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  • CLASSES

    Protease Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Protease inhibitor (PI)
    For human immunodeficiency virus (HIV) infection when used in combination with other antiretroviral agents
    HIV strains resistant to other PIs are responsive to darunavir

    COMMON BRAND NAMES

    Prezista

    HOW SUPPLIED

    Prezista Oral Susp: 1mL, 100mg
    Prezista Oral Tab: 75mg, 150mg, 600mg, 800mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.
    Treatment-naive patients or treatment-experienced patients with no darunavir resistance associated substitutions.
    Oral dosage
    Adults

    800 mg PO once daily with ritonavir 100 mg PO once daily. HIV guidelines suggest using only twice-daily dosing (600 mg darunavir with 100 mg ritonavir PO) during pregnancy; however according to the manufacturer, the once-daily regimen may be considered for pregnant women who: are stable on the once-daily regimen prior to pregnancy; virologically suppressed (i.e., HIV RNA less than 50 copies/mL); and in whom switching to twice-daily regimen would compromise tolerability or compliance.

    Children and Adolescents weighing 40 kg or more

    800 mg PO once daily with ritonavir 100 mg PO once daily. However, HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children and Adolescents weighing 30 to 39 kg  

    675 mg PO once daily with ritonavir 100 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children 3 years and older weighing 15 to 29 kg   

    600 mg PO once daily with ritonavir 100 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children 3 years and older weighing 14 kg

    490 mg PO once daily with ritonavir 96 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children 3 years and older weighing 13 kg

    455 mg PO once daily with ritonavir 80 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children 3 years and older weighing 12 kg

    420 mg PO once daily with ritonavir 80 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children 3 years and older weighing 11 kg

    385 mg PO once daily with ritonavir 64 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Children 3 years and older weighing 10 kg

    350 mg PO once daily with ritonavir 64 mg PO once daily. However, the HIV treatment guidelines do not recommend that once-daily darunavir dosing be used as initial therapy in children younger than 12 years due to lack of efficacy data in this population. A switch to once-daily therapy may be considered in patients who have undetectable viral loads on twice-daily therapy to enhance ease of use and support compliance.

    Treatment-experienced patients with at least one darunavir resistance associated substitution.
    NOTE: Twice-daily dosing is also recommended as initial therapy in treatment-naive patients younger than 12 years by the HIV guidelines.
    Oral dosage
    Adults

    600 mg PO twice daily with ritonavir 100 mg PO twice daily. Twice daily dosing is also recommended when genotypic testing is not feasible. Guidelines suggest using only twice-daily dosing during pregnancy.

    Children and Adolescents weighing 40 kg or more

    600 mg PO twice daily with ritonavir 100 mg PO twice daily.

    Children and Adolescents weighing 30 to 39 kg

    450 mg PO twice daily with ritonavir 100 mg PO twice daily is recommended by HIV guidelines; 450 mg PO twice daily with ritonavir 60 mg PO twice daily is the FDA-approved dosage.

    Children 3 years and older weighing 15 to 29 kg

    375 mg PO twice daily with ritonavir 48 mg PO twice daily.

    Children 3 years and older weighing 14 kg

    280 mg PO twice daily with ritonavir 48 mg PO twice daily.

    Children 3 years and older weighing 13 kg

    260 mg PO twice daily with ritonavir 40 mg PO twice daily.

    Children 3 years and older weighing 12 kg

    240 mg PO twice daily with ritonavir 40 mg PO twice daily.

    Children 3 years and older weighing 11 kg

    220 mg PO twice daily with ritonavir 32 mg PO twice daily.

    Children 3 years and older weighing 10 kg  

    200 mg PO twice daily with ritonavir 32 mg PO twice daily.

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

    Guidelines recommend darunavir 800 mg PO once daily boosted with ritonavir 100 mg PO once daily in combination with either tenofovir or zidovudine and either emtricitabine or lamivudine as acceptable HIV post-exposure prophylaxis (PEP) regimens. Alternative darunavir/ritonavir dosing is 600 mg/100 mg PO twice daily. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

    For human immunodeficiency virus (HIV) prophylaxis† after nonoccupational exposure, including sexual assault.
    NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
    Oral dosage
    Adults

    800 mg PO once daily boosted with ritonavir 100 mg PO once daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine (patients with renal dysfunction [CrCl 59 mL/minute or less]) for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in adults. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Adolescents

    800 mg PO once daily boosted with ritonavir 100 mg PO once daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine (patients with renal dysfunction [CrCl 59 mL/minute or less]) for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in adolescents. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children weighing 40 kg or more

    600 mg PO twice daily boosted with ritonavir 100 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children weighing 30 to 39 kg

    450 mg PO twice daily boosted with ritonavir 100 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 3 years and older weighing 15 to 29 kg

    375 mg PO twice daily boosted with ritonavir 48 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 3 years and older weighing 14 kg

    280 mg PO twice daily boosted with ritonavir 48 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 3 years and older weighing 13 kg

    260 mg PO twice daily boosted with ritonavir 40 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 3 years and older weighing 12 kg

    240 mg PO twice daily boosted with ritonavir 40 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 3 years and older weighing 11 kg

    220 mg PO twice daily boosted with ritonavir 32 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    Children 3 years and older weighing 10 kg

    200 mg PO twice daily boosted with ritonavir 32 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1200 mg/day PO.

    Geriatric

    1200 mg/day PO.

    Adolescents

    weighing 40 kg or more: 1200 mg/day PO.
    weighing 30 to 39 kg: 900 mg/day PO.

    Children

    3 to 12 years weighing 40 kg or more: 1200 mg/day PO.
    3 to 12 years weighing 30 to 39 kg: 900 mg/day PO.
    3 to 12 years weighing 15 to 29 kg: 750 mg/day PO.
    3 to 12 years weighing 14 to 14.9 kg: 560 mg/day PO.
    3 to 12 years weighing 13 to 13.9 kg: 520 mg/day PO.
    3 to 12 years weighing 12 to 12.9 kg: 480 mg/day PO.
    3 to 12 years weighing 11 to 11.9 kg: 440 mg/day PO.
    3 to 12 years weighing 10 to 10.9 kg: 400 mg/day PO.
    3 to 12 years weighing less than 10 kg: Not recommended.
    younger than 3 years: Not recommended.

    Infants

    Not recommended.

    Neonates

    Not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage adjustments are not necessary for patients with mild or moderate hepatic impairment. Darunavir is not recommended for use in patients with severe hepatic impairment; no pharmacokinetic or safety data are available.

    Renal Impairment

    No dose adjustment is required in patients with mild or moderate renal impairment. Specific guidelines for dosage adjustments in severe renal impairment are not available; however a decrease in clearance is not expected because renal clearance of darunavir is limited.
     
     
    Intermittent hemodialysis
    Darunavir is not expected to be significantly removed by hemodialysis.
     
    Peritoneal dialysis
    Darunavir is not expected to be significantly removed by peritoneal dialysis.

    ADMINISTRATION

    Oral Administration

    Administer with food.
    Must be administered with a pharmacokinetic enhancer (i.e., cobicistat or low dose ritonavir) to assure appropriate serum concentrations.

    Oral Liquid Formulations

    Shake well before each use.
    Administer using the oral dosing syringe supplied by the manufacturer.
    Rinse measuring device after each administration and before storage.

    STORAGE

    Prezista:
    - Avoid excessive heat (above 104 degrees F)
    - Do not freeze
    - Do not refrigerate
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Darunavir is indicated for use in conjunction with a pharmacokinetic enhancer (i.e., cobicistat or low dose ritonavir) to assure appropriate darunavir concentrations; DO NOT use without a concurrently administered pharmacokinetic enhancer. Darunavir; cobicistat is available as a co-formulated combination product.
     
    Genotypic or phenotypic testing of HIV strains and/or a detailed medication treatment history should guide the use of darunavir in each individual patient.
     
    Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Health care providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities. [46638] [42452]

    Sulfonamide hypersensitivity

    Darunavir contains a sulfonamide moiety and should, therefore, be used with caution and appropriate monitoring in patients with a known sulfonamide hypersensitivity.

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

    Drug-induced hepatitis (including acute hepatitis and cytolytic hepatitis) has been reported with use of darunavir; in clinical trials, hepatitis was reported in 0.5% of patients receiving darunavir with ritonavir. Patients with preexisting hepatic disease or dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities (e.g., jaundice), including severe hepatic adverse events. Postmarketing cases of hepatic injury (unspecified), including fatalities, have been reported. The cases have generally occurred in patients with advanced HIV disease receiving multiple concomitant medications, having co-morbidities including hepatitis B and HIV coinfection or hepatitis C and HIV coinfection, and developing immune reconstitution syndrome. A causal relationship with darunavir has not been established. Prior to and during treatment with darunavir, monitor hepatic function with appropriate laboratory testing. Increased monitoring of AST/ALT concentrations should be considered in patients with underlying chronic hepatitis, especially during the first several months of darunavir treatment. Consider interrupting or discontinuing treatment if there is evidence of new or worsening hepatic dysfunction (including clinically significant elevation of hepatic enzymes and symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly).[32432] HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweigh the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral-naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Patients that present with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. All patients who are coinfected with HIV and HBV should be started on a fully suppressive ARV regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide 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. [46638] [34362]

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

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

    Diabetes mellitus, diabetic ketoacidosis, hyperglycemia

    Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during treatment with protease inhibitors, including darunavir. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

    Bleeding, hemophilia

    Protease inhibitors, such as darunavir, should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A casual relationship has not been established.

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend darunavir boosted with ritonavir as a preferred protease inhibitor-based treatment regimen for use in pregnant women and women who are trying to conceive. Available data from the Antiretroviral Pregnancy Registry (APR), which includes over 640 first trimester exposures to darunavir, 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. The prevalence of birth defects when exposure occurred in the first trimester was 3.7% (95% CI: 2.4 to 5.5). Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to darunavir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[27468] [23512]

    Children, infants, neonates

    The safety, efficacy, and pharmacokinetics of darunavir in children younger than 3 years of age have not been established by the manufacturer. The manufacturer states that darunavir should not be used in neonates, infants, or children younger than 3 years of age due to toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg).

    Breast-feeding

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

    Hyperlipidemia, hypertriglyceridemia, pancreatitis

    Patients with advanced acquired immunodeficiency syndrome (AIDS) may be at increased risk for developing hypertriglyceridemia and pancreatitis. Patients who exhibit signs or symptoms of pancreatitis should discontinue treatment with darunavir. Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of protease inhibitors. Triglyceride and cholesterol testing should be performed prior to beginning darunavir and at regular intervals during treatment. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during treatment with a protease inhibitor, possible interventions include dietary modification, use of lipid lowering agents, or discontinuation of the protease inhibitor. Clinicians should be aware of the potential drug interaction between certain cholesterol-lowering agents and darunavir.

    Human immunodeficiency virus (HIV) infection resistance

    Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. It should also be noted that varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of darunavir therapy following loss of viral suppression may increase the likelihood of antimicrobial resistance to other protease inhibitors. Darunavir displays a less than 10-fold decreased susceptibility against 90% (n=3,309) of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir. Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir in cell culture. However, 6 of 9 darunavir-resistant viruses selected in cell culture from protease inhibitor-resistant viruses showed a fold change in EC50 values less than 3 for tipranavir, indicating limited cross-resistance between darunavir and tipranavir. Of viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily, 41% were still susceptible to tipranavir, 10% were susceptible to saquinavir, and less than 2% were susceptible to other protease inhibitors.

    Serious rash

    Patients receiving darunavir may be at increase risk of developing serious rash. Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir plus raltegravir. According to the manufacturer, 10.3% of patients receiving treatment with darunavir/ritonavir developed a rash; most occurred within the first 4 weeks of treatment, were mild/moderate in severity, and resolved with continued treatment. However, darunavir therapy has also been associated with more severe rashes. During the clinical development program (n = 3063), 0.4% of patients reported a severe skin reaction. Further, cases of Stevens-Johnson Syndrome (< 0.1%), toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have also been rarely reported. Discontinue treatment immediately in any patient who develops signs of severe skin reactions, such as severe rash or rash accompanied with fever, fatigue, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, or eosinophilia.

    Pregnancy testing

    Pregnancy testing is recommended for women diagnosed with HIV, as early initiation of antiretroviral therapy has been associated with lower risk of perinatal transmission. HIV guidelines suggest using only twice-daily dosing (i.e., 600 mg darunavir with 100 mg ritonavir PO) during pregnancy; however according to the manufacturer, the once-daily regimen (i.e., 800 mg darunavir with 100 mg ritonavir PO) may be considered for pregnant women who: are stable on the once-daily regimen prior to pregnancy; virologically suppressed (i.e., HIV RNA less than 50 copies/ml); and in whom switching to twice-daily regimen would compromise tolerability or compliance. Health care providers are advised that use of darunavir may reduce the effectiveness of combined hormonal contraceptives. Instruct patients using hormonal contraception to use an effective alternative contraception method or to add a barrier method of contraception to prevent pregnancy and HIV transmission.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / 0-2.0
    pancreatitis / Delayed / 0-2.0
    osteonecrosis / Delayed / 0-2.0
    Stevens-Johnson syndrome / Delayed / 0-0.1
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 1.0-25.0
    hyperlipidemia / Delayed / 3.0-14.0
    hyperglycemia / Delayed / 0-11.0
    hypertriglyceridemia / Delayed / 1.0-10.0
    elevated hepatic enzymes / Delayed / 0-9.0
    hyperamylasemia / Delayed / 1.0-7.0
    diabetes mellitus / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 0-1.0
    hepatitis / Delayed / 0.5-0.5
    eosinophilia / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    hematoma / Early / Incidence not known

    Mild

    vomiting / Early / 2.0-33.0
    nausea / Early / 4.0-25.0
    diarrhea / Early / 9.0-24.0
    rash / Early / 5.0-19.0
    abdominal pain / Early / 5.0-10.0
    headache / Early / 3.0-9.0
    pruritus / Rapid / 0-8.3
    anorexia / Delayed / 2.0-5.0
    fatigue / Early / 0-3.0
    asthenia / Delayed / 0-3.0
    urticaria / Rapid / 0-2.0
    flatulence / Early / 0-2.0
    dyspepsia / Early / 0-2.0
    nightmares / Early / 0-2.0
    myalgia / Early / 0-2.0
    malaise / Early / Incidence not known
    fever / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    Cushingoid features / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abemaciclib: (Major) If coadministration with darunavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If darunavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of darunavir. Abemaciclib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and darunavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Acarbose: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with darunavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of darunavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Darunavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals like the protease inhibitors, 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).
    Ado-Trastuzumab emtansine: (Major) Avoid coadministration of darunavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until darunavir has cleared from the circulation (approximately 3 half-lives of darunavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; darunavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Aldesleukin, IL-2: (Moderate) Caution is warranted when darunavir is administered with aldesleukin, IL-2 as there is a potential for elevated concentrations of darunavir. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4; darunavir is a substrate of CYP3A4.
    Alfentanil: (Moderate) Alfentanil is metabolized by the hepatic isoenzyme CYP3A4. Drugs that inhibit this enzyme, such as protease inhibitors, may alter responses to alfentanil. A dose reduction of one or both drugs may be warranted. Monitor closely for oversedation and respiratory depression.
    Alfuzosin: (Contraindicated) Coadministration of alfuzosin with protease inhibitors is contraindicated due to potential hypotension. Alfuzosin is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors.
    Aliskiren: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Aliskiren; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Aliskiren; Valsartan: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
    Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with darunavir is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and darunavir should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
    Alogliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Alogliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Alogliptin; Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Alosetron: (Major) Caution is warranted when darunavir is administered with alosetron as there is a potential for elevated alosetron concentrations. Alosetron is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4.
    Alpha-glucosidase Inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
    Alprazolam: (Contraindicated) Coadministration of darunavir and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with darunavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
    Amiodarone: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, like amiodarone, is expected with concurrent use. Coadminister with extreme caution, therapeutic monitoring of antiarrhythmic concentrations is recommended.
    Amitriptyline: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4.
    Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amlodipine; Benazepril: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amlodipine; Celecoxib: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amlodipine; Olmesartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amlodipine; Valsartan: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Amobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
    Apalutamide: (Major) Coadministration of darunavir with apalutamide is not recommended as there is a potential for decreased darunavir concentrations; exposure to apalutamide may also increase. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Apixaban: (Major) Coadministration of apixaban and darunavir may increase apixaban plasma concentrations and risk of adverse events such as bleeding. The apixaban manufacturer recommends reducing the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as darunavir. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and darunavir.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of darunavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased darunavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in darunavir- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Darunavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Darunavir is also 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 additionally increase plasma concentrations of darunavir. 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: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as darunavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.
    Armodafinil: (Major) Coadministration of darunavir with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
    Artemether; Lumefantrine: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of lumefantrine are elevated when artemether; lumefantrine, a CYP3A4 substrate, is administered concurrently with darunavir, a CYP3A4 substrate/inhibitor. Although dose adjustments are not required, concomitant use warrants caution due to the potential for increased side effects, including an increased potential for QT prolongation.
    Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with darunavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
    Asenapine: (Moderate) Caution is warranted when darunavir is administered with asenapine as there is a potential for increased aspenapine concentrations. Asenapine is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with darunavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of darunavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Darunavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Omeprazole: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Aspirin, ASA; Pravastatin: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with pravastatin. If treatment with darunavir is required, consider using an alternate HMG-CoA reductase inhibitor (such as pitavastatin or fluvastatin). When concurrent administration is unavoidable, initiate pravastatin at the lowest possible dose with gradual dose increases based on clinical response. Carefully monitor for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. When pravastatin is coadministered with darunavir (in the FDA approved dosage regimen), its AUC is increased by 81% and its Cmax is increased by 63%.
    Atazanavir: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance.
    Atazanavir; Cobicistat: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance.
    Atogepant: (Major) Limit the dose of atogepant to 10 mg PO once daily if coadministered with darunavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and darunavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant exposure and a 2.15-fold increase in atogepant peak concentration.
    Atomoxetine: (Moderate) The plasma concentrations of atomoxetine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as dizziness, drowsiness, hypertension, and other cardiac adverse events, is recommended during coadministration and dosage adjustments for atomoxetine may be warranted. Darunavir is a CYP2D6 inhibitor, and atomoxetine is a CYP2D6 substrate.
    Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
    Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin.
    Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of darunavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
    Avanafil: (Major) Coadministration of avanifil with darunavir is not recommended. Concurrent use may increase avanafil concentrations. Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors, including darunavir, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Avapritinib: (Major) Avoid coadministration of avapritinib with darunavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
    Axitinib: (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Barbiturates: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as darunavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, darunavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with darunavir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of darunavir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Darunavir is a strong inhibitor of CYP3A4.
    Berotralstat: (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
    Betamethasone: (Moderate) Consider an alternative corticosteroid that is less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly for long-term use, in patients receiving darunavir. Coadministration may significantly increase betamethasone exposure increasing the risk for Cushing's syndrome and adrenal suppression. Darunavir is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%.
    Boceprevir: (Major) Concurrent administration of boceprevir and darunavir is not recommended due to the potential for HIV and hepatitis C treatment failures. Use of boceprevir with darunavir plus a pharmacokinetic enhancer results in decreased serum concentrations of all 3 drugs. Predictions about the interaction can be made based on metabolic pathways. Both boceprevir and darunavir are inhibitors and substrates of the hepatic isoenzyme CYP3A4. If used in combination, health care providers are advised to closely monitor for decreased treatment response and virologic rebound. Health care providers are also encouraged to report any drug-related adverse reactions to the FDA MedWatch Program.
    Bortezomib: (Moderate) The plasma concentrations of bortezomib may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
    Bosentan: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and darunavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
    Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and darunavir may increase exposure of monomethyl auristatin E (MMAE); if concurrent administration is necessary, monitor patients for adverse reactions. MMAE is one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; darunavir is a CYP3A4 inhibitor.
    Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
    Brigatinib: (Major) Avoid coadministration of brigatinib with darunavir if possible due to increased plasma exposure of brigatinib and altered exposure to darunavir. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy or side effect profile of the antiretroviral regimen and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); if darunavir is discontinued, resume the brigatinib dose that was tolerated prior to initiation of darunavir. Brigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Darunavir is also a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase exposure to P-gp substrates.
    Brimonidine; Timolol: (Moderate) A dose decrease may be needed for timolol when administered with darunavir/ritonavir as serum concentrations for timolol may be increased. Caution is warranted and clinical monitoring is recommended.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with darunavir ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; boosted darunavir is a strong inhibitor of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Budesonide: (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Budesonide; Formoterol: (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Bupivacaine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Bupivacaine; Lidocaine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Bupivacaine; Meloxicam: (Moderate) The plasma concentrations of meloxicam may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while meloxicam is a CYP3A4 substrate. (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
    Buprenorphine: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together.
    Buprenorphine; Naloxone: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together.
    Buspirone: (Moderate) The plasma concentrations of buspirone may be elevated when administered concurrently with darunavir. Close clinical monitoring is recommended during coadministration; buspirone dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Darunavir is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of buspirone. These drugs used in combination may result in elevated buspirone plasma concentrations, causing an increased risk for buspirone-related adverse events.
    Butabarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Butalbital; Acetaminophen: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Butalbital; Acetaminophen; Caffeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with darunavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Cabotegravir; Rilpivirine: (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.
    Cabozantinib: (Major) Avoid concomitant use of cabozantinib and darunavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with darunavir 2 to 3 days after discontinuation of darunavir. Cabozantinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
    Canagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Canagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with darunavir is necessary. Capmatinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Carbamazepine: (Major) Closely monitor for carbamazepine toxicity during coadministration; clinical monitoring of carbamazepine concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and carbamazepine may result in increased carbamazepine concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with carbamazepine.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as darunavir, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
    Celecoxib; Tramadol: (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Cenobamate: (Moderate) Coadministration of darunavir with cenobamate may result in significant decreases in the plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
    Ceritinib: (Major) Avoid concomitant use of ceritinib with darunavir due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions; darunavir exposure may also increase. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After darunavir is discontinued, resume the dose of ceritinib taken prior to initiating darunavir. Both drugs are CYP3A substrates and a strong CYP3A4 inhibitosr. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
    Chloramphenicol: (Moderate) Caution is warranted when darunavir is administered with chloramphenicol as there is a potential for elevated concentrations of darunavir. Chloramphenicol is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
    Chlordiazepoxide: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
    Chlordiazepoxide; Amitriptyline: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
    Chlordiazepoxide; Clidinium: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with darunavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of darunavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Darunavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with darunavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of darunavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Darunavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ciclesonide: (Moderate) Coadministration of ciclesonide with darunavir may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Cidofovir: (Moderate) Additive adverse effects may be seen when cidofovir is given with other agents that cause neutropenia. Patients receiving anti-retroviral protease inhibitors in combination with cidofovir may have an increased risk of iritis or uveitis.
    Cilostazol: (Major) Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Cinacalcet: (Moderate) Caution is warranted when darunavir is administered with cinacalcet as there is a potential for elevated cinacalcet concentrations. Cinacalcet is a CYP2D6 and CYP3A4 substrate. Darunavir is an inhibitor of both CYP3A4 and CYP2D6.
    Ciprofloxacin: (Moderate) Caution is warranted when darunavir is administered with ciprofloxacin as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
    Cisapride: (Contraindicated) Concurrent use of cisapride with anti-retroviral protease inhibitors (PI) is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Cisapride is metabolized by CYP3A4, and all PIs inhibit this enzyme; thus, coadministration may increases cisapride plasma concentrations and increase the risk of adverse events. Cases of QT prolongation and ventricular arrhythmias, including TdP and death, have been observed during post-marketing surveillance when cisapride is administered with potent CYP3A4 inhibitors.
    Clarithromycin: (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
    Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of darunavir as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4.
    Clobazam: (Major) Coadministration of darunavir with clobazam is not recommended. There is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
    Clonazepam: (Moderate) Use protease inhibitors cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Protease inhibitors are CYP3A4 inhibitors.
    Clopidogrel: (Major) Avoid coadministration of clopidogrel with darunavir. Concomitant use may reduce concentrations of the active metabolite of clopidogrel, therefore decreasing the antiplatelet activity of clopidogrel.
    Clorazepate: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate, and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    Clozapine: (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobimetinib: (Major) Avoid coadministration of darunavir with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
    Cocaine: (Moderate) Caution is warranted when darunavir is administered with cocaine as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Both drugs are substrates and inhibitors of CYP3A4.
    Codeine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and darunavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Darunavir can inhibit colchicine's CYP3A4 metabolism, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken darunavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Contraindicated) Coadministration of conivaptan and darunavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase darunavir exposure and risk for darunavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Conjugated Estrogens: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and darunavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; darunavir is a strong CYP3A inhibitor.
    Crizotinib: (Major) Avoid concomitant use of darunavir and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; darunavir exposure may also increase. If concomitant use is necessary for patients with non-small cell lung cancer, reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for patients with anaplastic large cell lymphoma, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of darunavir. Crizotinib is a CYP3A substrate and moderate inhibitor. Darunavir is a CYP3A4 substrate and strong inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
    Cyclophosphamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
    Cyclosporine: (Major) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms.
    Dabrafenib: (Major) The concomitant use of dabrafenib and darunavir may lead to altered concentrations of either drug. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of darunavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; darunavir is a sensitive CYP3A4 substrate and a moderate CYP3A4 inhibitor.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with darunavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions. When darunavir is boosted with cobicistat, the dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily.
    Dalfopristin; Quinupristin: (Moderate) Caution is warranted when darunavir is administered with dalfopristin; quinupristin as there is a potential for elevated concentrations of darunavir. Quinupristin is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
    Danazol: (Moderate) Caution is warranted when darunavir is administered with danazol as there is a potential for elevated concentrations of darunavir. Danazol is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
    Dapagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dapagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Dapagliflozin; Saxagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Minor) Monitor patients taking saxagliptin with darunavir for changes in glycemic control.The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as darunavir. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Dapsone: (Minor) The plasma concentrations of dapsone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as hemolytic anemia, methemoglobinemia, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while dapsone is a CYP3A4 substrate.
    Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with darunavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
    Dasatinib: (Major) Avoid coadministration of dasatinib and darunavir due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to darunavir with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of darunavir is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If darunavir is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with darunavir. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; boosted darunavir is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Delavirdine: (Moderate) Delavirdine and darunavir are both substrates and inhibitors of CYP3A4. In addition, darunavir may inhibit the CYP2D6 metabolism of delavirdine. Coadministration may result in increased plasma concentrations of either drug. It is not clear if any dosage adjustments are needed.
    Desipramine: (Major) Coadministration of darunavir and desipramine may result in increased desipramine plasma concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of desipramine and ritonavir. If desipramine is used with a CYP3A inhibitor such as darunavir, the combination should be used with caution and a lower dose of desipramine should be considered.
    Desogestrel; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with desogestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of desogestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Dexamethasone: (Major) Avoid concurrent use of darunavir with dexamethasone. Coadministration may result in a reduction of antiretroviral efficacy and the potential development of viral resistance to darunavir; consider use of an alternative corticosteroid. In addition, serum concentrations of dexamethasone may be increased, potentially resulting in Cushing's syndrome and adrenal suppression. Dexamethasone is a CYP3A4 substrate and inducer; darunavir is a substrate of this enzyme as well as a strong CYP3A inhibitor. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Dextromethorphan; Quinidine: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. Coadministration of darunavir with quinidine should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended.
    Diazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity. Prolonged sedation and respiratory depression can occur. A decrease in the diazepam dose may be needed
    Diclofenac: (Moderate) Caution is warranted when darunavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Diclofenac; Misoprostol: (Moderate) Caution is warranted when darunavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Didanosine, ddI: (Moderate) While a drug interaction between darunavir and didanosine, ddi is not known, because of the specific administration guidelines didanosine (administered on an empty stomach) should be administered 1 hour before or 2 hours after darunavir (administered with food).
    Dienogest; Estradiol valerate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with dienogest have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of dienogest. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Diethylstilbestrol, DES: (Minor) Darunavir is expected to increase the metabolism of estrogens. If coadministration is necessary, monitor for decreased effect of diethylstilbestrol.
    Digoxin: (Major) The lowest dose of digoxin should initially be prescribed when given with darunavir/ritonavir, as increased serum concentrations of digoxin may occur. Monitor serum digoxin concentrations for dosage titration.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with darunavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of darunavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Darunavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Diltiazem: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Major) Darunavir can inhibit CYP3A4, an isoenzyme that is partially responsible for the metabolism of disopyramide. Although no definitive clinical data have yet confirmed this interaction, the concurrent use of disopyramide with darunavir should be approached with caution due to the potential for serious disopyramide toxicity.
    Disulfiram: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
    Docetaxel: (Major) Avoid coadministration of docetaxel with darunavir if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
    Dofetilide: (Major) Coadministration of CYP3A4 inhibitors, such as darunavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
    Dolasetron: (Major) The plasma concentrations of hydrodolasetron (primary dolasetron metabolite) may be elevated when dolasetron is administered concurrently with darunavir. Clinical monitoring for adverse effects, such as headache or cardiovascular effects, is recommended during coadministration. Darunavir is a CYP3A4 and CYP2D6 inhibitor, while hydrodolasetron is a CYP3A4 and CYP2D6 substrate.
    Dolutegravir; Rilpivirine: (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.
    Doravirine: (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events. (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Dorzolamide; Timolol: (Moderate) A dose decrease may be needed for timolol when administered with darunavir/ritonavir as serum concentrations for timolol may be increased. Caution is warranted and clinical monitoring is recommended.
    Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with darunavir. Darunavir is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
    Doxercalciferol: (Moderate) Protease inhibitors may decrease efficacy of doxercalciferol. Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including protease inhibitors, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if these drugs are administered together.
    Doxorubicin Liposomal: (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with darunavir is necessary, and closely monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Darunavir is a strong inhibitor of CYP3A4, and is contraindicated with sensitive drugs that are highly dependent on CYP3A4/5 for clearance. Dronabinol is a CYP2C9 and 3A4 substrate; concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Contraindicated) Coadministration of darunavir with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Dronedarone is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4.
    Drospirenone: (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms.
    Drospirenone; Estetrol: (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms.
    Drospirenone; Estradiol: (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Drospirenone; Ethinyl Estradiol: (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Dutasteride: (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity of both drugs when coadministered with darunavir. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; darunavir is a sensitive substrate and strong inhibitor of CYP3A. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as darunavir.
    Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
    Efavirenz: (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and darunavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and darunavir to 6 months. Monitor for elagolix-related side effects and reduced response to darunavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; darunavir is a strong inhibitor of CYP3A and a sensitive CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease darunavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and darunavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and darunavir to 6 months. Monitor for elagolix-related side effects and reduced response to darunavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; darunavir is a strong inhibitor of CYP3A and a sensitive CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease darunavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with darunavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Darunavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3.
    Eletriptan: (Contraindicated) Eletriptan is contraindicated for use within 72 hours of using any drug that is a potent CYP3A4 inhibitor as described in the prescribing information of the interacting drug including protease inhibitors. Eletriptan is metabolized via CYP3A4, and coadministration with protease inhibitors may cause increased eletriptan concentrations and thus toxicity.
    Elexacaftor; tezacaftor; ivacaftor: (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor when coadministered with darunavir; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor/tezacaftor/ivacaftor combination tablets twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with darunavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); darunavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Eliglustat: (Major) Coadministration of darunavir and eliglustat is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs). Use of these agents together is also contraindicated in any patient also receiving a moderate or strong CYP2D6 inhibitor, such as ritonavir. In extensive CYP2D6 metabolizers (EMs), coadministration of eliglustat and darunavir requires dosage adjustment of eliglustat to 84 mg PO once daily. Darunavir is a strong CYP3A inhibitor. Eliglustat is a CYP3A and CYP2D6 substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Use of these drugs together may result in increased plasma concentrations of eliglustat, increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is greatest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A
    Elvitegravir: (Moderate) Coadministration of darunavir boosted with cobicistat and elvitegravir is not recommended. Dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretrovirals, resulting in reduction of antiretroviral efficacy and development of viral resistance. However, elvitegravir may be administered with darunavir if boosted with ritonavir. When elvitegravir is administered in combination with darunavir and ritonavir, the recommended dosing is: elvitegravir 150 mg PO once daily with darunavir/ritonavir 600/100 mg PO twice daily. No data are available for use of other dosage for this combination.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of darunavir boosted with cobicistat and elvitegravir is not recommended. Dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretrovirals, resulting in reduction of antiretroviral efficacy and development of viral resistance. However, elvitegravir may be administered with darunavir if boosted with ritonavir. When elvitegravir is administered in combination with darunavir and ritonavir, the recommended dosing is: elvitegravir 150 mg PO once daily with darunavir/ritonavir 600/100 mg PO twice daily. No data are available for use of other dosage for this combination.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of darunavir boosted with cobicistat and elvitegravir is not recommended. Dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretrovirals, resulting in reduction of antiretroviral efficacy and development of viral resistance. However, elvitegravir may be administered with darunavir if boosted with ritonavir. When elvitegravir is administered in combination with darunavir and ritonavir, the recommended dosing is: elvitegravir 150 mg PO once daily with darunavir/ritonavir 600/100 mg PO twice daily. No data are available for use of other dosage for this combination. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Empagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Empagliflozin; Linagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Empagliflozin; Linagliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Empagliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Emtricitabine; Rilpivirine; 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (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) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Enalapril; Felodipine: (Moderate) Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
    Encorafenib: (Major) Avoid coadministration of encorafenib and darunavir due to increased encorafenib exposure. Increased or decreased darunavir exposure is also possible. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of darunavir. If darunavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of darunavir. Encorafenib is a CYP3A4 substrate; in vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. Darunavir is a strong CYP3A4 inhibitor and sensitive CYP3A4 substrate. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    Entrectinib: (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If darunavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of darunavir. Entrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Enzalutamide: (Major) Coadministration of darunavir with enzalutamide is not recommended as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
    Eplerenone: (Contraindicated) Coadministration of darunavir and eplerenone is contraindicated. Darunavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and darunavir due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If darunavir is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
    Ergoloid Mesylates: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Ergonovine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Ergot alkaloids: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Ergotamine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Ergotamine; Caffeine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Erlotinib: (Major) Avoid coadministration of erlotinib with darunavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
    Ertugliflozin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Ertugliflozin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Erythromycin: (Moderate) Concentrations of darunavir may be increased with coadministration, as erythromycin is a CYP3A4 inhibitor and darunavir is a CYP3A4 substrate. Patients should be monitored for increased side effects.
    Erythromycin; Sulfisoxazole: (Moderate) Concentrations of darunavir may be increased with coadministration, as erythromycin is a CYP3A4 inhibitor and darunavir is a CYP3A4 substrate. Patients should be monitored for increased side effects.
    Eslicarbazepine: (Major) Plasma concentrations of darunavir may be reduced if administered concurrently with eslicarbazepine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
    Estazolam: (Moderate) In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity (i.e., prolonged sedation and respiratory depression)
    Esterified Estrogens: (Moderate) Darunavir is expected to increase the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
    Esterified Estrogens; Methyltestosterone: (Moderate) Darunavir is expected to increase the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Estradiol: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Estradiol; Levonorgestrel: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Estradiol; Norethindrone: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Estradiol; Norgestimate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestimate have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestimate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Estradiol; Progesterone: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. (Moderate) Use caution if coadministration of darunavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Estropipate: (Moderate) Darunavir is expected to increase the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Ethinyl Estradiol; Norelgestromin: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Ethinyl Estradiol; Norgestrel: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Ethosuximide: (Moderate) Darunavir may inhibit the CYP3A4 metabolism of ethosuximide, and may necessitate up to a 50% dose reduction of ethosuximide. Closely monitor patients during concurrent therapy.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethynodiol diacetate have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethynodiol diacetate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
    Etonogestrel; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
    Etravirine: (Minor) In Phase 3 clinical trials of etravirine, darunavir (boosted with ritonavir) was used as part of the background treatment regimen. Coadministration of etravirine and darunavir is considered safe and effective, and although coadministration does result in a decreased mean systemic exposure (AUC) of etravirine, by about 37%, no dosage adjustments are required.
    Everolimus: (Major) Avoid coadministration of everolimus with darunavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
    Ezetimibe; Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Fedratinib: (Major) Avoid coadministration of fedratinib with darunavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If darunavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
    Felbamate: (Major) Coadministration of felbamate with darunavir is not recommended. Plasma concentrations of darunavir may be reduced if these drugs are administered concurrently, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer; darunavir is a substrate of CYP3A4.
    Felodipine: (Moderate) Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If darunavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with anti-retroviral protease inhibitors. Avoid use of fesoterodine and protease inhibitors in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
    Finerenone: (Contraindicated) Concomitant use of finerenone and darunavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
    Flecainide: (Major) Coadministration of darunavir with flecainide should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use.
    Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as darunavir, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. A similar contraindication applies to combination products containing darunavir such as darunavir; cobicistat.
    Fluconazole: (Moderate) Caution is warranted when darunavir is administered with fluconazole as there is a potential for elevated concentrations of darunavir. Fluconazole is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
    Flurazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. A decrease in the flurazepam dose may be needed.
    Flutamide: (Major) Caution is warranted when darunavir; cobicistat is administered with flutamide as there is a potential for elevated flutamide concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Flutamide is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
    Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
    Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
    Fluvastatin: (Moderate) Concurrent use of darunavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Darunavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, darunavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
    Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol; Mometasone: (Moderate) Coadministration of mometasone with darunavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Fosphenytoin: (Major) Closely monitor for decreased fosphenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and fosphenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
    Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Gilteritinib: (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Glasdegib: (Major) Consider an alternative to darunavir during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with darunavir is not recommended as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4. Additionally, darunavir is a P-gp substrate and glecaprevir is a P-gp inhibitor; concentrations of darunavir may also be increased. In drug interaction studies, coadministration of darunavir boosted with ritonavir with glecaprevir; pibrentasvir resulted in an approximately 5-fold increase in the AUC of glecaprevir and a 29% increase in the AUC of darunavir. (Major) Coadministration of pibrentasvir with darunavir is not recommended as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of the drug transporter P-glycoprotein (P-gp); darunavir is an inhibitor of P-gp. Additionally, darunavir is a P-gp substrate and pibrentasvir is a P-gp inhibitor; concentrations of darunavir may also be increased. In drug interaction studies, coadministration of darunavir boosted with ritonavir with glecaprevir; pibrentasvir resulted in a 29% increase in the AUC of darunavir.
    Glipizide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Glyburide; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Granisetron: (Minor) The plasma concentrations of granisetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while granisetron is a CYP3A4 substrate.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guanfacine: (Major) Darunavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If darunavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Darunavir is a strong CYP3A4 inhibitor, and when administered with ritonavir, potent inhibition is expected.
    Halofantrine: (Moderate) Protease Inhibitors significantly inhibit cytochrome CYP3A4,and may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity.
    Haloperidol: (Moderate) Darunavir is a substrate and inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with darunavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
    Ibrutinib: (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Idelalisib: (Major) Coadministration of idelalisib with darunavir may increase the exposure of both drugs; avoid use and use alternative agents if possible. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. The exposure of another sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Additionally, coadministration with a strong CYP3A inhibitor increased idelalisib expoure by 1.8-fold.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with darunavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Darunavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with darunavir. If darunavir is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
    Imatinib: (Major) Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended.
    Imipramine: (Moderate) Coadministration of darunavir and imipramine may result in increased imipramine plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope. Consider a lower dose of imipramine with concurrent use. Imipramine is metabolized by CYP2D6 and also partially metabolized by CYP3A4.
    Incretin Mimetics: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Indinavir: (Moderate) Concurrent administration of darunavir and indinavir results in increased darunavir and indinavir concentrations. The clinical significance of this interaction has not been established, and dosage adjustment recommendations have not been established. Use this combination with caution.
    Infigratinib: (Major) Avoid concomitant use of infigratinib and darunavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
    Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Interferon Alfa-2b; Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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.
    Interferons: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART 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. 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.
    Irinotecan Liposomal: (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Irinotecan: (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan.
    Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with darunavir is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; darunavir is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated darunavir concentrations would also be expected with coadministration, as darunavir is a CYP3A4 substrate and isavuconazole is a moderate CYP3A4 inhibitor.
    Isoniazid, INH: (Moderate) Isoniazid, INH is a CYP3A4 inhibitor, and serum concentrations of darunavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for darunavir toxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Darunavir is contraindicated for use with rifampin. Rifampin induces CYP3A4, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Moderate) Isoniazid, INH is a CYP3A4 inhibitor, and serum concentrations of darunavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for darunavir toxicity.
    Isoniazid, INH; Rifampin: (Contraindicated) Darunavir is contraindicated for use with rifampin. Rifampin induces CYP3A4, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Moderate) Isoniazid, INH is a CYP3A4 inhibitor, and serum concentrations of darunavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for darunavir toxicity.
    Isradipine: (Moderate) Concurrent administration of isradipine with protease inhibitors may result in elevated isradipine plasma concentrations and increased hypotensive effects. Isradipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with darunavir as istradefylline exposure and adverse effects may increase. Darunavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
    Itraconazole: (Major) If darunavir monotherapy is coadministered with itraconazole, high doses (i.e., more than 200 mg) of itraconazole should be avoided. When cobicistat is added to darunavir as in the darunavir; cobicistat combination product, avoid coadministration with itraconazole. Additionally, plasma concentrations of itraconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). Both darunavir and itraconazole are strong inhibitors and substrates of CYP3A.
    Ivabradine: (Contraindicated) Coadministration of ivabradine and darunavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with darunavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; darunavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of darunavir. If darunavir is discontinued, wait at least 5 half-lives of darunavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Darunavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors, such as darunavir, should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment is necessary, strongly consider reducing the adult dose of ixabepilone to 20 mg/m2 every 3 weeks; there are no clinical data with this dose adjustment. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Ketoconazole: (Moderate) Ketoconazole is a potent inhibitor and substrate of CYP3A. Concomitant systemic use of ketoconazole with darunavir may increase plasma concentrations of darunavir. Additionally, plasma concentrations of ketoconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). When coadministration is required, high doses (i.e., > 200 mg) of ketoconazole should be avoided.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
    Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like protease inhibitors, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Lapatinib: (Major) Avoid coadministration of lapatinib with darunavir due to increased plasma concentrations of lapatinib; darunavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily and monitor for an increase in treatment-related adverse reactions. If darunavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Darunavir is a strong CYP3A4 inhibitor and a P-gp substrate. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lefamulin: (Major) Avoid coadministration of darunavir with oral lefamulin due to increased lefamulin exposure; darunavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
    Lemborexant: (Major) Avoid coadministration of lemborexant and darunavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of darunavir may occur if given with letermovir; monitor for darunavir-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Darunavir is a CYP3A4 substrate. 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; Norethindrone: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Levamlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Levobupivacaine: (Minor) Levobupivacaine is metabolized by CYP3A4 and 1A2. Known inhibitors of CYP3A4 such as darunavir may result in increased systemic levels of levobupivacaine when given concurrently, with potential for toxicity.
    Levoketoconazole: (Moderate) Ketoconazole is a potent inhibitor and substrate of CYP3A. Concomitant systemic use of ketoconazole with darunavir may increase plasma concentrations of darunavir. Additionally, plasma concentrations of ketoconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). When coadministration is required, high doses (i.e., > 200 mg) of ketoconazole should be avoided.
    Levomethadyl: (Major) Agents that inhibit hepatic cytochrome P450 CYP 3A4, including darunavir, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Levonorgestrel: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Levonorgestrel; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Lidocaine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity.
    Lidocaine; Epinephrine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity.
    Lidocaine; Prilocaine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity.
    Linagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Linagliptin; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Lomitapide: (Contraindicated) Concomitant use of darunavir and lomitapide is contraindicated due to the potential for markedly increased lomitapide concentrations and the associated elevation of serum transaminases. Darunavir is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence another strong CYP3A4 inhibitor.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and darunavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are sensitive CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with darunavir, an inhibitor of CYP3A4 and CYP2D6. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with darunavir, an inhibitor of CYP3A4 and CYP2D6. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Coadministration of darunavir with lopinavir is not recommended. Coadministration of darunavir with lopinavir; ritonavir resulted in decreased darunavir exposure by approximately 38% to 41% depending on lopinavir; ritonavir dose. Appropriate dose adjustments for this combination have not been established.
    Lorlatinib: (Major) Avoid coadministration of lorlatinib with darunavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of darunavir may also occur, leading to a reduction of antiviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If darunavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of darunavir. Lorlatinib is a CYP3A substrate and moderate inducer. Darunavir is a strong CYP3A inhibitor as well as a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
    Losartan: (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Losartan; Hydrochlorothiazide, HCTZ: (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
    Lovastatin: (Contraindicated) Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
    Lovastatin; Niacin: (Contraindicated) Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
    Lumacaftor; Ivacaftor: (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and darunavir as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
    Lurasidone: (Contraindicated) Concurrent use of lurasidone with darunavir is contraindicated. Lurasidone is primarily metabolized by CYP3A4; darunavir is a CYP3A4 inhibitor. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and darunavir due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. Lurbinectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
    Maprotiline: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Darunavir is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Maraviroc: (Major) Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors such as darunavir; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCL less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with darunavir (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Darunavir is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Meloxicam: (Moderate) The plasma concentrations of meloxicam may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while meloxicam is a CYP3A4 substrate.
    Mephobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Mestranol; Norethindrone: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with mestranol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of mestranol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Metformin; Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Metformin; Rosiglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Metformin; Saxagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Minor) Monitor patients taking saxagliptin with darunavir for changes in glycemic control.The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as darunavir. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Metformin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Methadone: (Moderate) Coadministration of darunavir with methadone is expected to result in decreased methadone concentrations. Patients should be monitored for opiate abstinence syndrome; an increase in methadone dosage may be considered based on clinical response.
    Methamphetamine: (Moderate) The plasma concentrations of methamphetamine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP2D6 inhibitor, while methamphetamine is a CYP2D6 substrate.
    Methohexital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Methylergonovine: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Methylprednisolone: (Moderate) Coadministration of methylprednisolone with darunavir may cause elevated methylprednisolone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Monitor closely. For long-term use, consider an alternative corticosteroid, such as beclomethasone and prednisolone, if appropriate. whose concentrations are less affected by strong CYP3A4 inhibitors. Methylprednisolone is a CYP3A4 substrate and darunavir is a strong inhibitor of CYP3A4.
    Methysergide: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Metoprolol: (Moderate) A dose decrease may be needed for metroprolol when administered with darunavir/ritonavir as serum concentrations for metoprolol may be increased. Caution is warranted and clinical monitoring is recommended.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) A dose decrease may be needed for metroprolol when administered with darunavir/ritonavir as serum concentrations for metoprolol may be increased. Caution is warranted and clinical monitoring is recommended.
    Mexiletine: (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with darunavir. Concurrent use may result in elevated mexiletine plasma concentration. Mexiletine is a substrate for CYP2D6; darunavir is an inhibitor of this enzyme.
    Midazolam: (Major) The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Parenteral midazolam can be used with protease inhibitors in a setting that allows for close clinical monitoring with the ability to manage respiratory depression or sedation should they occur; a reduction in the dose of parenteral midazolam may be warranted. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. Midazolam is metabolized by hepatic isozyme CYP3A4. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and darunavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
    Mifepristone: (Major) Caution is advised when administering darunavir with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with darunavir should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving darunavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with darunavir is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with darunavir is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with darunavir is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with darunavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and darunavir are substrates and strong inhibitors of CYP3A4.
    Miglitol: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
    Mirtazapine: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
    Mitapivat: (Major) Avoid coadministration of mitapivat with darunavir due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
    Mitotane: (Contraindicated) Darunavir is contraindicated for use with mitotane due to potential decreased darunavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and darunavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of darunavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.44 (90% CI, 0.4 to 0.48) and AUC, 0.21 (90% CI, 0.19 to 0.23).
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and darunavir. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
    Modafinil: (Major) Coadministration of darunavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
    Mometasone: (Moderate) Coadministration of mometasone with darunavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Nafcillin: (Major) Caution is warranted when darunavir is administered with nafcillin as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Darunavir is a CYP3A4 substrate.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with darunavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; darunavir is a strong CYP3A4 inhibitor.
    Naloxegol: (Contraindicated) Concomitant use of naloxegol with darunavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as darunavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with darunavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Nateglinide: (Moderate) Concurrent administration of nateglinide with some protease inhibitors may result in elevated nateglinide plasma concentrations via inhibition of CYP2C9. Ritonavir may induce CYP2C9 leading to a reduction of nateglinide concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia or hyperglycemia could occur. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Monitor blood glucose concentrations during coadministration. Caution and close monitoring are advised if these drugs are administered together.
    Nefazodone: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment.
    Neratinib: (Major) Avoid concomitant use of darunavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Darunavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Darunavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
    Nevirapine: (Moderate) Concurrent administration of darunavir with nevirapine may result in increased nevirapine concentrations and decreased darunavir concentratation. Nevirapine is a substrate and inducer of CYP3A4; darunavir is a substrate and inhibitor of CYP3A4.
    Niacin; Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Nicardipine: (Moderate) Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Nifedipine: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Nifedipine undergoes significant metabolism via CYP3A4 and increased plasma concentrations would be expected with coadministration. Cautious dose titration of calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and darunavir; increased plasma concentrations of either drug may occur. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If darunavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and darunavir is a sensitive substrate and strong inhibitor of CYP3A4.
    Nimodipine: (Moderate) Anti-retroviral protease inhibitors are CYP3A4 inhibitors and may decrease the hepatic metabolism of nimodipine, leading to increased plasma concentrations of nimodipine. In addition, ritonavir and calcium channel blockers both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. Monitor therapeutic response and for adverse effects, such as hypotension. Decreased calcium-channel blocker doses may be warranted.
    Nisoldipine: (Moderate) Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. In addition, ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Norethindrone: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Norethindrone; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Norgestimate; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestimate have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestimate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Norgestrel: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
    Nortriptyline: (Moderate) Coadministration of darunavir and nortriptyline may result in increased nortriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope. Consider a lower dose of nortriptyline with concurrent use. Nortriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4.
    Octreotide: (Moderate) Caution is warranted when darunavir is administered with octreotide as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Octreotide inhibits CYP3A4; darunavir is a CYP3A4 substrate.
    Olaparib: (Major) Avoid coadministration of olaparib with darunavir due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after darunavir is discontinued. Olaparib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and darunavir is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and darunavir may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If darunavir is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Darunavir trough concentrations (Cmin) are reduced when darunavir (boosted with ritonavir) is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Avoid concurrent use of these drugs in treatment experienced patients with 1 or more darunavir-associated mutations or with no baseline resistance data. However, for treatment-naive and treatment-experienced patients with no darunavir-associated mutations, darunavir may be administered with the 3- or 4-drug hepatitis C treatment regimens if: darunavir is dosed at 800 mg daily; darunavir is given WITHOUT ritonavir; darunavir is given at the same time as the hepatitis C treatment regimen. The darunavir dose should be re-adjusted after completion of the hepatitis C treatment regimen.
    Omeprazole: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Coadministration is expected to result in increased rifabutin and decreased darunavir plasma concentrations. If these drugs are coadministered, the manufacturer recommends the adult dose of rifabutin should be reduced by 75% (150 mg every other day), with appropriate monitoring and further dose reductions if necessary. The CDC recommends rifabutin 150 mg daily or 300 mg three times per week. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
    Omeprazole; Sodium Bicarbonate: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
    Ondansetron: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6. Ondansetron is a CYP3A4 and CYP2D6, and substrate.
    Oritavancin: (Major) Darunavir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of darunavir may be reduced if these drugs are administered concurrently.
    Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral protease inhibitors. Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
    Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half during coadministration of darunavir; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
    Osimertinib: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with osimertinib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor. Coadministration with drugs that inhibit P-gp may decrease the clearance of darunavir, resulting in increased plasma concentrations.
    Ospemifene: (Moderate) Caution is warranted when darunavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene adverse effects is recommended. Darunavir is an inhibitor of CYP3A4.
    Oxcarbazepine: (Major) Oxcarbazepine may increase the metabolism of darunavir and lead to decreased antiretroviral efficacy. Treatment failures have been reported with other protease inhibitors when carbamazepine was used concomitantly. If darunavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitor serum concentrations.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Caution should be used when oxybutynin is given in combination with inhibitors of CYP3A4, such as protease inhibitors. Monitor for adverse effects if these drugs are administered together.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Pacritinib: (Contraindicated) Concurrent use of pacritinib with darunavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
    Palbociclib: (Major) Avoid coadministration of darunavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of darunavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If darunavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of darunavir) to the dose used before initiation of darunavir. Palbociclib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while darunavir is a sensitive CYP3A4 substrate.
    Palonosetron: (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
    Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as protease inhibitors. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Paroxetine: (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
    Pazopanib: (Major) Avoid coadministration of pazopanib and darunavir due to the potential for increased pazopanib exposure. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and darunavir due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If darunavir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of darunavir. Pemigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
    Pentamidine: (Moderate) The plasma concentrations of pentamidine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as nephrotoxicity or electrolyte disorders, is recommended during coadministration. Darunavir is a CYP2D6 inhibitor, while pentamidine is a CYP2D6 substrate.
    Pentobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Perampanel: (Major) Caution is warranted when darunavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
    Pergolide: (Contraindicated) Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
    Perindopril; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Perphenazine: (Moderate) The plasma concentrations of perphenazine may be elevated when administered concurrently with darunavir. During coadministration, a reduction in the perphenazine dose may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Darunavir is an inhibitor of CYP2D6, an isoenzyme responsible for the metabolism of perphenazine. These drugs used in combination may result in elevated perphenazine plasma concentrations, causing an increased risk for perphenazine-related adverse events.
    Perphenazine; Amitriptyline: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (Moderate) The plasma concentrations of perphenazine may be elevated when administered concurrently with darunavir. During coadministration, a reduction in the perphenazine dose may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Darunavir is an inhibitor of CYP2D6, an isoenzyme responsible for the metabolism of perphenazine. These drugs used in combination may result in elevated perphenazine plasma concentrations, causing an increased risk for perphenazine-related adverse events.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with darunavir as concurrent use may increase pexidartinib exposure. Concurrent use may also result in decreased plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. If concurrent use cannot be avoided, reduce the dose of pexidartinib as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. If darunavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of darunavir. Pexidartinib is a CYP3A4 substrate and moderate CYP3A4 inducer; darunavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%.
    Phenobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Phentermine; Topiramate: (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Phenytoin: (Major) Closely monitor for decreased phenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and phenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Pimozide: (Contraindicated) Coadministration of pimozide with protease inhibitors is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Pimozide is thought to be metabolized through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide plasma levels are probable when coadministered with CYP450 inhibitors, such as the protease inhibitors. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP.
    Pioglitazone; Metformin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Pirfenidone: (Moderate) Caution is warranted when darunavir is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a substrate/inhibitor of CYP3A4 and a CYP2D6 inhibitor. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
    Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of darunavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
    Ponatinib: (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Posaconazole: (Moderate) Posaconazole and darunavir should be coadministered with caution due to an increased potential for adverse events. Both posaconazole and darunavir are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of darunavir. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and darunavir, ultimately resulting in an increased risk of adverse events.
    Pralsetinib: (Major) Avoid coadministration of darunavir with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. Pralsetinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with a combined P-gp and strong CYP3A inhibitor increased the AUC of pralsetinib by 251%.
    Pramlintide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
    Pravastatin: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with pravastatin. If treatment with darunavir is required, consider using an alternate HMG-CoA reductase inhibitor (such as pitavastatin or fluvastatin). When concurrent administration is unavoidable, initiate pravastatin at the lowest possible dose with gradual dose increases based on clinical response. Carefully monitor for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. When pravastatin is coadministered with darunavir (in the FDA approved dosage regimen), its AUC is increased by 81% and its Cmax is increased by 63%.
    Prednisone: (Moderate) Coadministration of prednisone with darunavir may cause elevated prednisone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Prednisone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    Primidone: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and darunavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Darunavir can inhibit colchicine's CYP3A4 metabolism, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken darunavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Progesterone: (Moderate) Use caution if coadministration of darunavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Propafenone: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use.
    Quazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. A decrease in the quazepam dose may be needed.
    Quetiapine: (Major) Avoid concurrent use of quetiapine and darunavir. Darunavir may inhibit the CYP3A4 metabolism of quetiapine, resulting in elevated quetiapine plasma concentrations. If coadministration is required, reduce the quetiapine dose to one-sixth of the current dose and monitor for quetiapine-related adverse events. If darunavir is discontinued, increase the quetiapine dose by 6-fold.
    Quinidine: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. Coadministration of darunavir with quinidine should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended.
    Quinine: (Major) Anti-retroviral protease inhibitors can inhibit the metabolism of CYP3A4 substrates such as quinine. In theory, this interaction could potentially result in drug accumulation and quinine toxicity. Monitor for potential quinine toxicity and decrease quinine dosage if needed.
    Ramelteon: (Moderate) The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
    Ranitidine: (Minor) No change in darunavir concentrations was observed when coadministered with ranitidine. Darunavir can be coadministered with H2-blockers without any dosage adjustments.
    Ranolazine: (Contraindicated) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
    Red Yeast Rice: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when anti-retroviral protease inhibitors are given in combination with most HMG-CoA reductase inhibitors. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, coadministration of red yeast rice with anti-retroviral protease inhibitors is not recommended.
    Regorafenib: (Major) Avoid coadministration of regorafenib with darunavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
    Repaglinide: (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP.
    Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as darunavir boosted with ritonavir, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
    Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. 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: (Contraindicated) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Contraindicated) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
    Rifabutin: (Major) Coadministration is expected to result in increased rifabutin and decreased darunavir plasma concentrations. If these drugs are coadministered, the manufacturer recommends the adult dose of rifabutin should be reduced by 75% (150 mg every other day), with appropriate monitoring and further dose reductions if necessary. The CDC recommends rifabutin 150 mg daily or 300 mg three times per week.
    Rifampin: (Contraindicated) Darunavir is contraindicated for use with rifampin. Rifampin induces CYP3A4, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
    Rifapentine: (Major) Avoid coadministration of protease inhibitors and rifapentine as concurrent use may result in significant decreases in the plasma concentrations of the antiretroviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended.
    Rilpivirine: (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.
    Rimegepant: (Major) Avoid coadministration of rimegepant with darunavir; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
    Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with darunavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
    Risperidone: (Major) Decreased risperidone doses may be required when coadministered with darunavir/ritonavir. Darunavir/ritonavir is expected to decrease the hepatic metabolism of the risperidone, resulting in increased risperidone concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
    Romidepsin: (Moderate) Concurrent administration of romidepsin and darunavir may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. Romidepsin is a substrate for CYP3A4. Darunavir is an inhibitor of CYP3A4.
    Ropivacaine: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
    Rosuvastatin: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicisat.
    Rosuvastatin; Ezetimibe: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicisat.
    Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with darunavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of darunavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
    Salmeterol: (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Saquinavir: (Major) Coadministration of darunavir and saquinavir results in decreased exposure to darunavir (26% decrease in AUC). Appropriate dosage adjustments for this combination have not been established. Coadministration, with or without additional low-dose ritonavir, is not recommended
    Saxagliptin: (Minor) Monitor patients taking saxagliptin with darunavir for changes in glycemic control.The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP3A4/5 inhibitors such as darunavir. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
    Secobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Minor) Coadministration of segesterone and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of segesterone.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and darunavir due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If darunavir is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of darunavir. Selpercatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and darunavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If darunavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of darunavir. Selumetinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
    Sertraline: (Moderate) Use caution when coadministering darunavir with sertraline, as decreased SSRI concentrations may be seen. If sertraline is coadministered with darunavir, carefully titrate the dose of sertraline based on a clinical assessment of antidepressant response.
    Sildenafil: (Major) Sildenafil is contraindicated for use with darunavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Silodosin: (Major) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as anti-retroviral protease inhibitors may cause significant increases in silodosin plasma concentrations.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and darunavir boosted with ritonavir. Inhibition of CYP3A4 by darunavir/ritonavir causes increased plasma concentrations of simeprevir, potentially resulting in adverse effects.
    Simvastatin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
    Simvastatin; Sitagliptin: (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Siponimod: (Moderate) Concomitant use of siponimod and darunavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
    Sirolimus: (Major) Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
    Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Solifenacin: (Major) If coadministered with darunavir, do not exceed a 5 mg daily dose of solifenacin in adults; do not exceed the initial starting dose in pediatric patients. The plasma concentrations of solifenacin may be elevated when administered concurrently with darunavir. Monitor for excessive anticholinergic effects. Solifenacin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold.
    Sonidegib: (Major) Avoid concomitant use of sonidegib and darunavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Darunavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
    Sorafenib: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with sorafenib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Sotorasib: (Moderate) Coadministration of darunavir with sotorasib may result in decreased plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
    St. John's Wort, Hypericum perforatum: (Contraindicated) Use of St. John's wort with protease inhibitors is contraindicated. St. John's wort is an inducer of CYP3A and is expected to significantly decrease the plasma concentrations of all currently marketed protease inhibitors. Reductions in plasma concentrations of these drugs could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV patients treated with these agents.
    Streptogramins: (Moderate) Caution is warranted when darunavir is administered with dalfopristin; quinupristin as there is a potential for elevated concentrations of darunavir. Quinupristin is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if a protease inhibitor must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of a protease inhibitor is necessary. If a protease inhibitor is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like protease inhibitors can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If a protease inhibitor is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sulfonylureas: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
    Sunitinib: (Major) Avoid coadministration of darunavir with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
    Suvorexant: (Major) Coadministration of suvorexant and darunavir is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
    Tacrolimus: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with darunavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and another protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; darunavir is a strong CYP3A4 inhibitor.
    Tadalafil: (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
    Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and darunavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as darunavir, may increase exposure to tasimelteon with the potential for adverse reactions.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with darunavir as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
    Telaprevir: (Major) Concurrent administration of darunavir and ritonavir with telaprevir is not recommended due to the potential for HIV and hepatitis C treatment failures. When administered in combination, the steady-state exposures of both darunavir and telaprevir were reduced. If darunavir/ritonavir and telaprevir are coadministered, monitor the patient closely for decreased treatment response and virologic rebound.
    Telithromycin: (Moderate) Concentrations of telithromycin and darunavir may be increased with coadministration, as both agents are CYP3A4 substrates and inhibitors. Additionally, darunavir is administered ('boosted') with ritonavir, which is a potent CYP3A4 inhibitior. Patients should be monitored for increased side effects.
    Telmisartan; Amlodipine: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
    Temsirolimus: (Major) Avoid coadministration of darunavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to darunavir may also be increased. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of darunavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Darunavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of darunavir.
    Teniposide: (Major) The plasma concentrations of teniposide may be significantly elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as myelosuppression, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4. Teniposide is a CYP3A4 substrate.
    Tenofovir, PMPA: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering darunavir. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; darunavir is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Terfenadine: (Contraindicated) Caution should be used in patients receiving protease inhibitors concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Protease inhibitors inhibit the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of terfenadine and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between protease inhibitors and terfenadine.
    Tezacaftor; Ivacaftor: (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with darunavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); darunavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Theophylline, Aminophylline: (Moderate) Caution is warranted when darunavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; darunavir is a CYP3A4 inhibitor.
    Thiazolidinediones: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
    Thiopental: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
    Thioridazine: (Major) Decreased thioridazine doses may be required when coadministered with darunavir/ritonavir. Darunavir/ritonavir is expected to decrease the hepatic metabolism of the thioridazine, resulting in increased thioridizine concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and darunavir if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; darunavir is a strong CYP3A4 inhibitor.
    Tiagabine: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
    Ticagrelor: (Major) Avoid coadministration of ticagrelor with darunavir due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Timolol: (Moderate) A dose decrease may be needed for timolol when administered with darunavir/ritonavir as serum concentrations for timolol may be increased. Caution is warranted and clinical monitoring is recommended.
    Tinidazole: (Major) The plasma concentrations of tinidazole may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while tinidazole is a CYP3A4 substrate.
    Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with darunavir is necessary due to increased monomethyl auristatin E (MMA