT or EDURANT PED for a condition for which it was not prescribed. Do not give EDURANT or EDURANT PED to other people even if they have the same condition you have. It may harm them.\n <br/>\n\t\t\tYou can ask your healthcare provider or pharmacist for information about EDURANT or EDURANT PED that is written for health professionals.\n </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the ingredients in EDURANT and EDURANT PED?\n <br/>\n\t\t\tActive ingredient: \n </span>rilpivirine.\n <br/>\n<span class=\"Bold\">Inactive ingredients:\n <br/>\n\t\t\tEDURANT 25 mg tablets: \n </span>croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium dioxide and triacetin.\n <br/>\n<span class=\"Bold\">EDURANT PED 2.5 mg tablets for oral suspension: </span>croscarmellose sodium, lactose monohydrate, mannitol, microcrystalline cellulose, povidone K30, polysorbate 20, sodium lauryl sulfate and sodium stearyl fumarate.\n <br/>\n\t\t\tManufactured for: Janssen Products, LP, Horsham PA 19044, USA\n <br/>\n\t\t\tFor patent information: www.janssenpatents.com\n <br/>\n\t\t\t© Johnson &amp; Johnson and its affiliates 2011, 2024\n <br/>\n\t\t\tFor more information go to www.EDURANT.com or call 1-800-526-7736\n </td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="2"><span class="Bold">INSTRUCTIONS FOR USE <br/> EDURANT <span class="Sup">® </span>PED </span>( <span class="Bold">ee dur ant ped</span>) <br/> <span class="Bold">(rilpivirine) <br/> tablets, for oral suspension </span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" valign="top">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</td><td align="right" valign="top">Revised: 11/2024</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2">This Instructions for Use contains information on how to prepare and give EDURANT PED. Read this Instructions for Use before your child starts taking EDURANT PED for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your child's medical condition or treatment. <br/> <span class="Bold">Important information you need to know before giving EDURANT PED:</span> <ul class="Disc"> <li>Take EDURANT PED exactly as your healthcare provider tells you.</li> <li> <span class="Bold">EDURANT PED tablets for oral suspension are provided in a blister package. Each time you receive your child's prescription, check to make sure that you received EDURANT PED tablets.</span> </li> <li> <span class="Bold">EDURANT PED tablets for oral suspension provided in a blister package are not the same as EDURANT tablets provided in a bottle and cannot be substituted for each other. </span>Contact your pharmacist or healthcare provider if you did not receive the correct dosage form. </li> <li>Your child's healthcare provider will tell you how many EDURANT PED tablets you will need for your child's dose based on their weight.</li> <li>Take EDURANT PED 1 time each day. <span class="Bold">EDURANT PED tablets must be dispersed in drinking water and must be taken with a meal</span>. </li> <li> <span class="Bold">Do not </span>crush, chew or swallow whole EDURANT PED tablets. </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Supplies needed to prepare and give EDURANT PED:</span> <ul class="Disc"> <li>EDURANT PED tablets</li> </ul> <span class="Bold">(not included with EDURANT PED):</span> <ul class="Disc"> <li>a small clean empty cup</li> <li>a teaspoon</li> <li>room temperature drinking water</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 1: Prepare EDURANT PED</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <p class="First"> <img alt="Step 1" src="/dailymed/image.cfm?name=edurant-02.jpg&amp;setid=03880372-2c68-45c6-a53a-f420c49541d6"/></p> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>Count the number of tablets you need for the prescribed dose and tear each unit from the blister pack along the dotted line.</li> <li>For each unit, peel back the foil gently in the direction of the arrow to remove the tablet.</li> <li> <span class="Bold">Do not </span>push the tablets out of the foil as they may break. </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 2: Place the tablets in a small cup</span></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <p class="First"> <img alt="Step 2" src="/dailymed/image.cfm?name=edurant-03.jpg&amp;setid=03880372-2c68-45c6-a53a-f420c49541d6"/></p> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>Gently place the tablets in a small cup. <span class="Bold">Do not </span>crush the tablets. </li> <li>Add 5 mL (1 teaspoon) of room temperature drinking water to the cup.</li> <li>Swirl the cup carefully for 1 to 2 minutes to disperse the tablets. The mixture will start to look cloudy.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <p class="First"> <img alt="Step 2" src="/dailymed/image.cfm?name=edurant-04.jpg&amp;setid=03880372-2c68-45c6-a53a-f420c49541d6"/></p> </td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2">If you spill any medicine, clean up the spill. Throw away the rest of the prepared medicine and make a new dose. <br/> <span class="Bold">You must give the prepared medicine right away. </span>If you do not give the prepared medicine right away, throw away the mixture and prepare a new dose of medicine. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 3: Give EDURANT PED</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li>Give all the prepared medicine right away <span class="Bold">or </span>add another 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce to help take the medicine. Swirl the mixture and give all of the medicine right away. A spoon can be used to give the prepared medicine if needed. </li> <li>Make sure the entire dose is taken and no medicine is left in the cup. If there is medicine left in the cup, add another 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce. Swirl and give all of the prepared medicine right away.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Step 4: Clean the dosing items</span> <ul class="Disc"> <li>Wash the cup and teaspoon thoroughly with water and make sure they are clean and dry before preparing the next daily dose.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">How should I store EDURANT PED?</span> <ul class="Disc"> <li>Store EDURANT PED at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep EDURANT PED tablets in the original package to protect from light and moisture.</li> </ul> <span class="Bold">Keep EDURANT PED and all medicines out of the reach of children.</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="2">Manufactured for: Janssen Products, LP, Horsham PA 19044, USA <br/> For patent information: www.janssenpatents.com <br/> © Johnson &amp; Johnson and its affiliates 2011, 2024 <br/> For more information go to www.EDURANT.com or call 1-800-526-7736 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n</colgroup>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">INSTRUCTIONS FOR USE\n <br/>\n\t\t\tEDURANT\n <span class=\"Sup\">® </span>PED \n </span>( \n <span class=\"Bold\">ee dur ant ped</span>)\n <br/>\n<span class=\"Bold\">(rilpivirine)\n <br/>\n\t\t\ttablets, for oral suspension\n </span></th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" valign=\"top\">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\" valign=\"top\">Revised: 11/2024</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">This Instructions for Use contains information on how to prepare and give EDURANT PED. Read this Instructions for Use before your child starts taking EDURANT PED for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your child's medical condition or treatment.\n <br/>\n<span class=\"Bold\">Important information you need to know before giving EDURANT PED:</span>\n<ul class=\"Disc\">\n<li>Take EDURANT PED exactly as your healthcare provider tells you.</li>\n<li>\n<span class=\"Bold\">EDURANT PED tablets for oral suspension are provided in a blister package. Each time you receive your child's prescription, check to make sure that you received EDURANT PED tablets.</span>\n</li>\n<li>\n<span class=\"Bold\">EDURANT PED tablets for oral suspension provided in a blister package are not the same as EDURANT tablets provided in a bottle and cannot be substituted for each other. </span>Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.\n </li>\n<li>Your child's healthcare provider will tell you how many EDURANT PED tablets you will need for your child's dose based on their weight.</li>\n<li>Take EDURANT PED 1 time each day. \n <span class=\"Bold\">EDURANT PED tablets must be dispersed in drinking water and must be taken with a meal</span>.\n </li>\n<li>\n<span class=\"Bold\">Do not </span>crush, chew or swallow whole EDURANT PED tablets.\n </li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Supplies needed to prepare and give EDURANT PED:</span>\n<ul class=\"Disc\">\n<li>EDURANT PED tablets</li>\n</ul>\n<span class=\"Bold\">(not included with EDURANT PED):</span>\n<ul class=\"Disc\">\n<li>a small clean empty cup</li>\n<li>a teaspoon</li>\n<li>room temperature drinking water</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 1: Prepare EDURANT PED</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<p class=\"First\">\n<img alt=\"Step 1\" src=\"/dailymed/image.cfm?name=edurant-02.jpg&amp;setid=03880372-2c68-45c6-a53a-f420c49541d6\"/></p>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>Count the number of tablets you need for the prescribed dose and tear each unit from the blister pack along the dotted line.</li>\n<li>For each unit, peel back the foil gently in the direction of the arrow to remove the tablet.</li>\n<li>\n<span class=\"Bold\">Do not </span>push the tablets out of the foil as they may break.\n </li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 2: Place the tablets in a small cup</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\">\n<p class=\"First\">\n<img alt=\"Step 2\" src=\"/dailymed/image.cfm?name=edurant-03.jpg&amp;setid=03880372-2c68-45c6-a53a-f420c49541d6\"/></p>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>Gently place the tablets in a small cup. \n <span class=\"Bold\">Do not </span>crush the tablets.\n </li>\n<li>Add 5 mL (1 teaspoon) of room temperature drinking water to the cup.</li>\n<li>Swirl the cup carefully for 1 to 2 minutes to disperse the tablets. The mixture will start to look cloudy.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">\n<p class=\"First\">\n<img alt=\"Step 2\" src=\"/dailymed/image.cfm?name=edurant-04.jpg&amp;setid=03880372-2c68-45c6-a53a-f420c49541d6\"/></p>\n</td><td align=\"left\" class=\"Rrule\"></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">If you spill any medicine, clean up the spill. Throw away the rest of the prepared medicine and make a new dose.\n <br/>\n<span class=\"Bold\">You must give the prepared medicine right away. </span>If you do not give the prepared medicine right away, throw away the mixture and prepare a new dose of medicine.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 3: Give EDURANT PED</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Give all the prepared medicine right away \n <span class=\"Bold\">or </span>add another 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce to help take the medicine. Swirl the mixture and give all of the medicine right away. A spoon can be used to give the prepared medicine if needed.\n </li>\n<li>Make sure the entire dose is taken and no medicine is left in the cup. If there is medicine left in the cup, add another 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce. Swirl and give all of the prepared medicine right away.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Step 4: Clean the dosing items</span>\n<ul class=\"Disc\">\n<li>Wash the cup and teaspoon thoroughly with water and make sure they are clean and dry before preparing the next daily dose.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How should I store EDURANT PED?</span>\n<ul class=\"Disc\">\n<li>Store EDURANT PED at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Keep EDURANT PED tablets in the original package to protect from light and moisture.</li>\n</ul>\n<span class=\"Bold\">Keep EDURANT PED and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">Manufactured for: Janssen Products, LP, Horsham PA 19044, USA\n <br/>\n\t\t\tFor patent information: www.janssenpatents.com\n <br/>\n\t\t\t© Johnson &amp; Johnson and its affiliates 2011, 2024\n <br/>\n\t\t\tFor more information go to www.EDURANT.com or call 1-800-526-7736\n </td>\n</tr>\n</tbody>\n</table></div>" }

30 Tablets NDC59676-278-01

{ "type": "p", "children": [], "text": "30 Tablets \n \nNDC59676-278-01\n\n " }

EDURANT® (rilpivirine) tablets

{ "type": "p", "children": [], "text": "\nEDURANT®\n\n(rilpivirine) tablets\n" }

25 mg

{ "type": "p", "children": [], "text": "\n25 mg\n" }

Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

{ "type": "p", "children": [], "text": "Each tablet contains 27.5 mg of rilpivirine \n hydrochloride, which is equivalent to 25 mg \n of rilpivirine.\n " }

ALERT: Find out about medicines that should NOT be taken with EDURANT ®from your healthcare provider.

{ "type": "p", "children": [], "text": "\nALERT: Find out about \n medicines that should NOT be \n taken with EDURANT\n \n ®from \n your healthcare provider.\n \n \n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

NDC 59676-280-90 Rx only

{ "type": "p", "children": [], "text": "NDC 59676-280-90 \n Rx only\n " }

EDURANT ®PED

{ "type": "p", "children": [], "text": "EDURANT\n \n ®PED\n\n " }

(rilpivirine) tablets for oral suspension

{ "type": "p", "children": [], "text": "(rilpivirine) \n tablets for oral suspension\n " }

2.5 mg

{ "type": "p", "children": [], "text": "2.5 mg" }

90 tablets 9 blister cards, 10 tablets each

{ "type": "p", "children": [], "text": "90 tablets \n 9 blister cards, 10 tablets each\n " }

Attention: EDURANT PED is NOT a substitute for EDURANT

{ "type": "p", "children": [], "text": "\nAttention: EDURANT PED is NOT a substitute for EDURANT\n" }

DISPERSE IN DRINKING WATER Do not crush, chew, or swallow whole, see Instructions for Use

{ "type": "p", "children": [], "text": "\nDISPERSE IN DRINKING WATER\n Do not crush, chew, or swallow whole, see Instructions for Use\n \n " }

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:

{ "type": "p", "children": [], "text": "Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:" }

{ "type": "", "children": [], "text": "" }

Limitations of Use:

{ "type": "p", "children": [], "text": "Limitations of Use:" }

{ "type": "", "children": [], "text": "" }

Prior to or when initiating emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.5)].

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with food [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

For pregnant patients who are already on emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of emtricitabine, rilpivirine and tenofovir disoproxil fumarate taken once daily may be continued. Lower exposures of rilpivirine, a component of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute) [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].

If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, take an additional 25 mg tablet of rilpivirine (Edurant®) with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].

Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets are available containing 200 mg of emtricitabine, 27.5 mg of rilpivirine hydrochloride equivalent to 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil.

{ "type": "p", "children": [], "text": "Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets are available containing 200 mg of emtricitabine, 27.5 mg of rilpivirine hydrochloride equivalent to 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil." }

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

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Test all patients with HIV-1 for the presence of chronic hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, two of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Patients coinfected with HIV-1 and HBV who discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects receiving RPV plus FTC/TDF. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1 and 6.2)].

Discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, 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 should be initiated.

Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-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 emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.

The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with RPV. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits.

During the Phase 3 trials in adults (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV (n=686) or efavirenz (EFV, n=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1% for both RPV and EFV. The incidence of discontinuation due to depressive disorders among RPV or EFV 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 RPV arm.

During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving RPV through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2)].

Prior to initiation of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.4)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Emtricitabine and TDF are principally eliminated by the kidney; however, RPV is not. Since emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a combination product and the dose of the individual components cannot be altered, emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are not recommended in patients with estimated creatinine clearance below 50 mL per minute [see Use in Specific Populations (8.6)].

In clinical trials in HIV-1-infected adults, TDF, a component of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF.

Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1-infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1-infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B-infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.

The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF [see Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [See Warnings and Precautions (5.5)].

The concomitant use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and other drugs may result in potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.5), Contraindications (4), and Drug Interactions (7)]:

In healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets when coadministered with a drug that is known to have a risk of Torsade de Pointes [see Drug Interactions (7) and Clinical Pharmacology (12.2)].

See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablet therapy and review concomitant medications during emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablet therapy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and FTC, components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, alone or in combination with other antiretrovirals. Treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. 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 jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Studies C209 and C215

The safety assessment of RPV, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 subjects in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1-infected adult subjects. A total of 686 subjects received RPV in combination with other antiretroviral drugs as background regimen; most (N=550) received FTC/TDF as background regimen. The number of subjects randomized to the control arm EFV was 682, of which 546 received FTC/TDF as background regimen [see Clinical Studies (14)]. The median duration of exposure for subjects in either treatment arm was 104 weeks.

Adverse reactions observed at Week 96 in subjects who received RPV or EFV + FTC/TDF as background regimen are shown in Table 1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant).

The proportion of subjects who discontinued treatment with RPV or EFV + FTC/TDF due to adverse reactions, regardless of severity, was 2% and 5%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the RPV + FTC/TDF arm and 12 (2.2%) subjects in the EFV + FTC/TDF arm. Rash led to discontinuation in 1 (0.2%) subject in the RPV + FTC/TDF arm and 10 (1.8%) subjects in the EFV + FTC/TDF arm.

Common Adverse Reactions: Clinical adverse reactions to RPV or EFV of at least moderate intensity (≥ Grade 2) reported in at least 2% of adult subjects are shown in Table 1.

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 1 Selected Adverse Reactions<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> (Grades 2–4) Reported in ≥ 2% of Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis)</span> </caption> <col width="46%"/> <col width="27%"/> <col width="26%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Frequencies of adverse reactions are based on all Grades 2–4 treatment-emergent adverse events assessed to be related to study drug. </dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">RPV</span> </p> <p> <span class="Bold">+ FTC/TDF</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">EFV</span> </p> <p> <span class="Bold">+ FTC/TDF</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=550</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=546</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Depressive disorders<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Insomnia </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abnormal dreams</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Rash</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5%</p> </td> </tr> </tbody> </table></div>

Rilpivirine: Adverse reactions of at least moderate intensity (≥Grade 2) that occurred in less than 2% of subjects treated with RPV plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.

No new adverse reactions to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets were identified in stable, virologically suppressed subjects switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% (Study 106) after switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.

Emtricitabine and Tenofovir DF: The most common adverse reactions that occurred in at least 10% of HIV-1-infected treatment-naïve adult subjects in a Phase 3 clinical trial of FTC and TDF in combination with another antiretroviral agent were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving FTC or TDF with other antiretroviral agents in clinical trials included abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.

Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

The percentage of subjects treated with RPV + FTC/TDF or EFV + FTC/TDF in studies C209 and C215 with selected laboratory abnormalities (Grades 1–4), representing worst-grade toxicity, is presented in Table 2.

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 2 Selected Laboratory Abnormalities (Grades 1–4) Reported in Adult Subjects Who Received RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis)</span> </caption> <col width="40%"/> <col width="24%"/> <col width="18%"/> <col width="18%"/> <tfoot> <tr> <td align="left" colspan="4" valign="top">N=number of subjects per treatment group </td> </tr> <tr> <td align="left" colspan="4" valign="top">ULN=Upper limit of normal value.</td> </tr> <tr> <td align="left" colspan="4" valign="top">Note: Percentages were calculated versus the number of subjects in ITT population with FTC + TDF as background regimen.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Laboratory Parameter Abnormality</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">DAIDS Toxicity Range</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">RPV + FTC/TDF</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">EFV + FTC/TDF</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=550</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=546</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">BIOCHEMISTRY</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Increased Creatinine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 1 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.1–1.3 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;1.3–1.8 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;1.8–3.4 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 4 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;3.4 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Increased AST </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 1 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.25–2.5 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">19%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;2.5–5.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;5.0–10.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 4 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;10.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Increased ALT </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 1 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.25–2.5 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">19%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;2.5–5.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;5.0–10.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 4 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;10.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Increased Total Bilirubin </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 1 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1.1–1.5 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;1.5–2.5 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;2.5–5.0 × ULN</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Increased Total Cholesterol (fasted) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 1 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200–239 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">31%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">240–300 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">18%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;300 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt; 1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Increased LDL Cholesterol (fasted)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 1 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">130–159 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">28%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">160–190 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;190 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Increased Triglycerides (fasted) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 2 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500–750 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Grade 3 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">751–1200 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">     Grade 4 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&gt;1200 mg/dL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1%</p> </td> </tr> </tbody> </table></div>

Emtricitabine or Tenofovir DF: The following Grade 3 or 4 laboratory abnormalities have been previously reported in subjects treated with FTC or TDF with other antiretroviral agents in other clinical trials: increased pancreatic amylase (>2.0 × ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 × ULN), increased alkaline phosphatase (>550 U/L), increased or decreased serum glucose (<40 or >250 mg/dL), increased glycosuria (≥3+), increased creatine kinase (M: >990 U/L; F: >845 U/L), decreased neutrophils (<750/mm3), and increased hematuria (>75 RBC/HPF).

Adrenal Function: In the pooled Phase 3 trials of C209 and C215, in subjects treated with RPV plus any of the allowed background regimens (N=686), at Week 96 there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the RPV group, and of -0.02 (-0.48, 0.44) micrograms/dL in the EFV group.

In the RPV group, 43/588 (7.3%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the EFV group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the RPV group and 9 subjects in the EFV group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the RPV group is not known.

Serum Creatinine: In the pooled Phase 3 trials of C209 and C215 in subjects treated with RPV plus any of the allowed background regimens (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with RPV. Most of this increase occurred within the first 4 weeks of treatment, with a mean change of 0.1 mg/dL (range -0.3 to 0.6 mg/dL) observed through Week 96. 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. Creatinine increases were comparable by background N(t)RTIs.

Serum Lipids: Changes from baseline in total cholesterol, LDL-cholesterol, and triglycerides are presented in Table 3.

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 3 Lipid Values Reported in Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></span> </caption> <col width="17%"/> <col width="7%"/> <col width="13%"/> <col width="11%"/> <col width="11%"/> <col width="7%"/> <col width="13%"/> <col width="11%"/> <col width="11%"/> <tfoot> <tr> <td align="left" colspan="9" valign="top">N = number of subjects per treatment group </td> </tr> <tr> <td align="left" colspan="9"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Excludes subjects who received lipid lowering agents during the treatment period.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="8" valign="middle"> <p class="First"> <span class="Bold">Pooled Data from the Week 96 Analysis of C209 and C215 Trials</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">RPV + FTC/TDF</span> </p> <p> <span class="Bold">N=550</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <p class="First"> <span class="Bold">EFV + FTC/TDF</span> </p> <p> <span class="Bold">N=546</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Baseline</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Week 96</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Baseline</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">Week 96</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Mean</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean (mg/dL)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean (mg/dL)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean Change<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a> (mg/dL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean (mg/dL)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean (mg/dL)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Mean Change<a class="Sup" href="#footnote-4">†</a> (mg/dL)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Total Cholesterol (fasted) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">430</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">162</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">164</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">401</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">160</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">186</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">26</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">HDL-cholesterol (fasted) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">429</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">42</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">45</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">399</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">11</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">LDL-cholesterol (fasted) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">427</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">97</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">97</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">-1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">397</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">96</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">110</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Triglycerides (fasted) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">430</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">123</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">109</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">-14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">401</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">127</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">133</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6</p> </td> </tr> </tbody> </table></div>

Adult Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In adult subjects coinfected with hepatitis B or C virus receiving RPV in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving RPV who were not coinfected. The same increase was also observed in the EFV arm. The pharmacokinetic exposure of RPV in coinfected subjects was comparable to that in subjects without coinfection.

Adverse Reactions from Clinical Trials Experience in Pediatric Subjects

Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA® prescribing information.

Rilpivirine: The safety assessment is based on the Week 48 analysis of the single-arm, open-label Phase 2 trial, TMC278-C213, in which 36 antiretroviral treatment-naïve HIV-1-infected subjects 12 to less than 18 years of age and weighing at least 32 kg received RPV (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for subjects was 63.5 weeks. No subjects discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.

Adverse reactions were reported in 19 pediatric subjects (52.8%). Most adverse reactions were Grade 1 or 2. The most common adverse reactions reported in at least 2 subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%), and rash (5.6%).

Observed laboratory abnormalities were comparable to those in adults. For additional information, please consult the Edurant prescribing information.

In trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL.

Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level < 18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known.

Tenofovir DF: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions (5.6)]. For additional information, including information on bone mineral density changes, please consult the VIREAD® prescribing information.

The following adverse reactions have been identified during postmarketing experience in patients receiving RPV- or TDF-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets:

Metabolism and Nutrition Disorders:weight increased

Skin and Subcutaneous Tissue Disorders severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

Rilpivirine:

Renal and Urinary Disorders: nephrotic syndrome

Emtricitabine:

No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir DF:

Immune System Disorders allergic reaction, including angioedema

Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders dyspnea

Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT)

Skin and Subcutaneous Tissue Disorders rash

Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

This section describes clinically relevant drug interactions with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Drug interaction studies were conducted with the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (FTC, RPV, and TDF as single agents) or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product [see Dosage and Administration (2), Contraindications (4), and Clinical Pharmacology (12.3)].

Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.

Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration [see Contraindications (4) and Clinical Pharmacology (12.3)].

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

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

Important drug interaction information for emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product, or are potential drug interactions [see Clinical Pharmacology (12.3), Tables 9–14]. For list of contraindicated drugs, [see Contraindications (4)].

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 4 Significant<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> Drug Interactions</span> </caption> <col width="31%"/> <col width="27%"/> <col width="42%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>This table is not all inclusive.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>Increase = ↑; Decrease = ↓; No Effect = ↔ </dd> <dt> <a href="#footnote-reference-7" name="footnote-7">‡</a> </dt> <dd>The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. </dd> <dt> <a href="#footnote-reference-8" name="footnote-8">§</a> </dt> <dd>This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Concomitant Drug Class:<br/>Drug Name </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Effect on Concentration</span><a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Clinical Comment</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Antacids: </span> </p> <p>     antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔ RPV</p> <p>(antacids taken at least 2 hours before or at least 4 hours after RPV) </p> <p> </p> <p>↓ RPV</p> <p>(concomitant intake) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Administer antacids at least 2 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Anticonvulsants:</span> </p> <p>     carbamazepine</p> <p>     oxcarbazepine</p> <p>     phenobarbital</p> <p>     phenytoin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ RPV</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Antimycobacterials: </span> </p> <p>     rifampin</p> <p>     rifapentine</p> </td><td valign="top"> <p class="First">↓ RPV</p> </td><td class="Lrule Rrule Toprule" valign="top"> <p class="First">Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     rifabutin</p> </td><td valign="top"> <p class="First">↓ RPV<a class="Sup" href="#footnote-7" name="footnote-reference-7">‡</a> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of rifabutin coadministration.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Azole Antifungal Agents:</span> </p> <p>     fluconazole</p> <p>     itraconazole</p> <p>     ketoconazole</p> <p>     posaconazole</p> <p>     voriconazole </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ RPV<a class="Sup" href="#footnote-7">‡</a>,<a class="Sup" href="#footnote-8" name="footnote-reference-8">§</a> </p> <p>↓ ketoconazole<a class="Sup" href="#footnote-7">‡</a>,<a class="Sup" href="#footnote-8">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">No dose adjustment is required when emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Glucocorticoid<br/>(systemic):</span> </p> <p>     dexamethasone</p> <p>     (more than a single-dose treatment)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ RPV</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Hepatitis C Antiviral Agents:</span> </p> <p>     ledipasvir/sofosbuvir</p> <p>     sofosbuvir/velpatasvir</p> <p>     sofosbuvir/velpatasvir/</p> <p>     voxilaprevir</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ tenofovir<a class="Sup" href="#footnote-7">‡</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Patients receiving emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI<span class="Sup">®</span> (ledipasvir/sofosbuvir), EPCLUSA<span class="Sup">®</span> (sofosbuvir/velpatasvir), or VOSEVI<span class="Sup">®</span> (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">H<span class="Sub">2</span>-Receptor Antagonists: </span> </p> <p>     cimetidine </p> <p>     famotidine</p> <p>     nizatidine</p> <p>     ranitidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↔ RPV<a class="Sup" href="#footnote-7">‡</a>,<a class="Sup" href="#footnote-8">§</a> </p> <p>(famotidine taken 12 hours before RPV or 4 hours after RPV)</p> <p> </p> <p>↓ RPV<a class="Sup" href="#footnote-7">‡</a>,<a class="Sup" href="#footnote-8">§</a> </p> <p>(famotidine taken 2 hours before RPV)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Administer H<span class="Sub">2</span>-receptor antagonists at least 12 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Herbal Products:</span> </p> <p>     St John’s wort<br/>     (<span class="Italics">Hypericum perforatum</span>)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ RPV</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Macrolide or Ketolide Antibiotics: </span> </p> <p>     clarithromycin</p> <p>     erythromycin</p> <p>     telithromycin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↑ RPV</p> <p>↔ clarithromycin</p> <p>↔ erythromycin</p> <p>↔ telithromycin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Where possible, alternatives such as azithromycin should be considered.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Narcotic Analgesics:</span> </p> <p>     methadone </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ R(−) methadone<a class="Sup" href="#footnote-7">‡</a> </p> <p>↓ S(+) methadone<a class="Sup" href="#footnote-7">‡</a> </p> <p>↔ RPV<a class="Sup" href="#footnote-7">‡</a> </p> <p>↔ methadone<a class="Sup" href="#footnote-7">‡</a> (when used with tenofovir)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">No dose adjustments are required when initiating coadministration of methadone with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Proton Pump Inhibitors:</span> </p> <p>     e.g., dexlansoprazole</p> <p>     esomeprazole</p> <p>     lansoprazole</p> <p>     omeprazole</p> <p>     pantoprazole</p> <p>     rabeprazole</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">↓ RPV</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.</p> </td> </tr> </tbody> </table></div>

No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF.

No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir, or tacrolimus in studies conducted in healthy subjects.

No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. RPV did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period [see Clinical Pharmacology (12.3)]. The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.

Based on the experience of HIV-1-infected pregnant individuals who completed a clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on a stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of RPV were observed during pregnancy, therefore viral load should be monitored closely [see Data and Clinical Pharmacology (12.3)].

In animal studies, no adverse developmental effects were observed when the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data). Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.

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

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

Rilpivirine: RPV in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant subjects on an RPV-based regimen during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6-12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period [see Clinical Pharmacology (12.3)]. One subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with available HIV test results, all were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum (all 10 infants received prophylactic treatment with zidovudine). RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV-1-infected adults.

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

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

Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.

Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.

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

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

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

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

Rilpivirine: In animals, no studies have been conducted to assess the excretion of RPV directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).

The safety and effectivness of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a complete regimen for the treatment of HIV-1 infection was established in pediatric subjects 12 years of age and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in this age group weighing at least 35 kg is supported by adequate and well-controlled studies of RPV + FTC + TDF in adults with HIV-1 infection as well as data from pediatric studies of the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV, FTC, and TDF) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should only be administered to pediatric patients with a body weight greater than or equal to 35 kg. Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate is a fixed-dose combination tablet, the dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets cannot be adjusted for patients of lower weight. Safety and effectiveness for emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets have not been established in pediatric patients weighing less than 35 kg [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Clinical studies of FTC, RPV, or TDF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a fixed-dose combination, and cannot be dose adjusted, they are not recommended in patients with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

No dose adjustment of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets have not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets consists of general supportive measures, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.

{ "type": "p", "children": [], "text": "If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets consists of general supportive measures, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. " }

Emtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.

{ "type": "p", "children": [], "text": "\nEmtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis. " }

Rilpivirine: There is no specific antidote for overdose with RPV. Human experience of overdose with RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV.

{ "type": "p", "children": [], "text": "\nRilpivirine: There is no specific antidote for overdose with RPV. Human experience of overdose with RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV. " }

Tenofovir DF: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

{ "type": "p", "children": [], "text": "\nTenofovir DF: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose." }

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are fixed-dose combination tablets containing FTC, rilpivirine hydrochloride, and TDF. Emtricitabine (FTC) is a synthetic nucleoside analog of cytidine. Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

{ "type": "p", "children": [], "text": "Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are fixed-dose combination tablets containing FTC, rilpivirine hydrochloride, and TDF. Emtricitabine (FTC) is a synthetic nucleoside analog of cytidine. Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. " }

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are for oral administration. Each tablet contains 200 mg of FTC, 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: corn starch, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, talc, titanium dioxide, triacetin and yellow iron oxide.

{ "type": "p", "children": [], "text": "Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are for oral administration. Each tablet contains 200 mg of FTC, 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: corn starch, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, talc, titanium dioxide, triacetin and yellow iron oxide." }

Emtricitabine: The chemical name of FTC is 4-Amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

{ "type": "p", "children": [], "text": "\nEmtricitabine: The chemical name of FTC is 4-Amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. " }

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.25. It has the following structural formula:

{ "type": "p", "children": [], "text": "It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.25. It has the following structural formula: " }

FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25°C.

{ "type": "p", "children": [], "text": "FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25°C. " }

Rilpivirine: RPV is available as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-{[4-({4-[(E)-2-Cyanoethenyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino}benzonitrile. Hydrochloride. Its molecular formula is C22H18N6 • HCl and its molecular weight is 402.9. Rilpivirine hydrochloride has the following structural formula:

{ "type": "p", "children": [], "text": "\nRilpivirine: RPV is available as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-{[4-({4-[(E)-2-Cyanoethenyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino}benzonitrile. Hydrochloride. Its molecular formula is C22H18N6 • HCl and its molecular weight is 402.9. Rilpivirine hydrochloride has the following structural formula: " }

Rilpivirine hydrochloride is an off-white to yellow colored powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.

{ "type": "p", "children": [], "text": "Rilpivirine hydrochloride is an off-white to yellow colored powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. " }

Tenofovir DF: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is

{ "type": "p", "children": [], "text": "\nTenofovir DF: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is " }

9-[2-(R)-[[bis[[(isopropoxy carbonyl) oxy] methoxy]phosphinoyl]methoxy]propyl]-adenine fumaric acid (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.51. It has the following structural formula:

{ "type": "p", "children": [], "text": "9-[2-(R)-[[bis[[(isopropoxy carbonyl) oxy] methoxy]phosphinoyl]methoxy]propyl]-adenine fumaric acid (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.51. It has the following structural formula:" }

TDF is a white to off-white powder with a solubility of 13.4 mg per mL in water at 25°C. All dosages are expressed in terms of TDF except where otherwise noted.

{ "type": "p", "children": [], "text": "TDF is a white to off-white powder with a solubility of 13.4 mg per mL in water at 25°C. All dosages are expressed in terms of TDF except where otherwise noted." }

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of the antiretroviral drugs FTC, RPV, and TDF [see Microbiology (12.4)].

The effect of RPV 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 doses of 75 mg once daily and 300 mg once daily of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) 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 RPV 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 RPV [see Warnings and Precautions (5.7)].

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

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

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6.

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 5 Pharmacokinetic Properties of the Components of Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets</span> </caption> <col width="39%"/> <col width="19%"/> <col width="21%"/> <col width="21%"/> <tfoot> <tr> <td align="left" colspan="4" valign="top">NC = Not Calculated</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>Median</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">†</a> </dt> <dd>Oral bioavailability of tenofovir from VIREAD.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">‡</a> </dt> <dd>Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets light meal = 390 kcal, 12 g fat; emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets standard meal = 540 kcal, 21 g fat. High fat meal not evaluated. Increase = ↑; Decrease = ↓; No Effect = ↔</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">§</a> </dt> <dd>Mean±SD</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">¶</a> </dt> <dd>t<span class="Sub">1/2</span> values refer to median terminal plasma half-life.</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">#</a> </dt> <dd>Dosing in mass balance studies: FTC (single dose administration of [<span class="Sup">14</span>C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [<span class="Sup">14</span>C] RPV); mass balance study not conducted for tenofovir.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">RPV</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">FTC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Tenofovir</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Absorption</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     T<span class="Sub">max</span> (h)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4-5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1-2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     % Fasted oral bioavailability<a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NC</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">93</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25<a class="Sup" href="#footnote-10" name="footnote-reference-10">†</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Effect of a light meal</p> <p>     (relative to fasting)<a class="Sup" href="#footnote-11" name="footnote-reference-11">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑9%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑28%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Effect of a standard meal</p> <p>     (relative to fasting)<a class="Sup" href="#footnote-11">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑16%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑38%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Distribution</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     % Bound to human plasma proteins</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">~99</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;0.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Source of protein binding data</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">In vitro</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">In vitro</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">In vitro</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Metabolism</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Metabolism</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">CYP3A</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First">Not significantly metabolized</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Elimination</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Major route of elimination</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Metabolism</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First">Glomerular filtration and active tubular secretion</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     CL<span class="Sub">renal</span><a class="Sup" href="#footnote-12" name="footnote-reference-12">§</a> (mL/min)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NC</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">213±89</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">243±33</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     t<span class="Sub">1/2</span> (h)<a class="Sup" href="#footnote-13" name="footnote-reference-13">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     % Of dose excreted in urine<a class="Sup" href="#footnote-14" name="footnote-reference-14">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">86</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">70-80</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">     % Of dose excreted in feces<a class="Sup" href="#footnote-14">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">85</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">~14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NC</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 6 Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected Adults</span> </caption> <col width="38%"/> <col width="19%"/> <col width="21%"/> <col width="21%"/> <tfoot> <tr> <td align="left" colspan="4" valign="top">NA = Not Applicable; SD = Standard Deviation</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-15" name="footnote-15">*</a> </dt> <dd>Population PK estimates of RPV 25 mg once daily in antiretroviral treatment-naïve HIV-1-infected adult subjects (pooled data from Phase 3 trials through Week 96; n = 679)</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">†</a> </dt> <dd>Multiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n = 20)</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">‡</a> </dt> <dd>Single 300 mg dose of TDF to HIV-1-infected subjects in the fasted state</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">§</a> </dt> <dd>Data presented as steady state values</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">¶</a> </dt> <dd>AUC<span class="Sub">0-24h</span> </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Parameter</span> </p> <p> <span class="Bold">Mean ± SD</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">RPV</span><a class="Sup" href="#footnote-15" name="footnote-reference-15">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">FTC</span><a class="Sup" href="#footnote-16" name="footnote-reference-16">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Tenofovir</span><a class="Sup" href="#footnote-17" name="footnote-reference-17">‡</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">C<span class="Sub">max</span> (μg/mL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NA</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.80±0.72<a class="Sup" href="#footnote-18" name="footnote-reference-18">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.30±0.09</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">AUC<span class="Sub">tau</span> (μg•hr/mL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.24±0.85<a class="Sup" href="#footnote-18">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10.0±3.12<a class="Sup" href="#footnote-18">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.29±0.69<a class="Sup" href="#footnote-19" name="footnote-reference-19">¶</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">C<span class="Sub">0h</span> (μg/mL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.08±0.04<a class="Sup" href="#footnote-18">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.09±0.07<a class="Sup" href="#footnote-18">§</a> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">NA</p> </td> </tr> </tbody> </table></div>

Specific Populations

Geriatric Patients

The pharmacokinetics of FTC, RPV, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)].

Pediatric Patient

Pediatric trials have not been conducted using emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Pediatric information is based on trials conducted with the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets [see Use in Specific Populations (8.4)].

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

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

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 7 Population Pharmacokinetic Estimates of RPV 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48)</span> </caption> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Parameter</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">RPV 25 mg once daily</span> </p> <p> <span class="Bold">N = 34</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">AUC<span class="Sub">24h</span> (ng•h/mL) </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Mean ± Standard Deviation </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2424 ± 1024</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Median (Range) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2269 (417−5166)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">C<span class="Sub">0h</span> (ng/mL)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     Mean ± Standard Deviation </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">85 ± 40</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">     Median (Range) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">79 (7−202)</p> </td> </tr> </tbody> </table></div>

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

Gender

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

Race

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

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

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

Patients with Renal Impairment

Emtricitabine and Tenofovir DF: The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, Cmax and AUC of FTC and tenofovir were increased [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].

Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

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

Rilpivirine: RPV is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. RPV has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7)].

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

Hepatitis B and/or Hepatitis C Virus Coinfection

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

Pregnancy and Postpartum

The exposure (C0h and AUC24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.

<div class="scrollingtable"><table class="Noautorules" width="100.1%"> <caption> <span>Table 8 Pharmacokinetic Results of Total RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum</span> </caption> <col width="37%"/> <col width="21%"/> <col width="21%"/> <col width="21%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Pharmacokinetics of total RPV</span> </p> <p>(mean ± SD, tmax: median [range])</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Postpartum</span> </p> <p> <span class="Bold">(6-12 Weeks)</span> </p> <p> <span class="Bold">(n=11)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">2<span class="Sup">nd</span> Trimester</span> </p> <p> <span class="Bold">of pregnancy</span> </p> <p> <span class="Bold">(n=15)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">3<span class="Sup">rd</span> Trimester</span> </p> <p> <span class="Bold">of pregnancy</span> </p> <p> <span class="Bold">(n=13)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">C<span class="Sub">0h</span>, ng/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">111 ± 69.2</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">65.0 ± 23.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">63.5 ± 26.2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">C<span class="Sub">min</span>, ng/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">84.0 ± 58.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">54.3 ± 25.8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">52.9 ± 24.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">C<span class="Sub">max</span>, ng/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">167 ± 101</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">121 ± 45.9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">123 ± 47.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">t<span class="Sub">max</span>, h</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.00 (2.03−25.08)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.00 (1.00−9.00)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4.00 (2.00−24.93)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">AUC<span class="Sub">24h</span>, ng•h/mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2,714 ± 1,535</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1,792 ± 711</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1,762 ± 662</p> </td> </tr> </tbody> </table></div>

Drug Interaction Studies

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

RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

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

FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug [see Drug Interactions (7.4, 7.6)].

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

The drug interaction studies described in Tables 9-14 were conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV/FTC/TDF) or the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV, FTC, or TDF) administered individually.

The effects of coadministration of other drugs on the AUC, Cmax, and Cmin values of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, Cmax, and Cmin values of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see Drug Interactions (7).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered Drugs</span> </caption> <col width="18%"/> <col width="19%"/> <col width="13%"/> <col width="5%"/> <col width="16%"/> <col width="15%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="7" valign="top">NA=not available </td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-20" name="footnote-20">*</a> </dt> <dd>N=maximum number of subjects for C<span class="Sub">max</span>, AUC, or C<span class="Sub">min</span> </dd> <dt> <a href="#footnote-reference-21" name="footnote-21">†</a> </dt> <dd>Increase = ↑; Decrease = ↓; No Effect = ↔ </dd> <dt> <a href="#footnote-reference-22" name="footnote-22">‡</a> </dt> <dd>The interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug.</dd> <dt> <a href="#footnote-reference-23" name="footnote-23">§</a> </dt> <dd>Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir).</dd> <dt> <a href="#footnote-reference-24" name="footnote-24">¶</a> </dt> <dd>Comparison based on historic controls. </dd> <dt> <a href="#footnote-reference-25" name="footnote-25">#</a> </dt> <dd>Reference arm for comparison was 25 mg q.d. RPV administered alone.</dd> <dt> <a href="#footnote-reference-26" name="footnote-26">Þ</a> </dt> <dd>Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with EPCLUSA (sofosbuvir/velpatasvir).</dd> <dt> <a href="#footnote-reference-27" name="footnote-27">ß</a> </dt> <dd>Study conducted with ODEFSEY<span class="Sup">®</span> (FTC/RPV/tenofovir alafenamide).</dd> <dt> <a href="#footnote-reference-28" name="footnote-28">à</a> </dt> <dd>Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Coadministered Drug</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Dose of Coadministered Drug (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">RPV Dose (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span><a class="Sup" href="#footnote-20" name="footnote-reference-20">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Mean % Change of RPV Pharmacokinetic Parameters</span><a class="Sup" href="#footnote-21" name="footnote-reference-21">†</a> </p> <p> <span class="Bold">(90% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Cmin</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Acetaminophen </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500 single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22" name="footnote-reference-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑ 9</p> <p>(↑1 to ↑18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑16</p> <p>(↑10 to ↑22)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑26</p> <p>(↑16 to ↑38)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Atorvastatin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓9</p> <p>(↓21 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓10</p> <p>(↓19 to↓1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓10</p> <p>(↓16 to ↓4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Chlorzoxazone </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500 single dose taken 2 hours after RPV</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑17</p> <p>(↑8 to ↑27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑25</p> <p>(↑16 to ↑35)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑18</p> <p>(↑9 to ↑28)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ethinyl Estradiol/ Norethindrone </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.035 once daily/1 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔<a class="Sup" href="#footnote-23" name="footnote-reference-23">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔<a class="Sup" href="#footnote-23">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔<a class="Sup" href="#footnote-23">§</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="3" valign="middle"> <p class="First">Famotidine </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 single dose taken 12 hours before RPV</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 single dose<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓1</p> <p>(↓16 to ↑16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓9</p> <p>(↓22 to ↑7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 single dose taken 2 hours before RPV</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 single dose<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓85</p> <p>(↓88 to ↓81)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓76</p> <p>(↓80 to ↓72)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40 single dose taken 4 hours after RPV</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 single dose<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑21</p> <p>(↑6 to ↑39)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑13</p> <p>(↑1 to ↑27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ketoconazole </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑30</p> <p>(↑13 to ↑48)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑49</p> <p>(↑31 to ↑70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑76</p> <p>(↑57 to ↑97)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ledipasvir/ Sofosbuvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">90/400 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily<a class="Sup" href="#footnote-23">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓3</p> <p>(↓12 to ↑7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓6 to ↑11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑12</p> <p>(↑3 to ↑21)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Methadone </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">60–100 once daily individualized dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔<a class="Sup" href="#footnote-24" name="footnote-reference-24">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔<a class="Sup" href="#footnote-24">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔<a class="Sup" href="#footnote-24">¶</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Omeprazole </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓40</p> <p>(↓52 to ↓27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓40</p> <p>(↓49 to ↓29)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓33</p> <p>(↓42 to ↓22)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" rowspan="2" valign="middle"> <p class="First">Rifabutin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓31</p> <p>(↓38 to ↓24)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓42</p> <p>(↓48 to ↓35)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓48</p> <p>(↓54 to ↓41)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">18</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑43</p> <p>(↑30 to ↑56)<a class="Sup" href="#footnote-25" name="footnote-reference-25">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑16</p> <p>(↑6 to ↑26)<a class="Sup" href="#footnote-25">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓7</p> <p>(↓15 to ↑1)<a class="Sup" href="#footnote-25">#</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Rifampin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">600 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓69</p> <p>(↓73 to ↓64)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓80</p> <p>(↓82 to ↓77)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓89</p> <p>(↓90 to ↓87)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Simeprevir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">23</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑4</p> <p>(↓5 to ↑13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑12</p> <p>(↑5 to ↑19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑25</p> <p>(↑16 to ↑35)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sildenafil </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50 single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">75 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓8</p> <p>(↓15 to ↓1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓2</p> <p>(↓8 to ↑5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑4</p> <p>(↓2 to ↑9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir/ Velpatasvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400/100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily<a class="Sup" href="#footnote-26" name="footnote-reference-26">Þ</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓7</p> <p>(↓12 to ↓2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓5</p> <p>(↓10 to 0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓4</p> <p>(↓10 to ↑3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir/ Velpatasvir/ Voxilaprevir<a class="Sup" href="#footnote-27" name="footnote-reference-27">ß</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400/100/100 + 100 voxilaprevir<a class="Sup" href="#footnote-28" name="footnote-reference-28">à</a> once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓21</p> <p>(↓26 to ↓16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓20</p> <p>(↓24 to ↓15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓18</p> <p>(↓23 to ↓13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">TDF</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-22">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓4</p> <p>(↓19 to ↑13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑1</p> <p>(↓13 to ↑18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓1</p> <p>(↓17 to ↑16)</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drugs</span> </caption> <col width="18%"/> <col width="19%"/> <col width="13%"/> <col width="5%"/> <col width="16%"/> <col width="15%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="7" valign="top">NA=not available </td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-29" name="footnote-29">*</a> </dt> <dd>N=maximum number of subjects for C<span class="Sub">max</span>, AUC, or C<span class="Sub">min</span> </dd> <dt> <a href="#footnote-reference-30" name="footnote-30">†</a> </dt> <dd>Increase = ↑; Decrease = ↓; No Effect = ↔ </dd> <dt> <a href="#footnote-reference-31" name="footnote-31">‡</a> </dt> <dd>Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with HARVONI.</dd> <dt> <a href="#footnote-reference-32" name="footnote-32">§</a> </dt> <dd>Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with EPCLUSA.</dd> <dt> <a href="#footnote-reference-33" name="footnote-33">¶</a> </dt> <dd>Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.</dd> <dt> <a href="#footnote-reference-34" name="footnote-34">#</a> </dt> <dd>Study conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide).</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Coadministered Drug</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Dose of Coadministered Drug (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">FTC Dose (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span><a class="Sup" href="#footnote-29" name="footnote-reference-29">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Mean % Change of FTC Pharmacokinetic Parameters</span><a class="Sup" href="#footnote-30" name="footnote-reference-30">†</a> </p> <p> <span class="Bold">(90% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Famciclovir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500 × 1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 × 1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ledipasvir/ Sofosbuvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">90/400 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily<a class="Sup" href="#footnote-31" name="footnote-reference-31">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓2 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑5</p> <p>(↑2 to ↑8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑6</p> <p>(↓3 to ↑15)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir/ Velpatasvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400/100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily<a class="Sup" href="#footnote-32" name="footnote-reference-32">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓5</p> <p>(↓10 to 0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓1</p> <p>(↓3 to ↑2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑5</p> <p>(↓1 to ↑11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir/ Velpatasvir/ Voxilaprevir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400/100/100 + Voxilaprevir<a class="Sup" href="#footnote-33" name="footnote-reference-33">¶</a> 100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily<a class="Sup" href="#footnote-34" name="footnote-reference-34">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓12</p> <p>(↓17 to ↓7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓7</p> <p>(↓10 to ↓4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑7</p> <p>(↑1 to ↑14)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">TDF</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑20</p> <p>(↑12 to ↑29)</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drugs</span> </caption> <col width="18%"/> <col width="18%"/> <col width="14%"/> <col width="5%"/> <col width="16%"/> <col width="15%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-35" name="footnote-35">*</a> </dt> <dd>Subjects received VIREAD 300 mg daily.</dd> <dt> <a href="#footnote-reference-36" name="footnote-36">†</a> </dt> <dd>N=maximum number of subjects for Cmax, AUC, or Cmin</dd> <dt> <a href="#footnote-reference-37" name="footnote-37">‡</a> </dt> <dd>Increase = ↑; Decrease = ↓; No Effect = ↔</dd> <dt> <a href="#footnote-reference-38" name="footnote-38">§</a> </dt> <dd>Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with HARVONI.</dd> <dt> <a href="#footnote-reference-39" name="footnote-39">¶</a> </dt> <dd>Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with EPCLUSA.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Coadministered Drug</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Dose of Coadministered Drug (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">TDF Dose (mg)</span><a class="Sup" href="#footnote-35" name="footnote-reference-35">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span><a class="Sup" href="#footnote-36" name="footnote-reference-36">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Mean % Change of Tenofovir Pharmacokinetic Parameters</span><a class="Sup" href="#footnote-37" name="footnote-reference-37">‡</a> </p> <p> <span class="Bold">(90% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Entecavir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 once daily × 10 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Emtricitabine</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ledipasvir/ Sofosbuvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">90/400 once daily × 10 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily<a class="Sup" href="#footnote-38" name="footnote-reference-38">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑32</p> <p>(↑25 to ↑39)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑40</p> <p>(↑31 to ↑50)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑91</p> <p>(↑74 to ↑110)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir/ Velpatasvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400/100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑44</p> <p>(↑33 to ↑55)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑40</p> <p>(↑34 to ↑46)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑84</p> <p>(↑76 to ↑92)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Tacrolimus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.05 mg/kg twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily<a class="Sup" href="#footnote-39" name="footnote-reference-39">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑13</p> <p>(↑1 to ↑27)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV</span> </caption> <col width="19%"/> <col width="19%"/> <col width="12%"/> <col width="5%"/> <col width="16%"/> <col width="15%"/> <col width="14%"/> <tfoot> <tr> <td align="left" colspan="7" valign="top">NA=not available</td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-40" name="footnote-40">*</a> </dt> <dd>N=maximum number of subjects for Cmax, AUC, or Cmin</dd> <dt> <a href="#footnote-reference-41" name="footnote-41">†</a> </dt> <dd>Increase = ↑; Decrease = ↓; No Effect = ↔</dd> <dt> <a href="#footnote-reference-42" name="footnote-42">‡</a> </dt> <dd>The Interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily).</dd> <dt> <a href="#footnote-reference-43" name="footnote-43">§</a> </dt> <dd>The predominant circulating nucleoside metabolite of sofosbuvir.</dd> <dt> <a href="#footnote-reference-44" name="footnote-44">¶</a> </dt> <dd>Study conducted with ODEFSEY.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Coadministered Drug</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Dose of Coadministered Drug (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">RPV Dose (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span><a class="Sup" href="#footnote-40" name="footnote-reference-40">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Mean % Change of Coadministered Drug Pharmacokinetic Parameters</span><a class="Sup" href="#footnote-41" name="footnote-reference-41">†</a> </p> <p> <span class="Bold">(90% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Acetaminophen</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500 single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-42" name="footnote-reference-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓3</p> <p>(↓14 to ↑10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓8</p> <p>(↓15 to ↓1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Atorvastatin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">40 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑35</p> <p>(↑8 to ↑68)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑4</p> <p>(↓3 to ↑12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓ 15</p> <p>(↓ 31 to ↑ 3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">2-hydroxy-atorvastatin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑58</p> <p>(↑33 to ↑87)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑39</p> <p>(↑29 to ↑50)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑32</p> <p>(↑10 to ↑58)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">4-hydroxy-atorvastatin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑28</p> <p>(↑15 to ↑43)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑23</p> <p>(↑13 to ↑33)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Chlorzoxazone</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500 single dose taken 2 hours after RPV</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓2</p> <p>(↓15 to ↑13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑3</p> <p>(↓5 to ↑13)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Digoxin</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.5 single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑6</p> <p>(↓3 to ↑17)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓2</p> <p>(↓7 to ↑4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ethinyl estradiol </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.035 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑17</p> <p>(↑6 to ↑30)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑14</p> <p>(↑10 to ↑19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑9</p> <p>(↑3 to ↑16)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Norethindrone</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 mg once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓6</p> <p>(↓17 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓11</p> <p>(↓16 to ↓6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓1</p> <p>(↓10 to ↑8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ketoconazole </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">400 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓15</p> <p>(↓20 to ↓10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓24</p> <p>(↓30 to ↓18)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓66</p> <p>(↓75 to ↓54)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Ledipasvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">90 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">41</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑1</p> <p>(↓3 to ↑5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓3 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓2 to ↑7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">R(-) methadone </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">60−100 once daily individualized dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓14</p> <p>(↓22 to ↓5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓16</p> <p>(↓26 to ↓5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓22</p> <p>(↓33 to ↓9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">S(+) methadone </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓13</p> <p>(↓22 to ↓3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓16</p> <p>(↓26 to ↓4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓21</p> <p>(↓33 to ↓8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Metformin</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">850 single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓5 to ↑10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓3</p> <p>(↓10 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Omeprazole </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">15</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓14</p> <p>(↓32 to ↑9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓14</p> <p>(↓24 to ↓3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Rifampin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">600 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">150 once dailyc</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓7 to ↑12)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓1</p> <p>(↓8 to ↑7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">25-desacetylrifampin </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> <p>(↓13 to ↑15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓9</p> <p>(↓23 to ↑7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Simeprevir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑ 10</p> <p>(↓3 to ↑26)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑6</p> <p>(↓6 to ↑19)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓4</p> <p>(↓17 to ↑11)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Sildenafil </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">50 single dose</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">75 once daily<a class="Sup" href="#footnote-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓7</p> <p>(↓20 to ↑8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓3</p> <p>(↓13 to ↑8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">N-desmethyl-sildenafil</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓10</p> <p>(↓20 to ↑2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓8</p> <p>(↓15 to ↓1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">400 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑9</p> <p>(↓5 to ↑25)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑16</p> <p>(↑10 to ↑24)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">GS-331007<a class="Sup" href="#footnote-43" name="footnote-reference-43">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓4</p> <p>(↓10 to ↑1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑4</p> <p>(0 to ↑7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑ 12</p> <p>(↑7 to ↑17)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Velpatasvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">24</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓4</p> <p>(↓15 to ↑10)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓1</p> <p>(↓12 to ↑11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓9 to ↑15)</p> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle"> <p class="First">Sofosbuvir </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">400 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">25 once daily<a class="Sup" href="#footnote-44" name="footnote-reference-44">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓5</p> <p>(↓14 to ↑5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑1</p> <p>(↓3 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">GS-331007<a class="Sup" href="#footnote-43">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓2 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑4</p> <p>(↑1 to ↑6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Velpatasvir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily<a class="Sup" href="#footnote-44">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑5</p> <p>(↓4 to ↑16)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑1</p> <p>(↓6 to ↑7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑1</p> <p>(↓5 to ↑9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Voxilaprevir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">100 + 100 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25 once daily<a class="Sup" href="#footnote-44">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓4</p> <p>(↓16 to ↑11)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↓6</p> <p>(↓16 to ↑5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑2</p> <p>(↓8 to ↑12)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">TDF</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">150 once daily<a class="Sup" href="#footnote-42">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">16</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑19</p> <p>(↑6 to ↑34)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑23</p> <p>(↑16 to ↑31)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑24</p> <p>(↑10 to ↑38)</p> </td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTC</span> </caption> <col width="18%"/> <col width="18%"/> <col width="14%"/> <col width="5%"/> <col width="16%"/> <col width="15%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="7" valign="top">NA=not available </td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-45" name="footnote-45">*</a> </dt> <dd>All interaction trials conducted in healthy volunteers</dd> <dt> <a href="#footnote-reference-46" name="footnote-46">†</a> </dt> <dd>No Effect = ↔</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Coadministered Drug</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Dose of Coadministered Drug (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">FTC Dose (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span><a class="Sup" href="#footnote-45" name="footnote-reference-45">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Mean % Change of Coadministered Drug Pharmacokinetic Parameters</span><a class="Sup" href="#footnote-46" name="footnote-reference-46">†</a> </p> <p> <span class="Bold">(90% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Famciclovir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">500 × 1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 × 1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">NA</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">TDF</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td> </tr> </tbody> </table></div>

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDF</span> </caption> <col width="19%"/> <col width="18%"/> <col width="14%"/> <col width="5%"/> <col width="16%"/> <col width="14%"/> <col width="14%"/> <tfoot> <tr> <td align="left" colspan="7" valign="top">NA = not available </td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-47" name="footnote-47">*</a> </dt> <dd>All interaction trials conducted in healthy volunteers</dd> <dt> <a href="#footnote-reference-48" name="footnote-48">†</a> </dt> <dd>Increase = ↑; No Effect = ↔</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Coadministered Drug</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Dose of Coadministered Drug (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">TDF Dose (mg)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">N</span><a class="Sup" href="#footnote-47" name="footnote-reference-47">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Mean % Change of Coadministered Drug Pharmacokinetic Parameters</span><a class="Sup" href="#footnote-48" name="footnote-reference-48">†</a> </p> <p> <span class="Bold">(90% CI)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">AUC</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">C<span class="Sub">min</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Emtricitabine</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">200 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">17</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑20</p> <p>(↑12 to ↑29)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Entecavir</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 once daily × 10 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">28</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↑13</p> <p>(↑11 to ↑15)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Tacrolimus</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.05 mg/kg twice daily × 7 days</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">300 once daily</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">↔</p> </td> </tr> </tbody> </table></div>

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

Mechanism of Action

Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5′-triphosphate. Emtricitabine 5′-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5′-triphosphate and by being incorporated into nascent viral DNA, which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε, and mitochondrial DNA polymerase γ.

Rilpivirine: RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.

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

Antiviral Activity

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

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

Rilpivirine: RPV exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM. RPV demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510–10,830 nM). RPV demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07–1.01 nM and was less active against group O primary isolates with EC50 values ranging from 2.88–8.45 nM. The antiviral activity of RPV was not antagonistic when combined with the NNRTIs EFV, etravirine, or nevirapine; the N(t)RTIs abacavir, didanosine, FTC, lamivudine, stavudine, tenofovir, or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.

Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells, and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 μM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 μM–5.5 μM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, FTC, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, EFV, nevirapine, and RPV), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.

Resistance

In Cell Culture

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

Rilpivirine: RPV-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and M230I and L.

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

In the Week 96 pooled resistance analysis for adult subjects receiving RPV or EFV in combination with FTC/TDF in the Phase 3 clinical trials C209 and C215, the emergence of resistance was greater among subjects’ viruses in the RPV + FTC/TDF arm compared to the EFV + FTC/TDF arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the RPV + FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance analysis subjects in the EFV + FTC/TDF arm who had genotypic and/or phenotypic resistance to EFV. Moreover, genotypic and/or phenotypic resistance to FTC or tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the RPV arm compared to 26% (11/43) in the EFV arm.

Emerging NNRTI substitutions in the RPV resistance analysis of subjects’ viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6–621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The FTC and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance analysis subjects than in EFV resistance analysis subjects (See Table 15).

NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of ≤ 100,000 copies/mL compared to viruses from subjects with baseline viral loads of > 100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual FTC/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts ≥ 200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts < 200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 15 Proportion of Frequently Emerging Reverse Transcriptase Substitutions in the HIV-1 Virus of Resistance Analysis Adult Subjects<a class="Sup" href="#footnote-49" name="footnote-reference-49">*</a> Who Received RPV or EFV in Combination with FTC/TDF from Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis</span> </caption> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-49" name="footnote-49">*</a> </dt> <dd>Subjects who qualified for resistance analysis </dd> <dt> <a href="#footnote-reference-50" name="footnote-50">†</a> </dt> <dd>V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and M230 </dd> <dt> <a href="#footnote-reference-51" name="footnote-51">‡</a> </dt> <dd>This combination of NRTI and NNRTI substitutions is a subset of those with the E138K. </dd> <dt> <a href="#footnote-reference-52" name="footnote-52">§</a> </dt> <dd>A62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R </dd> <dt> <a href="#footnote-reference-53" name="footnote-53">¶</a> </dt> <dd>These substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2), D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in RPV resistance analysis subjects. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="3" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">C209 and C215</span> </p> <p> <span class="Bold">N=1096</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">RPV</span> </p> <p> <span class="Bold">+ FTC/TDF</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">EFV</span> </p> <p> <span class="Bold">+ FTC/TDF</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=550</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=546</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Subjects who Qualified for Resistance Analysis </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14% (77/550)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8% (43/546)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Subjects with Evaluable Postbaseline Resistance Data </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">70</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">31</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Emergent NNRTI Substitutions</span><a class="Sup" href="#footnote-50" name="footnote-reference-50">†</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Any </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">63% (44/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">55% (17/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">V90I </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14% (10/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">K101E/P/T/Q </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">19% (13/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10% (3/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">K103N </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1% (1/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">39% (12/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">E138K/A/Q/G </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">40% (28/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">     E138K+M184I<a class="Sup" href="#footnote-51" name="footnote-reference-51">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">30% (21/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">V179I/D </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6% (4/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10% (3/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Y181C/I/S </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">13% (9/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3% (1/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">V189I </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">9% (6/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">H221Y </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10% (7/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Emergent NRTI Substitutions</span><a class="Sup" href="#footnote-52" name="footnote-reference-52">§</a> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Any </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">63% (44/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">32% (10/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">M184I/V </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">59% (41/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">26% (8/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">K65R/N </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">11% (8/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6% (2/31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">A62V, D67N/G, K70E, Y115F, or K219E/R<a class="Sup" href="#footnote-53" name="footnote-reference-53">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">20% (14/70)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3% (1/31)</p> </td> </tr> </tbody> </table></div>

In Virologically-Suppressed HIV-1-Infected Adult Subjects

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

Cross Resistance

Rilpivirine, Emtricitabine, and Tenofovir DF:

In Cell Culture

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

Rilpivirine:

Site-Directed NNRTI Mutant Virus

Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-fold, 15-fold, and 12-fold decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to RPV compared to 2.8-fold for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to RPV. In another study, the Y188L substitution resulted in a reduced susceptibility to RPV of 9-fold for clinical isolates and 6-fold for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to RPV (fold change range of 3.7–554) in 38% and 66% of mutants, respectively.

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

Considering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.

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

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

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

Subjects whose virus expressed an L74V substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to TDF. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.

HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or RPV-associated substitutions, were susceptible to tenofovir.

Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (31 times the human systemic exposure at the therapeutic dose).

FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.

FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.

Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily).

RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.

In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.

Tenofovir DF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.

There were no effects on fertility, mating performance, or early embryonic development when TDF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats.

Tenofovir DF: Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

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

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

For subjects who received FTC/TDF (N=1096) in studies C209 and C215, the mean age was 37 years (range 18–78), 78% were male, 62% were White, 24% were Black, and 11% were Asian. The mean baseline CD4+ cell count was 265 cells/mm3 (range 1–888) and 31% had CD4+ cell counts <200 cells/mm3. The median baseline plasma HIV-1 RNA was 5 log10 copies/mL (range 2–7). Subjects were stratified by baseline HIV-1 RNA. Fifty percent of subjects had baseline viral load ≤100,000 copies/mL, 39% of subjects had baseline viral load between 100,000 copies/mL to 500,000 copies/mL, and 11% of subjects had baseline viral load >500,000 copies/mL.

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 16 Pooled Virologic Outcome of Randomized Treatment of Studies C209 and C215 at Week 96 in Adult Subjects With No Antiviral Treatment History in Combination with FTC/TDF) at Week 96<a class="Sup" href="#footnote-54" name="footnote-reference-54">*</a></span> </caption> <col width="47%"/> <col width="30%"/> <col width="24%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-54" name="footnote-54">*</a> </dt> <dd>Analyses were based on the last observed viral load data within the Week 96 window (Week 90–103). </dd> <dt> <a href="#footnote-reference-55" name="footnote-55">†</a> </dt> <dd>Predicted difference (95% CI) of response rate is 0.5% (–4.5% to 5.5%) at Week 96. </dd> <dt> <a href="#footnote-reference-56" name="footnote-56">‡</a> </dt> <dd>Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral load value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. </dd> <dt> <a href="#footnote-reference-57" name="footnote-57">§</a> </dt> <dd>Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. </dd> <dt> <a href="#footnote-reference-58" name="footnote-58">¶</a> </dt> <dd>Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">RPV</span> </p> <p> <span class="Bold">+ FTC/TDF</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">EFV</span> </p> <p> <span class="Bold">+ FTC/TDF</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=550</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=546</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HIV-1 RNA &lt;50 copies/mL</span><a class="Sup" href="#footnote-55" name="footnote-reference-55">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">77%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">77%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">HIV-1 RNA ≥50 copies/mL</span><a class="Sup" href="#footnote-56" name="footnote-reference-56">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">14%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">No Virologic Data at Week 96 Window</span> </p> <p> <span class="Bold">Reasons</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Discontinued study due to adverse event or death<a class="Sup" href="#footnote-57" name="footnote-reference-57">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">9%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Discontinued study for other reasons<a class="Sup" href="#footnote-58" name="footnote-reference-58">¶</a> and the last available HIV-1 RNA &lt;50 copies/mL (or missing) </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Missing data during window but on study </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt; 1%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt; 1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">HIV-1 RNA &lt;50 copies/mL by Baseline HIV-1 RNA (copies/mL) </span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">≤100,000 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">83%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">80%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">&gt;100,000 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">71%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">74%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HIV-1 RNA ≥50 copies/mL</span><a class="Sup" href="#footnote-56">‡</a><span class="Bold"> by Baseline HIV-1 RNA (copies/mL)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">≤100,000 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">&gt;100,000 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HIV-1 RNA &lt;50 copies/mL by Baseline CD4+ Cell Count (cells/mm<span class="Sup">3</span>)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">&lt;200 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">68%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">72%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">≥200 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">82%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">79%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HIV-1 RNA ≥ 50 copies/mL</span><a class="Sup" href="#footnote-56">‡</a><span class="Bold"> by Baseline CD4+ Cell Count (cells/mm<span class="Sup">3</span>)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">&lt;200 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">27%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">≥200 </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">8%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">7%</p> </td> </tr> </tbody> </table></div>

Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from baseline at Week 96 was 226 cells/mm3 for RPV + FTC/TDF-treated subjects and 223 cells/mm3 for EFV + FTC/TDF-treated subjects.

In Virologically Suppressed HIV-1-Infected Adult Subjects

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

Treatment outcomes are presented in Table 17.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 17 Virologic Outcomes of Study GS-US-264-0106 in Virologically Suppressed Subjects</span> </caption> <col width="34%"/> <col width="33%"/> <col width="33%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-59" name="footnote-59">*</a> </dt> <dd>Week 48 window is between Day 295 and 378 (inclusive).</dd> <dt> <a href="#footnote-reference-60" name="footnote-60">†</a> </dt> <dd>For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, the Week 24 window is between Day 127 and first dose day on emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</dd> <dt> <a href="#footnote-reference-61" name="footnote-61">‡</a> </dt> <dd>Predicted difference (95% CI) of response rate for switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at Week 48 compared to staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study design) is –0.7% (–6.4% to 5.1%).</dd> <dt> <a href="#footnote-reference-62" name="footnote-62">§</a> </dt> <dd>Includes subjects who had HIV-1 RNA ≥50 copies/mL in the time window, subjects who discontinued early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event or death and at the time of discontinuation had a viral load value of ≥50 copies/mL.</dd> <dt> <a href="#footnote-reference-63" name="footnote-63">¶</a> </dt> <dd>Includes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.</dd> <dt> <a href="#footnote-reference-64" name="footnote-64">#</a> </dt> <dd>Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets</span> </p> <p> <span class="Bold">Week 48</span><a class="Sup" href="#footnote-59" name="footnote-reference-59">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Stayed on Baseline Regimen</span> </p> <p> <span class="Bold">(SBR)</span> </p> <p> <span class="Bold">Week 24</span><a class="Sup" href="#footnote-60" name="footnote-reference-60">†</a> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=317</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">N=159</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HIV-1 RNA &lt;50 copies/mL</span><a class="Sup" href="#footnote-61" name="footnote-reference-61">‡</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">89% (283/317)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">90% (143/159)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">HIV-1 RNA ≥50 copies/mL</span><a class="Sup" href="#footnote-62" name="footnote-reference-62">§</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3% (8/317)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5% (8/159)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">No Virologic Data at Week 24 Window</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Discontinued study drug due to AE or death<a class="Sup" href="#footnote-63" name="footnote-reference-63">¶</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2% (7/317)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">     Discontinued study drug due to other reasons and last available HIV-1 RNA &lt;50 copies/mL<a class="Sup" href="#footnote-64" name="footnote-reference-64">#</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">5% (16/317)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3% (5/159)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Missing data during window but on study drug</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1% (3/317)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2% (3/159)</p> </td> </tr> </tbody> </table></div>

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

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

Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets are available containing 200 mg of emtricitabine, 27.5 mg of rilpivirine hydrochloride equivalent to 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil.

{ "type": "p", "children": [], "text": "Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets are available containing 200 mg of emtricitabine, 27.5 mg of rilpivirine hydrochloride equivalent to 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil." }

The 200 mg/25 mg/300 mg tablets are yellow, film-coated, capsule shaped, unscored tablets debossed with M on one side of the tablet and ERT on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "The 200 mg/25 mg/300 mg tablets are yellow, film-coated, capsule shaped, unscored tablets debossed with M on one side of the tablet and ERT on the other side. They are available as follows:" }

NDC 0378-5440-93bottles of 30 tablets

{ "type": "p", "children": [], "text": "NDC 0378-5440-93bottles of 30 tablets" }

NDC 0378-5440-77bottles of 90 tablets

{ "type": "p", "children": [], "text": "NDC 0378-5440-77bottles of 90 tablets" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]\n" }

Keep container tightly closed.

{ "type": "p", "children": [], "text": "Keep container tightly closed." }

Dispense only in original container.

{ "type": "p", "children": [], "text": "Dispense only in original container." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information). " }

Posttreatment Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

{ "type": "p", "children": [], "text": "\nPosttreatment Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV\n" }

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and who have discontinued products containing FTC or TDF [see Warnings and Precautions (5.1)]. Advise patients to not discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets without first informing their healthcare provider.

{ "type": "p", "children": [], "text": "Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and who have discontinued products containing FTC or TDF [see Warnings and Precautions (5.1)]. Advise patients to not discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets without first informing their healthcare provider." }

Severe Skin Reactions and Hypersensitivity

{ "type": "p", "children": [], "text": "\nSevere Skin Reactions and Hypersensitivity\n" }

Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as DRESS severe hypersensitivity: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue, or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as DRESS severe hypersensitivity: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue, or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.2)]." }

Hepatotoxicity

{ "type": "p", "children": [], "text": "\nHepatotoxicity\n" }

Inform patients that hepatotoxicity has been reported with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and that monitoring for hepatotoxicity is recommended [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients that hepatotoxicity has been reported with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and that monitoring for hepatotoxicity is recommended [see Warnings and Precautions (5.3)]." }

Depressive Disorders

{ "type": "p", "children": [], "text": "\nDepressive Disorders\n" }

Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Advise patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Advise patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.4)]." }

New Onset or Worsening Renal Impairment

{ "type": "p", "children": [], "text": "\nNew Onset or Worsening Renal Impairment\n" }

Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.5)]. " }

Bone Loss and Mineralization Defects

{ "type": "p", "children": [], "text": "\nBone Loss and Mineralization Defects\n" }

Inform patients that decreases in bone mineral density have been observed with the use of TDF. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Inform patients that decreases in bone mineral density have been observed with the use of TDF. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.6)]." }

Drug Interactions

{ "type": "p", "children": [], "text": "\nDrug Interactions\n" }

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets may interact with many drugs and are not recommended to be coadministered with numerous drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort [see Contraindications (4), Warnings and Precautions (5.7), and Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets may interact with many drugs and are not recommended to be coadministered with numerous drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort [see Contraindications (4), Warnings and Precautions (5.7), and Drug Interactions (7)]." }

For patients receiving rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of rifabutin coadministration.

{ "type": "p", "children": [], "text": "For patients receiving rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of rifabutin coadministration. " }

Lactic Acidosis and Severe Hepatomegaly

{ "type": "p", "children": [], "text": "\nLactic Acidosis and Severe Hepatomegaly\n" }

Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.8)]. " }

Immune Reconstitution Syndrome

{ "type": "p", "children": [], "text": "\nImmune Reconstitution Syndrome\n" }

Inform patients to inform their healthcare provider immediately of any signs and symptoms of inflammation from previous infections, which may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Inform patients to inform their healthcare provider immediately of any signs and symptoms of inflammation from previous infections, which may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.9)]." }

Dosing Instructions

{ "type": "p", "children": [], "text": "\nDosing Instructions\n" }

Advise patients that it is important to take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets on a regular dosing schedule with food and to avoid missing doses. A protein drink is not a substitute for food. If the healthcare provider decides to stop emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and the patient is switched to new medicines to treat HIV that include RPV tablets, the RPV tablets should be taken only with a meal.

{ "type": "p", "children": [], "text": "Advise patients that it is important to take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets on a regular dosing schedule with food and to avoid missing doses. A protein drink is not a substitute for food. If the healthcare provider decides to stop emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and the patient is switched to new medicines to treat HIV that include RPV tablets, the RPV tablets should be taken only with a meal. " }

Pregnancy Registry

{ "type": "p", "children": [], "text": "\nPregnancy Registry\n" }

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy [see Use in Specific Populations (8.1)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Instruct patients with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Instruct patients with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)]." }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets</p> <p> </p> <p>(em″ trye sye′ ta been ril″ pi vir′ een ten of′ oh vir dye″ soe prox′ il fue′ ma rate)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</span> For more information, see the section <span class="Bold">“What should I tell my healthcare provider before taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?”</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</span> </p> <p> </p> <p> <span class="Bold">Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can cause serious side effects, including:</span> </p> <p> </p> <p> <span class="Bold">Worsening of Hepatitis B virus (HBV) infection.</span> Your healthcare provider will test you for HBV before starting treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If you have HBV infection and take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, your HBV may get worse (flare-up) if you stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. </p> <dl> <dt>•</dt> <dd>Do not stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets without first talking to your healthcare provider. </dd> <dt>•</dt> <dd>Do not run out of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Refill your prescription or talk to your healthcare provider before your emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are all gone. </dd> <dt>•</dt> <dd>If you stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd> </dl> <p>For more information about side effects, see the section <span class="Bold">“What are the possible side effects of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?”.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First">What are emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</p> <p> </p> <p>Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a prescription medicine that is used to treat Human Immunodeficiency Virus-1 (HIV-1) in people weighing at least 77 lb (35 kg) who:</p> <dl> <dt>•</dt> <dd>have <span class="Bold">never</span> taken HIV-1 medicines before, and who have an amount of HIV-1 in their blood (this is called ‘viral load’) that is no more than 100,000 copies/mL before they start taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, </dd> <dt> </dt> <dd> <span class="Bold">or</span> </dd> <dt>•</dt> <dd>in certain people who have a viral load that is less than 50 copies/mL when they start taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, to replace their current HIV-1 medicines.</dd> </dl> <p>HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets do not cure HIV-1 or AIDS.</p> <p> </p> <p>Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets contain 3 medicines (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) combined in one tablet. Emtricitabine (EMTRIVA<span class="Sup">®</span>) and tenofovir disoproxil fumarate (VIREAD<span class="Sup">®</span>) are HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). Rilpivirine (Edurant<span class="Sup">®</span>) is an HIV-1 non-nucleoside analog reverse transcriptase inhibitor (NNRTI). </p> <p> </p> <p>It is not known if emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are safe and effective in children less than 12 years of age or who weigh less than 77 lb (35 kg).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Who should not take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</span> </p> <p> </p> <p> <span class="Bold">Do not take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets if you also take: </span> </p> <dl> <dt>•</dt> <dd>anti-seizure medicines: <dl> <dt>o</dt> <dd>carbamazepine</dd> <dt>o</dt> <dd>oxcarbazepine</dd> <dt>o</dt> <dd>phenobarbital</dd> <dt>o</dt> <dd>phenytoin</dd> </dl> </dd> <dt>•</dt> <dd>anti-tuberculosis (anti-TB) medicines: <dl> <dt>o</dt> <dd>rifampin </dd> <dt>o</dt> <dd>rifapentine</dd> </dl> </dd> <dt>•</dt> <dd>proton pump inhibitor (PPI) medicine for certain stomach or intestinal problems: <dl> <dt>o</dt> <dd>dexlansoprazole</dd> <dt>o</dt> <dd>esomeprazole</dd> <dt>o</dt> <dd>lansoprazole</dd> <dt>o</dt> <dd>omeprazole</dd> <dt>o</dt> <dd>pantoprazole sodium</dd> <dt>o</dt> <dd>rabeprazole</dd> </dl> </dd> <dt>•</dt> <dd>more than 1 dose of the steroid medicine dexamethasone or dexamethasone sodium phosphate </dd> <dt>•</dt> <dd>St. John’s wort (<span class="Italics">Hypericum perforatum</span>)</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</span> </p> <p> </p> <p> <span class="Bold">Before taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, tell your healthcare provider about all your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have liver problems, including hepatitis B or C virus infection </dd> <dt>•</dt> <dd>have kidney problems </dd> <dt>•</dt> <dd>have a history of depression or suicidal thoughts</dd> <dt>•</dt> <dd>have bone problems </dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. It is not known if emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can harm your unborn child. Tell your healthcare provider if you become pregnant during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.<br/> <br/> <span class="Bold">Pregnancy Registry.</span> There is a pregnancy registry for those who take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry. </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. <dl> <dt>o</dt> <dd>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. </dd> <dt>o</dt> <dd>At least two of the medicines contained in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can be passed to your baby in your breast milk. </dd> <dt>o</dt> <dd>Talk with your healthcare provider about the best way to feed your baby during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd> </dl> </dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p> <p> </p> <p>Some medicines interact with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</p> <dl> <dt>•</dt> <dd>You can ask your healthcare provider or pharmacist for a list of medicines that can interact with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</dd> <dt>•</dt> <dd>Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with other medicines.</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">How should I take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </span> </p> <dl> <dt>•</dt> <dd>Take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets exactly as your healthcare provider tells you to take them. </dd> <dt>•</dt> <dd>Take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with food. Taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with food is important to help get the right amount of medicine in your body. A protein drink does not replace food. If your healthcare provider decides to stop emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and you are switched to new medicines to treat HIV-1 that include rilpivirine tablets, the rilpivirine tablets should be taken only with a meal.</dd> <dt>•</dt> <dd>Do not change your dose or stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</dd> <dt>•</dt> <dd>If you miss a dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets within 12 hours of the time you usually take it, take your dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets <span class="Bold">with food</span> as soon as possible. Then, take your next dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at the regularly scheduled time. If you miss a dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets by more than 12 hours of the time you usually take it, wait and then take the next dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at the regularly scheduled time. </dd> <dt>•</dt> <dd>Do not take more than your prescribed dose to make up for a missed dose. </dd> <dt>•</dt> <dd>If you take too many emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, contact your local poison control center or go to the nearest hospital emergency room right away.</dd> <dt>•</dt> <dd>When your emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets supply starts to run low, get more from your healthcare provider or pharmacy. It is very important not to run out of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. The amount of virus in your blood may increase if the medicine is stopped for even a short time.</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </span> </p> <p> </p> <p> <span class="Bold">Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can cause serious side effects, including: </span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">See “What is the most important information I should know about emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?”</span> </dd> <dt>•</dt> <dd> <span class="Bold">Severe skin rash and allergic reactions.</span> Skin rash is a common side effect of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Rash can be serious. Call your healthcare provider right away if you get a rash. In some cases, rash and allergic reaction may need to be treated in a hospital. <span class="Bold">If you get a rash with any of the following symptoms, stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and call your healthcare provider or get medical help right away:</span> </dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>•</dt> <dd>fever</dd> <dt>•</dt> <dd>skin blisters</dd> <dt>•</dt> <dd>mouth sores</dd> <dt>•</dt> <dd>redness or swelling of the eyes (conjunctivitis)</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>swelling of the face, lips, mouth, tongue or throat</dd> <dt>•</dt> <dd>trouble breathing or swallowing</dd> <dt>•</dt> <dd>pain on the right side of the stomach (abdominal) area</dd> <dt>•</dt> <dd>dark or “tea-colored” urine</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Severe liver problems.</span> In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.</dd> <dt>•</dt> <dd> <span class="Bold">Change in liver enzymes.</span> People with a history of hepatitis B or C virus infection or who have certain liver enzyme changes may have an increased risk of developing new or worsening liver problems during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Liver problems can also happen during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in people without a history of liver disease. Your healthcare provider may need to do tests to check your liver enzymes before and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd> <dt>•</dt> <dd> <span class="Bold">Depression or mood changes. Tell your healthcare provider right away if you have any of the following symptoms: </span> <dl> <dt>•</dt> <dd>feel sad or hopeless </dd> <dt>•</dt> <dd>feel anxious or restless </dd> <dt>•</dt> <dd>have thoughts of hurting yourself (suicide) or have tried to hurt yourself </dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">New or worse kidney problems, including kidney failure,</span> can happen in some people who take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Your healthcare provider should do blood tests to check your kidneys before starting treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If you have had kidney problems in the past or need to take another medicine that can cause kidney problems, your healthcare provider may need to do blood tests to check your kidneys during your treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd> <dt>•</dt> <dd> <span class="Bold">Bone problems</span> can happen in some people who take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Bone problems include bone pain, softening, or thinning (which may lead to fractures). Your healthcare provider may need to do additional tests to check your bones. </dd> <dt>•</dt> <dd> <span class="Bold">Too much lactic acid in your blood (lactic acidosis).</span> Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.</dd> <dt>•</dt> <dd> <span class="Bold">Changes in your immune system (Immune Reconstitution Syndrome)</span> can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. </dd> </dl> <p class="First"> </p> <p>The most common side effects of rilpivirine, one of the medicines in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, include:</p> <dl> <dt>•</dt> <dd>depression</dd> <dt>•</dt> <dd>trouble sleeping</dd> <dt>•</dt> <dd>headache</dd> </dl> <p>The most common side effects of emtricitabine and tenofovir disoproxil fumarate, two of the medicines in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, include:</p> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>•</dt> <dd>diarrhea </dd> <dt>•</dt> <dd>nausea </dd> <dt>•</dt> <dd>tiredness</dd> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>dizziness</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>depression</dd> <dt>•</dt> <dd>trouble sleeping</dd> <dt>•</dt> <dd>abnormal dreams</dd> <dt>•</dt> <dd>rash</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First">These are not all the possible side effects of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </p> <p>Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">How should I store emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </span> </p> <dl> <dt>•</dt> <dd>Store emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at room temperature between 20° to 25°C (68° to 77°F).</dd> <dt>•</dt> <dd>Keep emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in their original container and keep the container tightly closed. </dd> <dt>•</dt> <dd>Do not use emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets if the seal over the bottle opening is broken or missing. </dd> </dl> <p> </p> <p> <span class="Bold">Keep emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and all other medicines out of reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">General information about safe and effective use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets </span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets for a condition for which they were not prescribed. Do not give emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your healthcare provider or pharmacist for information about emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets that is written for health professionals. </p> <p> </p> <p>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">What are the ingredients of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </p> <p> </p> <p> <span class="Bold">Active ingredients:</span> emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate. </p> <p> <span class="Bold">Inactive ingredients:</span> corn starch, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, talc, titanium dioxide, triacetin and yellow iron oxide.</p> <p> </p> <p> <span class="Bold">Manufactured for:</span> Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.</p> <p> <span class="Bold">Manufactured by:</span> Mylan Laboratories Limited, Hyderabad – 500 096, India</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets</p>\n<p> </p>\n<p>(em″ trye sye′ ta been ril″ pi vir′ een ten of′ oh vir dye″ soe prox′ il fue′ ma rate)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</span> For more information, see the section <span class=\"Bold\">“What should I tell my healthcare provider before taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?”</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</span>\n</p>\n<p> </p>\n<p>\n<span class=\"Bold\">Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can cause serious side effects, including:</span>\n</p>\n<p> </p>\n<p>\n<span class=\"Bold\">Worsening of Hepatitis B virus (HBV) infection.</span> Your healthcare provider will test you for HBV before starting treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If you have HBV infection and take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, your HBV may get worse (flare-up) if you stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. </p>\n<dl>\n<dt>•</dt>\n<dd>Do not stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets without first talking to your healthcare provider. </dd>\n<dt>•</dt>\n<dd>Do not run out of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Refill your prescription or talk to your healthcare provider before your emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are all gone. </dd>\n<dt>•</dt>\n<dd>If you stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd>\n</dl>\n<p>For more information about side effects, see the section <span class=\"Bold\">“What are the possible side effects of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?”.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">What are emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</p>\n<p> </p>\n<p>Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a prescription medicine that is used to treat Human Immunodeficiency Virus-1 (HIV-1) in people weighing at least 77 lb (35 kg) who:</p>\n<dl>\n<dt>•</dt>\n<dd>have <span class=\"Bold\">never</span> taken HIV-1 medicines before, and who have an amount of HIV-1 in their blood (this is called ‘viral load’) that is no more than 100,000 copies/mL before they start taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, </dd>\n<dt> </dt>\n<dd>\n<span class=\"Bold\">or</span>\n</dd>\n<dt>•</dt>\n<dd>in certain people who have a viral load that is less than 50 copies/mL when they start taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, to replace their current HIV-1 medicines.</dd>\n</dl>\n<p>HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets do not cure HIV-1 or AIDS.</p>\n<p> </p>\n<p>Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets contain 3 medicines (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) combined in one tablet. Emtricitabine (EMTRIVA<span class=\"Sup\">®</span>) and tenofovir disoproxil fumarate (VIREAD<span class=\"Sup\">®</span>) are HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). Rilpivirine (Edurant<span class=\"Sup\">®</span>) is an HIV-1 non-nucleoside analog reverse transcriptase inhibitor (NNRTI). </p>\n<p> </p>\n<p>It is not known if emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are safe and effective in children less than 12 years of age or who weigh less than 77 lb (35 kg).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</span>\n</p>\n<p> </p>\n<p>\n<span class=\"Bold\">Do not take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets if you also take: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>anti-seizure medicines: <dl>\n<dt>o</dt>\n<dd>carbamazepine</dd>\n<dt>o</dt>\n<dd>oxcarbazepine</dd>\n<dt>o</dt>\n<dd>phenobarbital</dd>\n<dt>o</dt>\n<dd>phenytoin</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>anti-tuberculosis (anti-TB) medicines: <dl>\n<dt>o</dt>\n<dd>rifampin </dd>\n<dt>o</dt>\n<dd>rifapentine</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>proton pump inhibitor (PPI) medicine for certain stomach or intestinal problems: <dl>\n<dt>o</dt>\n<dd>dexlansoprazole</dd>\n<dt>o</dt>\n<dd>esomeprazole</dd>\n<dt>o</dt>\n<dd>lansoprazole</dd>\n<dt>o</dt>\n<dd>omeprazole</dd>\n<dt>o</dt>\n<dd>pantoprazole sodium</dd>\n<dt>o</dt>\n<dd>rabeprazole</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>more than 1 dose of the steroid medicine dexamethasone or dexamethasone sodium phosphate </dd>\n<dt>•</dt>\n<dd>St. John’s wort (<span class=\"Italics\">Hypericum perforatum</span>)</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?</span>\n</p>\n<p> </p>\n<p>\n<span class=\"Bold\">Before taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, tell your healthcare provider about all your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver problems, including hepatitis B or C virus infection </dd>\n<dt>•</dt>\n<dd>have kidney problems </dd>\n<dt>•</dt>\n<dd>have a history of depression or suicidal thoughts</dd>\n<dt>•</dt>\n<dd>have bone problems </dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. It is not known if emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can harm your unborn child. Tell your healthcare provider if you become pregnant during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.<br/> <br/>\n<span class=\"Bold\">Pregnancy Registry.</span> There is a pregnancy registry for those who take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry. </dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. <dl>\n<dt>o</dt>\n<dd>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. </dd>\n<dt>o</dt>\n<dd>At least two of the medicines contained in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can be passed to your baby in your breast milk. </dd>\n<dt>o</dt>\n<dd>Talk with your healthcare provider about the best way to feed your baby during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd>\n</dl>\n</dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. </p>\n<p> </p>\n<p>Some medicines interact with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</p>\n<dl>\n<dt>•</dt>\n<dd>You can ask your healthcare provider or pharmacist for a list of medicines that can interact with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</dd>\n<dt>•</dt>\n<dd>Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with other medicines.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets exactly as your healthcare provider tells you to take them. </dd>\n<dt>•</dt>\n<dd>Take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with food. Taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with food is important to help get the right amount of medicine in your body. A protein drink does not replace food. If your healthcare provider decides to stop emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and you are switched to new medicines to treat HIV-1 that include rilpivirine tablets, the rilpivirine tablets should be taken only with a meal.</dd>\n<dt>•</dt>\n<dd>Do not change your dose or stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets.</dd>\n<dt>•</dt>\n<dd>If you miss a dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets within 12 hours of the time you usually take it, take your dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets <span class=\"Bold\">with food</span> as soon as possible. Then, take your next dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at the regularly scheduled time. If you miss a dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets by more than 12 hours of the time you usually take it, wait and then take the next dose of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at the regularly scheduled time. </dd>\n<dt>•</dt>\n<dd>Do not take more than your prescribed dose to make up for a missed dose. </dd>\n<dt>•</dt>\n<dd>If you take too many emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, contact your local poison control center or go to the nearest hospital emergency room right away.</dd>\n<dt>•</dt>\n<dd>When your emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets supply starts to run low, get more from your healthcare provider or pharmacy. It is very important not to run out of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. The amount of virus in your blood may increase if the medicine is stopped for even a short time.</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </span>\n</p>\n<p> </p>\n<p>\n<span class=\"Bold\">Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets can cause serious side effects, including: </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">See “What is the most important information I should know about emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets?”</span>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Severe skin rash and allergic reactions.</span> Skin rash is a common side effect of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Rash can be serious. Call your healthcare provider right away if you get a rash. In some cases, rash and allergic reaction may need to be treated in a hospital. <span class=\"Bold\">If you get a rash with any of the following symptoms, stop taking emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and call your healthcare provider or get medical help right away:</span>\n</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>fever</dd>\n<dt>•</dt>\n<dd>skin blisters</dd>\n<dt>•</dt>\n<dd>mouth sores</dd>\n<dt>•</dt>\n<dd>redness or swelling of the eyes (conjunctivitis)</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>swelling of the face, lips, mouth, tongue or throat</dd>\n<dt>•</dt>\n<dd>trouble breathing or swallowing</dd>\n<dt>•</dt>\n<dd>pain on the right side of the stomach (abdominal) area</dd>\n<dt>•</dt>\n<dd>dark or “tea-colored” urine</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Severe liver problems.</span> In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Change in liver enzymes.</span> People with a history of hepatitis B or C virus infection or who have certain liver enzyme changes may have an increased risk of developing new or worsening liver problems during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Liver problems can also happen during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in people without a history of liver disease. Your healthcare provider may need to do tests to check your liver enzymes before and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Depression or mood changes. Tell your healthcare provider right away if you have any of the following symptoms: </span>\n<dl>\n<dt>•</dt>\n<dd>feel sad or hopeless </dd>\n<dt>•</dt>\n<dd>feel anxious or restless </dd>\n<dt>•</dt>\n<dd>have thoughts of hurting yourself (suicide) or have tried to hurt yourself </dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">New or worse kidney problems, including kidney failure,</span> can happen in some people who take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Your healthcare provider should do blood tests to check your kidneys before starting treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If you have had kidney problems in the past or need to take another medicine that can cause kidney problems, your healthcare provider may need to do blood tests to check your kidneys during your treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Bone problems</span> can happen in some people who take emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Bone problems include bone pain, softening, or thinning (which may lead to fractures). Your healthcare provider may need to do additional tests to check your bones. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Too much lactic acid in your blood (lactic acidosis).</span> Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Changes in your immune system (Immune Reconstitution Syndrome)</span> can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. </dd>\n</dl>\n<p class=\"First\"> </p>\n<p>The most common side effects of rilpivirine, one of the medicines in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, include:</p>\n<dl>\n<dt>•</dt>\n<dd>depression</dd>\n<dt>•</dt>\n<dd>trouble sleeping</dd>\n<dt>•</dt>\n<dd>headache</dd>\n</dl>\n<p>The most common side effects of emtricitabine and tenofovir disoproxil fumarate, two of the medicines in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, include:</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>diarrhea </dd>\n<dt>•</dt>\n<dd>nausea </dd>\n<dt>•</dt>\n<dd>tiredness</dd>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>dizziness</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>depression</dd>\n<dt>•</dt>\n<dd>trouble sleeping</dd>\n<dt>•</dt>\n<dd>abnormal dreams</dd>\n<dt>•</dt>\n<dd>rash</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">These are not all the possible side effects of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. </p>\n<p>Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets at room temperature between 20° to 25°C (68° to 77°F).</dd>\n<dt>•</dt>\n<dd>Keep emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in their original container and keep the container tightly closed. </dd>\n<dt>•</dt>\n<dd>Do not use emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets if the seal over the bottle opening is broken or missing. </dd>\n</dl>\n<p> </p>\n<p>\n<span class=\"Bold\">Keep emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and all other medicines out of reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about safe and effective use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets </span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets for a condition for which they were not prescribed. Do not give emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your healthcare provider or pharmacist for information about emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets that is written for health professionals. </p>\n<p> </p>\n<p>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">What are the ingredients of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets? </p>\n<p> </p>\n<p>\n<span class=\"Bold\">Active ingredients:</span> emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate. </p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span> corn starch, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, talc, titanium dioxide, triacetin and yellow iron oxide.</p>\n<p> </p>\n<p>\n<span class=\"Bold\">Manufactured for:</span> Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.</p>\n<p>\n<span class=\"Bold\">Manufactured by:</span> Mylan Laboratories Limited, Hyderabad – 500 096, India</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration." }

The brands listed are trademarks of their respective owners.

{ "type": "p", "children": [], "text": "The brands listed are trademarks of their respective owners." }

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Pharmaceuticals Inc.\nMorgantown, WV 26505 U.S.A." }

Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, IndiaCode No.: MH/DRUGS/AD/089

{ "type": "p", "children": [], "text": "Manufactured by:\nMylan Laboratories Limited\nHyderabad — 500 096, IndiaCode No.: MH/DRUGS/AD/089" }

Revised: 12/2024

{ "type": "p", "children": [], "text": "Revised: 12/2024" }

75057890

{ "type": "p", "children": [], "text": "75057890" }

MXA:EMRITE:R4

{ "type": "p", "children": [], "text": "MXA:EMRITE:R4" }

NDC 0378-5440-93

{ "type": "p", "children": [], "text": "\nNDC 0378-5440-93\n" }

Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets 200 mg/25 mg/300 mg

{ "type": "p", "children": [], "text": "\nEmtricitabine, Rilpivirine\n\nand Tenofovir Disoproxil\n\nFumarate\n\nTablets\n\n200 mg/25 mg/300 mg\n" }

Note to pharmacist: Do not cover ALERT box with pharmacy label.

{ "type": "p", "children": [], "text": "\nNote to pharmacist: Do not cover ALERT\n\nbox with pharmacy label.\n" }

ALERT: Find out about medicines that should NOT be taken with Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets.

{ "type": "p", "children": [], "text": "\nALERT: Find out about medicines that should\n\nNOT be taken with Emtricitabine, Rilpivirine\n\nand Tenofovir Disoproxil Fumarate Tablets.\n" }

Rx only 30 Tablets

{ "type": "p", "children": [], "text": "\nRx only 30 Tablets\n" }

Each film-coated tablet contains 200 mgof emtricitabine, 27.5 mg of rilpivirinehydrochloride, which is equivalent to 25 mgof rilpivirine, and 300 mg of tenofovirdisoproxil fumarate, which is equivalentto 245 mg of tenofovir disoproxil.

{ "type": "p", "children": [], "text": "Each film-coated tablet contains 200 mgof emtricitabine, 27.5 mg of rilpivirinehydrochloride, which is equivalent to 25 mgof rilpivirine, and 300 mg of tenofovirdisoproxil fumarate, which is equivalentto 245 mg of tenofovir disoproxil." }

Usual Dosage: See accompanyingprescribing information.

{ "type": "p", "children": [], "text": "\nUsual Dosage: See accompanyingprescribing information." }

Keep this and all medication out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep this and all medication out of\n\nthe reach of children.\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F). [See\n\nUSP Controlled Room Temperature.]\n" }

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Pharmaceuticals Inc.\nMorgantown, WV 26505 U.S.A." }

Made in India

{ "type": "p", "children": [], "text": "Made in India" }

Mylan.com

{ "type": "p", "children": [], "text": "\nMylan.com\n" }

RMXA5440H1

{ "type": "p", "children": [], "text": "\nRMXA5440H1\n" }

Dispense only in original container.

{ "type": "p", "children": [], "text": "Dispense only in original container." }

Keep container tightly closed.

{ "type": "p", "children": [], "text": "Keep container tightly closed." }

Code No.: MH/DRUGS/AD/089

{ "type": "p", "children": [], "text": "Code No.: MH/DRUGS/AD/089" }