Cabotegravir; rilpivirine is an injectable combination of a human immunodeficiency virus type-1 (HIV-1) integrase strand transfer inhibitor (INSTI) and an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). It is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years and older weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. The cabotegravir; rilpivirine extended-release injections are administered intramuscularly by a health care provider either once monthly or every 2 months. Prior to initiating treatment, counsel potential drug recipients about the importance of adhering to the scheduled dosing visits; select only those patients who agree to the required monthly or every 2 month dosing schedule. Following administration of the extended-release injections, residual concentrations of both cabotegravir and rilpivirine may remain in systemic circulation for up to 12 months or longer.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Must be administered by a healthcare professional.
NOTE: Prior to initiating treatment, counsel potential drug recipients about the importance of adhering to the scheduled dosing visits; select only those patients who agree to the required monthly or every 2 month dosing schedule. Adherence to the dosing schedule helps to maintain viral suppression and reduces the risk of developing resistance. Patients who miss a scheduled injection visit should be reevaluated to determine if resumption of therapy is appropriate.
Route-Specific Administration
Injectable Administration
-A complete dose requires 2 injections; 1 injection of cabotegravir and 1 injection of rilpivirine.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever the solution and container permits. The cabotegravir vial has a brown tint to the glass which may limit visual inspection. Discard the cabotegravir and rilpivirine vials if either drug exhibits particulate matter or discoloration.
Intramuscular Administration
Preparation
-Remove the cabotegravir and rilpivirine vials from the refrigerator and allow the suspensions to acclimate to room temperature for at least 15 minutes. The vials may remain in the carton at room temperature [not to exceed 25 degrees C (77 degrees F)] for up to 6 hours; do not put the vials back into the refrigerator. If not used within 6 hours, the vials must be discarded.
-Shake each vial vigorously for a full 10 seconds so that the suspensions look uniform. Invert the vials to inspect the suspensions. If the suspensions are not uniform, shake the vials again. Small air bubbles are expected and acceptable.
-Remove the caps from the vials and wipe the rubber stoppers with an alcohol swab.
-Peal off the paper backing from the vial adaptor packaging. Press the vial adaptors straight down onto the vials using the packaging; the vial adaptors should snap securely into place. Lift off the vial adaptor packaging. To ensure that the vial adaptor is used correctly and to avoid leakage, refer to the Instructions for Use for illustrated instructions.
-Draw 1 mL of air into the syringes. Screw the syringes firmly onto the vial adaptors and press the plungers all the way down to push air into the vials.
-Invert the syringes and vials and slowly withdraw as much of the suspensions as possible into the syringes. There may be more suspension than the dose amount.
-Unscrew the syringes from the vial adaptors while keeping the syringes upright to avoid leakage. Ensure the suspensions look uniform and milky white.
-Keeping the syringes upright, firmly twist the syringes onto the needles. When preparing the dose, consider the body mass index (BMI) of the patient to ensure the needle is of sufficient length to reach the gluteal muscle. Longer needles (not included in the kit) may be required for patients with higher BMI (e.g., greater than 30 kg/m2) to ensure the dose is administered intramuscularly.
-Write the name of the suspension on each syringe label.
-Storage: Once drawn into the syringes, the dose should be administered as soon as possible; however, the suspensions may remain in the syringes for up to 2 hours. Discard the suspensions, syringes, and needles if not administered within 2 hours. It is recommended to label the syringes with the time the suspensions were drawn up if the dose is not administered immediately. The filled syringes should not be placed in the refrigerator.
Intramuscular injection
-Holding the syringes upright, press the plungers to the appropriate dosing mark (either 2 mL or 3 mL) to remove extra suspension and any air bubbles.
-Clean the injection sites with an alcohol wipe and allow the skin to air dry.
-Administer each intramuscular injection at separate gluteal injections sites (on opposite sides or at least 2 cm apart) during the same visit. The ventrogluteal site is recommended; however, the dorsogluteal approach (upper outer quadrant) is also acceptable. DO NOT administer by any other route or anatomical site.
In clinical trials evaluating the safety of cabotegravir; rilpivirine once monthly injections (i.e., FLAIR and ATLAS), 83% of adult drug recipients developed an injection site reaction. The majority of these reactions were mild (Grade 1, 75%) to moderate (Grade 2, 36%); however, 4% experienced a severe reaction (Grade 3) and 1% discontinued treatment due to an injection site reaction. Localized pain or discomfort (79%) was the most common manifestation. Other reported effects included nodules (14%), induration (12%), edema or swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%), and hematoma (2%). Injection site reactions were also reported in the ATLAS-2M (every 2 month injection) clinical trial, occurring in 75% of adults receiving the injections either monthly or every 2 months. In this trial, severity was generally mild (Grade 1, 70% and 71%) or moderate (Grade 2, 28% and 27%) with the monthly and every 2 month dosing regimens, respectively. However, severe Grade 3 reactions were noted in 4% of patients receiving monthly injections and 3% of patients in the every 2 month group; and less than 1% discontinued treatment due to an injection site reaction. The incidence for specific reactions in adults receiving once monthly and every 2 month injections, respectively, were localized pain or discomfort (71% and 73%), nodules (17% and 10%), induration (7% and 8%), edema or swelling (5% and 6%), erythema (3% and 2%), pruritus (5% and 5%), bruising (2% and 2%), warmth (2% and 1%), and hematoma (3% and less than 1%). Anesthesia, abscess, cellulitis, and hemorrhage or bleeding at the injection site were each reported in less than 1% of adults. The median duration of the injection site reactions was 3 days. Data from the Week 16 analysis of the MOCHA trial, involving 23 adolescents (ages 12 to 17 years and weighing at least 35 kg), showed a safety profile that was consistent with cabotegravir plus rilpivirine use in adults. In the MOCHA trial, 62% of adolescent drug recipients reported at least 1 injection site reaction; with the most common reported reaction being injection site pain (n = 13). All injection site reactions reported in the MOCHA trial were Grade 1 or 2 in severity.
During clinical trials, 8% of patients receiving cabotegravir; rilpivirine developed a fever. In the ATLAS-2M (every 2 month injection) trial, fever led to treatment withdrawal in 1 patient receiving monthly injections and 1 patient in the every 2 month injection group. Other injection-associated reactions included musculoskeletal pain and discomfort (3%), back pain, myalgia, pain in the extremities, sciatica, and vasovagal or pre-syncopal reactions (less than 1%).
Fatigue, including asthenia and malaise, was reported by 5% of adults treated with cabotegravir; rilpivirine during clinical trials. Additionally, 2% of adults experienced sleep disorders (i.e., insomnia, poor quality sleep, somnolence). Data from the Week 16 analysis of the MOCHA trial, involving 23 adolescents (ages 12 to 17 years and weighing at least 35 kg), showed a safety profile that was consistent with cabotegravir plus rilpivirine use in adults. In the MOCHA trial, 2 adolescent drug recipients experienced insomnia.
Psychiatric disorders (e.g., abnormal dreams, anxiety, depression, depressed or altered mood, mood swings, irritability, dysphoria, negative thoughts, suicidal ideation, suicide attempts) have been reported in less than 2% of patients treated with cabotegravir and rilpivirine. Other neurologic adverse events reported by recipients of cabotegravir; rilpivirine during clinical trials included headache (4%) and dizziness (2%).
Nausea was reported by 3% of patients treated with cabotegravir; rilpivirine during clinical trials. Other gastrointestinal adverse events reported by less than 2% of drug recipients included abdominal pain, diarrhea, dyspepsia, flatulence, gastritis, and vomiting.
During clinical trials, rash (including, erythematous rash, macular rash, erythema, pruritus, and purpura) was reported in 2% of adults treated with cabotegravir; rilpivirine. Hypersensitivity reactions were reported in less than 2% of adult drug recipients. Data from the Week 16 analysis of the MOCHA trial, involving 23 adolescents (ages 12 to 17 years and weighing at least 35 kg), showed a safety profile that was consistent with cabotegravir plus rilpivirine use in adults. In the MOCHA trial, 1 adolescent drug recipient experienced a Grade 3 hypersensitivity reaction that lead to discontinuation of rilpivirine during oral lead-in therapy. Hypersensitivity reactions reported during postmarketing use of cabotegravir- or rilpivirine-containing regimens include angioedema, urticaria, and severe skin reactions [e.g., Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)]. In some cases, these skin reactions were accompanied by constitutional findings (i.e., fever) or organ dysfunction (i.e., elevated hepatic serum biochemistries).
During clinical trials, up to 2% of patients treated with cabotegravir; rilpivirine developed elevated hepatic enzymes (at least 5-times the upper limit of normal). Hepatotoxicity developed in less than 2% of patients, and occurred in individuals with or without known preexisting hepatic disease or identifiable risk factors.
Weight gain was observed in less than 2% of patients receiving cabotegravir; rilpivirine during clinical trials. Data from the FLAIR and ATLAS trials showed patients treated with cabotegravir plus rilpivirine had a median weight gain of 1.5 kg at treatment Week 48, compared to 1 kg for the comparator group. In the ATLAS-2M (every 2 month injection) trial, the median weight gain at Week 48 was 1 kg for both the cabotegravir; rilpivirine monthly and every 2 month treatment groups.
Hyperbilirubinemia (i.e., total bilirubin at least 2.6-times upper limit of normal) was observed in less than 1% of patients treated with cabotegravir; rilpivirine during clinical trials. These small non-progressive increases in total bilirubin (without clinical jaundice) were not considered clinically relevant, as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1). Other laboratory abnormalities observed during clinical trials included increased creatine phosphokinase (at least 10-times ULN, 3% to 8%) and elevated lipase (at least 3-times ULN, 2% to 5%).
Adrenocortical insufficiency has been observed with rilpivirine treatment. In adult clinical trials, adrenocortical insufficiency was observed as a 0.69 mcg/dL decrease in basal cortisol concentrations from baseline at treatment week 96. In patients receiving rilpivirine, 7.3% developed an abnormal 250 micrograms ACTH stimulation test compared with 3.2% of patients receiving comparator (efavirenz). In pediatric clinical trials, there was an overall mean increase in cortisol of 1.59 mcg/dL compared from baseline in patients receiving rilpivirine. An abnormal 250 micrograms ACTH stimulation test developed in 20% of patients receiving rilpivirine. Despite the altered cortisol concentrations, no serious adverse events, deaths, or treatment discontinuations were attributed to adrenal insufficiency. The significance of the higher abnormal rate of 250 micrograms ACTH stimulation test in patients receiving rilpivirine is not known.
During clinical trials, some patients (less than 1%) experienced post-injection reactions [i.e., dyspnea, bronchospasm, agitation, abdominal cramping, rash, urticaria, dizziness, flushing, diaphoresis (sweating), oral numbness, changes in blood pressure, chest pain (unspecified), back pain] within minutes of the rilpivirine injection. These reactions may have been associated with inadvertent (partial) intravenous administration.
Nephrotic syndrome has been noted during postmarketing use of rilpivirine. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Prior to initiating treatment with cabotegravir; rilpivirine extended-release injection, counsel potential drug recipients about the importance of adhering to the scheduled dosing visits; select only those patients who agree to the required monthly or every 2 month dosing schedule. Patients who miss a scheduled injection visit should be reevaluated to determine if resumption of the extended-release therapy is appropriate. An oral regimen of 30 mg cabotegravir plus 25 mg rilpivirine PO once daily, or any other fully suppressive oral antiretroviral regimen, may be given if a patient misses a scheduled injection by more than 7 days. 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 patients on the potential risks and closely monitor for any clinical or laboratory abnormalities.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Cabotegravir; rilpivirine is contraindicated for use in patients with a history of hypersensitivity reactions to cabotegravir or rilpivirine. Use of rilpivirine-containing regimens during the postmarketing period has been associated with the development of serious rash, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). In some cases, these skin reactions were accompanied by constitutional findings (i.e., pyrexia) or organ dysfunction (i.e., elevated hepatic enzymes). Severe hypersensitivity reactions have also been associated with the use of other integrase strand transfer inhibitors and could occur with cabotegravir. Healthcare providers are advised to closely monitor the clinical status of patients, including liver function tests, during treatment. Immediately discontinue cabotegravir; rilpivirine and initiate appropriate therapy in any patient who develops signs of hypersensitivity reactions, such as serious rash or rash accompanied by pyrexia, fatigue, general malaise, muscle or joint aches, blisters or peeling of skin, oral lesions, conjunctivitis, hepatitis, facial edema, angioedema, difficulty breathing, or eosinophilia. Prior to administering the extended-release injections, consider use of oral lead-in dosing to assess the tolerability of cabotegravir and rilpivirine; treatment with the extended-release injections may result in residual concentrations of both cabotegravir and rilpivirine remaining in systemic circulation for prolonged periods (up to 12 months or longer).
A single cabotegravir; rilpivirine dose is composed of 2 intramuscular (IM) injections, 1 cabotegravir injection and 1 rilpivirine injection. The gluteal IM injections should be administered slowly at separate sites (on opposite sides or at least 2 cm apart) during the same visit. When preparing the dose, consider the body mass index (BMI) of the patient to ensure the needle is of sufficient length to reach the gluteal muscle. Longer needles may be required for patients with obesity (e.g., BMI greater than 30 kg/m2) to ensure the dose is not given via subcutaneous administration. In addition, ensure the injections are not accidentally administered intravenously. During clinical trials, some patients experienced post-injection reactions (i.e., dyspnea, bronchospasm, agitation, abdominal cramping, rash, urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, back and chest pain) within minutes of the rilpivirine injection. These reactions may have been associated with inadvertent intravenous administration. Observe drug recipients for approximately 10 minutes after the injections. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.
Depressive disorders (e.g., depression, depressed or altered mood, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been associated with the use of cabotegravir; rilpivirine or the individual drug components. During clinical trials, depression, suicidal ideation, and suicide attempts occurred in less than 2% of cabotegravir; rilpivirine recipients. These events were primarily observed in patients with a pre-existing history of depression or other psychiatric illness. Healthcare providers are advised to promptly evaluate patients with depressive symptoms to assess whether the symptoms are drug related and to determine if the benefits of continuing therapy outweigh the risks.
Use caution and carefully monitor for adverse effects when administering cabotegravir; rilpivirine to patients with severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (CrCl less than 15 mL/min). The effects of renal failure on the pharmacokinetics of cabotegravir or rilpivirine are unknown. Dialysis is not expected to alter the exposures of cabotegravir or rilpivirine, as both drugs are more than 99% bound to human plasma proteins.
Cabotegravir and rilpivirine have been associated with hepatotoxicity in patients with and without pre-existing hepatic disease or identifiable risk factors. Patients with underlying hepatic disease or elevated hepatic enzymes prior to initiating treatment may be at increased risk. Closely monitor liver function tests; discontinue cabotegravir; rilpivirine if hepatotoxicity is suspected. Residual concentrations of both cabotegravir and rilpivirine may remain in systemic circulation for prolonged periods (up to 12 months or longer); therefore, use of the oral lead-in dosing prior to administration of the extended-release injection may be considered to help identify patients who may be at risk for a hepatotoxicity.
Patients who present with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to ensure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide 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 a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require 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 coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. The effect of HBV coinfection on the pharmacokinetics of cabotegravir is unknown. No clinically relevant differences in the pharmacokinetics of oral rilpivirine have been observed with HBV coinfection.
A pharmacokinetic analysis found the concentrations of cabotegravir and rilpivirine in patients who were hepatitis C virus (HCV) antibody-positive at baseline were similar to those in the overall study population. HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for HCV. For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Starting an integrase inhibitor-containing regimen (such as cabotegravir; rilpivirine) in treatment-naive patients has been associated with weight gain. Predictors and mechanisms for the increase in weight are still unclear; however, the weight gain appears to disproportionately affect females, Hispanic patients, and Black patients (particularly Black women). It is unknown whether the increase in weight is associated with significant cardio-metabolic risks or if it is reversible upon treatment discontinuation. During the FLAIR and ATLAS clinical trials, patients treated with cabotegravir; rilpivirine had a median weight gain of 1.5 kg at treatment Week 48, compared to 1 kg for the comparator group. In the ATLAS-2M (every 2 month injection) trial, the median weight gain at Week 48 was 1 kg for both the cabotegravir; rilpivirine monthly and every 2 month treatment groups.
Antiretroviral therapy should be provided to all patients 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. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Data regarding the use of injectable cabotegravir; rilpivirine during pregnancy are limited; therefore, HIV guidelines recommend against starting treatment with cabotegravir; rilpivirine in people who are pregnant. For people who conceive while suppressed on injectable cabotegravir; rilpivirine, guidelines recommend the provider and patient engage in shared decision-making regarding continued use. If the decision is made with the patient to continue use of injectable cabotegravir; rilpivirine during pregnancy, viral loads should be monitored more frequently (i.e., every 1 to 2 months). If the decision is to switched to a recommended oral antiretroviral regimen, take into account the long half-life of the injectable formulations and the fact that the drugs are detected in systemic circulation for up to 12 months or longer after discontinuation. With the monthly dosing schedule, the change to an oral regimen should occur no later than 1 month after the last intramuscular dose. With the every 2 month dosing schedule, the change to an oral regimen should occur no later than 2 months after the last intramuscular dose. Available data from the Antiretroviral Pregnancy Registry, which includes 668 first trimester exposures to oral rilpivirine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When oral rilpivirine exposure occurred in the first trimester, the prevalence of defects was 2.1% (95% CI: 1.2 to 3.5). Data regarding the use of cabotegravir during pregnancy are insufficient to determine the drug-associated risk of birth defects and miscarriages. In clinical trials of cabotegravir; rilpivirine, 25 of 325 patients of reproductive potential became pregnant while exposed to cabotegravir; rilpivirine (5 oral, 20 long-acting injectable). Of the 25 pregnancies, there were 8 elective abortions, 6 spontaneous abortions (5 in the first trimester), 1 ectopic pregnancy, and 10 live births (1 oral, 9 long-acting injectable). Of the 10 live births, there was one congenital ptosis in a term infant with intrauterine growth restriction and 1 late preterm delivery due to labor induction. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for the development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. It is strongly recommended that healthcare providers report cases of antenatal antiretroviral drug exposure to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; the Antiretroviral Pregnancy Registry is also accessible online.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). Rilpivirine is present in human breast milk; however, data do not allow for determination of the amount of rilpivirine that is transferred to milk. There are no data on the presence of cabotegravir in human milk, but the drug is present in animal milk. It is also not known if the cabotegravir or rilpivirine affect milk production or have effects on the breast-fed infant. Residual exposures of cabotegravir (if present) and rilpivirine may remain in human milk for 12 months or longer after administration of the last injection.
Counsel drug recipients about the potential reproductive risk associated with integrase inhibitor therapy. Data from an observational study suggest the use of another integrase inhibitor (dolutegravir) at the time of conception may be associated with an increased risk for neural tube defects; it is unknown if this birth defect is an integrase inhibitor class effect. If the decision to use cabotegravir; rilpivirine in a woman of childbearing age is made, the patient should be informed of the potential risk for birth defects.
Administration of supratherapeutic rilpivirine oral doses (75 and 300 mg per day) to healthy subjects have resulted in prolongation of the QT interval. The mean steady-state peak concentrations (Cmax) of these supratherapeutic oral doses were 4.4- and 11.6-fold higher than the Cmax associated with the 600 mg monthly injection and 4.1- and 10.7-fold higher than the Cmax associated with the 900 mg every 2 month injection. Use rilpivirine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or torsade de pointes or to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. 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. Cabotegravir; rilpivirine extended-release injection is indicated for use only in patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to either cabotegravir or rilpivirine. In order to minimize the risk of developing resistance to cabotegravir or rilpivirine; patients must adhere to the required monthly or every 2 month dosing schedule. If a scheduled extended-release injection is or will be missed by more than 7 days, it is essential that an alternative, fully suppressive antiretroviral regimen be initiated no later than 1 month after the last injection when dosed monthly and no later than 2 months after the last injection when dosed every 2 months. If virologic failure is suspected, switch to an alternative regimen as soon as possible. Additionally, healthcare providers are advised to monitor the use of concomitant medications, as certain drug interactions may result in loss of therapeutic effect and possible development of resistance. Cabotegravir; rilpivirine is contraindicated for use with certain strong inducers of CYP3A4 or uridine diphosphate (UDP)-glucuronosyl transferase (UGT1A1/1A9).
Patients with substance abuse may struggle to adhere to the selected recommended dosing regimen; thereby, increasing the risk for developing HIV drug resistance. Consider the following when evaluating the use of cabotegravir; rilpivirine extended-release injections in patients with substance abuse: the extended-release injections may be a trigger for injection of illicit substances; administration in conjunction with methadone may be of benefit in opioid use disorders; discuss adherence during multiple, nonjudgmental conversations; scheduling of the doses should be flexible to accommodate walk-ins; screen and vaccinate for hepatitis B virus infections; screen for depressive disorders.
Initiation of therapy for HIV infection:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-Recommended as an optimization strategy for patients with HIV-1 infections who are currently on oral antiretroviral therapy with documented viral suppression for at least 3 months and who meet the following criteria:
--no baseline resistance to cabotegravir or rilpivirine (HIV-2 infections are intrinsically resistant to rilpivirine)
-no prior virologic failures
-do not have active hepatitis B virus (HBV) coinfection (unless also receiving treatment for HBV)
-are not pregnant or planning to become pregnant
-are not receiving concurrent treatment with an interacting medication
-Not recommended for use as initial therapy due to lack of data supporting efficacy of this combination in treatment-naive patients.
-Cabotegravir; rilpivirine is a complete antiretroviral regimen.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection in patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and no known or suspected resistance to either cabotegravir or rilpivirine:
NOTE: The extended-release injections can be administered either monthly or every 2 months. Prior to starting therapy, discuss these 2 dosing options with the patient and decide which dosing frequency would be the most appropriate option for that patient.
NOTE: Counsel patients about the importance of adhering to the selected dosing schedule. The extended-release injections should be started only in those patients who agree to the required monthly or every 2 month dosing schedule.
-for use after the oral lead-in regimen:
NOTE: Before starting treatment with the extended-release injections, an oral lead-in regimen of 30 mg cabotegravir and 25 mg rilpivirine may be given once daily for approximately 1 month (at least 28 days) to assess tolerability of cabotegravir and rilpivirine.
Intramuscular dosage (Once monthly regimen):
Adults: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the oral lead-in regimen, then 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly. Monthly injections may be given up to 7 days before or after the scheduled dosing date.
Children and Adolescents 12 to 17 years weighing 35 kg or more: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the oral lead-in regimen, then 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly. Monthly injections may be given up to 7 days before or after the scheduled dosing date.
Intramuscular dosage (Every 2 month regimen):
Adults: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the oral lead-in regimen. One month later (i.e., Month 2), 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once. Then starting on Month 4, 600 mg cabotegravir IM and 900 mg rilpivirine IM once every 2 months. The injections may be given up to 7 days before or after the scheduled dosing date.
Children and Adolescents 12 to 17 years and older weighing 35 kg or more: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the oral lead-in regimen. One month later (i.e., Month 2), 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once. Then starting on Month 4, 600 mg cabotegravir IM and 900 mg rilpivirine IM once every 2 months. The injections may be given up to 7 days before or after the scheduled dosing date.
-for use without an oral lead-in regimen (i.e., direct to injection):
Intramuscular dosage (Once monthly regimen):
Adults: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the current antiretroviral therapy, then 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly. Monthly injections may be given up to 7 days before or after the scheduled dosing date.
Children and Adolescents 12 to 17 years weighing 35 kg or more: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the current antiretroviral therapy, then 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly. Monthly injections may be given up to 7 days before or after the scheduled dosing date.
Intramuscular dosage (Every 2 month regimen):
Adults: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the current antiretroviral therapy. One month later (i.e., Month 2), 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once. Then starting on Month 4, 600 mg cabotegravir IM and 900 mg rilpivirine IM once every 2 months. The injections may be given up to 7 days before or after the scheduled dosing date.
Children and Adolescents 12 to 17 years and weighing 35 kg or more: An initial dose of 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once on the last day of the current antiretroviral therapy. One month later (i.e., Month 2), 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once. Then starting on Month 4, 600 mg cabotegravir IM and 900 mg rilpivirine IM once every 2 months. The injections may be given up to 7 days before or after the scheduled dosing date.
-for use after missed injection(s):
NOTE: Reassess the appropriateness of resuming the extended-release injections in patients who have repeatedly missed or delayed the scheduled injections or have missed or delayed scheduled injections by more than 7 days and not taken oral therapy in the interm (i.e., unplanned missed injections). Plasma viral load testing should be performed before the transition. If plasma viremia is present, consider drug-resistance testing.
Intramuscular dosage (Once monthly regimen):
NOTE: If a patient plans to miss a scheduled injection by more than 7 days, the missed injection visits should be replaced with either cabotegravir 30 mg PO plus rilpivirine 25 mg PO once daily for a duration of up to 2 months OR any other fully suppressive oral antiretroviral regimen until the injections are resumed. The first dose of the selected oral regimen should be taken approximately 1 month (+/- 7 days) after the last extended-release injection was given. Continue the oral regimen until the day the extended-release injections are restarted. If the duration of oral therapy is expected to be greater than 2 months, use of oral cabotegravir plus rilpivirine is not recommended; an alternative oral regimen should be selected.
Adults: IF 1 TO 2 MONTHS HAVE ELAPSED since administration of the last extended-release injection, resume dosing with 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly as soon as possible. IF MORE THAN 2 MONTHS HAVE ELAPSED, reinitiate dosing 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once. Then continue the 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly dosing schedule.
Children and Adolescents 12 to 17 years weighing 35 kg or more: IF 1 TO 2 MONTHS HAVE ELAPSED since administration of the last extended-release injection, resume dosing with 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly as soon as possible. IF MORE THAN 2 MONTHS HAVE ELAPSED, reinitiate dosing 600 mg cabotegravir IM and 900 mg rilpivirine IM administered once. Then continue the 400 mg cabotegravir IM and 600 mg rilpivirine IM once monthly dosing schedule.
Intramuscular dosage (Every 2 month regimen):
NOTE: If a patient plans to miss a scheduled injection by more than 7 days, the missed injection visits should be replaced with either cabotegravir 30 mg PO plus rilpivirine 25 mg PO once daily for a duration of up to 2 months to replace 1 missed injection visit OR any other fully suppressive oral antiretroviral regimen until the injections are resumed. The first dose of the selected oral regimen should be taken approximately 2 months after the last extended-release injection was given. Continue the oral regimen until the day the extended-release injections are restarted. If the duration of oral therapy is expected to be greater than 2 months, use of oral cabotegravir plus rilpivirine is not recommended; an alternative oral regimen should be selected.
Adults: FOR INJECTION 2 (MONTH 2) IF 1 TO 2 MONTHS HAVE ELAPSED since administration of the last extended-release injection, resume dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections as soon as possible. Then continue to follow the every 2 month injection dosing schedule. FOR INJECTION 2 (MONTH 2) IF MORE THAN 2 MONTHS HAVE ELAPSED, reinitiate dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections, followed by the second initiation injection dose 1 month later. Then continue to follow the every 2 month injection dosing schedule thereafter. FOR INJECTION 3 OR LATER (MONTH 4 ONWARDS) IF 3 MONTHS OR LESS HAVE ELAPSED, resume dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections as soon as possible. Then continue to follow the every 2 month injection dosing schedule. FOR INJECTION 3 OR LATER (MONTH 4 ONWARDS) IF MORE THAN 3 MONTHS HAVE ELAPSED, reinitiate dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections, followed by the second initiation injection dose 1 month later. Then continue to follow the every 2 month injection dosing schedule thereafter.
Children and Adolescents 12 to 17 years weighing 35 kg or more: FOR INJECTION 2 (MONTH 2) IF 1 TO 2 MONTHS HAVE ELAPSED since administration of the last extended-release injection, resume dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections as soon as possible. Then continue to follow the every 2 month injection dosing schedule. FOR INJECTION 2 (MONTH 2) IF MORE THAN 2 MONTHS HAVE ELAPSED, reinitiate dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections, followed by the second initiation injection dose 1 month later. Then continue to follow the every 2 month injection dosing schedule thereafter. FOR INJECTION 3 OR LATER (MONTH 4 ONWARDS) IF 3 MONTHS OR LESS HAVE ELAPSED, resume dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections as soon as possible. Then continue to follow the every 2 month injection dosing schedule. FOR INJECTION 3 OR LATER (MONTH 4 ONWARDS) IF MORE THAN 3 MONTHS HAVE ELAPSED, reinitiate dosing with 600 mg cabotegravir IM and 900 mg rilpivirine IM injections, followed by the second initiation injection dose 1 month later. Then continue to follow the every 2 month injection dosing schedule thereafter.
-for patients switching from the once monthly regimen to the every 2 month regimen:
Intramuscular dosage:
Adults: Patients switching from the monthly continuation injection schedule to the every 2 month dosing schedule should receive 600 mg cabotegravir IM and 900 mg rilpivirine IM once 1 month after the last monthly continuation dose. Then follow the every 2 month injection dosing schedule thereafter.
Children and Adolescents 12 to 17 years weighing 35 kg or more: Patients switching from the monthly continuation injection schedule to the every 2 month dosing schedule should receive 600 mg cabotegravir IM and 900 mg rilpivirine IM once 1 month after the last monthly continuation dose. Then follow the every 2 month injection dosing schedule thereafter.
-for patients switching from the every 2 month regimen to the once monthly regimen:
Intramuscular dosage:
Adults: Patients switching from the every 2 month continuation injection schedule to the monthly dosing schedule should receive 400 mg cabotegravir IM and 600 mg rilpivirine IM once 2 months after the last continuation dose. Then administer injections monthly thereafter.
Children and Adolescents 12 to 17 years weighing 35 kg or more: Patients switching from the every 2 month continuation injection schedule to the monthly dosing schedule should receive 400 mg cabotegravir IM and 600 mg rilpivirine IM once 2 months after the last continuation dose. Then administer injections monthly thereafter.
Maximum Dosage Limits:
-Adults
600 mg per dose IM for cabotegravir; 900 mg per dose IM for rilpivirine.
-Geriatric
600 mg per dose IM for cabotegravir; 900 mg per dose IM for rilpivirine.
-Adolescents
weight 35 kg or more: 600 mg per dose IM for cabotegravir; 900 mg per dose IM for rilpivirine.
weight less than 35 kg: Safety and efficacy have not been established.
-Children
12 years and weight 35 kg or more: 600 mg per dose IM for cabotegravir; 900 mg per dose IM for rilpivirine.
1 to 11 years or weight less than 35 kg: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
Dosage adjustments are not required for mild to moderate renal impairment. Use with caution in patients with severe renal impairment (CrCl 15 to 29 mL/min) or end-stage renal disease (CrCl less than 15 mL/min) and monitor carefully for adverse effects.
*non-FDA-approved indication
Adagrasib: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Adefovir: (Major) Patients who are concurrently taking adefovir (a nucleotide analog) with antiretrovirals (i.e., anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Alfuzosin: (Moderate) Caution is advised when administering rilpivirine with alfuzosin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation and alfuzosin may also prolong the QT interval in a dose-dependent manner.
Aluminum Hydroxide: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Amiodarone: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with rilpivirine. Amisulpride causes dose- and concentration- dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
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; Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
Antacids: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Apalutamide: (Contraindicated) Coadministration of cabotegravir and apalutamide is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; apalutamide is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with rilpivirine since concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Moderate) Use caution if rilpivirine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in rilpivirine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rilpivirine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of rilpivirine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Moderate) Concomitant use of aripiprazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Armodafinil: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, rilpivirine should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Artemether; Lumefantrine: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as asenapine.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Aspirin, ASA; Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Atazanavir: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Atazanavir; Cobicistat: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Azithromycin: (Major) Concomitant use of rilpivirine and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
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.
Berotralstat: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Bexarotene: (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
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.
Buprenorphine: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Buprenorphine; Naloxone: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Butalbital; Acetaminophen: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Butalbital; Acetaminophen; Caffeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Butalbital; Acetaminophen; 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.
Butalbital; Aspirin; 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.
Calcium (oral): (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Calcium Acetate: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Calcium Carbonate: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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; Simethicone: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Simethicone: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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 Gluconate: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Calcium; Vitamin D: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Carbamazepine: (Contraindicated) Coadministration of cabotegravir and carbamazepine is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; carbamazepine is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Coadministration of carbamazepine and rilpivirine is contraindicated due to the potential for loss of virologic response and possible resistance to rilpivirine or the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rilpivirine is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer.
Cenobamate: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Ceritinib: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold.
Chloramphenicol: (Moderate) Close clinical monitoring is advised when administering chloramphenicol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Chloroquine: (Major) Avoid coadministration of chloroquine with rilpivirine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Chlorpheniramine; Pseudoephedrine: (Moderate) Administer oral zinc at least two hours before or four hours after taking oral cabotegravir. Zinc is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
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.
Chromium: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Cimetidine: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Cisapride: (Contraindicated) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Because of the potential for torsades de pointes, use of cisapride with rilpivirine is contraindicated.
Citalopram: (Major) Concomitant use of rilpivirine and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Clarithromycin: (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Class IA Antiarrhythmics: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Clofazimine: (Moderate) Concomitant use of clofazimine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Clozapine: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Codeine; Promethazine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Conivaptan: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
Crizotinib: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Dabrafenib: (Major) The concomitant use of dabrafenib and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Dabrafenib is a moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
Danazol: (Moderate) Close clinical monitoring is advised when administering danazol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Darunavir: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Darunavir; Cobicistat: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Dasatinib: (Moderate) Caution is advised when administering rilpivirine with dasatinib as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Delavirdine: (Major) Coadministration of delavirdine and rilpivirine is not recommended. If they are coadministered, close clinical monitoring is advised due to the increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Delavirdine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Deutetrabenazine: (Moderate) Caution is advised when administering rilpivirine with deutetrabenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Contraindicated) Concurrent use of dexamethasone (more than 1 dose) and rilpivirine is contraindicated. Concomitant use may decrease the exposure and efficacy of rilpivirine leading to potential development of viral resistance. Rilpivirine is a CYP3A substrate and dexamethasone is an inducer of CYP3A4.
Dexlansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Dextromethorphan; Quinidine: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Didanosine, ddI: (Moderate) While no dosage adjustments are required, because didanosine, ddI is administered on an empty stomach and rilpivirine is given with food, do not give didanosine within at least two hours before or at least four hours after rilpivirine.
Diltiazem: (Moderate) Close clinical monitoring is advised when administering diltiazem with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Diltiazem is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Disopyramide: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Dofetilide: (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Donepezil: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Dronedarone: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Efavirenz: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
Elagolix: (Major) The concomitant use of elagolix and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Elagolix is a weak to moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
Elagolix; Estradiol; Norethindrone acetate: (Major) The concomitant use of elagolix and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Elagolix is a weak to moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
Eliglustat: (Moderate) Caution is advised when administering rilpivirine with eliglustat as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Encorafenib: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated.
Entrectinib: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Enzalutamide: (Contraindicated) Concurrent use of enzalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Enzalutamide is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Eribulin: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Erythromycin: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as erythromycin.
Escitalopram: (Moderate) Concomitant use of escitalopram and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Eslicarbazepine: (Contraindicated) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
Esomeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Etrasimod: (Moderate) Concomitant use of etrasimod and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
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.
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.
Fedratinib: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor.
Ferric Maltol: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Fexinidazole: (Major) Concomitant use of fexinidazole and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Flecainide: (Major) Concomitant use of rilpivirine and flecainide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Fluconazole: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Fluphenazine: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Flutamide: (Moderate) Close clinical monitoring is advised when administering flutamide with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Flutamide is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
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.
Fosamprenavir: (Moderate) Coadministration of rilpivirine with fosamprenavir may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as rilpivirine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Contraindicated) Coadministration of cabotegravir and fosphenytoin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; fosphenytoin is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Fostemsavir: (Moderate) Caution is advised when administering rilpivirine with fostemsavir due to the potential for QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Moderate) Caution is advised when administering rilpivirine with gemifloxacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and rilpivirine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Granisetron: (Moderate) Use granisetron with caution in combination with rilpivirine due to the risk of QT prolongation. Granisetron has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Haloperidol: (Moderate) Caution is advised when administering rilpivirine with haloperidol as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of rilpivirine and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Ibuprofen; 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.
Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Idelalisib: (Moderate) Coadministration of rilpivirine with idelalisib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor.
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.
Indinavir: (Moderate) Close clinical monitoring is advised when administering indinavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Indinavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Iron Salts: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Iron: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with rilpivirine may result in increased serum concentrations of rilpivirine. Rilpivirine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Coadministration of cabotegravir and rifampin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifampin is an inducer of UGT. Coadministration with rifampin decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Isoniazid, INH; Rifampin: (Contraindicated) Coadministration of cabotegravir and rifampin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifampin is an inducer of UGT. Coadministration with rifampin decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Itraconazole: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with itraconazole.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Lansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Lefamulin: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Lenacapavir: (Moderate) Coadministration of rilpivirine with lenacapavir may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Lithium: (Moderate) Concomitant use of lithium and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Lonafarnib: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Loperamide: (Moderate) Caution is advised when administering rilpivirine with loperamide as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Moderate) Caution is advised when administering rilpivirine with loperamide as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Major) Avoid coadministration of lopinavir with rilpivirine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Lorlatinib: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as rilpivirine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Magnesium Citrate: (Moderate) Administer oral magnesium citrate at least two hours before or four hours after taking oral cabotegravir. Magnesium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Magnesium Hydroxide: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Magnesium Salts: (Moderate) Administer antacids at least two hours before or four hours after taking oral cabotegravir. The chemical structure of these antacids contains aluminum or magnesium which can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (Moderate) Administer oral magnesium oxide at least two hours before or four hours after taking oral cabotegravir. Magnesium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir. (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.
Maprotiline: (Moderate) Caution is advised when administering rilpivirine with maprotiline as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Mavacamten: (Moderate) Coadministration of rilpivirine with mavacamten may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Methadone: (Major) Close clinical monitoring is advised with coadministration. Use of these drugs together may cause the plasma concentration of methadone to decrease, thereby resulting in decreased methadone efficacy. No dose adjustments are required when initiating concurrent treatment; however, the maintenance dose of methadone may need to be adjusted in some patients. In addition, due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with methadone. A careful assessment of treatment risks versus benefits should be conducted prior to coadministration. When initiating concurrent treatment no dose adjustments are required; however, the dose of methadone may need to be adjusted during maintenance therapy. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
Methohexital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Metronidazole: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
Midostaurin: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Mifepristone: (Major) Avoid use together if possible due to the risk of elevated rilpivirine exposure and a combined risk for QT prolongation. Consider alternatives to rilpivirine when coadministered with a drug with a known risk of QT prolongation and torsade de pointes (TdP), such as mifepristone when it is used for chronic hormonal conditions, such as Cushing's syndrome. Mifepristone is an inhibitor of CYP3A4; rilpivirine is a CYP3A4 substrate. Coadministration is likely to increase rilpivirine plasma concentrations. Monitor for rilpivirine-related side effects, including rash, mood changes or depression, fast, irregular heart rate, and hepatotoxicity. To minimize the risk of QT prolongation, the lowest effect dose of mifepristone should always be used.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
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.
Mobocertinib: (Major) Concomitant use of mobocertinib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Modafinil: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Moxifloxacin: (Major) Concurrent use of rilpivirine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nafcillin: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Naproxen; Esomeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
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. Concomitant use may also cause a significant decrease in rilpivirine plasma concentrations and, thus, a loss of therapeutic effect. Rilpivirine is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nicardipine: (Moderate) Close clinical monitoring is advised when administering nicardipine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nicardipine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Nirmatrelvir; Ritonavir: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
Nirogacestat: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
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.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Olanzapine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Olanzapine; Samidorphan: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Coadministration of rifabutin and cabotegravir; rilpivirine injection is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir and rilpivirine, which may result in potential loss of virologic response and development of resistance. Rifabutin may be coadministered with cabotegravir extended-release injection; however, dosage adjustments are needed. When rifabutin is started before or concomitantly with the first initiation injection of cabotegravir injection, the recommended dosing of cabotegravir injection is one 600-mg injection, followed 2 weeks later by a second 600-mg initiation injection and monthly thereafter while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of cabotegravir injection is 600 mg monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of cabotegravir injection is 600 mg every 2 months. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifabutin is an inducer of UGT. Coadministration with rifabutin decreased cabotegravir exposure by 33%. Rifabutin may be coadministered with oral cabotegravir monotherapy. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Omeprazole; Sodium Bicarbonate: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Ondansetron: (Major) Concomitant use of rilpivirine and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Oritavancin: (Major) Rilpivirine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of rilpivirine may be reduced if these drugs are administered concurrently.
Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with rilpivirine as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Osimertinib: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Supratherapeutic doses of rilpivirine (75 to 300 mg per day) have caused QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxcarbazepine: (Contraindicated) Coadministration of cabotegravir and oxcarbazepine is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; oxcarbazepine is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of oxcarbazepine and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Oxcarbazepine is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking rilpivirine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Pacritinib: (Major) Concomitant use of pacritinib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Panobinostat: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Pantoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Pazopanib: (Major) Concurrent use of pazopanib and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be continued, closely monitor the patient for QT interval prolongation. Pazopanib has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and rilpivirine, a CYP3A4 substrate, may cause an increase in systemic concentrations of rilpivirine.
Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Pentamidine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with pentamidine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Pentamidine has also been associated with QT prolongation.
Pentobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Perphenazine: (Minor) Caution is advised when administering rilpivirine with perphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Caution is advised when administering rilpivirine with perphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pexidartinib: (Moderate) Coadministration of rilpivirine with pexidartinib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Contraindicated) Coadministration of cabotegravir and phenobarbital is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenobarbital is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Coadministration of cabotegravir and phenobarbital is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenobarbital is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Phentermine; Topiramate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Phenytoin: (Contraindicated) Coadministration of cabotegravir and phenytoin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenytoin is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP) and coadministration with other drugs associated with a possible risk for QT prolongation and TdP, such as rilpivirine, should be avoided.
Pitolisant: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Polysaccharide-Iron Complex: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking rilpivirine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Posaconazole: (Contraindicated) Concurrent use of posaconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of ripivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for rilpivirine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Primidone: (Contraindicated) Coadministration of cabotegravir and primidone is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenobarbital, the active metabolite of primidone, is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Procainamide: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Prochlorperazine: (Minor) Caution is advised when administering rilpivirine with prochlorperazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Propafenone: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Proton pump inhibitors: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Pyridoxine, Vitamin B6: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Quetiapine: (Major) Concomitant use of rilpivirine and quetiapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
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.
Quizartinib: (Major) Concomitant use of quizartinib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Rabeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Ranitidine: (Moderate) Coadministration with ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
Ranolazine: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Relugolix: (Moderate) Caution is advised when administering rilpivirine with relugolix. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is advised when administering rilpivirine with relugolix. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Repotrectinib: (Moderate) Coadministration of rilpivirine with repotrectinib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Ribociclib: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Major) Coadministration of rifabutin and cabotegravir; rilpivirine injection is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir and rilpivirine, which may result in potential loss of virologic response and development of resistance. Rifabutin may be coadministered with cabotegravir extended-release injection; however, dosage adjustments are needed. When rifabutin is started before or concomitantly with the first initiation injection of cabotegravir injection, the recommended dosing of cabotegravir injection is one 600-mg injection, followed 2 weeks later by a second 600-mg initiation injection and monthly thereafter while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of cabotegravir injection is 600 mg monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of cabotegravir injection is 600 mg every 2 months. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifabutin is an inducer of UGT. Coadministration with rifabutin decreased cabotegravir exposure by 33%. Rifabutin may be coadministered with oral cabotegravir monotherapy. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Rifampin: (Contraindicated) Coadministration of cabotegravir and rifampin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifampin is an inducer of UGT. Coadministration with rifampin decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Rifapentine: (Contraindicated) Coadministration of cabotegravir and rifapentine is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; rifapentine is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of rifapentine and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifapentine is a strong CYP3A4 inducer, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Risperidone: (Moderate) Use risperidone and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ritlecitinib: (Moderate) Coadministration of rilpivirine with ritlecitinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ropeginterferon alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Saquinavir: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
Secobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with rilpivirine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Sertraline: (Moderate) Concomitant use of sertraline and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
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.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Sodium Bicarbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Administer oral iron at least two hours before or four hours after taking oral cabotegravir. Iron is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Solifenacin: (Moderate) Caution is advised when administering rilpivirine with solifenacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Solifenacin has also been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
Sorafenib: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Sotalol: (Major) Concomitant use of sotalol and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Sotorasib: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Sunitinib can prolong the QT interval.
Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Telavancin: (Moderate) Caution is advised when administering rilpivirine with telavancin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Telavancin has also been associated with QT prolongation.
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.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and TdP. Thioridazine is considered contraindicated for use along with rilpivirine which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Ticagrelor: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
Tipranavir: (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Tolterodine: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Topiramate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Toremifene: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Trandolapril; Verapamil: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Trazodone: (Major) Concomitant use of trazodone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Trifluoperazine: (Minor) Caution is advised when administering rilpivirine with trifluoperazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trifluoperazine is also associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Tucatinib: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Vandetanib: (Major) Avoid coadministration of vandetanib with rilpivirine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Vardenafil: (Moderate) Concomitant use of vardenafil and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Vemurafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
Venlafaxine: (Moderate) Concomitant use of venlafaxine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
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.
Vitamin D: (Moderate) Administer oral calcium at least two hours before or four hours after taking oral cabotegravir. Calcium is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Voclosporin: (Moderate) Concomitant use of voclosporin and rilpivirine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Both voclosporin and rilpivirine have been associated with QT prolongation at supratherapeutic doses.
Vonoprazan: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Vonoprazan; Amoxicillin: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (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.
Voriconazole: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole.
Vorinostat: (Moderate) Caution is advised when administering rilpivirine with vorinostat. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Vorinostat therapy is also associated with a risk of QT prolongation.
Voxelotor: (Moderate) Coadministration of rilpivirine with voxelotor may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
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.
Zinc Salts: (Moderate) Administer oral zinc at least two hours before or four hours after taking oral cabotegravir. Zinc is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Zinc: (Moderate) Administer oral zinc at least two hours before or four hours after taking oral cabotegravir. Zinc is a polyvalent cation that can bind cabotegravir in the GI tract. Taking these drugs simultaneously may result in reduced oral bioavailability of cabotegravir.
Ziprasidone: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Cabotegravir; rilpivirine is a combination antiretroviral agent containing an integrase strand transfer inhibitor (INSTI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI). During clinical testing, administration of these drugs together was not antagonistic.
Cabotegravir: Cabotegravir inhibits HIV integrase by binding to the integrase active site. This binding of cabotegravir prevents insertion of unintegrated linear viral DNA into the host DNA by strand transfer, which is essential for HIV replication.
Rilpivirine: Rilpivirine is a diarylpyrimidine NNRTI. 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. Human cellular DNA polymerase alpha, beta, and gamma are not inhibited by rilpivirine.
Pooled data from FLAIR (Week 124 analysis) and ATLAS (Week 96 analysis) identified 8 confirmed virologic failures with cabotegravir plus rilpivirine (n = 8 of 591; 1.4%). Of the 8 virologic failures, 7 had treatment-emergent NNRTI resistance-associated substitutions in reverse transcriptase (i.e., K101E, V106V/A, V108I, E138A/G/K, H221H/L, or M230L); 6 showed reduced phenotypic susceptibility to rilpivirine (range: 2- to 27-fold). One additional subject in the ATLAS Extension Switch on cabotegravir plus rilpivirine had emergent NNRTI resistance substitution E138A at Week 80 with HIV-1 RNA more than 50 copies/mL and less than 200 copies/mL. Treatment-emergent INSTI resistance-associated substitutions were also identified in 5 of the virologic failures and included Q148R (n = 2, 5- and 9-fold reduced susceptibility to cabotegravir), G140R (n = 1; 7-fold reduced susceptibility), N155H (n = 1; 3-fold reduced susceptibility), or N155H+R263K (n = 1; 9-fold reduced susceptibility). There was another confirmed virologic failure subject at Week 112 in FLAIR who had switched to cabotegravir plus rilpivirine direct to injection at Week 100; however, there were no INSTI resistance-associated substitutions detected at failure. Data from the ATLAS-2M (every 2 month injection) trial identified 11 confirmed virologic failures through Week 48: 9 in the every 2 month treatment arm and 2 in the monthly treatment arm. Four of the 9 failures in the every 2 month arm transitioned from the oral current antiretroviral regimen arm of the ATLAS trial into the ATLAS-2M trial. In the every 2 month treatment arm, 8 of the 9 failures had NNRTI resistance-associated substitutions (E138E/K+V179V/I, K101E+E138A, A98G+K103N, E138K, V179I+Y188L+P225H, Y188L, K103N+E138A, or K101E). Decreased rilpivirine susceptibility for these 8 patient isolates ranged from 2- to 30-fold. Six of the 8 with NNRTI resistance-associated substitutions also had INSTI resistance-associated substitutions [L74I+Q148Q/R+N155N/H (n = 2), L74I+T97A+N155H, L74I+N155H, N155H, or L74I+Q148R]. The cabotegravir reduced susceptibility ranged from 1- to 9-fold. In the monthly treatment arm of the ATLAS-2M trial, both of the confirmed failures had NNRTI resistance-associated substitutions (K101E+M230L or Y188F+G190Q) with decreased susceptibility to rilpivirine of 17- and more than 119.2-fold, respectively. Both patients also had INSTI resistance-associated substitutions (N155N/H or Q148R+E138E/K) with decreased cabotegravir susceptibility of 2- and 5-fold, respectively.
Cross-resistance has been observed among INSTIs and among NNRTIs.
Avoid the use of rilpivirine in patients with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The 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.
Cabotegravir; rilpivirine is administered intramuscularly via 2 separate injections.
-Cabotegravir: Once in systemic circulation, cabotegravir is more than 99.8% bound to plasma proteins and has a blood-to-plasma ratio of 0.52; the CSF-to-plasma concentration ratio is 0.003. The drug is primarily metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT1A1) with minor contributions from UGT1A9. Excretion occurs via feces (59% of the dose) and urine (27% of the dose). The mean elimination half-life of cabotegravir is 5.6 to 11.5 weeks; the prolonged half-life is a result of slow absorption from the injection site.
-Rilpivirine: Rilpivirine is 99.7% bound to human plasma protein (predominantly to albumin) and has a blood-to-plasma ratio of 0.7; the CSF-to-plasma concentration ratio is 0.01. Metabolism occurs primarily via oxidation by the hepatic isoenzyme CYP3A4. Excretion occurs mainly through the feces (85%) with only 6% of the dose eliminated in the urine. The mean elimination half-life is 13 to 28 weeks; the prolonged half-life is a result of slow absorption from the injection site.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A1, UGT1A9, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT1/3)
Rilpivirine is primarily metabolized by CYP3A4; cabotegravir is metabolized by UGT1A1 with some minor contributions from UGT1A9. Inhibitors and inducers of CYP3A4 may increase and decrease, respectively, the plasma concentrations of rilpivirine. Concurrent administration with strong inducers of UGT1A1 and UGT1A9 is expected to decrease cabotegravir plasma concentrations; no clinically relevant interactions are expected during concurrent administration with UGT1A1 inhibitors. In vitro, cabotegravir is also a substrate for the drug transporters P-gp and BCRP; however, due to the drugs high permeability, no alteration in cabotegravir absorption is expected when administered with P-gp or BCRP inhibitors. Cabotegravir inhibits renal OAT1 and OAT3 in vitro. Based on modeling, cabotegravir may increase the exposure of OAT1/3 substrates by up to about 80%.
-Route-Specific Pharmacokinetics
Intramuscular Route
-Cabotegravir: The pharmacokinetics of intramuscularly administered cabotegravir (i.e., 400 mg and 600 mg doses) compared to the oral lead-in dose (i.e., 30 mg once daily) at steady-state are as follows:
--Exposure (AUC), peak concentration (Cmax) and trough (Cmin) for the oral lead-in dose are 145 mcg x hour/mL, 8 mcg/mL, and 4.6 mcg/mL, respectively.
-AUC, Cmax, and Cmin for the 600 mg IM initiation dose after oral lead-in are 1,591 mcg x hour/mL, 8 mcg/mL, and 1.5 mcg/mL, respectively.
-Cmax and Cmin for the 600 mg IM initiation dose with direct to injection are 1.89 mcg/mL and 1.43 mcg/mL, respectively.
-AUC, Cmax, and Cmin for the 400 mg IM monthly dose are 2,415 mcg x hour/mL, 4.2 mcg/mL, and 2.8 mcg/mL, respectively.
-AUC, Cmax, and Cmin for the 600 mg IM every 2 month dose are 3,764 mcg x hour/mL, 4 mcg/mL, and 1.6 mcg/mL, respectively.
-Rilpivirine: The pharmacokinetics of intramuscularly administered rilpivirine (i.e., 600 mg and 900 mg doses) compared to the oral lead-in dose (i.e., 25 mg once daily) at steady-state are as follows:
--AUC, Cmax, and Cmin for the oral lead-in dose are 2,083 ng x hour/mL, 116 ng/mL, and 79.4 ng/mL, respectively.
-AUC, Cmax, and Cmin for the 900 mg IM initiation dose after oral lead-in are 44,842 ng x hour/mL, 144 ng/mL, and 41.9 ng/mL, respectively.
-Cmax and Cmin for the 900 mg IM initiation dose with direct to injection are 68 ng/mL and 48.9 ng/mL, respectively.
-AUC, Cmax, and Cmin for the 600 mg IM monthly dose are 68,324 ng x hour/mL, 121 ng/mL, and 85.8 ng/mL, respectively.
-AUC, Cmax, and Cmin for the 900 mg IM every 2 month dose are 132,450 ng x hour/mL, 138 ng/mL, and 68.9 ng/mL, respectively.
NOTE: The above Cmin concentrations were obtained 24 hours after the oral cabotegravir and rilpivirine doses, 1 month after the IM monthly doses, and 2 months after the IM doses given every 2 months.
NOTE: The Cmax of the initial 600 mg cabotegravir and 900 mg rilpivirine IM doses after oral lead-in primarily reflect concentrations of the oral dosing, as the initial injections were administered on the same day as the last oral dose; however, the AUC and Cmin reflect the initial injections of cabotegravir and rilpivirine. The Cmax of the initial 600 mg cabotegravir and 900 mg rilpivirine IM doses with direct to injection were obtained 1 week after the initial injection; AUC were not calculated based on observed data.
-Special Populations
Hepatic Impairment
-Cabotegravir: No clinically significant differences in the pharmacokinetics of cabotegravir are expected in mild to moderate hepatic impairment (Child-Pugh A and B). Pharmacokinetic studies in patients with severe hepatic impairment (Child-Pugh C) have not been conducted. A pharmacokinetic analysis found the concentrations of cabotegravir in patients who were hepatitis C virus (HCV) antibody-positive at baseline were similar to those in the overall study population.
-Rilpivirine: No clinically significant differences in the pharmacokinetics of rilpivirine have been observed in mild to moderate hepatic impairment (Child-Pugh A and B). Pharmacokinetic parameters have not been studied in patients with severe hepatic impairment (Child-Pugh Class C). A pharmacokinetic analysis found the concentrations of rilpivirine in patients who were HCV antibody-positive at baseline were similar to those in the overall study population.
Renal Impairment
-Cabotegravir: No clinically significant differences in the pharmacokinetics of cabotegravir are expected with mild, moderate, or severe renal impairment. Pharmacokinetic studies have not been conducted in patients with end-stage renal disease not on dialysis (i.e., CrCl less than 15 mL/min). Dialysis is not expected to alter exposures of cabotegravir, as the drug is greater than 99% bound to plasma proteins.
-Rilpivirine: Analysis of rilpivirine pharmacokinetics indicate that exposure (AUC) in patients with mild renal impairment is comparable to the exposure observed in patients with normal renal function. There is limited information available regarding the pharmacokinetics in patients with moderate to severe renal impairment or in patients with end-stage renal disease. Dialysis is not likely to remove rilpivirine from plasma because a large percentage of circulating drug is bound to plasma proteins (greater than 99%).
Pediatrics
A population pharmacokinetic analysis found no clinically relevant differences in exposures of cabotegravir or rilpivirine between adolescents with HIV (age 12 years and older weighing at least 35 kg) and adults (with or without HIV). The predicted pharmacokinetic parameters following treatment with cabotegravir and rilpivirine in adolescents (12 to 17 years weighing at least 35 kg) are listed below.
-Cabotegravir: The pharmacokinetics of intramuscularly administered cabotegravir (i.e., 400 mg and 600 mg doses) compared to the oral lead-in dose (i.e., 30 mg once daily) at steady-state are as follows:-Exposure (AUC), peak concentration (Cmax) and trough (Cmin) for the oral lead-in dose are 193 mcg x hour/mL, 14.4 mcg/mL, and 5.79 mcg/mL, respectively.
-AUC, Cmax, and Cmin for the 600 mg IM initiation dose after oral lead-in are 2,123 mcg x hour/mL, 11.2 mcg/mL, and 1.84 mcg/mL, respectively.
-AUC, Cmax, and Cmin for the 400 mg IM monthly dose are 3,222 mcg x hour/mL, 7.88 mcg/mL, and 3.65 mcg/mL, respectively.
-AUC, Cmax, and Cmin for the 600 mg IM every 2 month dose are 4,871 mcg x hour/mL, 7.23 mcg/mL, and 2.01 mcg/mL, respectively.
-Rilpivirine: The pharmacokinetics of intramuscularly administered rilpivirine (i.e., 600 mg and 900 mg doses) compared to the oral lead-in dose (i.e., 25 mg once daily) at steady-state are as follows:-AUC, Cmax, and Cmin for the oral lead-in dose are 2,389 ng x hour/mL, 144 ng/mL, and 82.5 ng/mL, respectively.
-AUC, Cmax, and Cmin for the 900 mg IM initiation dose after oral lead-in are 41,515 ng x hour/mL, 156 ng/mL, and 39.7 ng/mL, respectively.
-AUC, Cmax, and Cmin for the 600 mg IM monthly dose are 74,717 ng x hour/mL, 128 ng/mL, and 97.3 ng/mL, respectively.
-AUC, Cmax, and Cmin for the 900 mg IM every 2 month dose are 114,139 ng x hour/mL, 111 ng/mL, and 63.1 ng/mL, respectively.
NOTE: The above Cmin concentrations were obtained 24 hours after the oral cabotegravir and rilpivirine doses, 1 month after the IM monthly doses, and 2 months after the IM doses given every 2 months.
NOTE: The Cmax of the initial 600 mg cabotegravir and 900 mg rilpivirine IM doses after oral lead-in primarily reflect concentrations of the oral dosing, as the initial injections were administered on the same day as the last oral dose; however, the AUC and Cmin reflect the initial injections of cabotegravir and rilpivirine.
Gender Differences
No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine have been observed based on gender.
Ethnic Differences
No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine have been observed based on ethnicity.
Obesity
No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine have been observed based on body mass index.
Other
UGT1A1 Polymorphism
No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine have been observed based on UGT1A1 polymorphism.
Pregnancy
-Cabotegravir: No studies have been conducted on the pharmacokinetics of intramuscular injections of long-acting cabotegravir; rilpivirine during pregnancy. However, a physiologically-based pharmacokinetic model of pregnant individuals starting long-acting cabotegravir; rilpivirine early in the second trimester predicted a 29.5% reduction in the first trough. After the sixth injection in the second and third trimesters, plasma concentrations were 31.1% lower. These reductions were attributed to the predicted induction of uridine diphosphate (UDP)-glucuronosyl transferase (UGT1A1) during the second and third trimesters.
-Rilpivirine: No studies have been conducted on the pharmacokinetics of intramuscular injections of long-acting cabotegravir; rilpivirine during pregnancy. However, a physiologically-based pharmacokinetic model of pregnant individuals starting long-acting cabotegravir; rilpivirine early in the second trimester predicted a 23% reduction in the first trough. After the sixth injection in the second and third trimesters, plasma concentrations were 29.2% lower. These reductions were attributed to the predicted induction of CYP3A4 during the second and third trimesters. In a study of 80 female oral rilpivirine recipients (second trimester, n = 19; third trimester, n = 31; postpartum, n = 30), reductions in systemic drug exposure (AUC) and trough concentrations (Cmin) were observed during pregnancy as compared to postpartum. Median Cmin values recorded during the second trimester, third trimester, and postpartum period were 65 ng/mL, 56 ng/mL, and 81 ng/mL, respectively. The median AUC value in the third trimester was 1.70 ng x hr/mL, compared to 2.39 ng x hr/mL during postpartum. Despite the lower AUC values during pregnancy, more than 90% of women in both the second and third trimesters achieved the target concentration of 0.88 ng x hr/mL. Similar results were observed in another study, where exposure to oral rilpivirine was 30% to 40% lower during pregnancy (second and third trimesters) than during the postpartum period. In this study, the mean Cmin values observed during the second trimester (n = 15), third trimester (n = 13), and postpartum period (n = 11) were 54.3 ng/mL, 52.9 ng/mL, and 84 ng/mL, respectively. The mean AUCs during the second and third trimesters were 1,792 and 1,762 ng x hour/mL, respectively, compared to the postpartum AUC of 2,714 ng x hour/mL. These reductions in exposures are not considered clinically relevant in patients who are virologically suppressed; therefore, no dosage adjustments are recommended. Rilpivirine is more than 99% bound to plasma proteins during pregnancy and the postpartum period and has moderate to high placental transfer to the fetus.