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  • CLASSES

    Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)s

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, non-nucleoside reverse transcriptase inhibitor (NNRTI)
    Used in combination with other antiretrovirals for treatment of HIV-1 infection in antiretroviral treatment-naive patients 12 years and older and weighing at least 35 kg with HIV-1 RNA of 100,000 copies/mL or less at initiation of therapy; also used in combination with cabotegravir for adults who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and no known or suspected resistance to rilpivirine or cabotegravir
    Virologic failures more common if baseline HIV-1 RNA concentrations are more than 100,000 copies/mL

    COMMON BRAND NAMES

    EDURANT

    HOW SUPPLIED

    EDURANT Oral Tab: 25mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.
    For the treatment of HIV infection in antiretroviral treatment-naive patients with HIV-1 RNA concentrations less than or equal to 100,000 copies/mL at treatment initiation.
    Oral dosage
    Adults weighing 35 kg or more

    25 mg PO once daily with a meal. For patients receiving concurrent rifabutin, increase rilpivirine to 50 mg PO once daily with a meal. When rifabutin coadministration is stopped, reduce dose to 25 mg PO once daily with a meal.

    Children and Adolescents 12 to 17 years weighing 35 kg or more

    25 mg PO once daily with a meal. For patients receiving concurrent rifabutin, increase rilpivirine to 50 mg PO once daily with a meal. When rifabutin coadministration is stopped, reduce dose to 25 mg PO once daily with a meal.

    For the treatment of HIV infection in combination with cabotegravir in patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and no known or suspected resistance to rilpivirine or cabotegravir.
    Oral dosage
    Adults receiving oral lead-in dosing to assess tolerability of rilpivirine prior to administration of cabotegravir; rilpivirine extended-release injection

    25 mg in combination with 30 mg of cabotegravir PO once daily starting at least 28 days prior to administering cabotegravir; rilpivirine extended-release injection. Administer the rilpivirine and cabotegravir tablets at approximately the same time each day with a meal. The last oral dose should be taken on the same day the extended-release injections are started.

    Adults who will miss planned dosing with cabotegravir; rilpivirine extended-release injection

    25 mg in combination with 30 mg of cabotegravir PO once daily starting approximately 1 month after the last cabotegravir; rilpivirine extended-release injection was given. Administer the rilpivirine and cabotegravir tablets at approximately the same time each day with a meal. Continue the oral dose until the day the extended-release injections are restarted. The daily oral therapy may be given if a patient plans to miss a scheduled injection by more than 7 days. The daily oral therapy may be used to replace up to 2 consecutive monthly injections.

    For human immunodeficiency virus (HIV) prophylaxis† after occupational exposure to HIV.
    Oral dosage
    Adults

    The US Public Health Service guidelines suggest rilpivirine 25 mg PO once daily in combination with one of the following combinations (in order of preference) as acceptable alternative regimens for HIV post-exposure prophylaxis (PEP): tenofovir plus emtricitabine; tenofovir plus lamivudine; zidovudine plus lamivudine; zidovudine plus emtricitabine. However, according to the World Health Organization (WHO) and the New York State Department of Health AIDS Institute (NYSDOH AI), data on use of rilpivirine containing regimens for PEP are lacking. The WHO and NYSDOH AI recommend use of rilpivirine only after consultation with a clinician experienced in the management of PEP. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    25 mg/day PO; 50 mg/day PO when administered with rifabutin.

    Geriatric

    25 mg/day PO; 50 mg/day PO when administered with rifabutin.

    Adolescents

    weight 35 kg or more: 25 mg/day PO; 50 mg/day PO when administered with rifabutin.
    weight less than 35 kg: Safety and efficacy have not been established.

    Children

    12 years and weight 35 kg or more: 25 mg/day PO; 50 mg/day PO when administered with rifabutin.
    1 to 11 years or weight less than 35 kg: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage adjustments are not required for mild to moderate hepatic impairment (Child-Pugh Class A and B); rilpivirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

    Renal Impairment

    Dosage adjustments are not required for mild to moderate renal impairment. Use with caution in patients with severe renal impairment or end-stage renal disease and monitor carefully for adverse effects.

    ADMINISTRATION

     
    NOTE: Must be administered in combination with other antiretroviral medications; never administer as monotherapy.

    Oral Administration

    Administer orally with a meal.

    STORAGE

    EDURANT:
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend rilpivirine-containing regimens as alternative treatment options for use during pregnancy. However, because pharmacokinetic data show decreased rilpivirine exposures during the second and third trimesters, close monitoring of viral loads is recommended during pregnancy (i.e., every 1 to 2 months). Available data from the Antiretroviral Pregnancy Registry, which includes 495 first trimester exposures to rilpivirine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When rilpivirine exposure occurred in the first trimester, the prevalence of defects was 1.4% (95% CI: 0.6 to 2.9). Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations more than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for the development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to rilpivirine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[23512] [44376]

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

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

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

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

    Depression, suicidal ideation

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

    Children, infants, neonates

    The safety and efficacy of rilpivirine have not been established in neonates, infants, or children younger than 12 years of age or those weighing less than 35 kg.

    Breast-feeding

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including rilpivirine. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] There are limited data regarding the use of rilpivirine during breast-feeding and excretion into human breast milk is unknown. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

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

    Human immunodeficiency virus (HIV) infection resistance

    Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, antimicrobial resistance can develop when rilpivirine is used either alone or in combination with other agents. Monotherapy is not recommended. Cross-resistance between rilpivirine and other non-nucleoside reverse transcriptase inhibitors has been observed.

    Hepatic disease, hepatitis B and HIV coinfection, hepatitis C and HIV coinfection

    Hepatotoxicity has occurred in adult patients treated with rilpivirine. Individuals at increased risk for developing hepatic dysfunction include those with hepatitis and HIV coinfection or other preexisting hepatic disease. In these patients, appropriate laboratory monitoring is recommended prior to and during treatment. Liver function monitoring should also be considered for patients with no preexisting hepatic disease, as a few cases of hepatotoxicity have been reported in rilpivirine-treated patients with no identifiable risk factors for hepatic disease.[44376] HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweigh the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral-naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Patients presenting with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive ARV regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide with emtricitabine or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct hepatitis and HIV coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.[46638] [34362]

    Serious rash

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

    ADVERSE REACTIONS

    Severe

    depression / Delayed / 1.0-5.6
    suicidal ideation / Delayed / 0.6-2.8
    cholecystitis / Delayed / 0-2.0
    glomerulonephritis / Delayed / 0-2.0
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 0-17.0
    dysphoria / Early / 9.0-9.0
    elevated hepatic enzymes / Delayed / 0-5.0
    cholelithiasis / Delayed / 0-2.0
    nephrolithiasis / Delayed / 0-2.0
    hypertriglyceridemia / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 1.0-1.0
    adrenocortical insufficiency / Delayed / Incidence not known
    lipodystrophy / Delayed / Incidence not known

    Mild

    headache / Early / 3.0-19.4
    drowsiness / Early / 0-13.9
    nausea / Early / 1.0-11.1
    abdominal pain / Early / 2.0-8.3
    dizziness / Early / 1.0-8.3
    vomiting / Early / 1.0-5.6
    rash / Early / 3.0-5.6
    insomnia / Early / 3.0-3.0
    anxiety / Delayed / 0-2.0
    diarrhea / Early / 0-2.0
    fatigue / Early / 2.0-2.0
    abnormal dreams / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    Cushingoid features / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as abarelix. In addition to avoiding drug interactions, the potential for Torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Aclidinium; Formoterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Adefovir: (Major) Patients who are concurrently taking adefovir (a nucleotide analog) with antiretrovirals (i.e., anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir 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).
    Albuterol: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aldesleukin, IL-2: (Moderate) Close clinical monitoring is advised when administering aldesleukin, IL-2 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Aldesleukin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Alfuzosin: (Moderate) Caution is advised when administering rilpivirine with alfuzosin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation and alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) The concomitant use of amiodarone and rilpivirine should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with rilpivirine. Amisulpride causes dose- and concentration- dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Amitriptyline: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Amoxicillin; Clarithromycin; Lansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
    Antacids: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Apalutamide: (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with rilpivirine since concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if rilpivirine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in rilpivirine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rilpivirine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of rilpivirine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Caution is advised when administering rilpivirine with aripiprazole as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Armodafinil: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, rilpivirine should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Artemether; Lumefantrine: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as asenapine.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Aspirin, ASA; Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Atazanavir: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Atazanavir; Cobicistat: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
    Atomoxetine: (Moderate) Caution is advised when administering rilpivirine with atomoxetine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation has also occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Azithromycin: (Major) Avoid coadministration of azithromycin with rilpivirine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Bepridil: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as bepridil. In addition to avoiding drug interactions, the potential for Torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP.
    Berotralstat: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
    Bexarotene: (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
    Boceprevir: (Moderate) Although dose adjustments are not recommended, close clinical monitoring is advised when administering boceprevir with rilpivirine due to an increased potential for rilpivirine-related adverse events. When these drugs are administered concurrently, the Cmax and AUC of rilpivirine are significantly increased. Predictions about the interaction can be made based on metabolic pathways of boceprevir and rilpivirine. Boceprevir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Bosentan: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Budesonide; Formoterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as rilpivirine, Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may further increase the risk of QT prolongation and TdP.
    Buprenorphine; Naloxone: (Major) Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as rilpivirine, Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may further increase the risk of QT prolongation and TdP.
    Butabarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Butalbital; Acetaminophen: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Calcium Carbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Calcium Carbonate; Risedronate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Calcium Carbonate; Simethicone: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Carbamazepine: (Contraindicated) Coadministration of carbamazepine and rilpivirine is contraindicated due to the potential for loss of virologic response and possible resistance to rilpivirine or the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rilpivirine is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer.
    Cenobamate: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Ceritinib: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold.
    Chloramphenicol: (Moderate) Close clinical monitoring is advised when administering chloramphenicol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Chloroquine: (Major) Avoid coadministration of chloroquine with rilpivirine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Chlorpromazine: (Major) Concurrent use of chlorpromazine and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Phenothiazines have also been associated with QT prolongation and/or TdP. This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
    Cimetidine: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Ciprofloxacin: (Moderate) Caution is advised when administering rilpivirine with ciprofloxacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Because of the potential for torsades de pointes, use of cisapride with rilpivirine is contraindicated.
    Citalopram: (Major) Concurrent use of citalopram and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If concurrent therapy is considered essential, ECG monitoring is recommended. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Citalopram also causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
    Class IA Antiarrhythmics: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with rilpivirine. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Clomipramine: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Conivaptan: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Crizotinib: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
    Dabrafenib: (Major) The concomitant use of dabrafenib and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Dabrafenib is a moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
    Danazol: (Moderate) Close clinical monitoring is advised when administering danazol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Darunavir: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Darunavir; Cobicistat: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
    Dasatinib: (Moderate) Caution is advised when administering rilpivirine with dasatinib as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Delavirdine: (Major) Coadministration of delavirdine and rilpivirine is not recommended. If they are coadministered, close clinical monitoring is advised due to the increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Delavirdine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Desipramine: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Moderate) Caution is advised when administering rilpivirine with deutetrabenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dexamethasone: (Contraindicated) Concurrent use of dexamethasone (more than 1 dose) and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Dexamethasone is an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Dexlansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Dextromethorphan; Quinidine: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Didanosine, ddI: (Moderate) While no dosage adjustments are required, because didanosine, ddI is administered on an empty stomach and rilpivirine is given with food, do not give didanosine within at least two hours before or at least four hours after rilpivirine.
    Diltiazem: (Moderate) Close clinical monitoring is advised when administering diltiazem with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Diltiazem is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Disopyramide: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Dofetilide: (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Donepezil: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Doxepin: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Efavirenz: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Elagolix: (Major) The concomitant use of elagolix and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Elagolix is a weak to moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
    Elagolix; Estradiol; Norethindrone acetate: (Major) The concomitant use of elagolix and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Elagolix is a weak to moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
    Eliglustat: (Moderate) Caution is advised when administering rilpivirine with eliglustat as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
    Encorafenib: (Major) Avoid coadministration of encorafenib and rilpivirine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Enflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Entrectinib: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Enzalutamide: (Contraindicated) Concurrent use of enzalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Enzalutamide is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Eribulin: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as erythromycin.
    Erythromycin; Sulfisoxazole: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as erythromycin.
    Escitalopram: (Moderate) Use escitalopram with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Eslicarbazepine: (Contraindicated) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
    Esomeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Esomeprazole; Naproxen: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Etravirine: (Major) Coadministration of etravirine and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Etravirine is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Ezogabine: (Moderate) Caution is advised when administering rilpivirine with ezogabine as concurrent use may increase the risk of QT prolongation. Ezogabine has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Famotidine: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Famotidine; Ibuprofen: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Fedratinib: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with flecinide. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
    Fluoxetine: (Moderate) Use fluoxetine and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Fluphenazine: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Flutamide: (Moderate) Close clinical monitoring is advised when administering flutamide with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Flutamide is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Fluticasone; Salmeterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
    Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Fosamprenavir: (Moderate) Close clinical monitoring is advised when administering fosamprenavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on the metabolic pathways of fosamprenavir and rilpivirine. Fosamprenavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as rilpivirine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Fostemsavir: (Moderate) Caution is advised when administering rilpivirine with fostemsavir due to the potential for QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Caution is advised when administering rilpivirine with gemifloxacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and rilpivirine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Glycopyrrolate; Formoterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use granisetron with caution in combination with rilpivirine due to the risk of QT prolongation. Granisetron has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Grapefruit juice: (Moderate) Close clinical monitoring is advised when administering grapefruit juice with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Grapefruit juice is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Halofantrine: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as halofantrine. In addition to avoiding drug interactions, the potential for Torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Haloperidol: (Moderate) Caution is advised when administering rilpivirine with haloperidol as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of rilpivirine and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with rilpivirine, a CYP3A substrate, as rilpivirine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Imatinib: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Imatinib is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Imipramine: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Indinavir: (Moderate) Close clinical monitoring is advised when administering indinavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Indinavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Interferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfa-2b; Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfacon-1: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Ipratropium; Albuterol: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with rilpivirine may result in increased serum concentrations of rilpivirine. Rilpivirine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Isoniazid, INH; Rifampin: (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Itraconazole: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with itraconazole.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine. Both rilpivirine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with rilpivirine (a CYP3A4 substrate) results in elevated rilpivirine plasma concentrations. Conversely, ketoconazole concentrations are decreased when administered with rilpivirine. If these drugs must be administered together, closely monitor for rilpivirine-related adverse events and the potential for breakthrough fungal infections. Rilpivirine dosage adjustments are not recommended.
    Lansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Lansoprazole; Naproxen: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Lefamulin: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of rilpivirine; monitor for potential reduction in efficacy. Rilpivirine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of rilpivirine; monitor for potential reduction in efficacy. Rilpivirine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Levalbuterol: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Moderate) Caution is advised when administering rilpivirine with levofloxacin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levomethadyl: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as levomethadyl. In addition to avoiding drug interactions, the potential for Torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP.
    Lithium: (Moderate) Caution is advised when administering rilpivirine with lithium as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Lonafarnib: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
    Long-acting beta-agonists: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Caution is advised when administering rilpivirine with loperamide as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Caution is advised when administering rilpivirine with loperamide as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with rilpivirine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Lorlatinib: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer.
    Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as rilpivirine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Maprotiline: (Moderate) Caution is advised when administering rilpivirine with maprotiline as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Meperidine; Promethazine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Mephobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Mesoridazine: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as mesoridazine. In addition to avoiding drug interactions, the potential for Torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP.
    Metaproterenol: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Close clinical monitoring is advised with coadministration. Use of these drugs together may cause the plasma concentration of methadone to decrease, thereby resulting in decreased methadone efficacy. No dose adjustments are required when initiating concurrent treatment; however, the maintenance dose of methadone may need to be adjusted in some patients. In addition, due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with methadone. A careful assessment of treatment risks versus benefits should be conducted prior to coadministration. When initiating concurrent treatment no dose adjustments are required; however, the dose of methadone may need to be adjusted during maintenance therapy. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
    Methohexital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Metronidazole: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
    Midostaurin: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Mifepristone: (Major) Avoid use together if possible due to the risk of elevated rilpivirine exposure and a combined risk for QT prolongation. Consider alternatives to rilpivirine when coadministered with a drug with a known risk of QT prolongation and torsade de pointes (TdP), such as mifepristone when it is used for chronic hormonal conditions, such as Cushing's syndrome. Mifepristone is an inhibitor of CYP3A4; rilpivirine is a CYP3A4 substrate. Coadministration is likely to increase rilpivirine plasma concentrations. Monitor for rilpivirine-related side effects, including rash, mood changes or depression, fast, irregular heart rate, and hepatotoxicity. To minimize the risk of QT prolongation, the lowest effect dose of mifepristone should always be used.
    Mirtazapine: (Moderate) Caution is advised when administering rilpivirine with mirtazapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Modafinil: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Moxifloxacin: (Major) Concurrent use of rilpivirine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nafcillin: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Nefazodone: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Nelfinavir: (Moderate) Close clinical monitoring is advised when administering nelfinavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Nelfinavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Nevirapine: (Major) Coadministration of nevirapine and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Nevirapine is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Nicardipine: (Moderate) Close clinical monitoring is advised when administering nicardipine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nicardipine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Nizatidine: (Moderate) Coadministration with nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with norfloxacin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Moderate) Use octreotide with caution in combination with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Caution is advised when administering rilpivirine with ofloxacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olanzapine; Fluoxetine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Use fluoxetine and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Olodaterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance.
    Omeprazole; Sodium Bicarbonate: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Ondansetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and rilpivirine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Oritavancin: (Major) Rilpivirine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of rilpivirine may be reduced if these drugs are administered concurrently.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with rilpivirine as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Osimertinib: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Supratherapeutic doses of rilpivirine (75 to 300 mg per day) have caused QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxcarbazepine: (Contraindicated) Concurrent use of oxcarbazepine and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Oxcarbazepine is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking rilpivirine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
    Pantoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Pasireotide: (Moderate) Use caution when using pasireotide in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Pazopanib: (Major) Concurrent use of pazopanib and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be continued, closely monitor the patient for QT interval prolongation. Pazopanib has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and rilpivirine, a CYP3A4 substrate, may cause an increase in systemic concentrations of rilpivirine.
    Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Pentamidine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with pentamidine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Pentamidine has also been associated with QT prolongation.
    Pentobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Perphenazine: (Minor) Caution is advised when administering rilpivirine with perphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Caution is advised when administering rilpivirine with perphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Pexidartinib: (Moderate) Coadministration of rilpivirine with pexidartinib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer.
    Phenobarbital: (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Phentermine; Topiramate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Phenytoin: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP) and coadministration with other drugs associated with a possible risk for QT prolongation and TdP, such as rilpivirine, should be avoided.
    Pirbuterol: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking rilpivirine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Posaconazole: (Contraindicated) Concurrent use of posaconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of ripivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for rilpivirine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
    Primaquine: (Moderate) Exercise caution when administering primaquine in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Primidone: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Procainamide: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Prochlorperazine: (Minor) Caution is advised when administering rilpivirine with prochlorperazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Promethazine; Dextromethorphan: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Promethazine; Phenylephrine: (Moderate) Caution is advised when administering rilpivirine with promethazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with propafenone. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval.
    Proton pump inhibitors: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Protriptyline: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Concurrent use of quetiapine and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Quinine: (Major) Concurrent use of quinine and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. In addition, concentrations of rilpivirine may be increased with concomitant use of quinine. Rilpivirine is a CYP3A4 substrate and quinine is a CYP3A4 inhibitor.
    Rabeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Ranitidine: (Moderate) Coadministration with ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Ranolazine: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
    Relugolix: (Moderate) Caution is advised when administering rilpivirine with relugolix. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is advised when administering rilpivirine with relugolix. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Ribociclib: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rifabutin: (Major) Administration of rifabutin with rilpivirine may significantly decrease rilpivirine plasma concentrations; therefore, if these drugs are given concurrently, an additional dose of rilpivirine (25 mg PO once daily) is required and the drugs should be administered with a meal. Rifabutin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Use of these drugs together may result in HIV treatment failure or the development of rilpivirine or NNRTI resistance.
    Rifampin: (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Rifapentine: (Contraindicated) Concurrent use of rifapentine and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifapentine is a strong CYP3A4 inducer, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Risperidone: (Moderate) Use risperidone and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Salmeterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Saquinavir: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
    Secobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with rilpivirine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering rilpivirine with sertraline. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Short-acting beta-agonists: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Sodium Bicarbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Solifenacin: (Moderate) Caution is advised when administering rilpivirine with solifenacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Solifenacin has also been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
    Sorafenib: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Sotalol: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Sotorasib: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
    St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Sunitinib can prolong the QT interval.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Tamoxifen: (Moderate) Use caution if coadministration of rilpivirine with tamoxifen is necessary due to the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Telavancin: (Moderate) Caution is advised when administering rilpivirine with telavancin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) When possible, alternative antibiotics to telithromycin should be considered in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation and rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate that has caused QT prolongation in supratherapeutic doses (75 to 300 mg/day). Telithromycin is a strong CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP).
    Terbutaline: (Minor) Caution is advised when administering rilpivirine with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer of tetrabenazine recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as rilpivirine.
    Thiopental: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and TdP. Thioridazine is considered contraindicated for use along with rilpivirine which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
    Ticagrelor: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
    Tiotropium; Olodaterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Tipranavir: (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Tolterodine: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Topiramate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Toremifene: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Trandolapril; Verapamil: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Trazodone: (Major) Avoid coadministration of trazodone and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with rilpivirine as concurrent use may increase the risk of QT prolongation. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Tricyclic antidepressants: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Caution is advised when administering rilpivirine with trifluoperazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trifluoperazine is also associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimipramine: (Minor) Caution is advised when administering rilpivirine with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Tucatinib: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Umeclidinium; Vilanterol: (Moderate) Caution is advised when administering rilpivirine with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as arformoterol, as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with rilpivirine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Vardenafil: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Vemurafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
    Venlafaxine: (Moderate) Caution is advised when administering rilpivirine with venlafaxine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Verapamil: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Voclosporin: (Moderate) Concomitant use of voclosporin and rilpivirine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Both voclosporin and rilpivirine have been associated with QT prolongation at supratherapeutic doses.
    Voriconazole: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole.
    Vorinostat: (Moderate) Caution is advised when administering rilpivirine with vorinostat. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Vorinostat therapy is also associated with a risk of QT prolongation.
    Zafirlukast: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Ziprasidone: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.

    PREGNANCY AND LACTATION

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend rilpivirine-containing regimens as alternative treatment options for use during pregnancy. However, because pharmacokinetic data show decreased rilpivirine exposures during the second and third trimesters, close monitoring of viral loads is recommended during pregnancy (i.e., every 1 to 2 months). Available data from the Antiretroviral Pregnancy Registry, which includes 495 first trimester exposures to rilpivirine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When rilpivirine exposure occurred in the first trimester, the prevalence of defects was 1.4% (95% CI: 0.6 to 2.9). Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations more than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for the development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to rilpivirine; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[23512] [44376]

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including rilpivirine. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] There are limited data regarding the use of rilpivirine during breast-feeding and excretion into human breast milk is unknown. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    MECHANISM OF ACTION

    Rilpivirine inhibits HIV-1 reverse transcriptase. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), it does not compete for binding nor does it require phosphorylation to be active. Rilpivirine binds directly to a site on reverse transcriptase that is distinct from where NRTIs bind. This binding causes disruption of the enzyme's active site thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. The 50% maximal inhibitory concentrations (EC50) for wild type laboratory-adapted strains of HIV-1 is 0.73 nanomolar. It has very limited activity against HIV-2 reverse transcriptase with an EC50 ranging from 2,510 to 10,830 nanomolar. Human cellular DNA polymerase alpha, beta, and gamma are not inhibited by rilpivirine.
     
    During clinical use, treatment-emergent genotypic and phenotypic resistance occurred more frequently in patients receiving rilpivirine (41%) than in patients treated with efavirenz (25%). Resistance to background antiretrovirals (emtricitabine, lamivudine, tenofovir, abacavir, or zidovudine) developed in 48% of rilpivirine virologic failures compared to 15% in the efavirenz arm. Cross-resistance to efavirenz, etravirine, and nevirapine is likely after virologic failure and development of rilpivirine resistance.
     
    Avoid the use of rilpivirine in patients with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The 2014 Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.

    PHARMACOKINETICS

    Rilpivirine is administered orally. Following systemic absorption, it is highly protein bound (99.7%), predominantly to albumin. It is unknown if there is distribution into compartments other than plasma, such as cerebrospinal fluid or gastrointestinal tract secretions. Metabolism occurs primarily via oxidation by the hepatic cytochrome (CYP) P450 3A system. Of note, rilpivirine is neither an inducer nor an inhibitor of CYP450 isoenzymes. The terminal elimination half-life is approximately 50 hours with excretion occurring predominately through the feces. Following administration of a single oral dose, an average of 85% is eliminated via the feces and 6.1% is excreted in the urine. Metabolites account for the majority of the excretion with only 25% of an administered dose excreted as unchanged rilpivirine (25% in feces, < 1% in urine).
     
    Affected cytochrome P450 isoenzymes: CYP3A
    Rilpivirine is primarily metabolized via oxidation by the hepatic cytochrome (CYP) P450 3A system.

    Oral Route

    The absolute oral bioavailability of rilpivirine is unknown; however, the time to reach maximum plasma concentrations (Tmax) is approximately 4—5 hours. Compared to fasting conditions, exposure (AUC) is increased by 40% when administered with a normal caloric (533 kcal) or high fat, high caloric meal (928 kcal). Administering with only a protein-rich nutritional drink decreases exposure by 50% when compared with fed conditions.