Edurant
(rilpivirine)Dosage & Administration
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Edurant Prescribing Information
Treatment of HIV-1 in Treatment-Naïve Patients
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
- More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14.1)] .
Treatment of HIV-1 in Combination with Cabotegravir
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)] :
- oral lead-in to assess the tolerability of rilpivirine prior to administration of rilpivirine extended-release injectable suspension, a component of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).
- oral therapy for patients who will miss planned injection dosing with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).
Overview of Different Dosage Forms
EDURANT is available in two dosage forms:
- EDURANT 25 mg film-coated tablets for adults and pediatric patients weighing at least 25 kg.
- EDURANT PED 2.5 mg tablets for oral suspension should only be given to pediatric patients weighing at least 14 kg to less than 25 kg [see Dosage and Administration (2.3)] .
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)].
Recommended Dosage in Treatment-Naïve Adult Patients
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)] .
Recommended Dosage in Treatment-Naïve Pediatric Patients 2 Years of Age and Older and Weighing at least 14 kg
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)] .
| Body Weight (kg) | EDURANT 25 mg Tablets | EDURANT PED 2.5 mg Tablets for Oral Suspension | Total Daily Dose |
|---|---|---|---|
| 14 kg to less than 20 kg | Not recommended | 5 tablets once daily | 12.5 mg EDURANT PED once daily |
| 20 kg to less than 25 kg | Not recommended | 6 tablets once daily | 15 mg EDURANT PED once daily |
| Greater than or equal to 25 kg | 1 tablet once daily | Not recommended | 25 mg EDURANT once daily |
Preparation and Administration Instructions for EDURANT PED Only
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:
- Place the tablets for oral suspension in a cup, add 5 mL (1 teaspoon) of drinking water at room temperature. Do not crush the tablets.
- Swirl the cup carefully for 1–2 minutes to disperse the tablets. The oral suspension will start to look cloudy.
- Take all the prepared oral suspension immediately or to aid in administration, the oral suspension can be further diluted with 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce. Swirl and take all the medicine immediately. A spoon can be used if needed.
- Make sure the entire dose is taken and no medicine is left in the cup. If required, add another 5 mL (1 teaspoon) of drinking water (or alternative beverage or soft food), swirl and drink immediately.
Recommended Dosage During Pregnancy
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)] .
Recommended Dosage in Combination with Cabotegravir in Adults and Adolescents 12 Years of Age and Older and Weighing at least 35 kg
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.
Recommended Dosage with Rifabutin Coadministration
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.
Pregnancy
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.
Lactation
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.
Pediatric Use
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.
- Cohort 1 evaluated the safety, efficacy and pharmacokinetics of EDURANT and enrolled 36 children aged 12 to less than 18 years of age and weighing at least 32 kg [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)] .
- Cohort 2 evaluated the safety, tolerability, antiviral activity and pharmacokinetics of EDURANT and EDURANT PED weight-adjusted doses 25, 15 and 12.5 mg daily, and enrolled 18 children aged 6 to less than 12 years of age and weighing at least 17 kg [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.4)] .
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)] .
Geriatric Use
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.
Renal Impairment
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)] .
Hepatic Impairment
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)] .
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)] .
| Drug Class | Contraindicated Drugs in Class | Clinical Comment |
|---|---|---|
| Anticonvulsants | Carbamazepine Oxcarbazepine Phenobarbital Phenytoin | Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response. |
| Antimycobacterials | Rifampin Rifapentine | |
| Glucocorticoid (systemic) | Dexamethasone (more than a single-dose treatment) | |
| Herbal Products | St. John's wort ( Hypericum perforatum) | |
| Proton Pump Inhibitors | e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole | Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response. |
Skin and Hypersensitivity Reactions
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.
Hepatotoxicity
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.
Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with 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.
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
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)] :
- Loss of therapeutic effect of EDURANT or EDURANT PED and possible development of resistance.
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
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.
Different Formulations Are Not Substitutable
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.