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  • CLASSES

    Combination HIV Antivirals

    BOXED WARNING

    Hepatitis, hepatitis B and HIV coinfection, hepatitis B exacerbation, hepatitis C and HIV coinfection

    Emtricitabine; rilpivirine; tenofovir alafenamide is not indicated for the treatment of hepatitis infections. Individuals who are coinfected with HIV and hepatitis B or C may be at increased risk for treatment-associated hepatotoxicities. 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 outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in 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 who present 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). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of emtricitabine; tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with 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 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. Patients with coexisting HBV and HIV infections who discontinue emtricitabine or tenofovir may experience severe acute hepatitis B exacerbation with some cases resulting in hepatic decompensation and hepatic failure. Therefore, patients coinfected with HBV and HIV who discontinue emtricitabine; rilpivirine; tenofovir should have transaminase concentrations monitored every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. If appropriate, resumption of anti-hepatitis B treatment may be required. 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.

    DEA CLASS

    Rx

    DESCRIPTION

    Combination of 2 NRTIs and 1 NNRTI
    Indicated as a complete regimen for treatment of HIV-1 infections in antiretroviral-naive patients 12 years and older (weighing at least 35 kg) with baseline HIV RNA of 100,000 copies/mL or less, and certain virologically-stable (HIV RNA < 50 copies/mL) patients without history of treatment failure or resistance
    Administered as a single tablet once daily with a meal

    COMMON BRAND NAMES

    ODEFSEY

    HOW SUPPLIED

    ODEFSEY Oral Tab: 200-25-25mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-naive patients with HIV-1 RNA concentrations 100,000 copies/mL or less at treatment initiation and certain virologically-stable (HIV-1 RNA less than 50 copies/mL) treatment-experienced patients.
    NOTE: Prior to initiating therapy, health care providers are advised to consider the following findings from rilpivirine clinical trials: virologic failures occurred more frequently in patients with baseline HIV-1 RNA concentrations more than 100,000 copies/mL than in patients with concentrations 100,000 copies/mL or less; patients with CD4 counts less than 200 cells/mm3 experienced more virologic failures than those with counts 200 cells/mm3 or more (regardless of HIV-1 RNA concentrations); virologic failures associated with resistance and cross-resistance to the NNRTI class occurred more frequently in rilpivirine-treated patients than efavirenz-treated patients; a higher rate of tenofovir and lamivudine/emtricitabine resistance developed in rilpivirine-treated patients than in efavirenz-treated patients.
    NOTE: Treatment-experienced patients should meet the following criteria: have displayed consistent viral suppression (HIV-1 RNA less than 50 copies/mL) for at least 6 months prior to switching; no history of virologic failure; no current or past history of resistance to emtricitabine, rilpivirine, or tenofovir. To assess potential virologic failure or rebound, additional HIV-1 RNA monitoring is recommended for these patients.
    NOTE: Not indicated for the treatment of chronic hepatitis B virus (HBV) infection; safety and efficacy have not been established in patients with HBV and HIV coinfection.
    Oral dosage
    Adults, Adolescents, and Children 12 years and older weighing 35 kg or more

    One tablet (200 mg emtricitabine; 25 mg rilpivirine; 25 mg tenofovir alafenamide) PO once daily with a meal. Emtricitabine; rilpivirine; tenofovir alafenamide is a complete regimen and should not be administered with other antiretroviral medications.

    MAXIMUM DOSAGE

    Adults

    1 tablet/day PO (200 mg emtricitabine; 25 mg rilpivirine; 25 mg tenofovir alafenamide).

    Geriatric

    1 tablet/day PO (200 mg emtricitabine; 25 mg rilpivirine; 25 mg tenofovir alafenamide).

    Adolescents

    weighing 35 kg or more: 1 tablet/day PO (200 mg emtricitabine; 25 mg rilpivirine; 25 mg tenofovir alafenamide).
    weighing less than 35 kg: Safety and efficacy have not been established.

    Children

    12 years and older weighing 35 kg or more: 1 tablet/day PO (200 mg emtricitabine; 25 mg rilpivirine; 25 mg tenofovir alafenamide).
    1 to 11 years or weighing 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); safety and efficacy of this fixed-dose combination treatment have not been established in patients with severe hepatic impairment (Child-Pugh Class C).

    Renal Impairment

    CrCl >= 30 mL/min: No dosage adjustment is needed.
    CrCl < 30 mL/min: Not recommended.

    ADMINISTRATION

     
    NOTE: Emtricitabine; rilpivirine; tenofovir alafenamide is a complete HIV treatment regimen. Do not administer with other antiretroviral medications.

    Oral Administration

    Administer with a meal.

    STORAGE

    ODEFSEY:
    - Store and dispense in original container
    - Store below 86 degrees F

    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 or 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 specific drugs 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.

    Alcoholism, females, hepatic disease, hepatomegaly, hepatotoxicity or lactic acidosis, obesity

    Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported following use of emtricitabine and tenofovir disoproxil fumarate (another prodrug of tenofovir), both alone and in combination with other antiretroviral medications. Treatment with emtricitabine; rilpivirine; tenofovir alafenamide should be suspended in any patient who develops clinical or laboratory findings suggestive of hepatotoxicity or lactic acidosis, which may include hepatomegaly and steatosis even in the absence of marked elevated hepatic enzymes. Although these adverse events may occur in any drug recipient, some risk factors include hepatic disease (e.g., alcoholism), obesity, and prolonged nucleoside exposure. In addition, a majority of these cases have been in females; it is unknown if being pregnant augments the incidence of this syndrome in patients receiving nucleoside analogs. However, because being pregnant itself can mimic some of the early symptoms of the lactic acid and hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly.

    Hepatitis, hepatitis B and HIV coinfection, hepatitis B exacerbation, hepatitis C and HIV coinfection

    Emtricitabine; rilpivirine; tenofovir alafenamide is not indicated for the treatment of hepatitis infections. Individuals who are coinfected with HIV and hepatitis B or C may be at increased risk for treatment-associated hepatotoxicities. 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 outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in 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 who present 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). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of emtricitabine; tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with 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 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. Patients with coexisting HBV and HIV infections who discontinue emtricitabine or tenofovir may experience severe acute hepatitis B exacerbation with some cases resulting in hepatic decompensation and hepatic failure. Therefore, patients coinfected with HBV and HIV who discontinue emtricitabine; rilpivirine; tenofovir should have transaminase concentrations monitored every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. If appropriate, resumption of anti-hepatitis B treatment may be required. 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.

    Depression, suicidal ideation

    Emtricitabine; rilpivirine; tenofovir alafenamide therapy may be associated with mood or behavior changes. Patients receiving treatment with rilpivirine have experienced adverse reactions affecting the central nervous system (CNS), including depressed mood, depression, dysphoria, negative thoughts, suicidal ideation, and suicide attempts. The majority of these psychiatric adverse events were mild to moderate in severity, with only 1% of patients requiring treatment discontinuation. Prior to initiating emtricitabine; rilpivirine; tenofovir alafenamide therapy, inform patients of the potential for psychiatric adverse events. Additionally, instruct patients to seek immediate medical evaluation if severe depressive symptoms, or other unusual moods or behaviors, develop during therapy.

    Renal failure, renal impairment

    Both emtricitabine and tenofovir are eliminated via the kidney; therefore use of emtricitabine; rilpivirine; tenofovir alafenamide in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended. In addition, tenofovir prodrugs (i.e., tenofovir disoproxil fumarate, tenofovir alafenamide) have been associated with the development of renal toxicity. Cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) have been reported with the use of tenofovir disoproxil fumarate; however no cases of Fanconi syndrome or proximal renal tubulopathy have been observed in patients receiving tenofovir alafenamide. During clinical trials, 1 to 3% of tenofovir alafenamide recipients required treatment discontinuation due to worsening renal function or renal adverse events; the majority of these discontinuations occurred in patients with a baseline estimated glomerular filtration rates between 30 and 50 mL/min. The manufacturer recommends that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed in all patients prior to treatment, and as indicated during treatment. In addition, closely evaluate the renal function of patients who experience persistent or worsening bone pain, pain in extremities, bone fractures, or muscle pain and weakness during treatment as these may be manifestations of proximal renal tubulopathy. Avoid concurrent use with or recently after a nephrotoxic agent, including high-dose or multiple non-steroidal antiinflammatory drugs (NSAIDS), as cases of acute renal failure requiring hospitalization and renal replacement therapy have been reported.

    Osteomalacia, osteoporosis

    During clinical trials, significant reductions in bone mineral density (BMD) were observed in up to 10% of treatment-naive adults receiving tenofovir alafenamide containing regimens. However, treatment-experienced patients who were switched from a tenofovir disoproxil fumarate regimen to a tenofovir alafenamide regimen experienced increased BMD at the lumbar spine (1.61% to 1.65%) and total hip (1.04% to 1.28%). The BMD for those patients continuing on a tenofovir disoproxil fumarate regimen remained stable or slightly decreased (-0.05% to 0.08% lumbar spine; -0.13% to -0.25% total hip). The clinical significance of the change in BMD and biochemical markers are unknown. Consideration may be given to monitoring BMD in drug recipients who have a history of pathologic bone fracture or are at substantial risk for osteopenia or osteoporosis. Close monitoring is also recommended for patients experiencing bone pain or pain in the extremities, as these may be signs of osteomalacia. While not reported during tenofovir alafenamide clinical trials, cases of osteomalacia secondary to proximal renal tubulopathy have been reported with the tenofovir disoproxil fumarate. If bone abnormalities are suspected, appropriate consultation should be obtained. In addition, consider supplementation with calcium and vitamin D for all patients.

    Serious rash

    Patients receiving emtricitabine; rilpivirine; tenofovir alafenamide 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 post-marketing use of rilpivirine containing regimens. 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 containing regimens 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.

    QT prolongation, torsade de pointes

    Supratherapeutic doses of rilpivirine (75 to 300 mg/day) administered to healthy subjects has resulted in prolongation of the QT interval. Healthcare providers are advised to use caution when co-administering emtricitabine; rilpivirine; tenofovir alafenamide with medications that have the potential to cause QT prolongation and torsade de pointes, or those that have the potential to reduce the elimination of rilpivirine.

    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 emtricitabine; rilpivirine; tenofovir alafenamide 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, 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 have become increasingly recognized side effects of antiretroviral agents. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during antiretroviral treatment, possible interventions include dietary modification, use of lipid lowering agents, or modification of treatment regimen. Monitoring of serum cholesterol and triglycerides is recommended during emtricitabine; rilpivirine; tenofovir alafenamide therapy.

    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 antimicrobial 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 the US and Europe, studies suggest that 6 to 16% of transmitted virus will be resistant to at least one antiretroviral drug, with 3 to 5% exhibiting reduced susceptibility to more than one class of drugs; 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. Resistance to the rilpivirine component of emtricitabine; rilpivirine; tenofovir alafenamide has been associated with virologic failure. In clinical studies, 44% of rilpivirine virologic failures had genotypic and phenotypic resistance to rilpivirine. Patients who develop rilpivirine resistance and experience treatment failure often have cross-resistance to other non-nucleoside reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine). Cross-resistance has not been demonstrated between rilpivirine and emtricitabine or tenofovir.

    Children, infants, neonates

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

    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 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. No well-controlled studies have been conducted to evaluate the risks of administering emtricitabine; rilpivirine; tenofovir alafenamide to pregnant females. Data involving first trimester exposures to tenofovir alafenamide are insufficient to draw conclusions regarding the potential for birth defects. Available data from the Antiretroviral Pregnancy Registry, which includes in utero exposures to emtricitabine (2,326 first trimester; 1,080 second and third trimesters) and rilpivirine (202 first trimester; 124 second and third trimesters), 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. For emtricitabine, when exposure occurred in the first trimester the prevalence of defects was 2.3% (95% CI: 1.7, 3.0). The prevalence of defects following first trimester exposure to rilpivirine was 0.5% (95% CI: 0.0, 2.7). Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. 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) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. 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. All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for 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 a HIV specialist is recommended. If a pregnant woman is exposed to emtricitabine; rilpivirine; tenofovir alafenamide, health care providers are encouraged to register the patient in the Antiretroviral Pregnancy Registry by telephoning 1-800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.

    Breast-feeding

    To reduce the risk of postnatal transmission, HIV-infected mothers 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 emtricitabine; rilpivirine; tenofovir alafenamide. There is limited experience using rilpivirine and tenofovir alafenamide during breast-feeding and their excretion into breast milk is unknown. Limited data suggest small amounts of emtricitabine is excreted into breast milk. One study estimated the exposure to emtricitabine in exclusively breast-fed infants at approximately 2% of the recommended infant dose. Other antiretroviral medications whose passage into human breast milk have been evaluated include tenofovir disoproxil fumarate, nevirapine, zidovudine, lamivudine, and nelfinavir.

    ADVERSE REACTIONS

    Severe

    depression / Delayed / 1.0-5.6
    rash (unspecified) / Early / 1.0-1.0
    suicidal ideation / Delayed / 0.6-0.6
    lactic acidosis / Delayed / Incidence not known
    hepatic decompensation / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

    Moderate

    dysphoria / Early / 9.0-9.0
    steatosis / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known

    Mild

    headache / Early / 0-19.0
    fatigue / Early / 1.0-14.0
    nausea / Early / 1.0-11.0
    dizziness / Early / 8.0-8.0
    abdominal pain / Early / 8.0-8.0
    vomiting / Early / 6.0-6.0
    insomnia / Early / 0-2.0
    diarrhea / Early / 1.0-1.0
    polyuria / Early / Incidence not known
    weakness / Early / Incidence not known
    myalgia / Early / Incidence not known
    weight gain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Severe) Coadministration of lamivudine, 3TC-containing products and emtricitabine-containing products is contraindicated. Due to similarities between emtricitabine and lamivudine, coadministration will result in therapeutic duplication.
    Abacavir; Lamivudine, 3TC: (Severe) Coadministration of lamivudine, 3TC-containing products and emtricitabine-containing products is contraindicated. Due to similarities between emtricitabine and lamivudine, coadministration will result in therapeutic duplication.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Severe) Coadministration of lamivudine, 3TC-containing products and emtricitabine-containing products is contraindicated. Due to similarities between emtricitabine and lamivudine, coadministration will result in therapeutic duplication.
    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; Aspirin, ASA; Caffeine: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Acetaminophen; Butalbital: (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.
    Acetaminophen; 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.
    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.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Acyclovir: (Moderate) Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Emtricitabine containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as acyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Adefovir: (Severe) Avoid coadministration of tenofovir alafenamide with adefovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein. (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). (Major) Patients who are concurrently taking adefovir with emtricitabine 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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with alfuzosin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Alfuzosin also has a slight QT prolonging effect, based on electrophysiology studies performed by the manufacturer. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg.
    Alogliptin; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Alogliptin; Pioglitazone: (Moderate) Close clinical monitoring is advised when administering pioglitazone 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. Pioglitazone 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.
    Amikacin: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aminoglycosides: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Moderate) Close clinical monitoring is advised when administering amiodarone with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Amiodarone is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Amitriptyline: (Minor) 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 tricyclic antidepressants. 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) 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 tricyclic antidepressants. 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: (Severe) 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. (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) 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. (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as amphotericin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Amphotericin B lipid complex (ABLC): (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as amphotericin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Amphotericin B liposomal (LAmB): (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as amphotericin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Amphotericin B: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as amphotericin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with apomorphine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data indicate that QT prolongation is also possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2 to 10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. 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. Rilpivirine should be used cautiously and with close monitoring with aripiprazole.
    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: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Carisoprodol: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Dipyridamole: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Omeprazole: (Severe) 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) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Oxycodone: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Aspirin, ASA; Pravastatin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Moderate) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together.
    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) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. (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 substrate/inhibitor of CYP3A4. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include rilpivirine.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Severe) 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. (Major) Administering tenofovir alafenamide with phenobarbital is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with azithromycin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation, and cases of QT prolongation and TdP have been reported with the post-marketing use of azithromycin.
    Bacitracin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as bacitracin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Barium Sulfate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Basiliximab: (Moderate) Close clinical monitoring is advised when administering basiliximab 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. Basiliximab is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    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: (Severe) 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. (Major) Administering tenofovir alafenamide with phenobarbital is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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.
    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: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine.
    Bismuth Subsalicylate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine. (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Moderate) Close clinical monitoring is advised when administering boceprevir with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Boceprevir is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Brigatinib: (Moderate) Monitor for decreased efficacy of rilpivirine if coadministration with brigatinib is necessary. Rilpivirine is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of rilpivirine may decrease. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Budesonide; Formoterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Cabozantinib: (Moderate) Monitor for an increase in tenofovir alafenamide-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of tenofovir alafenamide may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and tenofovir alafenamide is a substrate of P-gp; the clinical relevance of this finding is unknown. When tenofovir alafenamide is administered in combination with cobicistat, other inhibitors of P-gp or BCRP are not expected to further increase tenofovir alafenamide concentrations. Cabozantinib is also a CYP3A4 and Multidrug Resistance Protein 2 (MRP2) substrate, while tenofovir alafenamide is an MRP2 inhibitor and weak CYP3A4 inhibitor in vitro. The effect of tenofovir alafenamide on CYP3A4 is not expected to be clinically relevant; MRP2 inhibition may result in increased plasma concentrations of cabozantinib, but the clinical relevance is unknown.
    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; 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; Vitamin D: (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.
    Canagliflozin: (Moderate) Caution is advised when administering tenofovir alafenamide concurrently with inhibitors of P-glycoprotein (P-gp), such as canagliflozin. Coadministration may result in increased absorption of tenofovir alafenamide. Monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Canagliflozin; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Caution is advised when administering tenofovir alafenamide concurrently with inhibitors of P-glycoprotein (P-gp), such as canagliflozin. Coadministration may result in increased absorption of tenofovir alafenamide. Monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Carbamazepine: (Severe) The concurrent use of carbamazepine 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. Carbamazepine 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. (Major) Administering tenofovir alafenamide with carbamazepine is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure
    Carboplatin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Carvedilol: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with carvedilol, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as carvedilol, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Celecoxib: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Ceritinib: (Major) Avoid coadministration of ceritinib with rilpivirine due to increased rilpivirine exposure. If coadministration is unavoidable, monitor for rilpivirine-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Rilpivirine is metabolized by CYP3A4, and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    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) Concurrent use of chloroquine and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). The need to coadminister these drugs should be done with a careful assessment of risks versus benefits. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Chloroquine administration is also associated with an increased risk of QT prolongation and TdP.
    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.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Cidofovir: (Moderate) Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Emtricitabine -containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cidofovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus. (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cidofovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with ciprofloxacin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ciprofloxacin is associated with a possible risk for QT prolongation and TdP.
    Cisapride: (Severe) 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.
    Cisplatin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cisplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Moderate) Coadministration of clarithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Clarithromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a P-gp substrate. However, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Clomipramine: (Minor) 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 tricyclic antidepressants. 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: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with clozapine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation, while treatment with clozapine has been associated with QT prolongation, 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 substrate/inhibitor of CYP3A4. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
    Cobicistat; Elvitegravir; 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 substrate/inhibitor of CYP3A4. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Avoid coadministration of tenofovir alafenamide with medications that contain any of the same active components, such as tenofovir, PMPA as this would result in duplicate therapy. (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 substrate/inhibitor of CYP3A4. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include rilpivirine.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include rilpivirine.
    Conivaptan: (Moderate) Coadministration of conivaptan and tenofovir alafenamide may result in elevated tenofovir concentrations. Conivaptan is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor. (Minor) Close clinical monitoring is advised when administering conivaptan 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. Conivaptan is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with rilpivirine; also monitor for an increase in rilpivirine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients 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). Crizotinib is a moderate CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation.
    Cyclobenzaprine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with cyclobenzaprine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cyclobenzaprine is also associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose.
    Cyclosporine: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as cyclosporine. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. In addition, tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); cyclosporine is an inhibitor of all three transporters. Inhibition of P-gp, BCRP, and OATP by cyclosporine may further increase tenofovir plasma concentrations. When tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Daclatasvir: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with daclatasvir. Coadministration may result in increased tenofovir alafenamide plasma concentrations. Tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the organic anion transport protein (OATP1B1 and 1B3); daclatasvir is an inhibitor all three transporters. If these drugs are administered together, closely monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Dapagliflozin; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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 substrate/inhibitor of CYP3A4. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation.
    Dasatinib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with dasatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. In vitro studies have shown that dasatinib also has the potential to prolong cardiac ventricular repolarization (prolong QT interval). In addition, dasatinib is a weak inhibitor of CYP3A4. Coadministration of dasatinib with rilpivirine, a CYP3A4 substrates, may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation.
    Daunorubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (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. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include degarelix.
    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) 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 tricyclic antidepressants. 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: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with rilpivirine, assess the QTc interval before and after increasing the dosage of either medication. Caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval. Clinically relevant QTc prolongation may occur with deutetrabenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Dexamethasone: (Severe) Concurrent use of dexamethasone 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: (Severe) 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; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include 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.
    Diclofenac: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Diclofenac; Misoprostol: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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.
    Diflunisal: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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. (Moderate) Close clinical monitoring is advised when administering diltiazem with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Diltiazem is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Diphenhydramine; Ibuprofen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Diphenhydramine; Naproxen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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: (Severe) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Because of the potential for TdP, use of dofetilide with rilpivirine is contraindicated. (Major) Dofetilide should be co-administered with emtricitabine with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Major) Dofetilide should be co-administered with tenofovir alafenamide with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and rilpivirine should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Concurrent use may further increase the risk for QT prolongation.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include rilpivirine.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include rilpivirine.
    Doxepin: (Minor) 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 tricyclic antidepressants. 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).
    Doxorubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronedarone: (Severe) 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.
    Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
    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: (Severe) Avoid coadministration of tenofovir alafenamide with medications that contain any of the same active components, such as tenofovir, PMPA as this would result in duplicate therapy. (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).
    Eliglustat: (Major) Coadministration of tenofovir alafenamide and eliglustat may result in increased concentrations of tenofovir. Monitor patients closely for tenofovir-related adverse effects including nausea, diarrhea, headache, asthenia, and nephrotoxicity. Tenofovir is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor. For coadministration with P-gp substrates, eliglustat's product labeling recommends monitoring therapeutic drug concentrations of the P-gp substrate, if possible, or consideration of a dosage reduction and titrating to clinical effect. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor. (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include rilpivirine.
    Empagliflozin; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Severe) Avoid coadministration of tenofovir alafenamide with medications that contain any of the same active components, such as tenofovir, PMPA as this would result in duplicate therapy.
    Emtricitabine; Tenofovir disoproxil fumarate: (Severe) Avoid coadministration of tenofovir alafenamide with medications that contain any of the same active components, such as tenofovir, PMPA as this would result in duplicate therapy.
    Enalapril; Felodipine: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with felodipine, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as felodipine, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Enzalutamide: (Severe) 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.
    Epirubicin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with epirubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    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. (Moderate) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with erythromycin. Use of these drugs together may result in elevated tenofovir plasma concentrations. When possible, an alternative antibiotic such as azithromycin should be considered. Erythromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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. (Moderate) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with erythromycin. Use of these drugs together may result in elevated tenofovir plasma concentrations. When possible, an alternative antibiotic such as azithromycin should be considered. Erythromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as rilpivirine, should be done with caution and close monitoring.
    Eslicarbazepine: (Severe) 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: (Severe) 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: (Severe) 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) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Estradiol; Norgestimate: (Moderate) Consider the benefits and risk of administering tenofovir alafenamide with norgestimate. Concurrent use may result in elevated norgestimate serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS.
    Ethinyl Estradiol; Norgestimate: (Moderate) Consider the benefits and risk of administering tenofovir alafenamide with norgestimate. Concurrent use may result in elevated norgestimate serum concentrations. Risk associated with these altered concentrations may include increased insulin resistance, dyslipidemia, acne, and venous thrombosis. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS.
    Etodolac: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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.
    Ezetimibe; Simvastatin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with simvastatin as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as simvastatin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Ezogabine: (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. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include ezogabine.
    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) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (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.
    Felodipine: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with felodipine, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as felodipine, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Fenoprofen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Fingolimod: (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 fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). 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.
    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.
    Flibanserin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with flibanserin, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as flibanserin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Fluconazole: (Severe) 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: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including rilpivirine. In addition, close clinical monitoring is advised when administering fluoxetine 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. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including rilpivirine. In addition, close clinical monitoring is advised when administering fluoxetine 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. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with olanzapine. 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 in rare instances.
    Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with fluphenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Flurbiprofen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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. (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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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. (Moderate) Monitor for changes in serum creatinine and phosphorus if emtricitabine is administered in combination with nephrotoxic agents, such as foscarnet. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine and/or the co-administered drug. Drugs that decrease renal function may increase concentrations of emtricitabine. (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as foscarnet. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Fosphenytoin: (Severe) 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. (Major) Administering tenofovir alafenamide with fosphenytoin is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    Gadobutrol: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Gadoversetamide: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Ganciclovir: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as ganciclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with gemifloxacin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; 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: (Major) 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.
    Gentamicin: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and tenofovir alafenamide as coadministration may increase serum concentrations of tenofovir alafenamide and increase the risk of adverse effects. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1/3, and breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of all these drug transporters. (Moderate) Caution is advised with the coadministration of pibrentasvir and tenofovir alafenamide as coadministration may increase serum concentrations of tenofovir alafenamide and increase the risk of adverse effects. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1/3, and breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of all these drug transporters.
    Glimepiride; Pioglitazone: (Moderate) Close clinical monitoring is advised when administering pioglitazone 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. Pioglitazone 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.
    Glipizide; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Glyburide; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Glycopyrrolate; Formoterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Major) Rilpivirine should be used cautiously and with close monitoring with goserelin. 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. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), granisetron and rilpivirine should be used together cautiously. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron with drugs known to prolong the QT interval or are arrhythmogenic, may result in clinical consequences. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Grapefruit juice: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as grapefruit juice. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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.
    Griseofulvin: (Moderate) Close clinical monitoring is advised when administering griseofulvin 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. Griseofulvin 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.
    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: (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 haloperidol. 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.
    Hydrocodone; Ibuprofen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and rilpivirine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include rilpivirine.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Ibuprofen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Ibuprofen; Oxycodone: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Ibuprofen; Pseudoephedrine: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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.
    Idarubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, and idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Idelalisib: (Severe) 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) 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 tricyclic antidepressants. 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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    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.
    Indomethacin: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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-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. (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Interferons: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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.
    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. (Minor) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with isavuconazonium. Use of these drugs together may result in elevated tenofovir plasma concentrations. Isavuconazonium is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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: (Moderate) Close clinical monitoring is advised when administering isoniazid, INH 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. Isoniazid is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Severe) 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. (Major) Administering tenofovir alafenamide with rifampin is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure. (Moderate) Close clinical monitoring is advised when administering isoniazid, INH 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. Isoniazid is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Isoniazid, INH; Rifampin: (Severe) 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. (Major) Administering tenofovir alafenamide with rifampin is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure. (Moderate) Close clinical monitoring is advised when administering isoniazid, INH 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. Isoniazid is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Itraconazole: (Major) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine. Both rilpivirine and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with rilpivirine (a CYP3A4 substrate) results in elevated rilpivirine plasma concentrations; rilpivirine dosage adjustments are not recommended. If these drugs are administered together, closely monitor for rilpivirine-related adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors. (Minor) According to the manufacturer, interactions are not expected during coadministration of itraconazole and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Itraconazole is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and rilpivirine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as rilpivirine, can increase rilpivirine exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Use caution when administering ivacaftor and tenofovir alafenamide concurrently. Ivacaftor is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Concurrent use can increase tenofovir exposure leading to adverse events. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Kanamycin: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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. (Minor) According to the manufacturer, interactions are not expected during coadministration of ketoconazole and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Ketoconazole is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Ketoprofen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Ketorolac: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Lamivudine, 3TC: (Severe) Coadministration of lamivudine, 3TC-containing products and emtricitabine-containing products is contraindicated. Due to similarities between emtricitabine and lamivudine, coadministration will result in therapeutic duplication.
    Lamivudine, 3TC; Zidovudine, ZDV: (Severe) Coadministration of lamivudine, 3TC-containing products and emtricitabine-containing products is contraindicated. Due to similarities between emtricitabine and lamivudine, coadministration will result in therapeutic duplication.
    Lansoprazole: (Severe) 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: (Severe) 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) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Lapatinib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lapatinib can also prolong the QT interval. Additionally, lapatinib may inhibit the CYP3A4 metabolism of rilpivirine, potentially resulting in elevated rilpivirine serum concentrations and risk of adverse events, such as QT prolongation. (Minor) Close clinical monitoring is advised when administering lapatinib with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Ledipasvir; Sofosbuvir: (Minor) According to the manufacturer, interactions are not expected during coadministration of ledipasvir; sofosbuvir and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP. Use of these drugs together may increase tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Lenvatinib: (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. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously and with close monitoring with rilpivirine include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    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.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include rilpivirine.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include rilpivirine.
    Levalbuterol: (Minor) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Concurrent use of rilpivirine and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    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.
    Linagliptin; Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with rilpivirine. Lithium has been associated with 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.
    Long-acting beta-agonists: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like rilpivirine, should be used cautiously and with close monitoring with loperamide.
    Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like rilpivirine, should be used cautiously and with close monitoring with loperamide.
    Lopinavir; Ritonavir: (Major) Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with lopinavir; ritonavir. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lopinavir; ritonavir is also associated with QT prolongation. In addition, lopinavir; ritonavir may inhibit the CYP3A4 metabolism of rilpivirine, resulting in elevated rilpivirine plasma concentrations and an added risk of adverse reactions such as QT prolongation. (Moderate) Concurrent use of lopinavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); lopinavir is an OATP1B1 inhibitor. When 10 mg of tenofovir alafenamide was administered daily with lopinavir; ritonavir (800 mg/200 mg PO daily), the tenofovir Cmax and AUC increased by 2.19-fold and 1.47-fold, respectively. Monitor for increased toxicities if these drugs are given together.
    Lovastatin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with lovastatin, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as lovastatin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Lovastatin; Niacin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with lovastatin, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as lovastatin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Lumacaftor; Ivacaftor: (Severe) 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. (Moderate) Concomitant use of lumacaftor; ivacaftor and tenofovir alafenamide could potentially alter the systemic exposure of tenofovir. Tenofovir alafenamide is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor. (Minor) Use caution when administering ivacaftor and rilpivirine concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as rilpivirine, can increase rilpivirine exposure leading to increased or prolonged therapeutic effects and adverse events. (Minor) Use caution when administering ivacaftor and tenofovir alafenamide concurrently. Ivacaftor is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Concurrent use can increase tenofovir exposure leading to adverse events. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Lumacaftor; Ivacaftor: (Severe) 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. (Moderate) Concomitant use of lumacaftor; ivacaftor and tenofovir alafenamide could potentially alter the systemic exposure of tenofovir. Tenofovir alafenamide is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Magnesium Salicylate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Maprotiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with maprotiline. 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 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.
    Meclofenamate Sodium: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Mefenamic Acid: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with mefloquine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. There is also 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. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, like rilpivirine.
    Meloxicam: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include rilpivirine.
    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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Metformin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Pioglitazone: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Close clinical monitoring is advised when administering pioglitazone 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. Pioglitazone 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.
    Metformin; Repaglinide: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Rosiglitazone: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Saxagliptin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Metformin; Sitagliptin: (Moderate) According to the manufacturer, interactions are not expected when metformin is administered with tenofovir alafenamide; however, because tenofovir and metformin can compete for elimination through the kidneys, use of these medications together may increase the risk for side effects, such as lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir alafenamide, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include rilpivirine.
    Metyrapone: (Moderate) Close clinical monitoring is advised when administering metyrapone 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. Metyrapone 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.
    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, RU-486: (Major) Close clinical monitoring is advised when administering mifepristone, RU-486 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. Mifepristone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs, such as rilpivirine. To minimize the risk of QT prolongation, the lowest effect dose should always be used. (Moderate) Coadministration of mifepristone, RU-486 and tenofovir alafenamide may result in elevated tenofovir concentrations. Mifepristone is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and rilpivirine. Coadminister with caution. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with 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.
    Nabumetone: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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.
    Naproxen: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Naproxen; Pseudoephedrine: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Naproxen; Sumatriptan: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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.
    Niacin; Simvastatin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with simvastatin as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as simvastatin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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. (Minor) Close clinical monitoring is advised when administering nicardipine with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Nicardipine is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Nifedipine: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with nifedipine, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as nifedipine, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Non-Ionic Contrast Media: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Nonsteroidal antiinflammatory drugs: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    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) 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 tricyclic antidepressants. 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).
    Obeticholic Acid: (Minor) Obeticholic acid may increase the exposure to tenofovir alafenamide. Tenofavir alafenamide is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is coadministered with tenofovir alafenamide.
    Octreotide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with octreotide. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with ofloxacin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with olanzapine. 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 in rare instances.
    Olodaterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation.
    Omeprazole: (Severe) 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; Sodium Bicarbonate: (Severe) 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.
    Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued. (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with tenofovir, PMPA. Loss of virological control has been reported in HIV-infected patients taking orlistat with tenofovir disoproxil fumarate and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction 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. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir alafenamide is a BCRP substrate and osimertinib is a BCRP inhibitor.
    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.
    Oxaprozin: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Oxcarbazepine: (Severe) 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. (Major) Administering tenofovir alafenamide with oxcarbazepine is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. 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 considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Pamidronate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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: (Severe) 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.
    Paromomycin: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Pasireotide: (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 pasireotide. Coadministration may have additive effects on the prolongation of the QT interval.
    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.
    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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with perphenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with perphenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation. (Minor) 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 tricyclic antidepressants. 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).
    Phenobarbital: (Severe) 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. (Major) Administering tenofovir alafenamide with phenobarbital is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    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.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include rilpivirine.
    Phenytoin: (Severe) 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. (Major) Administering tenofovir alafenamide with phenytoin is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    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: (Severe) 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.
    Pioglitazone: (Moderate) Close clinical monitoring is advised when administering pioglitazone 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. Pioglitazone 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.
    Pirbuterol: (Minor) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Pirfenidone: (Moderate) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with pirfenidone. Use of these drugs together may result in elevated tenofovir plasma concentrations. Pirfenidone is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Piroxicam: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Polymyxin B: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Polymyxins: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as colistimethate sodium. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Posaconazole: (Severe) 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. (Moderate) Close clinical monitoring adverse events are advised when administering tenofovir alafenamide with posaconazole. Use of these drugs together may result in elevated tenofovir alafenamide plasma concentrations. Posaconazole is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include rilpivirine.
    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. (Moderate) Close clinical monitoring is advised when administering primidone with tenofovir alafenamide due to the potential for treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Primidone is an inducer of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in decreased tenofovir serum concentrations and impaired virologic response.
    Probenecid: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as probenecid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Phenothiazines, like prochlorperazine, have also been reported to prolong the QT interval.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include rilpivirine.
    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: (Severe) 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) 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 tricyclic antidepressants. 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: (Severe) 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: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Rilpivirine is a CYP3A4 substrate and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Caution is advised with coadministration. (Minor) Close clinical monitoring is advised when administering ranolazine with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Ranolazine is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Regadenoson: (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. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include regadenoson.
    Regorafenib: (Moderate) Use caution if coadministration of regorafenib with tenofovir alafenamide is necessary, and monitor for an increase in tenofovir alafenamide-related adverse reactions. Tenofovir alafenamide is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir alafenamide. However, when tenofovir alafenamide is administered in combination with cobicistat, other inhibitors of BCRP are not expected to further increase tenofovir alafenamide concentrations.
    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. (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    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 has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day) have caused QT prolongation. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and rilpivirine is a CYP3A4 substrate.
    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 has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day) have caused QT prolongation. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and rilpivirine is a CYP3A4 substrate.
    Rifabutin: (Major) Administration of rifabutin with emtricitabine; rilpivirine; tenofovir 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 and/or the development of rilpivirine or NNRTI resistance. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Rifampin: (Severe) 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. (Major) Administering tenofovir alafenamide with rifampin is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    Rifapentine: (Severe) 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 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. (Major) Coadministration is not recommended. Concurrent use may result in significant decreases in the plasma concentrations of tenofovir alafenamide, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended.
    Rifaximin: (Moderate) Caution is advised when administering tenofovir alafenamide with rifaximin, as there is a potential for elevated tenofovir alafenamide plasma concentrations. Rifaximin is an in vitro inhibitor of P-glycoprotein (P-gp) and the orgainic anion transporting polypeptide (OATP1B1/1B3); tenofovir alafenamide is a P-gp and OATP1B1/1B3 substrate. Concurrent use may cause increased absorption of tenofovir resulting in adverse effects. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Risperidone: (Major) Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Since risperidone may prolong the QT interval, it should be used cautiously with other agents also known to have this effect, taking into account the patient's underlying disease state(s) and additional potential risk factors. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with risperidone include 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.
    Ritonavir: (Major) Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation.
    Rivaroxaban: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with rivaroxaban, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as rivaroxaban, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Rofecoxib: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Rolapitant: (Moderate) Coadministration of rolapitant and tenofovir alafenamide may result in elevated tenofovir concentrations. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp); rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140 percent and 130 percent, respectively, on day 1 with rolapitant, and by 17 percent and 32 percent, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70 percent and 30 percent, respectively; the Cmax and AUC on day 8 were not studied.
    Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If romidepsin and rilpivirine must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Salicylates: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Salmeterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Salsalate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and tenofovir alafenamide as coadministration may result in increased systemic exposure of tenofovir alafenamide. Tenofovir alafenamide is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of tenofovir alafenamide.
    Saquinavir: (Major) Concurrent use of saquinavir and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. 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.
    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.
    Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include rilpivirine.
    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) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Simeprevir: (Moderate) Closely monitor for tenofovir-associated adverse reactions if simeprevir is administered with tenofovir alafenamide. Tenofovir alafenamide is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); simeprevir is an inhibitor of both P-gp and BCRP. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Simvastatin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with simvastatin as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as simvastatin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Simvastatin; Sitagliptin: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with simvastatin as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as simvastatin, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor patients for tenofovir-associated adverse reactions, such as renal toxicity, in patients receiving regimens containing tenofovir alafenamide and velpatasvir due to potential increases in tenofovir serum concentrations. Tenofovir alafenamide is a substrate of the breast cancer resistance protein (BCRP),P-glycoprotein (P-gP), OATP1B1, and OATB1B3 transporters, while velpatasvir inhibits these transporters.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor patients for tenofovir-associated adverse reactions, such as renal toxicity, in patients receiving regimens containing tenofovir alafenamide and velpatasvir due to potential increases in tenofovir serum concentrations. Tenofovir alafenamide is a substrate of the breast cancer resistance protein (BCRP),P-glycoprotein (P-gP), OATP1B1, and OATB1B3 transporters, while velpatasvir inhibits these transporters.
    Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with rilpivirine. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Sorafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with sorafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Sorafenib has also been associated with 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.
    St. John's Wort, Hypericum perforatum: (Severe) 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. (Major) Administering emtricitabine; tenofovir alafenamide with St. John's Wort, Hypericum perforatum is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
    Streptogramins: (Moderate) Close clinical monitoring is advised when administering dalfopristin; quinupristin 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. Dalfopristin; quinupristin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Streptomycin: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include rilpivirine.
    Sulindac: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Sunitinib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with sunitinib. Both sunitinib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Suvorexant: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with suvorexant, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as suvorexant, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tacrolimus: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with tacrolimus. If these drugs are coadministered, consider reducing the tacrolimus dose, closely monitor tacrolimus whole blood concentrations, and monitoring for QT prolongation. Both tacrolimus and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with emtricitabine. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Emtricitabine is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of emtricitabine with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabiner, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of emtricitabine. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein. (Major) Tacrolimus therapeutic drug monitoring is recommended when administered concurrently with tenofovir alafenamide. Use of these medications together may result in elevated tacrolimus serum concentrations. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as tacrolimus. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen and rilpivirine due to an increased risk of QT prolongation; increased rilpivirine exposure may also occur. 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 also been described when tamoxifen is used at lower doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Minor) Close clinical monitoring is advised when administering tamoxifen with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Tamoxifen is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tedizolid: (Moderate) If possible, stop use of tenofovir alafenamide temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for tenofovir-associated adverse events. Tenofovir plasma concentrations may be increased when tenofovir alafenamide is administered concurrently with oral tedizolid. Tenofovir alafenamide is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine. When tenofovir alafenamide is administered in combination with cobicistat, other inhibitors of BCRP are not expected to further increase tenofovir concentrations.
    Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with rilpivirine. Telavancin has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused prolongation of the QT interval.
    Telithromycin: (Major) Close clinical monitoring is advised when administering telithromycin with rilpivirine due to an increased potential for adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Telithromycin is an inhibitor of CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, both telithromycin and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. (Moderate) Coadministration of telithromycin and tenofovir alafenamide may result in elevated tenofovir concentrations. Telithromycin is an inhibitor of the drug transporters P-glycoprotein (P-gp) and organic anion transporting polypeptides (OATP). Tenofovir alafenamide is a substrate for P-gp and OATP1B1/1B3. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and rilpivirine is necessary, as the systemic exposure of rilpivirine may be decreased resulting in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. If these drugs are used together, monitor patients for suboptimal efficacy of rilpivirine; consider increasing the dose of rilpivirine if necessary. Rilpivirine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. The manufacturer of rilpivirine recommends a dose increase from 25 mg per day to 50 mg per day when administered with rifabutin, but recommendations for CYP3A4 inducers as a general class are not available.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with tenofovir alafenamide is necessary, and monitor for an increase in tenofovir alafenamide-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and tenofovir alafenamide is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to tenofovir alafenamide is likely to increase.
    Tenofovir, PMPA: (Severe) Avoid coadministration of tenofovir alafenamide with medications that contain any of the same active components, such as tenofovir, PMPA as this would result in duplicate therapy.
    Terbutaline: (Minor) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Testosterone: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with testosterone, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as testosterone, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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: (Severe) 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. (Minor) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with ticagrelor. Use of these drugs together may result in elevated tenofovir plasma concentrations. Ticagrelor is an inhibitor of the drug transporter P-glycoprotein (P-gp).Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tiotropium; Olodaterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tipranavir: (Major) Administering tenofovir alafenamide concurrently with tipranavir boosted with ritonavir is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure. Tenofovir alafenamide is a substrate of P-glycoprotein (P-gp); tipranavir boosted with ritonavir is an inducer of P-gp. (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.
    Tizanidine: (Major) Tizanidine should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in 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. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tobramycin: (Moderate) Tenofovir-containing products, should be avoided with concurrent or recent use of a nephrotoxic agent, such as aminoglycosides. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Tolmetin: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with rilpivirine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Tolvaptan: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with tolvaptan, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as tolvaptan, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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) 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. Drugs with a possible risk for QT prolongation and torsades de pointes that should be used cautiously with rilpivirine include toremifene.Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    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. (Moderate) Coadministration of verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    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.
    Tricyclic antidepressants: (Minor) 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 tricyclic antidepressants. 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) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with trifluoperazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trifluoperazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Trimipramine: (Minor) 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 tricyclic antidepressants. 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: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include rilpivirine.
    Trospium: (Moderate) Tenofovir-containing products should be avoided with concurrent trospium administration as both are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of either drug due to competition for the elimination pathway and patients should be carefully monitored.
    Ulipristal: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with ulipristal, as coadministration may result in elevated tenofovir alafenamide plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as ulipristal, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Umeclidinium; Vilanterol: (Moderate) 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 beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Valacyclovir: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as valacyclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Valdecoxib: (Moderate) Avoid administering tenofovir-containing medications concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment.
    Valganciclovir: (Moderate) Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir, with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as valganciclovir. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Valproic Acid, Divalproex Sodium: (Moderate) Caution is advised when administering tenofovir alafenamide with valproic acid, divalproex sodium, as there is a potential for decreased tenofovir plasma concentrations. Valproic acid is an in vitro inducer of P-glycoprotein (P-gp); tenofovir alafenamide is a P-gp substrate. Concurrent use may decrease absorption and alter metabolism of tenofovir.
    Vancomycin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as vancomycin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). 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. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. (Moderate) Use caution if coadministration of vandetanib with tenofovir alafenamide is necessary, due to a possible increase in tenofovir-related adverse reactions. Tenofovir is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Vardenafil: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). 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. (Moderate) Coadministration of vemurafenib and tenofovir alafenamide may result in elevated tenofovir concentrations. Vemurafenib is an inhibitor of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Tenofovir alafenamide is a P-gp and BCRP substrate. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Venlafaxine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with venlafaxine. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
    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. (Moderate) Coadministration of verapamil and tenofovir alafenamide may result in elevated tenofovir concentrations. Verapamil is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Voriconazole: (Major) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine. Both drugs are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with rilpivirine (a CYP3A4 substrate) results in elevated rilpivirine plasma concentrations; rilpivirine dosage adjustments are not recommended. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (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. Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with rilpivirine.
    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: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including rilpivirine.
    Zoledronic Acid: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Zonisamide: (Minor) Caution is advised when administering tenofovir alafenamide concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir alafenamide, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.

    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 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. No well-controlled studies have been conducted to evaluate the risks of administering emtricitabine; rilpivirine; tenofovir alafenamide to pregnant females. Data involving first trimester exposures to tenofovir alafenamide are insufficient to draw conclusions regarding the potential for birth defects. Available data from the Antiretroviral Pregnancy Registry, which includes in utero exposures to emtricitabine (2,326 first trimester; 1,080 second and third trimesters) and rilpivirine (202 first trimester; 124 second and third trimesters), 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. For emtricitabine, when exposure occurred in the first trimester the prevalence of defects was 2.3% (95% CI: 1.7, 3.0). The prevalence of defects following first trimester exposure to rilpivirine was 0.5% (95% CI: 0.0, 2.7). Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. 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) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. 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. All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for 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 a HIV specialist is recommended. If a pregnant woman is exposed to emtricitabine; rilpivirine; tenofovir alafenamide, health care providers are encouraged to register the patient in the Antiretroviral Pregnancy Registry by telephoning 1-800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.

    To reduce the risk of postnatal transmission, HIV-infected mothers 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 emtricitabine; rilpivirine; tenofovir alafenamide. There is limited experience using rilpivirine and tenofovir alafenamide during breast-feeding and their excretion into breast milk is unknown. Limited data suggest small amounts of emtricitabine is excreted into breast milk. One study estimated the exposure to emtricitabine in exclusively breast-fed infants at approximately 2% of the recommended infant dose. Other antiretroviral medications whose passage into human breast milk have been evaluated include tenofovir disoproxil fumarate, nevirapine, zidovudine, lamivudine, and nelfinavir.

    MECHANISM OF ACTION

    The combination therapy of emtricitabine; rilpivirine; tenofovir alafenamide is not antagonistic in cell culture.
     
    •Emtricitabine: Emtricitabine inhibits viral reverse transcriptase and has in vitro activity against both HIV-1 and hepatitis B virus (HBV). It is a synthetic nucleoside analog of cytosine, which is phosphorylated by cellular enzymes to emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the deoxycytidine 5'-triphosphate for incorporation into nascent viral DNA, resulting in chain termination. The 50% effective concentration (EC50) ranges from 0.0013—0.65 micromolar. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon and mitochondrial DNA polymerase-gamma.
     
    Emtricitabine selects for the M184V/I mutation in the HIV reverse transcriptase gene, producing resistance. People with the M184 mutation are cross-resistant to lamivudine, but retain susceptibility to didanosine, stavudine, tenofovir, zidovudine, and non-nucleoside reverse transcriptase inhibitors.
     
    •Tenofovir alafenamide: Tenofovir alafenamide (tenofovir AF) is a phosphonoamidate prodrug of tenofovir. Tenofovir AF is taken up by cells, where it undergoes hydrolysis by cathepsin A to form tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Subsequently, tenofovir is phosphorylated by cellular kinases to form the active metabolite, tenofovir diphosphate. Tenofovir diphosphate acts as a competitive inhibitor of RNA- and DNA-directed reverse transcriptase. Tenofovir diphosphate competes with the natural substrate deoxyadenosine 5'-triphosphate and, since it lacks a 3' hydroxyl group, causes premature DNA termination. The EC50 ranges from 2—14.7 nanomolar. In addition to inhibiting HIV reverse transcriptase, tenofovir diphosphate has activity against the hepatitis B virus (HBV). The drug is also a weak inhibitor of mammalian DNA polymerase alpha, beta, and mitochondrial DNA polymerase-gamma.
    HIV isolates with reduced susceptibility to tenofovir have been selected in vitro. Viruses with reduced susceptibility to tenofovir expressed the K65R and K70E substitutions in reverse transcriptase. These mutations confer cross-resistance with abacavir, didanosine, emtricitabine, and lamivudine.
     
    •Rilpivirine: 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 EC50 for wild type laboratory adapted strains of HIV-1 is 0.73 nM. It has very limited activity against HIV-2 reverse transcriptase with an EC50 ranging from 2510—10,830 nM. 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 emtricitabine; rilpivirine; tenofovir (61%; n = 47/77) than in patients treated with efavirenz; emtricitabine; tenofovir (42%; n = 18/43). Amino acid substitutions observed in these rilpivirine virologic failures included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L. In addition, resistance to emtricitabine or tenofovir developed in 57% (44/77) of patients in the rilpivirine group compared to 26% (11/43) in the efavirenz arm. Cross-resistance to efavirenz, etravirine, and nevirapine is likely after virologic failure and development of rilpivirine resistance.
     
    Avoid use of rilpivirine in patients infected 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

    Emtricitabine; rilpivirine; tenofovir alafenamide tablets are administered orally.
    Emtricitabine: Emtricitabine exhibits low plasma protein binding of less than 4%, and protein binding is independent of plasma concentration. The mean plasma to blood drug concentration ratio is 0.6. Emtricitabine is metabolized via oxidation to 3'-sulfoxide diastereomer (approximately 9% of dose) and via conjugation with glucuronic acid to 2'-O-glucuronide (approximately 4% of dose). The median terminal plasma half-life of emtricitabine is approximately 10 hours. Emtricitabine is excreted renally (70%) and via feces (13.7%). Renal clearance is greater than the estimated creatinine clearance; elimination is presumed to be by both glomerular filtration and active tubular secretion.
    Tenofovir alafenamide: Plasma protein binding of tenofovir AF is approximately 80%, with a mean blood to plasma ratio of 1. Intracellularly, tenofovir AF is converted to tenofovir via hydrolysis by cathepsin A. Subsequently, tenofovir undergoes phosphorylation to its active metabolite, tenofovir diphosphate. Neither tenofovir nor tenofovir diphosphate are substrates for CYP450 hepatic isoenzymes; however CYP3A enzymes play a minor role in the metabolism of the prodrug, tenofovir AF. Metabolism is the primary mechanism by which tenofovir AF is eliminated (more than 80% of the dose), with excretion via feces and urine accounting for 31.7% and less than 1%, respectively. Elimination of the tenofovir metabolite occurs primarily via the kidneys (70 to 80%) by a combination of glomerular filtration and active tubular secretion. The median terminal plasma half-life of tenofovir AF is 0.51 hours; however, the active metabolite (tenofovir diphosphate) has a half-life of 150 to 180 hours.
    Rilpivirine: Rilpivirine is highly protein bound (99%), 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 CYP3A system. The median 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% is excreted in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, P-gp, BCRP, OATP1B1, and OATP1B3
    Rilpivirine is primarily metabolized by CYP3A4; tenofovir alafenamide is a minor substrate of CYP3A. Tenofovir alafenamide is also a substrate for the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP1B1), and OATP1B3. In vitro, tenofovir alafenamide is a weak inhibitor of CYP3A4; however, these effects are not observed in vivo.

    Oral Route

    Administer emtricitabine; rilpivirine; tenofovir alafenamide with food.
     
    Emtricitabine: Emtricitabine is rapidly and extensively absorbed, with a mean absolute bioavailability of 93% and peak plasma concentrations occurring 3 hours post-dose; exposure (AUC) is not affected by food. The AUC and Cmax increase in proportion to oral dosage over the range of 25 to 200 mg.
    Tenofovir alafenamide: Peak plasma concentration (Cmax) is observed 1 hours after oral administration. Systemic exposure (AUC) is not significantly affected by the presence of food.
    Rilpivirine: Absolute oral bioavailability is unknown; however, the time to reach maximum plasma concentrations is approximately 4 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). Another study found the AUC and Cmax increased by 9% and 34%, respectively, with a light meal (390 kcal; 12 g fat) and 16% and 26%, respectively, with a standard meal (540 kcal; 21 g fat). Administering with only a protein-rich nutritional drink decreases AUC by 50% when compared with fed conditions.