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Uses

Treatment of HIV Infection

Darunavir with low-dose ritonavir (ritonavir-boosted darunavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults, adolescents, and children 3 years of age or older. The manufacturer advises that use of ritonavir-boosted darunavir in antiretroviral-experienced patients should be guided by results of genotypic and/or phenotypic viral resistance testing and the individual's prior antiretroviral treatment. Hepatic function should be assessed prior to initiation of ritonavir-boosted darunavir.(See Hepatic Effects under Cautions: Warnings/Precautions.)

Darunavir with cobicistat (cobicistat-boosted darunavir) is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naive or treatment-experienced adults. When cobicistat-boosted darunavir is included in an antiretroviral regimen, the fixed-combination preparation containing both drugs (darunavir/cobicistat) can be used or, alternatively, single-entity darunavir and single-entity cobicistat can be administered at the same time. The manufacturer of darunavir/cobicistat states that the fixed combination should not be used in patients who have HIV-1 with substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). In addition, use of darunavir/cobicistat in treatment-experienced patients should be guided by results of genotypic viral resistance testing; if such testing is not available, the fixed combination may be used in HIV protease inhibitor-naive (PI-naive) patients, but is not recommended in HIV PI-experienced patients. Estimated creatinine clearance should be assessed in all patients prior to initiation of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat).(See Renal Effects under Cautions: Warnings/Precautions.)

Darunavir should not be used without a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). A pharmacokinetic enhancer (pharmacokinetic booster) is necessary to improve the pharmacokinetic profile of darunavir. Although concomitant use of low-dose ritonavir or cobicistat with darunavir increases peak plasma concentrations and area under the plasma concentration-time curve (AUC) of the HIV protease inhibitor, these pharmacokinetic enhancers are not interchangeable in antiretroviral regimens since low-dose ritonavir and cobicistat have different dosage and administration requirements and are associated with different adverse effects, precautions, contraindications, and drug interactions. In addition, although ritonavir-boosted darunavir may be used in adults, adolescents, and children 3 years of age or older, efficacy and safety of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat) have been established only in adults.

Ritonavir-boosted darunavir or cobicistat-boosted darunavir should always be used in conjunction with one or more other antiretroviral agents and should not be used alone for the treatment of HIV infection.Ritonavir-boosted darunavir or cobicistat-boosted darunavir usually is used in an HIV PI-based regimen that includes 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

For initial treatment in HIV-infected adults and adolescents, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that ritonavir-boosted darunavir in conjunction with tenofovir alafenamide fumarate (TAF) and emtricitabine or ritonavir-boosted darunavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are recommended PI-based regimens. These experts state that cobicistat-boosted darunavir in conjunction with TAF and emtricitabine or cobicistat-boosted darunavir in conjunction with tenofovir DF and emtricitabine (or lamivudine) are alternative PI-based regimens for initial treatment in antiretroviral-naive adults and adolescents.Ritonavir-boosted darunavir or cobicistat-boosted darunavir in conjunction with abacavir and lamivudine (or emtricitabine) are considered additional alternative PI-based regimens for initial treatment in antiretroviral-naive patients, but should be used only in patients with baseline plasma HIV RNA levels less than 100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative. In addition, these experts state that ritonavir-boosted darunavir in conjunction with raltegravir (twice daily) is another regimen option for initial treatment in antiretroviral-naive adults and adolescents when TAF, TDF, or abacavir cannot be used, but should be used only in patients with baseline plasma HIV RNA levels less than 100,000 copies/mL and CD4 T-cell counts exceeding 200 cells/mm.

Clinical Experience

The comparative safety and efficacy of ritonavir-boosted darunavir and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) were evaluated in a phase 3, randomized, open-label study in 689 treatment-naive HIV-infected adults 18 years of age or older (study TMC114-C211, ARTEMIS). All patients had baseline plasma HIV-1 RNA levels of 5000 copies/mL or greater and were randomized to receive ritonavir-boosted darunavir (darunavir 800 mg once daily with ritonavir 100 mg once daily) or lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily or lopinavir 800 mg/ritonavir 200 mg once daily) in conjunction with tenofovir DF (300 mg once daily) and emtricitabine (200 mg once daily). Results at 48 weeks indicated noninferiority of ritonavir-boosted darunavir compared with lopinavir/ritonavir. At 192 weeks, 70% of patients receiving ritonavir-boosted darunavir and 61% of those receiving lopinavir/ritonavir had plasma HIV-1 RNA levels less than 50 copies/mL, and the median increase in CD4 T-cell count from baseline was 258 and 263 cells/mm, respectively. In patients receiving ritonavir-boosted darunavir, 81% of those with a confirmed virologic response less than 50 copies/mL at week 48 had undetectable levels at week 192 versus 68% of those receiving lopinavir/ritonavir. In the 192-week analysis, the ritonavir-boosted regimen was statistically superior to the lopinavir/ritonavir regimen in the intent-to-treat population (ITT).

The manufacturer of darunavir/cobicistat states that efficacy of the fixed combination is based on efficacy demonstrated in clinical trials of ritonavir-boosted darunavir. In addition, pharmacokinetic data indicate that a once-daily regimen of darunavir (800 mg) given in conjunction with cobicistat (150 mg) results in darunavir pharmacokinetic parameters that are comparable to those attained with a once-daily regimen of darunavir (800 mg) given in conjunction with low-dose ritonavir (100 mg).

Antiretroviral-experienced Adults

Clinical Experience

The comparative efficacy of once- and twice-daily regimens of ritonavir-boosted darunavir was evaluated in a randomized, open-label study (study TMC114-C229) in 590 antiretroviral-experienced adults 18 years of age or older with baseline plasma HIV-1 RNA levels greater than 1000 copies/mL and no mutations associated with darunavir resistance (i.e., V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). All patients had been receiving highly active antiretroviral therapy (HAART) for at least 12 weeks and then received ritonavir-boosted darunavir as a once-daily regimen (darunavir 800 mg once daily with ritonavir 100 mg once daily) or twice-daily regimen (darunavir 600 mg twice daily with ritonavir 100 mg twice daily) in conjunction with an optimized background antiretroviral regimen (OBR) consisting of at least 2 NRTIs. At 48 weeks, 69% of patients in each group had plasma HIV-1 RNA levels less than 50 copies/mL and the mean increase in CD4 T-cell count from baseline was similar (108 and 112 cells/mm).

The comparative safety and efficacy of ritonavir-boosted darunavir and lopinavir/ritonavir were evaluated in a phase 3, randomized, controlled, open-label study (study TMC114-C214; TITAN study) in 595 antiretroviral-experienced HIV-infected adults 18 years of age or older with baseline plasma HIV-1 RNA levels greater than 1000 copies/mL who had been receiving HAART for at least 12 weeks. Patients were randomized to receive ritonavir-boosted darunavir (darunavir 600 mg twice daily with ritonavir 100 twice daily) or lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily) in conjunction with an OBR consisting of at least 2 antiretrovirals (NRTIs with or without nonnucleoside reverse transcriptase inhibitors [NNRTIs]). At 96 weeks, 58% of patients receiving ritonavir-boosted darunavir and 52% of patients receiving lopinavir/ritonavir had plasma HIV-1 RNA levels less than 50 copies/mL and the median change in CD4 T-cell count from baseline was 81 and 93 cells/mm, respectively.

Ritonavir-boosted darunavir also was evaluated in 2 randomized, controlled, phase 2b studies (studies TMC114-C213 and TMC114-C202) in adults with clinically advanced HIV infection (baseline plasma HIV-1 RNA levels greater than 1000 copies/mL) who had received prior therapy with an antiretroviral regimen that included a PI, NRTI, and NNRTI and were receiving a stable PI-containing regimen for at least 8 weeks at study entry. All patients had at least 1 mutation in the HIV protease gene (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at baseline. These studies were conducted in 2 phases: an initial dose-finding phase and a long-term phase in which patients randomized to receive ritonavir-boosted darunavir received 600 mg of darunavir and 100 mg of ritonavir twice daily. Patients were randomized to receive ritonavir-boosted darunavir in conjunction with an OBR or a comparator ritonavir-boosted PI in conjunction with an OBR (36% received lopinavir, 34% amprenavir or fosamprenavir, 35% saquinavir, 17% atazanavir; 98% of control group received a ritonavir-boosted PI regimen and 23% of these were dual-boosted PIs). At 96 weeks, 57% of those receiving ritonavir-boosted darunavir (recommended regimen) and an OBR and 10% of those receiving a comparator ritonavir-boosted PI and an OBR were virologic responders (achieved and maintained a reduction in plasma HIV-1 RNA levels of at least 1 log10 copies/mL below baseline); 39% of those receiving ritonavir-boosted darunavir and an OBR and 9% of those receiving the comparator PI-containing regimen and an OBR had plasma HIV-1 RNA levels less than 50 copies/mL.

Pediatric Patients

Ritonavir-boosted darunavir is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in children 3 years of age or older. The indication for antiretroviral-experienced pediatric patients is based on analyses of plasma HIV-1 RNA levels and CD4 T-cell counts from 2 open-label phase 2 trials (24-week analysis of a trial in children 6 to less than 18 years of age and 48-week analysis of a trial in children 3 to less than 6 years of age). The indication for antiretroviral-naive or antiretroviral-experienced pediatric patients with no mutations associated with darunavir resistance is based on 48-week analysis of an open-label phase 2 trial in antiretroviral-naive patients 12 to less than 18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.

Efficacy and safety of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat) have not been established in patients younger than 18 years of age.

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a regimen that includes a ritonavir-boosted PI, NNRTI, or integrase strand transfer inhibitor (INSTI) in conjunction with 2 NRTIs (dual NRTIs). These experts state that ritonavir-boosted darunavir (twice daily) in conjunction with 2 NRTIs is a preferred regimen in children 3 years to less than 12 years of age and that once-daily ritonavir-boosted regimens should not be used in this age group. The panel also states that ritonavir-boosted darunavir (once daily) in conjunction with 2 NRTIs is a preferred regimen in children 12 years of age or older, but once-daily ritonavir-boosted darunavir regimens should not be used if darunavir resistance-associated substitutions are present. For further information on treatment of HIV infection in pediatric patients,

Clinical Experience

Safety and efficacy of ritonavir-boosted darunavir in conjunction with other antiretroviral agents have been evaluated in an open-label study in 80 antiretroviral-experienced HIV-infected children 6 to less than 18 years of age weighing at least 20 kg (study TMC114-C212). These children (median age 14 years, 71% male, 54% Caucasian, 30% black, mean baseline plasma HIV-1 RNA level 4.64 log10 copies/mL, median baseline CD4 T-cell count 330 cells/mm) were randomized to receive ritonavir-boosted darunavir plus a background regimen consisting of at least 2 non-PI antiretroviral agents; 79% had previously received at least 1 NNRTI and 96% had previously received at least 1 PI. At week 24, 64 and 50% of children had plasma HIV-1 RNA levels less than 400 and 50 copies/mL, respectively; the mean CD4 T-cell count increase from baseline was 117 cells/mm.

Safety and efficacy also were evaluated in an open-label study in 21 antiretroviral-experienced HIV-infected children 3 to less than 6 years of age weighing 10 kg to less than 20 kg (study TMC114-C228). These children (median age 4.4 years, 48% male, 57% black, 29% Caucasian, mean baseline plasma HIV-1 RNA level 4.34 log10 copies/mL, median baseline CD4 T-cell count 927 cells/mm, median baseline CD4 percentage 27.7%) received a ritonavir-boosted regimen of darunavir oral suspension and ritonavir oral solution in addition to a background regimen consisting of at least 2 active non-PI drugs; all patients previously received 2 or more NRTIs, 62% previously received at least 1 NNRTI, and 76% previously received at least 1 HIV PI. At week 48, 1 child had discontinued treatment and 71% of the remaining 20 children had plasma HIV-1 RNA levels less than 50 copies/mL. The mean change in CD4 T-cell count from baseline was 187 cells/mm and the mean increase in CD4 percentage from baseline was 4%.

In study TMC114-C230, safety and efficacy of ritonavir-boosted darunavir were evaluated in 12 antiretroviral-naive pediatric patients 12 to less than 18 years of age weighing at least 40 kg. Enrolled patients (median age 14.4 years, 33.3% male, 58.3% Caucasian, 41.7% black, mean baseline plasma HIV-1 RNA level 4.72 log10 copies/mL, median baseline CD4 T-cell count 282 cells/mm) received the adult recommended dosage of ritonavir-boosted darunavir (darunavir 800 mg once daily with ritonavir 100 mg once daily) in addition to background therapy consisting of at least 2 non-PI antiretroviral agents. At 48 weeks, data from the 12 patients indicated that 91.7 and 83.3% had plasma HIV-1 RNA levels less than 400 and 50 copies/mL, respectively. The mean increase in CD4 T-cell count from baseline was 221 cells/mm.

Postexposure Prophylaxis following Occupational Exposure to HIV

Ritonavir-boosted darunavir is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada). These experts state that ritonavir-boosted darunavir and 2 NRTIs is one of several alternative regimens recommended when the preferred regimen cannot be used. The preferred dual NRTI option for use with ritonavir-boosted darunavir for PEP is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Ritonavir-boosted darunavir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals who have had exposure to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada); the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

Darunavir is administered orally in conjunction with low-dose ritonavir (ritonavir-boosted darunavir) once or twice daily with food.

Alternatively, darunavir is administered orally in conjunction with cobicistat (cobicistat-boosted darunavir) once daily with food.

Darunavir should not be administered without low-dose ritonavir or cobicistat. Low-dose ritonavir and cobicistat are pharmacokinetic enhancers that improve the pharmacokinetic profile of darunavir.

Ritonavir-boosted Darunavir

When ritonavir-boosted darunavir is used, single-entity darunavir is administered as tablets or oral suspension at the same time as single-entity ritonavir capsules, tablets, or oral solution.

Oral Suspension

Darunavir oral suspension should be used in patients who have difficulty swallowing tablets.

The oral suspension should be administered using the oral dosing syringe supplied by the manufacturer. If an 800-mg dose of darunavir is indicated, the dose should be given as two 4-mL administrations of the suspension using the oral dosing syringe.

Darunavir oral suspension should be stored in the original container at 25°C, but may be exposed to 15-30°C; the suspension should not be refrigerated or frozen and should not be exposed to excessive heat.

The oral suspension is a white to off-white opaque suspension and should be shaken prior to each dose.

Tablets

Darunavir tablets should be swallowed whole with a drink (e.g., water, milk).

Children weighing 15 kg or more should be assessed for the ability to swallow the darunavir tablets; darunavir oral suspension should be considered in those unable to reliably swallow tablets.

Cobicistat-boosted Darunavir

When cobicistat-boosted darunavir is used, fixed-combination tablets containing both drugs are commercially available (darunavir/cobicistat). Alternatively, single-entity darunavir is administered as tablets or oral suspension at the same time as single-entity cobicistat tablets.

Dosage

Single-entity darunavir is commercially available as an oral suspension and tablets containing darunavir ethanolate; dosage is expressed in terms of darunavir.

Darunavir/cobicistat is commercially available as fixed-combination tablets containing darunavir ethanolate (800 mg of darunavir) and cobicistat (150 mg).

Adult Dosage

Treatment of HIV Infection in Antiretroviral-naive Adults

The recommended dosage of ritonavir-boosted darunavir for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive adults is 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL) once daily given in conjunction with single-entity ritonavir 100 mg once daily.

The recommended dosage of cobicistat-boosted darunavir for the treatment of HIV-1 infection in antiretroviral-naive adults without any substitutions associated with darunavir resistance is 800 mg of darunavir once daily given in conjunction with 150 mg of cobicistat once daily. When fixed-combination darunavir/cobicistat is used, adults should receive 1 tablet (800 mg of darunavir and 150 mg of cobicistat) once daily. Alternatively, adults can receive 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL) once daily given in conjunction with single-entity cobicistat 150 mg once daily. A cobicistat-boosted darunavir regimen that contains a darunavir dosage of 600 mg twice daily is not recommended.

Treatment of HIV Infection in Antiretroviral-experienced Adults

When ritonavir-boosted darunavir or cobicistat-boosted darunavir is used in antiretroviral-experienced patients, genotypic testing is recommended to identify substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

For the treatment of HIV-1 infection in antiretroviral-experienced adults without any substitutions associated with darunavir resistance, the recommended dosage of ritonavir-boosted darunavir is 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL) once daily given in conjunction with single-entity ritonavir 100 mg once daily.

For the treatment of HIV-1 infection in antiretroviral-experienced adults with at least 1 substitution associated with darunavir resistance, the recommended dosage of ritonavir-boosted darunavir is 600 mg of single-entity darunavir (one 600-mg tablet or 6 mL of the oral suspension containing 100 mg/mL) twice daily with single-entity ritonavir 100 mg twice daily.

If genotypic testing is not feasible, a ritonavir-boosted regimen of 600 mg of single-entity darunavir (one 600-mg tablet or 6 mL of the oral suspension containing 100 mg/mL) twice daily with single-entity ritonavir 100 mg twice daily is recommended.

For the treatment of HIV-1 infection in antiretroviral-experienced adults without any substitutions associated with darunavir resistance, the recommended dosage of cobicistat-boosted darunavir is 800 mg of darunavir once daily in conjunction with 150 mg of cobicistat once daily. When fixed combination darunavir/cobicistat is used, adults should receive 1 tablet (800 mg of darunavir and 150 mg of cobicistat) once daily. Alternatively, adults can receive 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL) once daily given in conjunction with single-entity cobicistat 150 mg once daily. A cobicistat-boosted darunavir regimen that contains a darunavir dosage of 600 mg twice daily is not recommended.

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel or other individuals, the preferred dosage of ritonavir-boosted darunavir is 800 mg of darunavir once daily with ritonavir 100 mg once daily. Alternatively, a dosage of 600 mg of darunavir twice daily with ritonavir 100 mg twice daily may be used.Ritonavir-boosted darunavir usually is used in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP), the usual adult dosage of ritonavir-boosted darunavir is 800 mg of darunavir once daily with ritonavir 100 mg once daily.Ritonavir-boosted darunavir usually is used in conjunction with emtricitabine and tenofovir DF.(See Uses: Postexposure Prophylaxis following Nonoccupational Exposure to HIV.)

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days. If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.

Pediatric Dosage

To avoid medication errors, extra care should be used in calculating the dose, transcribing the medication order, dispensing the prescription, and providing dosing instructions.

Dosage of ritonavir-boosted darunavir in children 3 years to less than 18 years of age weighing at least 10 kg is based on weight. Pediatric dosage should not exceed the recommended dosage for antiretroviral-experienced adults.

Treatment of HIV Infection in Antiretroviral-naive Pediatric Patients

For the treatment of HIV-1 infection in antiretroviral-naive pediatric patients 3 years to less than 18 years of age weighing at least 10 kg, the recommended dosage of ritonavir-boosted darunavir oral suspension is based on weight (approximately 35 mg/kg once daily with ritonavir 7 mg/kg once daily in those weighing less than 15 kg). (See Table 1 and Table 2.)

Table 1. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-naive Pediatric Patients 3 Years to Less Than 18 Years of Age Weighing 10 to Less Than 15 kg[1 ]
Body Weight Darunavir Dosage (Oral Suspension Containing 100 mg/mL) Ritonavir Dosage (Oral Solution Containing 80 mg/mL)
>=10 to <11 kg 350 mg (3.6 mL) once daily 64 mg (0.8 mL) once daily
>=11 to <12 kg 385 mg (4 mL) once daily 64 mg (0.8 mL) once daily
>=12 to <13 kg 420 mg (4.2 mL) once daily 80 mg (1 mL) once daily
>=13 to <14 kg 455 mg (4.6 mL) once daily 80 mg (1 mL) once daily
>=14 to <15 kg 490 mg (5 mL) once daily 96 mg (1.2 mL) once daily

Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.[1 ]

Table 2. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-naive Pediatric Patients 3 Years to Less Than 18 Years of Age Weighing at Least 15 kg[1 ]
Body Weight Darunavir Dosage (Oral Suspension Containing 100 mg/mL or Tablets) Ritonavir Dosage (Oral Solution Containing 80 mg/mL or 100-mg Capsules or Tablets)
>=15 to <30 kg 600 mg (6 mL) once daily 100 mg (1.25 mL) once daily
>=30 to <40 kg 675 mg (6.8 mL) once daily 100 mg (1.25 mL) once daily
>=40 kg 800 mg (8 mL) once daily 100 mg (1.25 mL) once daily

Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.[1 ]

Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients

When ritonavir-boosted darunavir is used in antiretroviral-experienced pediatric patients, genotypic testing is recommended to identify mutations associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

For the treatment of HIV-1 infection in antiretroviral-experienced pediatric patients 3 years to less than 18 years of age weighing at least 10 kg without any mutations associated with darunavir resistance, the recommended dosage of ritonavir-boosted darunavir oral suspension is based on weight (approximately 35 mg/kg once daily with ritonavir 7 mg/kg once daily in those weighing less than 15 kg). (See Table 3 and Table 4.)

Table 3. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-experienced Pediatric Patients 3 Years to Less Than 18 Years of Age Weighing 10 to Less Than 15 kg without Any Mutations Associated with Darunavir Resistance[1 ]
Body Weight Darunavir Dosage (Oral Suspension Containing 100 mg/mL) Ritonavir Dosage (Oral Solution Containing 80 mg/mL)
>=10 to <11 kg 350 mg (3.6 mL) once daily 64 mg (0.8 mL) once daily
>=11 to <12 kg 385 mg (4 mL) once daily 64 mg (0.8 mL) once daily
>=12 to <13 kg 420 mg (4.2 mL) once daily 80 mg (1 mL) once daily
>=13 to <14 kg 455 mg (4.6 mL) once daily 80 mg (1 mL) once daily
>=14 to <15 kg 490 mg (5 mL) once daily 96 mg (1.2 mL) once daily

Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.[1 ]

Table 4. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-naive Pediatric Patients 3 Years to Less Than 18 Years of Age Weighing at Least 15 kg without Any Mutations Associated with Darunavir Resistance[1 ]
Body Weight Darunavir Dosage (Oral Suspension Containing 100 mg/mL or Tablets) Ritonavir Dosage (Oral Solution Containing 80 mg/mL or 100-mg Capsules or Tablets)
>=15 to <30 kg 600 mg (6 mL) once daily 100 mg (1.25 mL) once daily
>=30 to <40 kg 675 mg (6.8 mL) once daily 100 mg (1.25 mL) once daily
>=40 kg 800 mg (8 mL) once daily 100 mg (1.25 mL) once daily

Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.[1 ]

For the treatment of HIV-1 infection in antiretroviral-experienced pediatric patients 3 years to less than 18 years of age weighing at least 10 kg with at least 1 mutation associated with darunavir resistance, the recommended dosage of ritonavir-boosted darunavir oral suspension is based on weight (approximately 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily in those weighing less than 15 kg). (See Table 5 and Table 6.)

Table 5. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-experienced Pediatric Patients 3 Years to Less Than 18 Years of Age Weighing 10 to Less Than 15 kg with at Least One Mutation Associated with Darunavir Resistance[1 ]
Body Weight Darunavir Dosage (Oral Suspension Containing 100 mg/mL) Ritonavir Dosage (Oral Solution Containing 80 mg/mL)
>=10 to <11 kg 200 mg (2 mL) twice daily 32 mg (0.4 mL) twice daily
>=11 to <12 kg 220 mg (2.2 mL) twice daily 32 mg (0.4 mL) twice daily
>=12 to <13 kg 240 mg (2.4 mL) twice daily 40 mg (0.5 mL) twice daily
>=13 to <14 kg 260 mg (2.6 mL) twice daily 40 mg (0.5 mL) twice daily
>=14 to <15 kg 280 mg (2.8 mL) twice daily 48 mg (0.6 mL) twice daily
Table 6. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-experienced Pediatric Patients 3 Years to Less Than 18 Years of Age Weighing at Least 15 kg with at Least One Mutation Associated with Darunavir Resistance[1 ]
Body Weight Darunavir Dosage (Oral Suspension Containing 100 mg/mL or Tablets) Ritonavir Dosage (Oral Solution Containing 80 mg/mL or 100-mg Capsules or Tablets)
>=15 to <30 kg 375 mg (3.8 mL) twice daily 48 mg (0.6 mL) twice daily
>=30 to <40 kg 450 mg (4.6 mL) twice daily 60 mg (0.75 mL) twice daily
>=40 kg 600 mg (6 mL) twice daily 100 mg (1.25 mL) twice daily

Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.[1 ]

Special Populations

Hepatic Impairment

Dosage of ritonavir-boosted darunavir or cobicistat-boosted darunavir does not need to be adjusted in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Ritonavir-boosted darunavir or cobicistat-boosted darunavir should not be used in patients with severe hepatic impairment (Child-Pugh class C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Some experts state that dosage of ritonavir-boosted darunavir does not need to be adjusted in patients with renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Prior to initiation of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat), estimated creatinine clearance should be assessed. Although some experts state that dosage adjustments are not necessary when cobicistat-boosted darunavir is used in patients with renal impairment, these experts and the manufacturer state that cobicistat-boosted darunavir should not be used in conjunction with tenofovir DF in patients with estimated creatinine clearances less than 70 mL/minute.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Pregnant Women

If darunavir is used during pregnancy, it should be administered as ritonavir-boosted darunavir.

For the treatment of HIV-1 infection in pregnant women, the recommended dosage of ritonavir-boosted darunavir is 600 mg of single-entity darunavir twice daily (one 600-mg tablet or 6 mL of the oral suspension containing 100 mg/mL twice daily) with single-entity ritonavir 100 mg twice daily.

The manufacturer states that a once-daily regimen of 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL once daily) with single-entity ritonavir 100 mg once daily should be considered during pregnancy only in women already stabilized on this once-daily regimen prior to pregnancy who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) and in whom a change to a twice-daily regimen may compromise tolerability or compliance. However, some experts state that once-daily regimens of ritonavir-boosted darunavir are not recommended in pregnant women.

Cautions

Contraindications

Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat) with drugs highly dependent on cytochrome P-450 (CYP) isoenzyme CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, dronedarone, ergot alkaloids, lovastatin, lurasidone, simvastatin, oral midazolam, triazolam, ranolazine, pimozide, sildenafil [Revatio] for treatment of pulmonary arterial hypertension) is contraindicated.(See Drug Interactions.)

Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir with drugs that may decrease darunavir concentrations resulting in possible loss of virologic response (e.g., rifampin, St. John's wort [Hypericum perforatum]) is contraindicated.(See Drug Interactions.)

Concomitant use of cobicistat-boosted darunavir and carbamazepine, phenobarbital, phenytoin, and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) is contraindicated.(See Drug Interactions.)

Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir with colchicine is contraindicated in patients with renal and/or hepatic impairment.(See Drug Interactions: Colchicine.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

Severe skin reactions, sometimes accompanied by fever and/or increases in serum transaminase concentrations, have occurred in patients receiving ritonavir-boosted darunavir. Stevens-Johnson syndrome has been reported rarely; toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute, generalized exanthematous pustulosis also have been reported.

Rash (usually of mild to moderate intensity) has occurred in 10.3% of patients receiving ritonavir-boosted darunavir; rash usually occurs during the first 4 weeks of therapy.Ritonavir-boosted darunavir was continued without interruption in most patients.

Although rash was reported more frequently in antiretroviral-experienced patients receiving ritonavir-boosted darunavir and raltegravir than in those receiving ritonavir-boosted darunavir without raltegravir or raltegravir without ritonavir-boosted darunavir, rash that was considered drug related occurred at similar rates in all 3 groups; rash generally was mild to moderate in severity and did not limit therapy or require discontinuance.

Ritonavir-boosted darunavir or cobicistat-boosted darunavir should be discontinued immediately if manifestations of severe skin reactions occur (e.g., severe rash, rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).

Sulfonamide Sensitivity

Darunavir contains a sulfonamide moiety, which may cause allergic-type reactions in certain susceptible individuals. In clinical studies evaluating ritonavir-boosted darunavir, the incidence of rash in patients with a history of sulfonamide sensitivity was similar to that in patients without a history of sulfonamide sensitivity.

Ritonavir-boosted darunavir and cobicistat-boosted darunavir should be used with caution in patients with known hypersensitivity to sulfonamide-containing drugs.

Hepatic Effects

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has occurred in patients receiving ritonavir-boosted darunavir in clinical studies. Patients with preexisting liver dysfunction, including HIV-infected patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV), have an increased risk for liver function abnormalities. There have been postmarketing reports of liver injury (in some cases fatal) in patients receiving ritonavir-boosted darunavir; liver injury generally has occurred in patients with advanced HIV infection who were receiving multiple concomitant drugs, were coinfected with HBV or HCV, and/or were developing immune reconstitution syndrome.

Appropriate laboratory tests should be performed to evaluate hepatic function prior to and periodically during treatment with ritonavir-boosted darunavir or cobicistat-boosted darunavir. Increased AST/ALT monitoring should be considered, especially during the first several months of therapy, in patients with hepatitis, cirrhosis, or elevated transaminase values prior to therapy.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Effects

Cobicistat decreases estimated creatinine clearance by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function; this effect should be considered when interpreting changes in estimated creatinine clearance in patients receiving cobicistat-boosted darunavir. This is particularly important in those needing creatinine clearance monitoring because of a medical condition or other concomitant drugs.

Estimated creatinine clearance should be assessed prior to initiating cobicistat-boosted darunavir. Although cobicistat may cause only modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, the patient should be closely monitored for renal safety if there is an increase in serum creatinine of more than 0.4 mg/dL from baseline during cobicistat-boosted darunavir therapy.

The manufacturer states that dosage recommendations are not available for drugs that require dosage adjustments in patients with renal impairment who are receiving cobicistat-boosted darunavir. Therefore, alternative drugs that do not require dosage adjustments based on renal impairment should be considered in patients receiving cobicistat-boosted darunavir.

New-onset or worsening renal impairment, including acute renal failure and Fanconi syndrome, has been reported in patients receiving cobicistat in an antiretroviral regimen that also included tenofovir disoproxil fumarate (tenofovir DF). Concomitant use of cobicistat-boosted darunavir and tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute or in patients who are receiving (or recently received) a nephrotoxic agent. Whenever cobicistat-boosted darunavir and tenofovir DF are used concomitantly, urine glucose and urine protein should be documented at baseline and estimated creatinine clearance, urine glucose, and urine protein should be routinely monitored throughout concomitant therapy. In addition, serum phosphorus should be monitored in those with or at risk for renal impairment.

Interactions

Darunavir must be used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). Failure to administer darunavir with the recommended dosage of ritonavir or cobicistat will result in subtherapeutic darunavir concentrations and inadequate antiretroviral response. When ritonavir-boosted darunavir or cobicistat-boosted darunavir is used, the cautions, precautions, contraindications, and drug interactions associated darunavir and the pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat) should be considered.

Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir with certain drugs is contraindicated or requires particular caution. Concomitant use with some drugs may result in clinically important adverse effects, including severe, life-threatening, or fatal events, due to higher exposures of the concomitant drug or higher exposures of darunavir and/or the pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted darunavir or cobicistat-boosted darunavir and possible development of resistance. Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern. However, concomitant use of cobicistat-boosted darunavir with other drugs may result in different drug interactions than those observed or expected with ritonavir-boosted darunavir because of complex or unknown mechanisms of drug interactions.

Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir with other drugs that are administered in conjunction with a pharmacokinetic enhancer (e.g., ritonavir-boosted HIV protease inhibitors [PIs], ritonavir-boosted paritaprevir, elvitegravir) is not recommended. Dosage recommendations for such regimens have not been established and concomitant use of more than one pharmacokinetic enhancer may result in complex drug interactions, including decreased plasma concentrations of the antiretroviral agents leading to loss of therapeutic effect and development of resistance.

Darunavir, ritonavir, and cobicistat are all available as single-entity preparations. In addition, fixed-combination darunavir/cobicistat is commercially available. Care should be taken to ensure that therapy is not duplicated; darunavir/cobicistat should not be used concomitantly with any other preparations containing darunavir, cobicistat, or ritonavir.

Potential drug interactions should be considered prior to and during use of ritonavir-boosted darunavir or cobicistat-boosted darunavir. Patients should be monitored for adverse effects associated with other drugs used concomitantly with ritonavir-boosted darunavir or cobicistat-boosted darunavir.(See Drug Interactions.)

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV PIs; diabetic ketoacidosis has occurred. It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents).

Immune Reconstitution Syndrome

Patients receiving antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy. Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (''buffalo hump''), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance have been reported in patients receiving antiretroviral therapy. The mechanisms and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.

Hemophilia A and B

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in patients with hemophilia A or B receiving HIV PIs. Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.

HIV Resistance

Potential for cross-resistance among PIs not evaluated in patients receiving ritonavir-boosted darunavir. The possible effect of ritonavir-boosted darunavir therapy on subsequent therapy with other PIs is unknown.

Specific Populations

Pregnancy

Available human and animal data suggest that darunavir does not increase the risk of major birth defects overall compared to the background rate.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that, although safety and pharmacokinetic data are limited in pregnant women, ritonavir-boosted darunavir (darunavir 600 mg twice daily with ritonavir 100 mg twice daily) and 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a preferred PI-based regimen for initial treatment in pregnant women. These experts state that once-daily regimens of ritonavir-boosted darunavir are not recommended in pregnant women.

The manufacturer states that cobicistat-boosted darunavir should be used during pregnancy only if potential benefits to the woman justify potential risks to the fetus. The HHS panel states that data are insufficient to date to recommend routine use of cobicistat-boosted darunavir for initial treatment in antiretroviral-naive pregnant women.

Pharmacokinetic data evaluating ritonavir-boosted darunavir in pregnant women indicate that darunavir and ritonavir exposures following administration of darunavir 800 mg once daily with ritonavir 100 mg once daily or darunavir 600 mg twice daily with ritonavir 100 mg twice daily generally are lower during pregnancy than exposures reported in postpartum women. In addition, reductions in plasma concentrations of unbound darunavir and ritonavir reported in pregnant women receiving a once-daily regimen of ritonavir-boosted darunavir are greater than reductions reported in pregnant women receiving a twice-daily regimen.(See Pregnant Women under Dosage and Administration: Special Populations.)

Antiretroviral Pregnancy Registry at 800-258-4263 or http://www.apregistry.com.

Based on prospective reports from the Antiretroviral Pregnancy Registry of approximately 532 live births following exposure to darunavir-containing antiretroviral regimens during pregnancy (including 333 first-trimester exposures), there was no difference in the rate of overall birth defects in those exposed to darunavir-containing regimens compared with the background rate of major birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (2.7%).

Lactation

It is not known whether darunavir, ritonavir, or cobicistat is distributed into human milk; darunavir and cobicistat are distributed into milk in rats.

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.

Pediatric Use

Darunavir is not recommended in pediatric patients younger than 3 years of age since toxicity and mortality have been observed in juvenile rats given darunavir.

Safety, pharmacokinetic profile, and efficacy of ritonavir-boosted darunavir have been evaluated in antiretroviral-naive and antiretroviral-experienced pediatric patients 3 years to less than 18 years of age weighing at least 10 kg. Adverse effects reported in pediatric patients were similar to those reported in adults.

Safety and efficacy of cobicistat-boosted darunavir (administered as darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat) have not been established in patients younger than 18 years of age.

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently to ritonavir-boosted darunavir or cobicistat-boosted darunavir than younger adults. Appropriate caution should be exercised in administration and monitoring because of age-related decreases in hepatic function and potential for concomitant disease and drug therapy.

Pharmacokinetics of darunavir do not differ substantially over an age range of 18-75 years of age.

Hepatic Impairment

Pharmacokinetics of ritonavir-boosted darunavir are not altered in patients with mild to moderate hepatic impairment (Child-Pugh class A or B); dosage adjustments are not needed in such individuals. Because darunavir pharmacokinetics have not been evaluated in patients with severe hepatic impairment, ritonavir-boosted darunavir is not recommended in patients with severe hepatic impairment.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

Pharmacokinetics of cobicistat-boosted darunavir have not been evaluated in patients with mild to moderate hepatic impairment (Child-Pugh class A or B); there were no clinically important pharmacokinetic changes when cobicistat was used alone in individuals with mild or moderate hepatic impairment. Based on recommendations for ritonavir-boosted darunavir, dosage adjustments of cobicistat-boosted darunavir are not needed in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Pharmacokinetics of cobicistat-boosted darunavir or cobicistat alone have not been evaluated in patients with severe hepatic impairment (Child-Pugh class C), and cobicistat-boosted darunavir is not recommended in such patients.(See Hepatic Impairment under Dosage and Administration: Special Populations.)

Limited data indicate that darunavir exposure is not altered in HIV-infected patients coinfected with HBV or HCV.

The risk of liver function abnormalities, including severe hepatic adverse effects, is increased in patients with preexisting hepatic impairment (e.g., HBV or HCV infection).

Liver function should be monitored during the first several months of treatment with ritonavir-boosted darunavir when the drug is used in patients with underlying chronic hepatitis or cirrhosis or in patients with pretreatment elevated liver enzymes.

If there is evidence of new or worsening liver disease (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly, clinically important increases in hepatic enzyme concentrations), interruption or discontinuance of ritonavir-boosted darunavir or cobicistat-boosted darunavir should be considered.

Renal Impairment

Pharmacokinetics of darunavir are not altered in patients with moderate renal impairment (creatinine clearance 30-60 mL/minute). Data are not available on darunavir pharmacokinetics in patients with severe renal impairment or end-stage renal disease. Because renal clearance of darunavir is limited, decreased clearance of the drug is not expected in patients with renal impairment.

Cobicistat-boosted darunavir has not been studied in individuals with renal impairment. Cobicistat has been shown to decrease estimated creatinine clearance without affecting renal glomerular function. Prior to initiation of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat), estimated creatinine clearance should be assessed.Cobicistat-boosted darunavir should not be used in conjunction with tenofovir DF in patients with estimated creatinine clearances less than 70 mL/minute.(See Renal Effects under Cautions: Warnings/Precautions.)

Darunavir, ritonavir, and cobicistat are highly bound to plasma proteins, and the drugs are unlikely to be removed by hemodialysis or peritoneal dialysis.

Common Adverse Effects

The most common adverse effects reported in patients receiving ritonavir-boosted darunavir in conjunction with other antiretrovirals are diarrhea, nausea, vomiting, abdominal pain, headache, and rash.

Drug Interactions

Darunavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat), and drug interactions associated with both darunavir and the pharmacokinetic enhancer should be considered. Because low-dose ritonavir and cobicistat are associated with different drug interactions, interactions reported or expected with ritonavir-boosted darunavir may differ from those reported or expected with cobicistat-boosted darunavir.

The following drug interactions are based on studies using ritonavir-boosted darunavir or studies using cobicistat alone. Drug interaction studies are not available to date using cobicistat-boosted darunavir administered either as the fixed combination containing darunavir and cobicistat (darunavir/cobicistat) or as single-entity darunavir given with single-entity cobicistat.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Darunavir, ritonavir, and cobicistat inhibit cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6; potential pharmacokinetic interaction with drugs metabolized by CYP3A or CYP2D6 (altered metabolism of drug metabolized by CYP3A or CYP2D6). Darunavir, ritonavir, and cobicistat are metabolized by CYP3A. Potential pharmacokinetic interactions with drugs that induce CYP3A (increased clearance of darunavir, ritonavir, or cobicistat, which may lead to loss of antiretroviral efficacy and development of resistance); potential pharmacokinetic interactions with drugs that inhibit CYP3A (increased plasma concentrations of darunavir, ritonavir, or cobicistat).

Caution is advised if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with substrates, inhibitors, or inducers of CYP3A4; such drug interactions may lead to severe, life-threatening, or fatal events due to increased exposures of certain drugs, adverse effects due to increased exposures to ritonavir-boosted or cobicistat-boosted darunavir, or loss of therapeutic effect and possible development of resistance to darunavir.

Cobicistat is metabolized by CYP2D6 to a minor extent. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or 2B6; based on in vivo data, cobicistat is not expected to induce CYP3A to a clinically important extent. It is not known whether cobicistat induces CYP2C9 or 2C19, but any effect is expected to be minimal based on in vitro CYP3A induction data.

Drugs Affected by P-glycoprotein Transport

Ritonavir-boosted darunavir is an inhibitor of the P-glycoprotein (P-gp) transport system; cobicistat also is a P-gp inhibitor. Potential pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted darunavir is used with drugs transported by P-gp (increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effects and may be associated with adverse effects).

In vitro data suggests that darunavir may be a P-gp substrate; potential pharmacokinetic interaction if darunavir is used concomitantly with drugs that inhibit P-gp (decreased clearance of darunavir and ritonavir, leading to increased plasma concentrations).

Drugs Affecting or Affected by Other Membrane Transporters

Cobicistat inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1 and 1B3. Potential pharmacokinetic interactions if cobicistat-boosted darunavir is used concomitantly with drugs that are substrates of BCRP, OATP1B1, or OATP1B3 (increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effects and may be associated with adverse effects).

Based on in vitro data, cobicistat is not expected to induce multidrug-resistance gene (MDR) 1 to a clinically important extent. It is not known whether cobicistat induces uridine diphosphate-glucuronosyl transferase (UGT) 1A1, but any effect is expected to be minimal based on in vitro CYP3A induction data.

Alfuzosin

Concomitant use of alfuzosin and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated because of the potential for serious and/or life-threatening reactions (e.g., hypotension).

Antiarrhythmic Agents

Possible pharmacokinetic interactions if certain antiarrhythmic agents (e.g., amiodarone, bepridil [no longer commercially available in the US], disopyramide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of the antiarrhythmic agent).

Ritonavir-boosted or cobicistat-boosted darunavir and antiarrhythmic agents should be used concomitantly with caution; plasma concentration monitoring of the antiarrhythmic agents, if available, is recommended.

Amiodarone

Some experts state that if amiodarone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the patient should be monitored for amiodarone toxicity and consideration given to ECG and amiodarone plasma concentration monitoring.

Dronedarone

Concomitant use of dronedarone and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

Anticoagulants

Apixaban

Pharmacokinetic interactions if apixaban is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased apixaban concentrations).

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with apixaban is not recommended.

Dabigatran

Pharmacokinetic interactions if dabigatran is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased dabigatran concentrations).

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with dabigatran is not recommended in certain patients with renal impairment, depending on the indication. Some experts state that concomitant use of dabigatran and ritonavir-boosted or cobicistat-boosted darunavir should be avoided in those with creatinine clearances less than 50 mL/minute.

Edoxaban

Possible pharmacokinetic interactions if edoxaban is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased edoxaban concentrations).

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and edoxaban should be avoided.

Rivaroxaban

Possible pharmacokinetic interactions if rivaroxaban is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased rivaroxaban concentrations and increased risk of bleeding).

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and rivaroxaban is not recommended.

Warfarin

Pharmacokinetic interactions if warfarin is used concomitantly with ritonavir-boosted darunavir (decreased warfarin concentrations; no change in darunavir concentrations). The effect of cobicistat-boosted darunavir on warfarin concentrations is not known.

If warfarin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the international normalized ratio (INR) should be monitored, especially when darunavir is initiated or discontinued; warfarin dosage should be adjusted as needed.

Some experts state that if ritonavir-boosted darunavir is switched to cobicistat-boosted darunavir, the effect of cobicistat on warfarin concentrations is not expected to be equivalent to the effect of ritonavir on warfarin concentrations.

Anticonvulsants

Carbamazepine

Pharmacokinetic interactions if carbamazepine is used concomitantly with ritonavir-boosted darunavir (increased carbamazepine concentrations; no change in darunavir concentrations). Dosage adjustments are not needed when initiating concomitant therapy with ritonavir-boosted darunavir and carbamazepine. However, plasma concentrations of carbamazepine should be monitored and dosage of the anticonvulsant adjusted to achieve the desired clinical effect.

Pharmacokinetic interactions if carbamazepine is used concomitantly with cobicistat-boosted darunavir (increased carbamazepine concentrations; decreased cobicistat concentrations; effect on darunavir concentrations unknown, but substantially decreased darunavir concentrations and loss of therapeutic effect and development of resistance are possible). Concomitant use of cobicistat-boosted darunavir and carbamazepine is contraindicated.

Eslicarbazepine

Concomitant use of cobicistat-boosted darunavir and eslicarbazepine may decrease cobicistat plasma concentrations, but effects on darunavir concentrations are unknown. An alternative anticonvulsant or alternative antiretroviral therapy should be considered; if concomitant use of eslicarbazepine and cobicistat-boosted darunavir is necessary, the patient should be monitored for lack or loss of antiretroviral response.

Ethosuximide

Possible pharmacokinetic interactions if ethosuximide is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased ethosuximide concentrations). If ethosuximide is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the patient should be clinically monitored for ethosuximide toxicities.

Lamotrigine

Possible pharmacokinetic interactions if lamotrigine is used concomitantly with ritonavir-boosted darunavir (decreased lamotrigine concentrations). An alternative anticonvulsant should be considered in patients receiving ritonavir-boosted darunavir. If lamotrigine is used concomitantly with ritonavir-boosted darunavir, increased lamotrigine dosage may be needed and lamotrigine plasma concentration monitoring should be considered.

Data are not available regarding concomitant use of cobicistat-boosted darunavir and lamotrigine. In patients receiving cobicistat-boosted darunavir, an alternative anticonvulsant should be considered or lamotrigine plasma concentrations should be monitored.

Oxcarbazepine

Pharmacokinetic interactions if oxcarbazepine is used concomitantly with cobicistat-boosted darunavir (decreased cobicistat concentrations; effect on darunavir concentrations unknown). An alternative anticonvulsant or alternative antiretroviral should be considered; if concomitant use of oxcarbazepine and cobicistat-boosted darunavir is necessary, the patient should be monitored for lack or loss of antiretroviral response.

Phenobarbital and Phenytoin

Possible pharmacokinetic interactions if phenobarbital or phenytoin is used concomitantly with ritonavir-boosted darunavir (decreased concentrations of the anticonvulsant; no change in darunavir concentrations). If ritonavir-boosted darunavir is used concomitantly with phenobarbital or phenytoin, plasma concentrations of the anticonvulsant should be monitored. Some experts suggest that alternatives to phenobarbital and phenytoin should be considered in patients receiving ritonavir-boosted darunavir.

Possible pharmacokinetic interactions if phenobarbital or phenytoin is used concomitantly with cobicistat-boosted darunavir (decreased cobicistat and darunavir concentrations expected and may result in loss of therapeutic effect and development of resistance). Concomitant use of cobicistat-boosted darunavir and phenobarbital or phenytoin is contraindicated.

Antifungal Agents

Isavuconazonium

Concomitant use of isavuconazonium sulfate (prodrug of isavuconazole) and ritonavir-boosted or cobicistat-boosted darunavir may result in increased isavuconazole concentrations and altered darunavir concentrations.

If isavuconazonium sulfate and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, the patient should be monitored for darunavir-associated adverse effects and virologic efficacy and isavuconazole concentration monitoring should be considered.

Itraconazole

Possible pharmacokinetic interactions if itraconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased itraconazole, darunavir, and cobicistat concentrations).

If itraconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for itraconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects and consideration given to monitoring itraconazole plasma concentrations. High itraconazole dosage (exceeding 200 mg daily) is not recommended in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, unless plasma concentrations of the antifungal are used to guide dosage.

Ketoconazole

Pharmacokinetic interactions if ketoconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased ketoconazole, darunavir, and cobicistat concentrations).

If ketoconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects. Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted darunavir.

Posaconazole

Possible pharmacokinetic interactions if posaconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased darunavir and cobicistat concentrations; posaconazole concentrations may be increased).

If posaconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for increased posaconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects; monitoring of posaconazole plasma concentrations should be considered.

Voriconazole

Possible pharmacokinetic interactions if voriconazole is used concomitantly with ritonavir-boosted darunavir (decreased voriconazole concentrations). Data are not available regarding concomitant use of voriconazole and cobicistat-boosted darunavir.

Concomitant use of voriconazole and ritonavir-boosted or cobicistat-boosted darunavir is not recommended unless potential benefits outweigh risks. If voriconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, experts state that consideration should be given to monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly.

Antimalarial Agents

Artemether and Lumefantrine

Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and ritonavir-boosted darunavir decreases plasma concentrations and area under the concentration-time curve (AUC) of artemether and the active metabolite of artemether (dihydroartemisinin), increases plasma concentrations and AUC of lumefantrine, and has no clinically important effect on plasma concentrations or AUC of darunavir. Concomitant use of artemether/lumefantrine and cobicistat-boosted darunavir is expected to result in increased lumefantrine concentrations; the effect on artemether concentrations is not known.

If artemether/lumefantrine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the patient should be monitored for antimalarial efficacy and lumefantrine toxicity (e.g., QT interval prolongation). Although dosage adjustments are not needed when artemether/lumefantrine is used concomitantly with ritonavir-boosted darunavir, the drugs should be used concomitantly with caution.

Antimycobacterial Agents

Bedaquiline

Possible pharmacokinetic interactions if bedaquiline is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased bedaquiline concentrations); clinical importance is unknown.

Some experts state that bedaquiline may be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir if potential benefits outweigh risks, but caution is advised and patients should be monitored for corrected QT (QTc) interval prolongation and liver dysfunction.

Rifabutin

Pharmacokinetic interactions if rifabutin is used concomitantly with ritonavir-boosted darunavir (increased rifabutin concentrations; increased darunavir concentrations). Possible pharmacokinetic interactions if rifabutin is used concomitantly with cobicistat-boosted darunavir (increased rifabutin concentrations expected; effects on darunavir and cobicistat concentrations unknown).

If rifabutin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, dosage of the antimycobacterial agent should be reduced (e.g., 150 mg once every other day; further dosage reduction may be necessary) and increased monitoring for rifabutin-associated adverse effects (e.g., neutropenia, uveitis) is warranted. Some experts recommend a rifabutin dosage of 150 mg once daily or 300 mg 3 times weekly and state that patients should be monitored for antimycobacterial response and therapeutic drug concentration monitoring should be considered.

Rifampin

Possible pharmacokinetic interactions if rifampin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (substantially decreased darunavir concentrations) with possible loss of antiretroviral effects.

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and rifampin is contraindicated. If a rifamycin is indicated in a patient receiving ritonavir-boosted or cobicistat-boosted darunavir, some experts state that rifabutin should be considered as an alternative to rifampin.

Rifapentine

Possible pharmacokinetic interactions if rifapentine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (decreased darunavir concentrations). Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and rifapentine is not recommended. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in HIV patients.

Antineoplastic Agents

Possible pharmacokinetic interactions if certain antineoplastic agents (e.g, dasatinib, nilotinib, vinblastine, vincristine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased antineoplastic agent concentrations).

If dasatinib or nilotinib is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, reduction of the dosage of the antineoplastic agent may be needed.

If vincristine or vinblastine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, consideration should be given to temporarily withholding the antiretroviral regimen in patients who develop clinically important hematologic or GI adverse effects. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to changing to a different antiretroviral regimen that does not include a CYP3A or P-gp inhibitor.

Antipsychotic Agents

Lurasidone

Potential for serious and/or life-threatening adverse effects if lurasidone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and lurasidone is contraindicated.

Perphenazine, Risperidone, and Thioridazine

Possible pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with perphenazine, risperidone, or thioridazine (increased plasma concentrations of the antipsychotic agent).

If perphenazine, risperidone, or thioridazine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, a reduced dosage of the antipsychotic may be needed. Some experts state that the antipsychotic should be initiated using the lowest dosage, maintenance dosage should be adjusted as needed, and the patient should be monitored for toxicities associated with the antipsychotic.

Pimozide

Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias) if pimozide is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and pimozide is contraindicated.

Quetiapine

Pharmacokinetic interactions expected if quetiapine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased quetiapine concentrations).

Alternative antiretroviral therapy should be considered. If ritonavir-boosted or cobicistat-boosted darunavir is necessary in a patient receiving a stable dosage of quetiapine, the quetiapine dosage should be reduced to one-sixth of the original dosage and the patient monitored for quetiapine efficacy and adverse effects. If quetiapine is necessary in a patient receiving ritonavir-boosted or cobicistat-boosted darunavir, some experts recommend that quetiapine should be initiated using the lowest dosage and titrated as needed.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects between darunavir and enfuvirtide.

Maraviroc

Pharmacokinetic interactions if maraviroc is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased maraviroc plasma concentrations and AUC). If maraviroc is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the recommended maraviroc dosage is 150 mg twice daily.

No in vitro evidence of antagonistic antiretroviral effects between darunavir and maraviroc.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of dolutegravir and ritonavir-boosted darunavir does not appear to have a clinically important effect on the pharmacokinetics of either drug. Clinically important drug interactions are not expected if cobicistat-boosted darunavir is used with dolutegravir.

Dosage adjustments are not needed for either drug if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with dolutegravir.

Elvitegravir

Concomitant use of ritonavir-boosted darunavir (darunavir 600 mg twice daily and ritonavir 100 mg twice daily) and elvitegravir (125 mg once daily) does not result in clinically important changes in darunavir or elvitegravir AUC or trough plasma concentrations. If elvitegravir is used concomitantly with ritonavir-boosted darunavir, the recommended elvitegravir dosage is 150 mg once daily concomitantly with darunavir 600 mg twice daily and ritonavir 100 mg twice daily. Concomitant use of elvitegravir and cobicistat-boosted darunavir is not recommended.

Concomitant use of the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF) and ritonavir-boosted darunavir results in altered concentrations of elvitegravir, cobicistat, and/or darunavir. Concomitant use of cobicistat-boosted elvitegravir and cobicistat-boosted darunavir may result in decreased elvitegravir concentrations. Concomitant use of EVG/c/FTC/TDF and ritonavir-boosted or cobicistat-boosted darunavir is not recommended.

Raltegravir

Pharmacokinetic interactions if raltegravir is used concomitantly with ritonavir-boosted darunavir (decreased raltegravir AUC; no clinically important effect on pharmacokinetics of ritonavir-boosted darunavir). Although data are not available, clinically important drug interactions are not expected if cobicistat-boosted darunavir is used with raltegravir.

Dosage adjustments are not necessary if raltegravir and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

No in vitro evidence of antagonistic antiretroviral effects between darunavir and NNRTIs, including delavirdine, efavirenz, etravirine, nevirapine, and rilpivirine.

Efavirenz

Concomitant use of ritonavir-boosted darunavir (darunavir 300 mg and ritonavir 100 mg twice daily) and efavirenz (600 mg once daily) increased the AUC of efavirenz by 21% and decreased the AUC of darunavir by 13%. The clinical importance of this interaction remains to be established. Concomitant use of cobicistat-boosted darunavir and efavirenz may result in decreased darunavir and cobicistat concentrations.

If efavirenz is used concomitantly with ritonavir-boosted darunavir, dosage adjustments are not necessary. However, some experts state that the patient should be monitored closely and consideration given to monitoring plasma drug concentrations.

Concomitant use of efavirenz and cobicistat-boosted darunavir is not recommended because of possible loss of therapeutic effect and development of resistance to darunavir.

Etravirine

Pharmacokinetic interactions if etravirine is used concomitantly with ritonavir-boosted darunavir (decreased etravirine plasma concentrations and AUC; no clinically important effect on darunavir plasma concentrations and AUC). Safety and efficacy of concomitant use of etravirine and ritonavir-boosted darunavir was established in phase 3 clinical studies. Concomitant use of etravirine and cobicistat-boosted darunavir may result in decreased cobicistat concentrations; the effects on darunavir pharmacokinetics are not known.

If etravirine is used with ritonavir-boosted darunavir, dosage adjustments are not needed.

Concomitant use of etravirine and cobicistat-boosted darunavir is not recommended; possible loss of therapeutic effect and development of resistance to darunavir.

Nevirapine

Pharmacokinetic interactions if nevirapine is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of nevirapine and darunavir). Concomitant use of nevirapine and cobicistat-boosted darunavir may result in decreased cobicistat concentrations; the effects on darunavir pharmacokinetics are not known.

If nevirapine and ritonavir-boosted darunavir are used concomitantly, dosage adjustments are not needed.

Concomitant use of nevirapine and cobicistat-boosted darunavir is not recommended; possible loss of therapeutic effect and development of resistance to darunavir.

Rilpivirine

Concomitant use of rilpivirine and ritonavir-boosted darunavir has resulted in increased rilpivirine plasma concentrations and AUC, but did not have a clinically important effect on darunavir concentrations or AUC. Concomitant use of rilpivirine and cobicistat-boosted darunavir may result in increased rilpivirine concentrations, but clinically important changes in darunavir concentrations are not expected.

If rilpivirine and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, dosage adjustments are not needed.

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

No in vitro evidence of antagonistic antiretroviral effects between darunavir and NRTIs, including abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine.

Pharmacokinetic interactions are not expected if abacavir, emtricitabine, lamivudine, stavudine, or zidovudine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir. Dosage adjustments are not needed if ritonavir-boosted darunavir is used concomitantly with abacavir, emtricitabine, lamivudine, stavudine, or zidovudine.

Didanosine

Concomitant use of didanosine delayed-release capsules and ritonavir-boosted or cobicistat-boosted darunavir does not affect the pharmacokinetics of didanosine or darunavir. Dosage adjustments are not necessary, but didanosine doses should be given (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food) or cobicistat-boosted darunavir (with food).

Tenofovir Alafenamide Fumarate

Concomitant use of ritonavir-boosted darunavir and tenofovir alafenamide fumarate (TAF) or cobicistat-boosted darunavir and TAF does not substantially affect the AUC of tenofovir.

Some experts state that dosage adjustments are not needed if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with TAF.

Tenofovir Disoproxil Fumarate

Pharmacokinetic interactions if tenofovir disoproxil fumarate (tenofovir DF) is used concomitantly with ritonavir-boosted darunavir (increased tenofovir plasma concentrations and AUC; increased darunavir plasma concentrations and AUC). Possible pharmacokinetic interactions if tenofovir DF is used concomitantly with cobicistat-boosted darunavir.

The manufacturer of darunavir states that the usual dosage of ritonavir-boosted darunavir can be used concomitantly with the usual dosage of tenofovir DF. Some experts state that the clinical importance of increased tenofovir DF exposures is unknown, and patients receiving ritonavir-boosted darunavir concomitantly with tenofovir DF should be monitored for tenofovir toxicity.

If cobicistat-boosted darunavir is used concomitantly with tenofovir DF, baseline estimated creatinine clearance, urine glucose, and urine protein should be assessed and patients should be monitored for tenofovir toxicity. Concomitant use of cobicistat-boosted darunavir with tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute.(See Renal Effects under Cautions: Warnings/Precautions.)

HIV Protease Inhibitors (PIs)

Concomitant use of ritonavir-boosted darunavir with other HIV PIs (except atazanavir) has not been studied. The manufacturer of darunavir states that concomitant use with other HIV PIs is not recommended.

No in vitro evidence of antagonistic antiretroviral effects between darunavir and amprenavir (active metabolite of fosamprenavir), atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir.

Atazanavir

Concomitant use of atazanavir 300 mg once daily with ritonavir-boosted darunavir (darunavir 400 mg and ritonavir 100 mg twice daily [dosage differs from usually recommended dosage]) results in plasma concentrations of atazanavir that are similar to those attained with ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg once daily) and plasma concentrations of darunavir similar to those attained without atazanavir.

The manufacturer of darunavir states that concomitant use of darunavir and ritonavir-boosted atazanavir is not recommended.

Indinavir

Concomitant use of ritonavir-boosted darunavir and indinavir results in increased peak plasma concentrations and AUCs of darunavir and indinavir.

Appropriate dosages for concomitant use of ritonavir-boosted darunavir and indinavir are not established.

Lopinavir

Concomitant use of ritonavir-boosted darunavir and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) results in substantially decreased concentrations of darunavir and no change in lopinavir concentrations.

Concomitant use of lopinavir/ritonavir and ritonavir-boosted darunavir is not recommended; appropriate dosages for concomitant use with respect to safety and efficacy have not been established.

Ritonavir

Pharmacokinetic interactions if ritonavir is used concomitant with darunavir (increased plasma concentration and AUC of darunavir). Low-dose ritonavir is a pharmacokinetic enhancer (pharmacokinetic booster), and is used in conjunction with darunavir for therapeutic advantage (ritonavir-boosted darunavir).

Saquinavir

Concomitant use of ritonavir-boosted darunavir (darunavir 400 mg and ritonavir 100 mg twice daily) and saquinavir 1 g twice daily results in substantially decreased darunavir concentrations and no change in saquinavir concentrations.

Concomitant use of saquinavir and ritonavir-boosted darunavir is not recommended.

Benzodiazepines

Possible pharmacokinetic interactions if certain benzodiazepines (e.g., alprazolam, diazepam, estazolam, midazolam, triazolam) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of the benzodiazepine).

Alprazolam

Some experts state that other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered instead of alprazolam in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.

Clonazepam

Pharmacokinetic interactions if clonazepam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased clonazepam concentrations).

If clonazepam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, clinical monitoring is recommended. Although pharmacokinetic studies evaluating concomitant use are lacking, some experts state that other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered instead of clonazepam in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.

Diazepam

If diazepam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, diazepam dosage should be titrated, a lower diazepam dosage should be considered, and the patient should be monitored for adverse effects. Some experts state that other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered instead of diazepam in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.

Estazolam

If estazolam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, estazolam dosage should be titrated, a lower estazolam dosage should be considered, and the patient should be monitored for adverse effects.

Midazolam and Triazolam

Concomitant use of midazolam or triazolam with ritonavir-boosted or cobicistat-boosted darunavir potentially could result in serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).

Concomitant use of oral midazolam or triazolam with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

Concomitant use of parenteral midazolam and ritonavir-boosted or cobicistat-boosted darunavir should be undertaken with caution and in a monitored setting where respiratory depression and/or prolonged sedation can be managed. In addition, a reduced dosage of midazolam should be considered, especially if more than a single dose of midazolam is given. Some experts state that parenteral midazolam can be given in a single dose with caution in a monitored situation for procedural sedation in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.

β-Adrenergic Blocking Agents

Possible pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with carvedilol, metoprolol, or timolol (increased plasma concentrations of the β-adrenergic blocking agent).

If carvedilol, metoprolol, or timolol is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, clinical monitoring of the patient is recommended and reduction of the dosage of the β-adrenergic blocking agent may be needed. Alternatively, some experts state that use of β-adrenergic blocking agents that are not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol) should be considered.

Bosentan

Possible pharmacokinetic interactions if bosentan is used concomitantly with ritonavir-boosted darunavir (increased bosentan concentrations). Possible pharmacokinetic interactions if bosentan is used concomitantly with cobicistat-boosted darunavir (increased bosentan concentrations; decreased darunavir and cobicistat concentrations).

In patients who have been receiving ritonavir-boosted or cobicistat-boosted darunavir for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

In patients who have been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating ritonavir-boosted or cobicistat-boosted darunavir; after at least 10 days of ritonavir-boosted or cobicistat-boosted darunavir therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

In patients switching from ritonavir-boosted darunavir to cobicistat-boosted darunavir, the current bosentan dosage should be maintained.

Buspirone

Possible pharmacokinetic interactions if buspirone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased buspirone concentrations).

If buspirone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, buspirone dosage should be titrated, a lower buspirone dosage should be considered, and the patient should be monitored for prolonged or adverse effects.

Calcium-channel Blocking Agents

Possible pharmacokinetic interactions if certain calcium-channel blocking agents (e.g., amlodipine, felodipine, nicardipine, nifedipine, verapamil) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased concentrations of the calcium-channel blocking agent). These calcium-channel blocking agents should be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir with caution; clinical monitoring of the patient is recommended.

Possible pharmacokinetic interactions if diltiazem is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased diltiazem concentrations). Diltiazem should be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir with caution; diltiazem dosage should be adjusted based on clinical response and toxicities.

Cobicistat

Pharmacokinetic interactions if cobicistat is used concomitantly with darunavir (increased plasma concentrations and AUC of darunavir). Cobicistat is a pharmacokinetic enhancer (pharmacokinetic booster) and is used in conjunction with darunavir for therapeutic advantage (cobicistat-boosted darunavir).

Colchicine

Potential pharmacokinetic interactions if colchicine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased colchicine concentrations).

Concomitant use of colchicine and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated in patients with renal or hepatic impairment because of the potential for serious and/or life-threatening effects in such patients.

When colchicine is used for treatment of gout flares in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, an initial colchicine dose of 0.6 mg should be given followed by 0.3 mg 1 hour later; the colchicine dose should be repeated no earlier than 3 days later.

When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, colchicine dosage should be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.

Corticosteroids

Orally Inhaled or Intranasal Corticosteroids

Concomitant use of budesonide (inhaled or intranasal), fluticasone propionate (inhaled or intranasal), or mometasone (inhaled or intranasal) with ritonavir-boosted or cobicistat-boosted darunavir may result in increased concentrations of the corticosteroid and may result in adrenal insufficiency or Cushing's syndrome.

Budesonide (inhaled or intranasal), fluticasone (inhaled or intranasal), and mometasone (inhaled or intranasal) should not be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir unless potential benefits of the corticosteroid outweigh risks of systemic corticosteroid adverse effects. An alternative (e.g., beclomethasone) should be considered, especially when long-term use of the corticosteroid is anticipated.

Some experts state that concomitant use of beclomethasone (inhaled) and ritonavir-boosted darunavir does not result in clinically important pharmacokinetic interactions and dosage adjustments are not necessary if the drugs are used concomitantly. These experts also state that concomitant use of beclomethasone (inhaled) and cobicistat-boosted darunavir is not expected to result in clinically important pharmacokinetic interactions.

Local Injections of Corticosteroids

Concomitant use of intra-articular or other local injections of methylprednisolone, prednisolone, or triamcinolone with ritonavir-boosted darunavir may result in increased concentrations of the corticosteroid and may result in adrenal insufficiency or Cushing's syndrome.

Ritonavir-boosted or cobicistat-boosted darunavir should not be used concomitantly with local injections of methylprednisolone, prednisolone, or triamcinolone; other nonsteroidal therapies should be considered. If intra-articular corticosteroid therapy is required, an alternative antiretroviral that does not alter CYP3A4 activity should be considered (e.g., dolutegravir, raltegravir).

Systemic Corticosteroids

Concomitant use of systemic budesonide with ritonavir-boosted or cobicistat-boosted darunavir may increase corticosteroid concentrations and may result in adrenal insufficiency or Cushing's syndrome; decreased darunavir concentrations may also occur. Systemic budesonide should not be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, unless potential benefits outweigh the risks of systemic corticosteroid adverse effects.

Concomitant use of systemic prednisone with ritonavir-boosted or cobicistat-boosted darunavir may increase corticosteroid concentrations and may result in adrenal insufficiency or Cushing's syndrome. Systemic prednisone should not be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, unless potential benefits outweigh the risks of systemic corticosteroid adverse effects.

Concomitant use of systemic dexamethasone and ritonavir-boosted or cobicistat-boosted darunavir may result in decreased darunavir, ritonavir, or cobicistat concentrations and possible decreased antiretroviral efficacy. Systemic dexamethasone and ritonavir-boosted or cobicistat-boosted darunavir should be used concomitantly with caution; alternative corticosteroids should be considered for long-term use.

Dextromethorphan

Pharmacokinetic interactions if dextromethorphan is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of dextromethorphan).

Digoxin

Pharmacokinetic interactions if digoxin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased digoxin concentrations).

Ritonavir-boosted darunavir and digoxin should be used concomitantly with caution. The lowest possible dosage of digoxin should be used; digoxin plasma concentrations should be monitored and digoxin dosage adjusted to obtain the desired clinical effect.

Cobicistat-boosted darunavir and digoxin should be used concomitantly with caution. Digoxin dosage should be titrated and digoxin plasma concentrations monitored.

Eplerenone

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and eplerenone is expected to result in increased eplerenone concentrations.

Some experts state that use of eplerenone and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

Ergot Alkaloids

Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) if ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir. Concomitant use of ergot alkaloids with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

If a woman receiving darunavir or any other PI as part of an antiretroviral regimen experiences uterine atony and excessive postpartum bleeding, methylergonovine maleate (Methergine) should be used for treatment of the hemorrhage only if alternative treatments cannot be used and the potential benefits of the ergot alkaloid outweigh the risks. In this situation, methylergonovine maleate should be used in the lowest dosage and shortest duration possible.

Estrogens and Progestins

Pharmacokinetic interactions if oral contraceptives containing ethinyl estradiol and norethindrone are used concomitantly with ritonavir-boosted darunavir (decreased ethinyl estradiol and norethindrone concentrations). Concomitant use of darunavir may also reduce efficacy of contraceptives containing only progestins. Data are not available regarding concomitant use of oral contraceptives and cobicistat-boosted darunavir and possible effects on estrogen and progestin concentrations.

Additional or alternative nonhormonal methods of contraception should be used in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.

Data are not available regarding use of transdermal contraceptive preparations containing ethinyl estradiol and norelgestromin or etonogestrel-releasing subdermal implant contraceptives in patients receiving ritonavir-boosted or cobicistat-boosted darunavir; some experts recommend use of alternative or additional methods of contraception or use of alternative antiretrovirals.

Flibanserin

Concomitant use of flibanserin and ritonavir-boosted or cobicistat-boosted darunavir is expected to increase flibanserin concentrations.

Some experts state that concomitant use of flibanserin and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

GI Drugs

Potential for serious and/or life-threatening adverse effects if cisapride is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (e.g., cardiac arrhythmias). Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and cisapride is contraindicated.

Antacids

Concomitant use of drugs affecting gastric acidity is not expected to alter darunavir exposures.

Clinically important drug interactions are not expected if antacids are used concomitantly with cobicistat-boosted darunavir.

Histamine H2-receptor Antagonists

No clinically important drug interactions are expected if histamine H2-receptor antagonists (e.g., ranitidine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Dosage adjustments are not needed if ranitidine or other histamine H2-receptor antagonists are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Proton-pump Inhibitors

Pharmacokinetic interactions if omeprazole is used concomitantly with ritonavir-boosted darunavir (decreased plasma concentrations of omeprazole; no change in plasma concentrations of darunavir). If ritonavir-boosted darunavir is used concomitantly with omeprazole, the patient should be monitored for decreased omeprazole efficacy; an increase in omeprazole dosage should be considered in patients whose symptoms are not well controlled, but omeprazole dosages exceeding 40 mg daily should be avoided.

No clinically important drug interactions are expected if proton pump inhibitors (PPIs) are used concomitantly with cobicistat-boosted darunavir; dosage adjustments are not needed.

HCV Antivirals

HCV Polymerase Inhibitors

Dasabuvir

Concomitant use of ritonavir-boosted darunavir and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir sodium results in decreased darunavir trough plasma concentrations. Concomitant use of ritonavir-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir is not recommended.

Data are not available regarding pharmacokinetic interactions between cobicistat-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir. Therefore, concomitant use of the drugs is not recommended.

Sofosbuvir

Concomitant use of sofosbuvir and ritonavir-boosted darunavir does not have a clinically important effect on the pharmacokinetics of either drug. Dosage adjustments are not needed.

Sofosbuvir and Velpatasvir

Concomitant use of the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) with ritonavir-boosted darunavir does not result in clinically important pharmacokinetic interactions.

Concomitant use of sofosbuvir/velpatasvir and ritonavir-boosted darunavir in conjunction with the fixed combination of emtricitabine and tenofovir DF (emtricitabine/tenofovir DF) results in increased tenofovir plasma concentrations and AUC. Patients should be monitored for tenofovir-associated adverse effects if sofosbuvir/velpatasvir is used concomitantly with any HIV antiretroviral regimen containing tenofovir DF.

HCV Protease Inhibitors

Paritaprevir

Concomitant use of ritonavir-boosted darunavir and the fixed combination of ombitasvir/paritaprevir/ritonavir results in decreased darunavir trough plasma concentrations. The manufacturer of ombitasvir/paritaprevir/ritonavir states that the fixed combination can be taken at the same time as darunavir (800 mg) without low-dose ritonavir.

Concomitant use of ritonavir-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir sodium results in decreased darunavir trough plasma concentrations. Concomitant use of ritonavir-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir is not recommended.

It is not known whether pharmacokinetic interactions occur between cobicistat-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir; concomitant use of the drugs is not recommended.

Simeprevir

Concomitant use of simeprevir and ritonavir-boosted darunavir increases simeprevir plasma concentrations and AUC and also increases darunavir plasma concentrations. Concomitant use of simeprevir and cobicistat-boosted darunavir results in increased simeprevir concentrations.

Concomitant use of simeprevir and ritonavir-boosted or cobicistat-boosted darunavir is not recommended.

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir with ritonavir-boosted darunavir does not have a clinically important effect on daclatasvir or darunavir exposures.

Dosage adjustments are not needed if daclatasvir is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Elbasvir and Grazoprevir

Concomitant use of ritonavir-boosted darunavir (600 mg of darunavir and 100 mg of ritonavir once daily) and elbasvir (50 mg once daily) results in increased elbasvir concentrations and AUC. Concomitant use of ritonavir-boosted darunavir (600 mg of darunavir and 100 mg of ritonavir once daily) and grazoprevir (200 mg once daily) results in substantially increased grazoprevir concentrations due to OATP1B1 and 1B3 inhibition by ritonavir-boosted darunavir. Concomitant use of cobicistat-boosted darunavir is expected to increase grazoprevir concentrations. Increased grazoprevir concentrations may increase the risk of ALT elevations.

Concomitant use of elbasvir/grazoprevir and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

Ledipasvir and Sofosbuvir

Concomitant use of a once-daily regimen of ritonavir-boosted darunavir (darunavir 800 mg and ritonavir 100 mg) and either ledipasvir (90 mg once daily) or sofosbuvir (single 400-mg dose) does not have a clinically important effect on the pharmacokinetics of darunavir, ritonavir, ledipasvir, or sofosbuvir. Clinically important pharmacokinetic interactions are not expected if the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Dosage adjustments are not needed if ledipasvir/sofosbuvir is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.

Concomitant use of ledipasvir/sofosbuvir and an HIV treatment regimen of ritonavir-boosted darunavir, emtricitabine, and tenofovir DF increases tenofovir concentrations. Safety of increased tenofovir concentrations in patients receiving ledipasvir/sofosbuvir concomitantly with an antiretroviral regimen that includes ritonavir-boosted darunavir and tenofovir DF has not been established. An alternative HCV treatment regimen or alternative antiretroviral regimen should be considered to avoid increased tenofovir exposures, especially in patients at risk for renal toxicity. If concomitant use is necessary, the patient should be monitored for tenofovir-associated adverse effects.

Ombitasvir

Concomitant use of ritonavir-boosted darunavir and the fixed combination of ombitasvir/paritaprevir/ritonavir results in decreased darunavir trough plasma concentrations. The manufacturer of ombitasvir/paritaprevir/ritonavir states that the fixed combination can be taken at the same time as darunavir (800 mg) without low-dose ritonavir.

Concomitant use of ritonavir-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir sodium results in decreased darunavir trough plasma concentrations. Concomitant use of ritonavir-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir is not recommended.

It is not known whether pharmacokinetic interactions occur between cobicistat-boosted darunavir and ombitasvir/paritaprevir/ritonavir with dasabuvir; concomitant use of the drugs is not recommended.

HMG-CoA Reductase Inhibitors

Pharmacokinetic interactions with HMG-CoA reductase inhibitors (statins) metabolized by CYP3A isoenzyme. Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and certain statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) may increase plasma concentrations and AUCs of the antilipemic agents and increase the risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.

Atorvastatin

If atorvastatin is used concomitantly with ritonavir-boosted darunavir, atorvastatin dosage should not exceed 20 mg daily. Dosage of atorvastatin should be titrated carefully; the lowest necessary dosage should be used and the patient monitored for adverse effects.

If atorvastatin is used concomitantly with cobicistat-boosted darunavir, atorvastatin should be initiated at the lowest dosage and titrated to the lowest necessary dosage; the patient should be monitored for safety.

Lovastatin

Concomitant use of lovastatin with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

Pitavastatin

Concomitant use of ritonavir-boosted darunavir (darunavir 800 mg and ritonavir 100 mg once daily) and pitavastatin (4 mg once daily) results in a 26% decrease in the AUC of pitavastatin, but does not have a clinically important effect on darunavir concentrations. Dosage adjustments are not necessary if pitavastatin is used concomitantly with ritonavir-boosted darunavir.

The effect of cobicistat-boosted darunavir on pitavastatin pharmacokinetics is not known. If pitavastatin is used concomitantly with cobicistat-boosted darunavir, pitavastatin should be initiated at the lowest dosage and titrated; the patient should be monitored for safety. Some experts state that dosage adjustments are not necessary if pitavastatin is used concomitantly with cobicistat-boosted darunavir.

Pravastatin

If pravastatin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, dosage of pravastatin should be titrated carefully and the lowest necessary dosage used with close monitoring for adverse effects.

Rosuvastatin

If rosuvastatin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, dosage of rosuvastatin should be titrated carefully and the lowest necessary dosage used with close monitoring for adverse effects.

Simvastatin

Concomitant use of simvastatin with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.

Immunosuppressive Agents

Pharmacokinetic interactions with cyclosporine, everolimus, sirolimus, tacrolimus (increased concentrations of the immunosuppressive agent expected).

If cyclosporine, sirolimus, or tacrolimus is

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