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Darunavir

Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: [(1S,2R) - 3 - [[(4 - Aminophenyl)sulfonyl](2 - methylpropyl)amino] - 2 - hydroxy - 1 - (phenylmethyl)propyl] - carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester
Molecular Formula: C27H37N3O7SC27H37N3O7S•C2H5OH
CAS Number: 206361-99-1
Brands: Prezista, Prezcobix

Introduction

Antiretroviral; HIV protease inhibitor (PI).1 2 3

Uses for Darunavir

Treatment of HIV Infection

Darunavir with low-dose ritonavir (ritonavir-boosted darunavir): Treatment of HIV-1 infection in adults, adolescents, and children ≥3 years of age;1 used in conjunction with other antiretrovirals.1 200 201

Darunavir with cobicistat (cobicistat-boosted darunavir): Treatment of HIV-1 infection in adults;237 239 used in conjunction with other antiretrovirals.200 237 239

Do not use darunavir without a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat).1 200 201 237 239 Pharmacokinetic enhancer (pharmacokinetic booster) necessary to improve darunavir's pharmacokinetic profile.1 200 237 239 Low-dose ritonavir and cobicistat are not interchangeable in antiretroviral regimens;200 237 239 these pharmacokinetic enhancers have different dosage and administration requirements and are associated with different adverse effects, precautions, contraindications, and drug interactions.200 237 239

When ritonavir-boosted darunavir used, single-entity darunavir is given with single-entity ritonavir.1 In antiretroviral-experienced patients, use results of genotypic and phenotypic viral resistance testing and individual’s prior antiretroviral treatment to guide treatment.1

When cobicistat-boosted darunavir used, fixed combination containing both drugs (darunavir/cobicistat) can be used;237 alternatively, single-entity darunavir is given with single-entity cobicistat.239 Assess estimated Clcr in all patients prior to initiation of cobicistat-boosted darunavir (see Renal Effects under Cautions).237 239 Do not use darunavir/cobicistat in patients with HIV-1 with substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).237 In antiretroviral-experienced patients, use results of genotypic viral resistance testing to guide treatment;237 if such testing not available, may use the fixed combination in HIV PI-naive patients, but not recommended in HIV PI-experienced patients.237

For initial treatment in antiretroviral-naive adults and adolescents, experts state that ritonavir-boosted darunavir (once daily) in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is a recommended PI-based regimen.200 These experts state that cobicistat-boosted darunavir in conjunction with tenofovir DF and emtricitabine (or lamivudine) is an alternative PI-based regimen for initial treatment in antiretroviral-naive adults, but use only in those with pretreatment estimated Clcr ≥70 mL/minute.200 Ritonavir-boosted darunavir or cobicistat-boosted darunavir in conjunction with abacavir and lamivudine (or emtricitabine) also alternative PI-based regimens for initial treatment, but use only in those who are human leukocyte antigen (HLA)-B*5701 negative.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that ritonavir-boosted darunavir (twice daily) and 2 nucleoside reverse transcriptase inhibitors (NRTIs) is an alternative (not preferred) PI-based regimen in children 3 years to <12 years of age and ritonavir-boosted darunavir (once daily) in conjunction with 2 NRTIs is an alternative (not preferred) PI-based regimen in children ≥12 years of age.201

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and others 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.199

USPHS recommends 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV.199 Ritonavir-boosted darunavir and 2 NRTIs is one of several alternative regimens.199 Preferred dual NRTI option for use with ritonavir-boosted darunavir is emtricitabine and tenofovir DF; alternatives are tenofovir DF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Darunavir Dosage and Administration

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted darunavir) once or twice daily with food.1

Alternatively, administer orally in conjunction with cobicistat (cobicistat-boosted darunavir) once daily with food.237 239

Do not administer without low-dose ritonavir or cobicistat.1 200 201 237 239

Ritonavir-boosted Darunavir

Administer single-entity darunavir as tablets or oral suspension at same time as single-entity ritonavir capsules, tablets, or oral solution.1 200

Oral suspension: Use in those who have difficulty swallowing tablets.1 Administer suspension using oral dosing syringe supplied by the manufacturer.1 If 800-mg dose is indicated, give dose as two 4-mL administrations using the oral dosing syringe.1 Supplied as a white to off-white opaque suspension;1 shake prior to each dose.1

Tablets: Swallow tablets whole with a drink (e.g., water, milk).1 Assess ability to swallow tablets in children weighing ≥15 kg; consider darunavir oral suspension in those unable to reliably swallow tablets.1

Cobicistat-boosted Darunavir

Administer fixed-combination tablets containing both drugs (darunavir/cobicistat).237 Alternatively, administer single-entity darunavir as tablets or oral suspension at same time as single-entity cobicistat tablets.239

Dosage

Single-entity darunavir available as oral suspension or tablets containing darunavir ethanolate; dosage expressed in terms of darunavir.1

Darunavir/cobicistat available as fixed-combination tablets containing darunavir ethanolate (800 mg of darunavir) and cobicistat (150 mg).237

Pediatric Patients

Treatment of HIV Infection

To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.1

Dosage of ritonavir-boosted darunavir in children and adolescents 3 years to <18 years of age weighing ≥10 kg is based on weight.1

Antiretroviral-naive Pediatric Patients
Oral

Ritonavir-boosted darunavir (pediatric patients 3 years to <18 years of age weighing ≥10 kg): Dosage based on weight (approximately 35 mg/kg once daily with ritonavir 7 mg/kg once daily in those weighing <15 kg).1 (See Table 1 and Table 2.)

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

Table 1. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-naive Pediatric Patients 3 Years to <18 Years of Age Weighing 10 to <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 <18 Years of Age Weighing ≥15 kg1

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

Antiretroviral-experienced Pediatric Patients
Oral

Genotypic testing recommended to identify substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).1

Ritonavir-boosted darunavir (pediatric patients 3 years to <18 years of age weighing ≥10 kg with no substitutions associated with darunavir resistance): Dosage based on weight (approximately 35 mg/kg once daily with ritonavir 7 mg/kg once daily in those weighing <15 kg).1 (See Table 3 and Table 4.)

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

Table 3. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-experienced Pediatric Patients 3 Years to <18 Years of Age Weighing 10 to <15 kg without Any Substitutions Associated with Darunavir Resistance1

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-experienced Pediatric Patients 3 Years to <18 Years of Age Weighing ≥15 kg without Any Substitutions Associated with Darunavir Resistance1

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

Ritonavir-boosted darunavir (pediatric patients 3 years to <18 years of age weighing ≥10 kg with at least 1 substitution associated with darunavir resistance): Dosage based on weight (approximately 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily in those weighing <15 kg).1 (See Table 5 and Table 6.)

Table 5. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-experienced Pediatric Patients 3 Years to <18 Years of Age Weighing 10 to <15 kg with ≥1 Substitution Associated with Darunavir Resistance1

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

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

Table 6. Dosage of Ritonavir-boosted Darunavir in Antiretroviral-experienced Pediatric Patients 3 Years to <18 Years of Age Weighing ≥15 kg with ≥1 Substitution Associated with Darunavir Resistance1

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

Adults

Treatment of HIV Infection
Antiretroviral-naive Adults
Oral

Ritonavir-boosted darunavir: Single-entity darunavir 800 mg (one 800-mg tablet or 8 mL of oral suspension containing 100 mg/mL) once daily in conjunction with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted darunavir: 1 tablet of darunavir/cobicistat (800 mg of darunavir and 150 mg of cobicistat) once daily.237 Alternatively, single-entity darunavir 800 mg (one 800-mg darunavir tablet or 8 mL of darunavir oral suspension containing 100 mg/mL) once daily in conjunction with single-entity cobicistat (150 mg once daily).239

Antiretroviral-experienced Adults
Oral

Genotypic testing recommended to identify substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).1 237

Ritonavir-boosted darunavir in patients with no substitutions associated with darunavir resistance: Single-entity darunavir 800 mg (one 800-mg tablet or 8 mL of oral suspension containing 100 mg/mL) once daily in conjunction with low-dose ritonavir (100 mg once daily).1

Ritonavir-boosted darunavir in patients with at least 1 substitution associated with darunavir resistance: Single-entity darunavir 600 mg (one 600-mg tablet or 6 mL of oral suspension containing 100 mg/mL) twice daily in conjunction with low-dose ritonavir (100 mg twice daily).1

Ritonavir-boosted darunavir when genotypic testing not feasible: Single-entity darunavir 600 mg (one 600-mg tablet or 6 mL of oral suspension containing 100 mg/mL) twice daily in conjunction with low-dose ritonavir (100 mg twice daily).1

Cobicistat-boosted darunavir: 1 tablet of darunavir/cobicistat (800 mg of darunavir and 150 mg of cobicistat) once daily.237 Alternatively, single-entity darunavir 800 mg (one 800-mg darunavir tablet or 8 mL of darunavir oral suspension containing 100 mg/mL) once daily in conjunction with single-entity cobicistat (150 mg once daily).239

Darunavir dosage of 600 mg twice daily in conjunction with cobicistat not recommended.239

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

Ritonavir-boosted darunavir: Single-entity darunavir 800 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).199 Alternatively, single-entity darunavir 600 mg twice daily in conjunction with low-dose ritonavir (100 mg twice daily).199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Do not exceed dosage recommended for antiretroviral-experienced adults.1

Special Populations

Hepatic Impairment

Ritonavir-boosted darunavir: Dosage adjustments not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1 200 Do not use in those with severe hepatic impairment (Child-Pugh class C).1 200

Cobicistat-boosted darunavir: Dosage adjustments not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).200 237 239 Do not use in those with severe hepatic impairment (Child-Pugh class C).200 237 239

Renal Impairment

Ritonavir-boosted darunavir: Experts state dosage adjustments not necessary in patients with renal impairment.200

Cobicistat-boosted darunavir: Assess estimated Clcr prior to initiation of fixed-combination darunavir/cobicistat or, alternatively, single-entity darunavir with single-entity cobicistat.237 239 Experts state dosage adjustments of cobicistat-boosted darunavir not necessary in patients with renal impairment.200 However, these experts and manufacturer state do not use cobicistat-boosted darunavir in conjunction with tenofovir DF in patients with estimated Clcr <70 mL/minute.200 237 239

Geriatric Patients

Ritonavir-boosted or cobicistat-boosted darunavir: Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 237

Cautions for Darunavir

Contraindications

  • Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with drugs highly dependent on 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, simvastatin, oral midazolam, triazolam, ranolazine, pimozide, sildenafil [Revatio] for treatment of pulmonary arterial hypertension);1 237 239 concomitant use of cobicistat-boosted darunavir and lurasidone.237 (See Specific Drugs under Interactions.)

  • Concomitant use of ritonavir-boosted 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]).1 237 (See Specific Drugs under Interactions.)

  • Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and colchicine in patients with renal and/or hepatic impairment.1 237 (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

Severe skin reactions, sometimes accompanied by fever and/or increased serum transaminase concentrations, reported with ritonavir-boosted darunavir.1 237 Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute, generalized exanthematous pustulosis reported.1 237

Immediately discontinue ritonavir-boosted or cobicistat-boosted darunavir 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).1 237

Sulfonamide Sensitivity

Darunavir contains a sulfonamide moiety; may cause allergic-type reaction in certain susceptible individuals.1 237

Use ritonavir-boosted or cobicistat-boosted darunavir with caution and close monitoring in patients with known hypersensitivity to sulfonamide-containing drugs.1 237

Hepatic Effects

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) reported in clinical studies.1 237 Patients with preexisting liver dysfunction, including HIV-infected patients coinfected with HBV or HCV, have increased risk for liver function abnormalities.1 237 Postmarketing reports of liver injury (in some cases fatal) in patients receiving ritonavir-boosted darunavir;1 237 liver injury generally 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.1 237

Conduct appropriate laboratory tests to evaluate hepatic function prior to and periodically during ritonavir-boosted or cobicistat-boosted darunavir therapy.1 237 Consider increased AST/ALT monitoring in patients with hepatitis, cirrhosis, or elevated transaminase concentrations prior to therapy, especially during first several months of therapy.1 237

Consider interrupting or discontinuing ritonavir-boosted or cobicistat-boosted darunavir in patients who develop manifestations suggestive of new or worsening hepatic impairment (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly, clinically important increases in hepatic enzyme concentrations).1 237

Renal Effects

Cobicistat decreases estimated Clcr by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function;237 239 consider this effect when interpreting changes in estimated Clcr in patients receiving cobicistat-boosted darunavir, particularly those needing Clcr monitoring due to a medical condition or other concomitant drugs.237 239

Assess estimated Clcr prior to initiating cobicistat-boosted darunavir.237 239 Although cobicistat may cause only modest increases in Scr and modest declines in estimated Clcr without affecting renal glomerular function, closely monitor patient for renal safety if Scr increases >0.4 mg/dL from baseline during cobicistat-boosted darunavir therapy.237 239

Manufacturer states dosage recommendations not available for drugs requiring dosage adjustments in patients with renal impairment who are receiving cobicistat-boosted darunavir;237 239 consider alternative concomitant drugs that do not require dosage adjustments based on renal impairment.237 239

New-onset or worsening renal impairment, including acute renal failure and Fanconi syndrome, reported in patients receiving cobicistat in an antiretroviral regimen that also includes tenofovir DF.237 239 Concomitant use of cobicistat-boosted darunavir and tenofovir DF not recommended in patients with estimated Clcr <70 mL/minute or in patients who are receiving (or recently received) a nephrotoxic agent.237 239 Whenever cobicistat-boosted darunavir and tenofovir DF are used concomitantly, document urine glucose and urine protein at baseline and monitor estimated Clcr, urine glucose, and urine protein throughout concomitant therapy.237 239 In addition, monitor serum phosphorus in those with or at risk for renal impairment.237 239

Interactions

Darunavir must be used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat).1 200 237 239 Failure to administer darunavir with recommended dosage of ritonavir or cobicistat may result in subtherapeutic darunavir concentrations and inadequate antiviral response.1 200 237 239 When ritonavir-boosted or cobicistat-boosted darunavir used, consider cautions, precautions, contraindications, and drug interactions associated with darunavir and the pharmacokinetic enhancer.1 200 237 239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with certain drugs is contraindicated or requires particular caution.1 200 237 239 Concomitant use with some drugs may result in clinically important adverse effects 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).1 200 237 239 Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted or cobicistat-boosted darunavir and possible development of resistance.1 200 237 239 Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern.1 200 237 239

Consider that concomitant use of cobicistat-boosted darunavir with other drugs may result in different drug interactions than those observed or expected with ritonavir-boosted darunavir due to complex or unknown mechanisms of drug interactions.237 239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with other drugs that are administered in conjunction with a pharmacokinetic enhancer (e.g., ritonavir-boosted HIV PIs, ritonavir-boosted paritaprevir, elvitegravir) not recommended.200 237 239 Dosage recommendations for such regimens not established; concomitant use of more than one pharmacokinetic enhancer may result in complex drug interactions, including decreased plasma concentrations of the antiretroviral leading to loss of therapeutic effect and development of resistance.200 237 239

Darunavir, ritonavir, and cobicistat are all available as single-entity preparations.1 209 239 In addition, fixed-combination darunavir/cobicistat is commercially available.237 Ensure that therapy is not duplicated; do not use darunavir/cobicistat concomitantly with any other preparations containing darunavir, cobicistat, or ritonavir.237 239

Consider potential drug interactions prior to and during use of ritonavir-boosted or cobicistat-boosted darunavir.1 237 239 Monitor for adverse effects associated with drugs used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1 237 239 (See Interactions.)

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.1 237

Initiate or adjust antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) as needed.1 237

Immune Reconstitution Syndrome

During initial treatment, patients who respond 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.1 237

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 237

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.1 237 Mechanisms and long-term consequences unknown; causal relationship not established.1 237

Hemophilia A and B

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported with HIV PIs;1 237 causal relationship not established.1 237

Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.1 237

HIV Resistance

Possibility of cross-resistance to other HIV PIs not evaluated.1 Effect of ritonavir-boosted darunavir therapy on subsequent therapy with other PIs unknown.1

Specific Populations

Pregnancy

Ritonavir-boosted darunavir and cobicistat-boosted darunavir: Category C.1 237

No adequate, well-controlled studies of darunavir in pregnant women.1 237 Use ritonavir-boosted or cobicistat-boosted darunavir only if potential benefits to the woman justify potential risks to fetus.1 237

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 237

Although data are limited regarding use in pregnant women, experts state that ritonavir-boosted darunavir and 2 NRTIs can be considered an alternative PI-based regimen for initial treatment in pregnant women.202

Lactation

Not known whether darunavir, ritonavir, or cobicistat distributed into human milk;1 209 237 darunavir and cobicistat distributed into milk in rats.1 237

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 237

Pediatric Use

Do not use darunavir in children <3 years of age;1 237 toxicity and mortality reported in juvenile rats.1 237

Adverse effects of ritonavir-boosted darunavir in children 3 years to <18 years of age similar to those reported in adults.1

Safety and efficacy of cobicistat-boosted darunavir not established in patients <18 years of age.237

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 237

Ritonavir-boosted or cobicistat-boosted darunavir: Use with caution and monitor because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 237

Hepatic Impairment

Ritonavir-boosted darunavir: Pharmacokinetics not altered in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Pharmacokinetics not evaluated in patients with severe hepatic impairment (Child-Pugh class C);1 not recommended in such patients.1

Cobicistat-boosted darunavir: Pharmacokinetics not established in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B);237 239 no clinically important pharmacokinetic changes when cobicistat used alone in individuals with mild or moderate hepatic impairment.237 239 Pharmacokinetics of cobicistat-boosted darunavir or cobicistat alone not evaluated in patients with severe hepatic impairment (Child-Pugh class C);237 239 cobicistat-boosted darunavir not recommended in such patients.237

Risk for liver function abnormalities, including severe adverse hepatic effects, increased in patients with preexisting hepatic impairment, including those with HBV or HCV infection.1 237 Consider interruption or discontinuance of ritonavir-boosted or cobicistat-boosted darunavir if there is evidence of new or worsening liver disease.1 237

Darunavir exposure not altered in HIV-infected patients coinfected with HBV or HCV.1

Renal Impairment

Ritonavir-boosted darunavir: Pharmacokinetics not altered in patients with Clcr ≥30 mL/minute.1 Not studied in patients with severe renal impairment or end-stage renal disease.1

Cobicistat-boosted darunavir: Not studied in individuals with renal impairment.237 Cobicistat decreases estimated Clcr without affecting renal glomerular function.237 Assess estimated Clcr in all patients prior to initiation of cobicistat-boosted darunavir (see Renal Effects under Cautions).237 239 Do not use cobicistat-boosted darunavir in conjunction with tenofovir DF in patients with estimated Clcr <70 mL/minute.200 237 239 (See Renal Effects under Cautions.)

Common Adverse Effects

Diarrhea,1 9 nausea,1 9 vomiting,1 abdominal pain,1 headache,1 9 rash.1

Interactions for Darunavir

Darunavir, ritonavir, and cobicistat metabolized principally by CYP3A.1 237 239

Darunavir, ritonavir, and cobicistat inhibit CYP3A4 and CYP2D6.1 237 239

Ritonavir-boosted darunavir inhibits P-glycoprotein (P-gp) transport system;1 cobicistat is a P-gp inhibitor.237 239

Cobicistat inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1 and 1B3.237 239

Darunavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat);1 200 201 237 239 consider drug interactions associated with both darunavir and the pharmacokinetic enhancer.1 200 237 239 Interactions reported or expected with ritonavir-boosted darunavir may differ from those reported or expected with cobicistat-boosted darunavir.200 237 239

The following drug interactions are based on studies using ritonavir-boosted darunavir1 or studies using cobicistat alone.237 239 Drug interaction studies not available to date using cobicistat-boosted darunavir administered either as fixed-combination darunavir/cobicistat or as single-entity darunavir given with single-entity cobicistat.237 239

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A inducers: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (increased clearance of darunavir, ritonavir, or cobicistat; possible loss of antiretroviral efficacy and development of resistance).1 237 239

CYP3A inhibitors: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of darunavir, ritonavir, or cobicistat).1 237 239

CYP3A substrates: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (altered metabolism of CYP3A substrates).1 237 239

CYP2D6 substrates: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of CYP2D6 substrates; possible increased or prolonged therapeutic effects and increased risk of associated adverse effects).1 237 239

Drugs Affected by P-glycoprotein Transport

P-gp substrates: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of P-gp substrates; possible increased or prolonged therapeutic effects and increased risk of associated adverse effects).1 237 239

P-gp inhibitors: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (decreased clearance of darunavir and ritonavir leading to increased plasma concentrations).1

Drugs Affecting or Affected by Other Membrane Transporters

BCRP, OATP1B1, or OATP1B3 substrates: Potential pharmacokinetic interactions with cobicistat-boosted darunavir (increased plasma concentrations of such substrates; possible increased or prolonged therapeutic effects and increased risk of associated adverse effects).237 239

Specific Drugs

Drug

Interaction

Comments

Abacavir

Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions not expected1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Alfuzosin

Ritonavir-boosted or cobicistat-boosted darunavir: Potential for serious and/or life-threatening reactions (e.g., hypotension)1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated1 237 239

Antacids

Acid-modifying drugs not expected to alter darunavir exposures1

Cobicistat-boosted darunavir: Clinically important interactions not expected237

Antiarrhythmic agents (amiodarone, disopyramide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine)

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased antiarrhythmic agent concentrations1 237 239

Amiodarone: If used with ritonavir-boosted or cobicistat-boosted darunavir, experts state monitor for amiodarone toxicity and consider ECG and amiodarone concentration monitoring200

Dronedarone: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 237 239

Disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Use concomitantly with caution;200 monitor antiarrhythmic concentrations1 200 237

Anticoagulants, oral (apixaban, dabigatran, rivaroxaban, warfarin)

Apixaban, dabigatran, rivaroxaban: Possible increased anticoagulant concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir1 200 237

Warfarin: Decreased warfarin concentrations and no change in darunavir concentrations if used with ritonavir-boosted darunavir;1 effect of concomitant use with cobicistat-boosted darunavir unknown200 237 239

Apixaban, rivaroxaban: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended1 200 237

Dabigatran: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended in certain patients with renal impairment depending on indication;1 237 experts state avoid concomitant use in patients with Clcr <50 mL/minute200

Warfarin: Monitor INR if used with ritonavir-boosted or cobicistat-boosted darunavir1 200 237 239 (especially when initiating or discontinuing darunavir) and adjust warfarin dosage as needed;200 if ritonavir-boosted darunavir switched to cobicistat-boosted darunavir, effect on warfarin concentrations not expected to be equivalent200

Anticonvulsants (carbamazepine, clonazepam, ethosuximide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin)

Carbamazepine: If used with ritonavir-boosted darunavir, increased carbamazepine concentrations and no change in darunavir concentrations;1 if used with cobicistat-boosted darunavir, increased carbamazepine concentrations, decreased cobicistat concentrations, and possibility of substantially decreased darunavir concentrations200 237 239

Clonazepam: If used with cobicistat-boosted darunavir, increased clonazepam concentrations237 239

Ethosuximide: Possible increased ethosuximide concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir200

Lamotrigine: If used with ritonavir-boosted darunavir, possible decreased lamotrigine concentrations;200 data not available regarding use with cobicistat-boosted darunavir200

Oxcarbazepine: If used with cobicistat-boosted darunavir, decreased cobicistat concentrations, but effect on darunavir concentrations unknown237 239

Phenobarbital: If used with ritonavir-boosted darunavir, possible decreased phenobarbital concentrations, but no change in darunavir concentrations;1 if used with cobicistat-boosted darunavir, decreased cobicistat concentrations, but effect on darunavir and phenobarbital concentrations unknown237 239

Phenytoin: If used with ritonavir-boosted darunavir, possible decreased phenytoin concentrations, but no change in darunavir concentrations;1 if used with cobicistat-boosted darunavir, possible decreased darunavir concentrations, but effect on phenytoin concentrations unknown200 237 239

Carbamazepine: If used with ritonavir-boosted darunavir, dosage adjustments not needed, but monitor carbamazepine concentrations and adjust anticonvulsant dosage to achieve appropriate clinical effect;1 in patients receiving cobicistat-boosted darunavir, consider alternative anticonvulsant or alternative antiretroviral or, if concomitant use necessary, monitor patient clinically, monitor concentrations of both drugs, and monitor for lack or loss of virologic response200 237 239

Clonazepam: If used with cobicistat-boosted darunavir, monitor patient clinically237 239

Ethosuximide: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for ethosuximide toxicities200

Lamotrigine: In patients receiving ritonavir-boosted or cobicistat-boosted darunavir, consider alternative anticonvulsant or monitor lamotrigine concentrations;200 if used with ritonavir-boosted darunavir increased lamotrigine dosage may be needed200

Oxcarbazepine: In patients receiving cobicistat-boosted darunavir, consider alternative anticonvulsant or alternative antiretroviral or, if concomitant use necessary, monitor for lack or loss of virologic response237 239

Phenobarbital: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor anticonvulsant concentrations1 237 239 and consider alternative anticonvulsant; if used with cobicistat-boosted darunavir, monitor anticonvulsant and darunavir concentrations and assess antiretroviral response200

Phenytoin: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor anticonvulsant concentrations1 237 239 and consider alternative anticonvulsant;200 if used with cobicistat-boosted darunavir, monitor anticonvulsant and darunavir concentrations and assess virologic response200

Antifungals, azoles (itraconazole, ketoconazole, posaconazole, voriconazole)

Itraconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased itraconazole, darunavir, and cobicistat concentrations1 237 239

Ketoconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, increased ketoconazole, darunavir, and cobicistat concentrations1 237 239

Posaconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased posaconazole, darunavir, and cobicistat concentrations1 200 237

Voriconazole: If used with ritonavir-boosted darunavir, possible decreased voriconazole concentrations;1 data not available regarding use with cobicistat-boosted darunavir200 237 239

Itraconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for itraconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects and consider monitoring itraconazole concentrations;200 237 itraconazole dosage >200 mg daily not recommended1 200 unless itraconazole concentrations used to guide dosage200

Ketoconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects;1 237 ketoconazole dosage >200 mg daily not recommended in those receiving ritonavir-boosted darunavir1

Posaconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for posaconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects;1 200 237 consider monitoring posaconazole concentrations200

Voriconazole: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended unless benefits outweigh risks;1 200 237 239 if used concomitantly, experts state consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly200

Antimalarial agents

Fixed combination of artemether and lumefantrine (artemether/lumefantrine): If used with ritonavir-boosted darunavir, decreased concentrations and AUC of artemether and active metabolite of artemether, increased concentrations and AUC of lumefantrine and increased risk of QT interval prolongation, but no effect on darunavir or ritonavir concentrations or AUC;1 if used with cobicistat-boosted darunavir, increased lumefantrine concentrations expected,200 but effect on artemether concentrations unknown200 237

Artemether/lumefantrine: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for antimalarial efficacy and lumefantrine toxicity (e.g., QT interval prolongation);1 200 237 dosage adjustments not needed if used with ritonavir-boosted darunavir, but use caution1

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased bedaquiline concentrations200

Rifabutin: If used with ritonavir-boosted darunavir, increased rifabutin and darunavir concentrations;1 200 if used with cobicistat-boosted darunavir, possible increased rifabutin concentrations, but effect on darunavir and cobicistat concentrations unknown200 237 239

Rifampin: If used with ritonavir-boosted or cobicistat-boosted darunavir, substantially decreased darunavir concentrations and possible loss of antiretroviral effects1 200 237 239

Rifapentine: If used with ritonavir-boosted or cobicistat-boosted darunavir, decreased darunavir concentrations expected 1 200 237

Bedaquiline: Clinical importance unknown;200 some experts state may be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir if benefits outweigh risks, but use caution and monitor for QTc interval prolongation and liver dysfunction200

Rifabutin: If used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, reduce rifabutin dosage to 150 mg once every other day (further reduction may be needed) and monitor for adverse effects (e.g., neutropenia, uveitis);1 200 237 239 also monitor for antimycobacterial response and consider therapeutic drug monitoring200

Rifampin: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated;1 237 239 experts state consider rifabutin as alternative if a rifamycin indicated200

Rifapentine: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended1 200 237

Antineoplastic agents (dasatinib, nilotinib, vinblastine, vincristine)

Dasatinib, nilotinib, vinblastine, vincristine: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased antineoplastic concentrations1 237 239

Dasatinib, nilotinib: If used with ritonavir-boosted or cobicistat-boosted darunavir, reduced dosage of the antineoplastic may be needed 1 237 239

Vincristine, vinblastine: If used with ritonavir-boosted or cobicistat-boosted darunavir, consider temporarily withholding antiretroviral regimen in patients with clinically important hematologic or GI adverse effects;1 237 239 if antiretroviral regimen must be withheld for a prolonged period, consider changing to different antiretroviral regimen that does not include a CYP3A or P-gp inhibitor1 237 239

Antipsychotics (lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine)

Lurasidone: If used with cobicistat-boosted darunavir, potential for serious and/or life-threatening adverse effects237 239

Perphenazine: If used with cobicistat-boosted darunavir, possible increased perphenazine concentrations237 239

Pimozide: If used with ritonavir-boosted or cobicistat-boosted darunavir, potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias)1 237 239

Quetiapine: If used with ritonavir-boosted or cobicistat-boosted darunavir, increased quetiapine concentrations expected1 200

Risperidone, thioridazine: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased concentrations of the antipsychotic1 237 239

Lurasidone: Concomitant use with cobicistat-boosted darunavir contraindicated;237 239 experts state do not use concomitantly with ritonavir-boosted darunavir200

Perphenazine: If used with cobicistat-boosted darunavir, lower perphenazine dosage may be needed237 239

Pimozide: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 237 239

Quetiapine: Consider alternative antiretroviral;1 if ritonavir-boosted or cobicistat-boosted darunavir necessary in patient receiving stable quetiapine dosage, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine efficacy and adverse effects;1 200 if quetiapine necessary in patient receiving ritonavir-boosted or cobicistat-boosted darunavir, experts state initiate using lowest quetiapine dosage and titrate as needed200

Risperidone, thioridazine: If used with ritonavir-boosted or cobicistat-boosted darunavir, lower antipsychotic dosage may be needed1 237 239

Atazanavir

Unboosted atazanavir: Depending on regimen used, no clinically important change in atazanavir or darunavir concentrations or AUC1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ritonavir-boosted atazanavir: Concomitant use with ritonavir-boosted darunavir not recommended1

Avanafil

Ritonavir-boosted or cobicistat-boosted darunavir: Increased avanafil concentrations and increased risk of avanafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection, syncope)1 200 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended1 200 237 239

Benzodiazepines (alprazolam, diazepam, estazolam, midazolam, triazolam)

Alprazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased alprazolam concentrations200

Diazepam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased diazepam concentrations200

Estazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased estazolam concentrations1 237 239

Midazolam or triazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased midazolam or triazolam concentrations and potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1 237 239

Alprazolam: In patients receiving ritonavir-boosted or cobicistat-boosted darunavir, consider alternative (e.g., lorazepam, oxazepam, temazepam)200

Diazepam: If used with ritonavir-boosted or cobicistat-boosted darunavir, titrate diazepam dosage, consider lower diazepam dosage, and monitor for adverse effects;1 237 239 experts state consider alternative (e.g., lorazepam, oxazepam, temazepam)200

Estazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, titrate estazolam dosage, consider lower estazolam dosage, and monitor for adverse effects1 237 239

Oral midazolam or triazolam: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 237 239

Parenteral midazolam: Use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir with caution and in monitored setting where respiratory depression and/or prolonged sedation can be managed;1 237 239 consider reduced midazolam dosage, especially if multiple midazolam doses are given;1 237 239 experts state a single parenteral midazolam dose can be used with caution in a monitored situation for procedural sedation200

β-Adrenergic blocking agents (carvedilol, metoprolol, timolol)

Carvedilol, metoprolol, timolol: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased concentrations of the β-blocker1 200 237 239

Carvedilol, metoprolol, timolol: If used with ritonavir-boosted or cobicistat-boosted darunavir, clinical monitoring recommended and reduced dosage of β-blocker may be needed;1 200 237 239 experts state consider alternative β-blocker not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol)200

Bosentan

Ritonavir-boosted darunavir: Possible increased bosentan concentrations1

Cobicistat-boosted darunavir: Possible increased bosentan concentrations and decreased darunavir and cobicistat concentrations237 239

In patients already receiving ritonavir-boosted or cobicistat-boosted darunavir for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 237 239

In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted or cobicistat-boosted darunavir; after ≥10 days of ritonavir-boosted or cobicistat-boosted darunavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 237 239

If ritonavir-boosted darunavir is switched to cobicistat-boosted darunavir, maintain current bosentan dosage237 239

Buprenorphine, buprenorphine/naloxone

Ritonavir-boosted darunavir: Increased norbuprenorphine concentrations and AUC1 200

Cobicistat-boosted darunavir: Effect on buprenorphine or buprenorphine/naloxone unknown200 237 239

Ritonavir-boosted darunavir: Dosage adjustments not needed;1 200 monitor patient200

Cobicistat-boosted darunavir: If initiating buprenorphine or buprenorphine/naloxone in patient already receiving cobicistat-boosted darunavir, use lowest possible dosage and carefully titrate to desired therapeutic effect;200 237 239 if initiating cobicistat-boosted darunavir in patient already receiving buprenorphine or buprenorphine/naloxone, monitor patient and consider that dosage adjustments may be needed237 239

Buspirone

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased buspirone concentrations1 237

Ritonavir-boosted or cobicistat-boosted darunavir: Titration of buspirone recommended, consider lower buspirone dosage, and monitor for adverse effects1 237

Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)

Ritonavir-boosted or cobicistat-boosted darunavir: Increased calcium-channel blocking agent concentrations1 200 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Use concomitantly with caution; clinical monitoring recommended;1 200 237 239 if used concomitantly with diltiazem, experts state adjust diltiazem dosage based on clinical response and toxicities200

Cisapride

Ritonavir-boosted or cobicistat-boosted darunavir: Potential for serious and/or life-threatening effects such as cardiac arrhythmias 1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated1 237 239

Cobicistat

Increased darunavir concentrations and AUC;200 237 239 used as a pharmacokinetic enhancer (pharmacokinetic booster) for therapeutic advantage (cobicistat-boosted darunavir)200 237 239

Colchicine

Ritonavir-boosted or cobicistat-boosted darunavir: Increased colchicine concentrations1 237 239

Patients with renal or hepatic impairment: Concomitant use of colchicine and ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 237 239

Colchicine for treatment of gout flares: In those receiving ritonavir-boosted or cobicistat-boosted darunavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 237 239

Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted or cobicistat-boosted darunavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 237 239

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted or cobicistat-boosted darunavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1 237 239

Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisolone, prednisone, triamcinolone)

Budesonide, fluticasone, mometasone (orally inhaled, intranasal): Increased corticosteroid concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir;1 200 237 239 may result in adrenal insufficiency or Cushing's syndrome200

Beclomethasone (orally inhaled): No clinically important pharmacokinetic interactions with ritonavir-boosted darunavir;200 clinically important interactions with cobicistat-boosted darunavir not expected200

Methylprednisolone, prednisolone, or triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations;200 may result in adrenal insufficiency or Cushing's syndrome200

Budesonide (systemic): Increased corticosteroid concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir;200 may result in adrenal insufficiency or Cushing's syndrome;200 decreased darunavir concentrations may occur200

Prednisone (systemic): Increased corticosteroid concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir;200 may result in adrenal insufficiency or Cushing's syndrome200

Dexamethasone (systemic): Decreased darunavir or ritonavir concentrations if used with ritonavir-boosted darunavir; decreased darunavir or cobicistat concentrations if used with cobicistat-boosted darunavir; possible decreased antiretroviral efficacy1 200 237 239

Budesonide, fluticasone, mometasone (orally inhaled, intranasal): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir unless potential benefits of the corticosteroid outweigh risks of systemic corticosteroid adverse effects;200 consider alternative (e.g., beclomethasone), especially when long-term corticosteroid use anticipated1 200 237 239

Beclomethasone (orally inhaled): Dosage adjustments not needed200

Methylprednisolone, prednisolone, or triamcinolone (intra-articular or other local injections): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir;200 consider alternative nonsteroidal therapies; if intra-articular corticosteroid required, use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir)200

Budesonide or prednisone (systemic): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir unless potential benefits outweigh risks of systemic corticosteroid adverse effects200

Dexamethasone (systemic): Use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir with caution;200 consider alternative corticosteroid for long-term use200

Daclatasvir

Ritonavir-boosted darunavir: Increased daclatasvir concentrations expected178

Ritonavir-boosted darunavir: Monitor for daclatasvir-associated adverse effects178

Dasabuvir

Ritonavir-boosted darunavir: Decreased darunavir trough concentrations if used with fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir180 200

Cobicistat-boosted darunavir: Data not available regarding pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir200

Ritonavir-boosted darunavir: Concomitant use with ombitasvir/paritaprevir/ritonavir with dasabuvir not recommended180 200

Cobicistat-boosted darunavir: Do not use concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir200

Delavirdine

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Didanosine

Didanosine delayed-release capsules: No change in didanosine or darunavir concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir1 237

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Administer didanosine (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food) or cobicistat-boosted darunavir (with food)1 237

Digoxin

Ritonavir-boosted or cobicistat-boosted darunavir: Increased digoxin concentrations1 237 239

Ritonavir-boosted darunavir: Use concomitantly with caution;200 use lowest possible initial digoxin dosage;1 monitor digoxin concentrations and adjust dosage as clinically indicated1

Cobicistat-boosted darunavir: Use concomitantly with caution;200 titrate digoxin dosage and monitor digoxin concentrations237 239

Dextromethorphan

Ritonavir-boosted darunavir: Increased dextromethorphan concentrations1

Dolutegravir

Ritonavir-boosted darunavir: No clinically important effect on pharmacokinetics of either drug1

Cobicistat-boosted darunavir: Clinically important interactions not expected237

Dosage adjustments not needed if used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir200

Efavirenz

Ritonavir-boosted darunavir: Decreased darunavir AUC; increased efavirenz AUC1 200

Cobicistat-boosted darunavir: Possible decreased darunavir and cobicistat concentrations;200 237 possible loss of therapeutic effect and development of darunavir resistance200 237

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ritonavir-boosted darunavir: Usual dosages can be used;1 200 some experts recommend close clinical monitoring;200 consider monitoring plasma concentrations of darunavir and efavirenz200

Cobicistat-boosted darunavir: Concomitant use not recommended200 237 239

Elvitegravir

Elvitegravir: No effect on darunavir or elvitegravir exposures if used with ritonavir-boosted darunavir;200 data not available regarding use with cobicistat-boosted darunavir200

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir (EVG/COBI/TDF/FTC): Altered concentrations of elvitegravir, cobicistat, and/or darunavir if used with ritonavir-boosted darunavir;200 possible decreased elvitegravir concentrations if cobicistat-boosted elvitegravir used with cobicistat-boosted darunavir200

Elvitegravir: If used concomitantly with ritonavir-boosted darunavir, recommended dosage is elvitegravir 150 mg once daily and darunavir 600 mg twice daily in conjunction with ritonavir 100 mg twice daily;200 concomitant use with cobicistat-boosted darunavir not recommended200

EVG/COBI/TDF/FTC: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended200

Emtricitabine

Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions not expected1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Etravirine

Ritonavir-boosted darunavir: Decreased etravirine AUC, but no change in darunavir concentrations;1 200 safety and efficacy of ritonavir-boosted darunavir and etravirine established in clinical studies1 200

Cobicistat-boosted darunavir: Possible decreased cobicistat concentrations;200 237 effect on darunavir pharmacokinetics unknown;200 237 possible loss of therapeutic effect and development of darunavir resistance237 239

No in vitro evidence of antagonistic antiretroviral effects with darunavir214

Ritonavir-boosted darunavir: Dosage adjustments not needed1 200

Cobicistat-boosted darunavir: Concomitant use not recommended200 237 239

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Ritonavir-boosted or cobicistat-boosted darunavir: Potential for serious or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)1 237 239

Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 237 239

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving darunavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Estrogens/progestins

Oral hormonal contraceptives containing ethinyl estradiol and norethindrone: Decreased ethinyl estradiol and norethindrone concentrations if used with ritonavir-boosted darunavir;1 data not available regarding use with cobicistat-boosted darunavir200 237 239

Transdermal contraceptives containing ethinyl estradiol and norelgestromin or subdermal implant contraceptives containing etonogestrel: Data not available regarding use with ritonavir-boosted or cobicistat-boosted darunavir200

Ritonavir-boosted or cobicistat-boosted darunavir: Use additional or alternative nonhormonal contraception methods1 200 237 239

Fentanyl

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased fentanyl concentrations200 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Carefully monitor patient for fentanyl therapeutic and adverse effects, including potentially fatal respiratory depression200 237 239

Histamine H2- receptor antagonists (e.g., ranitidine)

Ritonavir-boosted or cobicistat-boosted darunavir: No clinically important effects expected if used with ranitidine or other histamine H2- receptor antagonists1 200 237

Ranitidine or other histamine H2- receptor antagonists: Dosage adjustments not needed if used with ritonavir-boosted or cobicistat-boosted darunavir1 200

HMG-CoA reductase inhibitors (statins)

Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin: Increased antilipemic agent concentrations and AUC if used with ritonavir-boosted or cobicistat-boosted darunavir; increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186 200 237 239

Pitavastatin: Decreased pitavastatin AUC and no clinically important effect on darunavir concentrations if used with ritonavir-boosted darunavir;12 200 data not available regarding use with cobicistat-boosted darunavir237

Atorvastatin: If used with ritonavir-boosted darunavir, do not exceed atorvastatin dosage of 20 mg daily;1 186 200 carefully titrate atorvastatin dosage; use lowest necessary dosage with close monitoring for adverse effects;1 200 if used with cobicistat-boosted darunavir, initiate atorvastatin at lowest necessary dosage and monitor patient for safety237 239

Lovastatin: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 186 200 237 239

Pitavastatin: Dosage adjustments not necessary if used with ritonavir-boosted darunavir;200 if used with cobicistat-boosted darunavir, initiate pitavastatin at lowest necessary dosage, titrate dosage, and monitor patient for safety;237 experts state dosage adjustment not necessary if used with cobicistat-boosted darunavir200

Pravastatin: If used with ritonavir-boosted or cobicistat-boosted darunavir, carefully titrate pravastatin dosage; use lowest necessary dosage with close monitoring for adverse effects1 200

Rosuvastatin: If used with ritonavir-boosted or cobicistat-boosted darunavir, carefully titrate rosuvastatin dosage; use lowest necessary dosage with close monitoring for adverse effects1 200

Simvastatin: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated1 186 200

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine, everolimus, sirolimus, tacrolimus: Increased immunosuppressive agent concentrations expected if used with ritonavir-boosted or cobicistat-boosted darunavir1 200 237 239

Cyclosporine, sirolimus, tacrolimus: Monitor plasma concentrations of immunosuppressive agent if used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir1 237 239

Everolimus: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended1 237 239

Indinavir

Ritonavir-boosted darunavir: Increased concentrations and AUC of darunavir and indinavir1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Appropriate dosages for concomitant use not established1

Lamivudine

Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ledipasvir

Ritonavir-boosted or cobicistat-boosted darunavir: Clinically important pharmacokinetic interactions not expected if used with fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir)181 200

Ritonavir-boosted darunavir in conjunction with emtricitabine and tenofovir DF in patients receiving ledipasvir/sofosbuvir: Increased tenofovir concentrations;181 200 safety of increased tenofovir concentrations not established181 200

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed if used concomitantly with ledipasvir/sofosbuvir200

Ritonavir-boosted darunavir in conjunction with emtricitabine and tenofovir DF in patients receiving ledipasvir/sofosbuvir: Consider alternative HCV treatment regimen or alternative antiretroviral regimen;181 200 if concomitant use necessary, monitor for tenofovir-associated adverse effects181 200

Lopinavir/ritonavir

Ritonavir-boosted darunavir: Decreased darunavir concentrations; no change in lopinavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Concomitant use not recommended;1 appropriate dosages with respect to safety and efficacy not established1

Macrolides (clarithromycin, erythromycin, telithromycin)

Clarithromycin: Increased clarithromycin concentrations if used with ritonavir-boosted darunavir;1 increased darunavir, cobicistat, and clarithromycin concentrations if used with cobicistat-boosted darunavir200 237 239

Erythromycin, telithromycin: Increased darunavir, cobicistat, and macrolide concentrations if used with cobicistat-boosted darunavir237 239

Clarithromycin: If used concomitantly with ritonavir-boosted darunavir, modification of usual clarithromycin dosage not needed in patients with normal renal function, but reduce clarithromycin dosage by 50% if Clcr 30–60 mL/minute and reduce by 75% if Clcr <30 mL/minute;1 consider alternative (e.g., azithromycin) in patients receiving ritonavir-boosted or cobicistat-boosted darunavir200 237 239

Erythromycin, telithromycin: Consider alternative anti-infective in patients receiving cobicistat-boosted darunavir237 239

Maraviroc

Increased maraviroc concentrations and AUC if used with ritonavir-boosted or cobicistat-boosted darunavir1 200 224 237 239

No in vitro evidence of antagonistic antiretroviral effects with darunavir224

Ritonavir-boosted or cobicistat-boosted darunavir: Recommended maraviroc dosage is 150 mg twice daily 1 200 224 237 239

Methadone

Ritonavir-boosted darunavir: Decreased methadone concentrations1

Cobicistat-boosted darunavir: Effect on methadone pharmacokinetics unknown200 237 239

Ritonavir-boosted darunavir: Adjustment of methadone dosage not needed when initiating ritonavir-boosted darunavir,1 200 but closely monitor for opiate withdrawal since some patients may need adjustment of methadone maintenance dosage1 200

Cobicistat-boosted darunavir: Initiate methadone using lowest possible dosage and titrate carefully to desired therapeutic effect;200 237 239 if initiating cobicistat-boosted darunavir in patient already receiving methadone, monitor patient and consider that adjustment of methadone dosage may be needed237 239

Nelfinavir

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Nevirapine

Ritonavir-boosted darunavir: Increased nevirapine and darunavir concentrations1 200

Cobicistat-boosted darunavir: Possible decreased cobicistat concentrations;200 237 effect on darunavir pharmacokinetics unknown;200 237 possible loss of therapeutic effect and development of darunavir resistance237 239

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ritonavir-boosted darunavir: Dosage adjustments not needed1 200

Cobicistat-boosted darunavir: Concomitant use not recommended200 237 239

Ombitasvir

Ritonavir-boosted darunavir: Decreased darunavir concentrations if used with fixed combination of ombitasvir/paritaprevir/ritonavir179 or if used with fixed combination of ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir180

Cobicistat-boosted darunavir: Data not available regarding use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir200

Unboosted darunavir: Manufacturer of ombitasvir/paritaprevir/ritonavir states the fixed-combination HCV drug may be used concomitantly with darunavir (800 mg) without low-dose ritonavir179

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir not recommended180 200

Oxycodone

Cobicistat-boosted darunavir: Possible increased oxycodone concentrations237

Cobicistat-boosted darunavir: Carefully monitor patient for oxycodone therapeutic and adverse effects, including potentially fatal respiratory depression237

Paritaprevir

Ritonavir-boosted darunavir: Decreased darunavir trough concentrations if used with fixed combination of ombitasvir/paritaprevir/ritonavir179 or if used with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir180 200

Cobicistat-boosted darunavir: Data not available regarding use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir200

Unboosted darunavir: Manufacturer of ombitasvir/paritaprevir/ritonavir states the fixed combination HCV drug may be used concomitantly with darunavir (800 mg) without low-dose ritonavir179

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir not recommended180 200

Proton pump inhibitors (PPIs)

Ritonavir-boosted darunavir: Decreased omeprazole concentrations, but no change in darunavir concentrations1

Cobicistat-boosted darunavir: Clinically important interactions not expected237

Ritonavir-boosted darunavir: Dosage adjustments not needed if used concomitantly with omeprazole1

Cobicistat-boosted darunavir: Dosage adjustments not needed if used with PPIs200

Raltegravir

Ritonavir-boosted darunavir: No clinically important effect on pharmacokinetics of darunavir1 225

Cobicistat-boosted darunavir: Data not available,200 but clinically important interactions not expected237

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed1 200

Ranolazine

Ritonavir-boosted or cobicistat-boosted darunavir: Possible serious and/or life-threatening adverse effects1 237

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated1 237

Rilpivirine

Ritonavir-boosted darunavir: Increased rilpivirine concentrations and AUC, but no clinically important effect on darunavir concentrations or AUC226

Cobicistat-boosted darunavir: Possible increased rilpivirine concentrations;200 altered darunavir concentrations not expected200 237

No in vitro evidence of antagonistic antiretroviral effects with darunavir226

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed1 200 226

Ritonavir

Increased darunavir concentrations and AUC;1 2 200 low-dose ritonavir (100 mg once daily) used as a pharmacokinetic enhancer (pharmacokinetic booster) for therapeutic advantage (ritonavir-boosted darunavir)1 2 200

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ritonavir or ritonavir-containing preparations: Concomitant use with cobicistat-boosted darunavir not recommended237

St. John’s wort (Hypericum perforatum)

Ritonavir-boosted or cobicistat-boosted darunavir: Potential decreased darunavir concentrations; possible decreased antiretroviral efficacy1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated1 237 239

Salmeterol

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased salmeterol concentrations and increased risk of QT interval prolongation, palpitations, and sinus tachycardia1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended1 200 237 239

Saquinavir

Ritonavir-boosted darunavir: Decreased darunavir concentrations, but saquinavir concentrations unchanged1

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ritonavir-boosted darunavir: Concomitant use not recommended1

Selective serotonin-reuptake inhibitors (SSRIs)

Paroxetine, sertraline: Decreased SSRI concentrations and AUCs and no change in darunavir concentrations if used with ritonavir-boosted darunavir;1 200 possible pharmacokinetic interactions if used with cobicistat-boosted darunavir, but effect on SSRI concentrations unknown200 237 239

Fluvoxamine: Possible altered (increased or decreased) darunavir concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir200

Paroxetine, sertraline: Titrate SSRI dosage based on clinical response in patients receiving ritonavir-boosted or cobicistat-boosted darunavir;200 237 239 if ritonavir-boosted darunavir initiated in those on stable SSRI dosage, monitor for clinical response1

Fluvoxamine: Experts state consider alternative to fluvoxamine in patients receiving ritonavir-boosted or cobicistat-boosted darunavir200

Sildenafil

Ritonavir-boosted or cobicistat-boosted darunavir: Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection, syncope)1 237 239

Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated;1 237 239 safe and effective dosage for concomitant use not established1

Sildenafil for treatment of erectile dysfunction: In patients receiving ritonavir-boosted or cobicistat-boosted darunavir, do not exceed sildenafil dosage of 25 mg once every 48 hours; closely monitor for sildenafil-associated adverse effects1 200 237 239

Simeprevir

Ritonavir-boosted darunavir: Increased concentrations and AUC of simeprevir and darunavir1 187 200

Cobicistat-boosted darunavir: Increased simeprevir concentrations237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended1 187 200 237 239

Sofosbuvir

Ritonavir-boosted darunavir: No clinically important pharmacokinetic interactions188

Ritonavir-boosted darunavir: Dosage adjustments not needed188

Cobicistat-boosted darunavir: May be used concomitantly200

Stavudine

Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions unlikely1 237 239

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Suvorexant

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased suvorexant concentrations200

Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended200

Tadalafil

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection, syncope)1 237 239

Tadalafil for treatment of PAH in patients who have been receiving ritonavir-boosted or cobicistat-boosted darunavir for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, may increase dosage to 40 mg once daily1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating ritonavir-boosted or cobicistat-boosted darunavir; after ≥1 week of the antiretroviral, may resume tadalafil at dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily1 237 239

Tadalafil for treatment of erectile dysfunction: In patients receiving ritonavir-boosted or cobicistat-boosted darunavir, do not exceed tadalafil dosage of 10 mg once every 72 hours; closely monitor for tadalafil-related adverse effects1 200 237 239

Tadalafil for treatment of benign prostatic hyperplasia: In patients receiving ritonavir-boosted or cobicistat-boosteddarunavir, do not exceed tadalafil dosage of 2.5 mg once daily200

Tenofovir

Ritonavir-boosted darunavir: Increased tenofovir concentrations and AUC;1 200 increased darunavir concentrations and AUC1

Cobicistat-boosted darunavir: Possible increased tenofovir concentrations200

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Ritonavir-boosted darunavir: Experts state clinical importance unknown; monitor for tenofovir toxicity;200 manufacturer of darunavir states usual dosage of ritonavir-boosted darunavir and tenofovir can be used 1

Cobicistat-boosted darunavir: Assess baseline estimated Clcr, urine glucose, and urine protein;237 239 not recommended in patients with estimated Clcr <70 mL/minute;200 237 239 experts state monitor for tenofovir toxicity200

Ticagrelor

Ritonavir-boosted or cobicistat-boosted darunavir: Increased ticagrelor concentrations expected200

Ritonavir-boosted or cobicistat-boosted darunavir: Avoid concomitant use200

Tipranavir

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Tramadol

Cobicistat-boosted darunavir: Increased tramadol concentrations237 239

Cobicistat-boosted darunavir: Decreased tramadol dosage may be needed237 239

Trazodone

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased trazodone concentrations and increased risk of nausea, dizziness, hypotension, syncope1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Use lowest possible trazodone dosage and monitor for adverse CNS and cardiovascular effects1 200 237 239

Tricyclic antidepressants (amitriptyline, desipramine, doxepin, imipramine, nortriptyline)

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased concentrations of the tricyclic antidepressant and increased risk of nausea, dizziness, hypotension, syncope1 200 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Use lowest possible antidepressant dosage; titrate antidepressant dosage based on clinical assessment and/or antidepressant concentrations1 200 237 239

Vardenafil

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection, syncope)1 237 239

Ritonavir-boosted or cobicistat-boosted darunavir: Vardenafil for treatment of erectile dysfunction: Do not exceed vardenafil dosage of 2.5 mg once every 72 hours; closely monitor for vardenafil-related adverse effects1 200 237 239

Vorapaxar

Ritonavir-boosted or cobicistat-boosted darunavir: Increased vorapaxar concentrations expected200

Ritonavir-boosted or cobicistat-boosted darunavir: Avoid concomitant use200

Zidovudine

Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions unlikely1 237

No in vitro evidence of antagonistic antiretroviral effects with darunavir1

Zolpidem

Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased zolpidem concentrations200

Ritonavir-boosted or cobicistat-boosted darunavir: Use low initial zolpidem dosage; dosage reduction may be necessary200

Darunavir Pharmacokinetics

Absorption

Bioavailability

Darunavir must be administered with low-dose ritonavir (ritonavir-boosted darunavir) or cobicistat (cobicistat-boosted darunavir).1 237 239 Ritonavir and cobicistat are pharmacokinetic enhancers (pharmacokinetic boosters) that decrease metabolism of darunavir, resulting in increased darunavir plasma concentrations and AUC.1 237 239

Pharmacokinetic parameters reported with once-daily regimen of ritonavir-boosted darunavir (darunavir 800 mg and ritonavir 100 mg) are similar to those reported with once-daily regimen of cobicistat-boosted darunavir (darunavir 800 mg and cobicistat 150 mg).237 239

Ritonavir-boosted darunavir: Peak plasma concentrations of darunavir attained approximately 2.5–4 hours after a dose.1

Cobicistat-boosted darunavir: Peak plasma concentrations of darunavir attained approximately 4–4.5 hours after a dose.237

Food

Food increases darunavir bioavailability.1

Ritonavir-boosted darunavir: Administration with food increases darunavir peak plasma concentrations and AUC by approximately 40%.1

Cobicistat-boosted darunavir: Administration with high-fat meal increases darunavir peak plasma concentrations and AUC by approximately 127 and 70%, respectively.237

Distribution

Extent

Darunavir distributed into CSF; clinical importance unknown.21

Not known whether darunavir distributed into human milk;1 distributed into milk in rats.1

Plasma Protein Binding

Darunavir: 95%.1

Binds principally to α1-acid-glycoprotein.1

Elimination

Metabolism

Darunavir extensively metabolized by CYP3A.1

Elimination Route

Following administration of ritonavir-boosted darunavir, darunavir eliminated principally in feces unchanged;1 approximately 80% of darunavir dose excreted in feces and 14% excreted in urine.1

Hemodialysis or peritoneal dialysis unlikely to remove darunavir, ritonavir, or cobicistat.1 237

Half-life

15 hours after dose of ritonavir-boosted darunavir.1

7 hours after dose of cobicistat-boosted darunavir.237

Special Populations

Ritonavir-boosted darunavir in pediatric patients 3 years to <18 years of age weighing ≥10 kg: Darunavir concentrations and AUC comparable to those reported in adults.1

Ritonavir-boosted darunavir in renal impairment: Darunavir pharmacokinetics not affected in those with moderate renal impairment (Clcr 30–60 mL/minute).1 Not studied in those with severe renal impairment or end-stage renal disease.1

Cobicistat-boosted darunavir in renal impairment: Pharmacokinetics not studied.237

Ritonavir-boosted darunavir in hepatic impairment: Pharmacokinetics in those with mild or moderate hepatic impairment (Child-Pugh class A or B) similar to those with normal hepatic function.1 Not studied in those with severe hepatic impairment.1

HBV or HCV coinfection: No effect on darunavir exposure in those receiving ritonavir-boosted darunavir;1 effect on pharmacokinetics of cobicistat-boosted darunavir not evaluated.237

Higher darunavir plasma concentrations reported in females receiving ritonavir-boosted darunavir compared with males; dosage adjustments not required.1

Stability

Storage

Oral

Suspension

Darunavir: 25°C (may be exposed to 15–30°C).1 Do not refrigerate or freeze;1 avoid excessive heat.1

Tablets

Darunavir: 25°C (may be exposed to 15–30°C).1

Darunavir/cobicistat: 20–25°C (may be exposed to 15–30°C).237

Actions and Spectrum

  • Darunavir is extensively metabolized by CYP3A and must be administered in conjunction with a pharmacokinetic enhancer (pharmacokinetic booster) to improve the pharmacokinetic profile of the drug.1 200 237 239

  • Concomitant use with low-dose ritonavir (ritonavir-boosted darunavir) or with cobicistat (cobicistat-boosted darunavir) results in decreased metabolism and increased plasma concentrations and AUC of darunavir.1 237 239

  • Antiretroviral activity is due to darunavir.1 237

  • Active against HIV-1.1 Also has some activity against HIV type 2 (HIV-2).13 200

  • Darunavir inhibits replication of HIV-1 by interfering with HIV proteases.1

  • Darunavir-resistant HIV-1, including strains with decreased susceptibility to other HIV PIs, has been reported.1 3

  • Varying degrees of cross-resistance occur among HIV PIs.1

  • Some clinical isolates of HIV-1 with reduced susceptibility to darunavir have been resistant to atazanavir, fosamprenavir, indinavir, lopinavir, and nelfinavir.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 200 237 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 237

  • Importance of using darunavir with low-dose ritonavir (ritonavir-boosted darunavir) or with cobicistat (cobicistat-boosted darunavir).1 237 239 Importance of using ritonavir-boosted or cobicistat-boosted darunavir in conjunction with other antiretrovirals.1 237 239

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 237

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200 237

  • Importance of reading patient information provided by the manufacturer.1 237

  • When using ritonavir-boosted darunavir, importance of taking darunavir with food and at the same time as ritonavir.1 Importance of swallowing darunavir tablets whole with a drink (e.g., water, milk).1

  • In patients taking ritonavir-boosted darunavir once daily, if a dose of darunavir or ritonavir is missed by <12 hours, take the dose as soon as it is remembered and take the next dose at the regularly scheduled time.1 If a dose of darunavir or ritonavir is missed by >12 hours, skip the dose and take the next dose at the regularly scheduled time.1 Do not take a double dose to make up for a missed dose.1

  • In patients taking ritonavir-boosted darunavir twice-daily, if a dose of darunavir or ritonavir is missed by <6 hours, take the dose as soon as it is remembered and take the next dose at the regularly scheduled time.1 If a dose of darunavir or ritonavir is missed by >6 hours, omit the dose and take the next dose at the regularly scheduled time.1 Do not take a double dose to make up for a missed dose.1

  • When using cobicistat-boosted darunavir, importance of taking fixed-combination darunavir/cobicistat with food;237 alternatively, importance of taking single-entity darunavir with food and at the same time as single-entity cobicistat.239

  • If a dose of cobicistat-boosted darunavir is missed by <12 hours, take the dose as soon as it is remembered and take the next dose at the regularly scheduled time.237 239 If a dose of cobicistat-boosted darunavir is missed by >12 hours, skip the dose and take the next dose at the regularly scheduled time.1 237 Do not take a double dose to make up for a missed dose.237 239

  • Advise patients that drug-induced hepatitis has occurred.1 237 Importance of notifying clinician if manifestations of liver disease occur (e.g., jaundice of skin or eyes; dark tea-colored urine; pale stools; nausea; vomiting; loss of appetite; pain, aching, or sensitivity in right upper quadrant of abdomen).1 237

  • Advise patients that mild to severe skin reactions have occurred.1 237 Importance of immediately discontinuing ritonavir-boosted or cobicistat-boosted darunavir and contacting clinician if manifestations of severe skin reactions occur (e.g., severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).1 237

  • Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1 237

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John’s wort), and any concomitant illnesses.1 237

  • Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, visual changes, priapism) and that any symptoms should be promptly reported to clinician.1 237 Should not be used concomitantly with sildenafil used for treatment of PAH.1 237

  • Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of potential interactions with hormonal contraceptives.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 237 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Darunavir Ethanolate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

100 mg (of darunavir) per mL

Prezista

Janssen

Tablets, film-coated

75 mg (of darunavir)

Prezista

Janssen

150 mg (of darunavir)

Prezista

Janssen

600 mg (of darunavir)

Prezista

Janssen

800 mg (of darunavir)

Prezista

Janssen

Darunavir Ethanolate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

800 mg (of darunavir) with Cobicistat 150 mg

Prezcobix

Janssen

AHFS DI Essentials. © Copyright, 2004-2016, Selected Revisions January 27, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Janssen Therapeutics. Prezista (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2015 May.

2. Koh Y, Nakata H, Maeda K et al. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 2003; 47:3123-9. [PubMed 14506019]

3. De Meyer S, Azijn H, Surleraux D et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005; 49:2314-21. [PubMed 15917527]

6. Banhegyi D, Esser S, Opravil M, Lefebvre E. TMC114/r outperforms investigator-selected PI(s) in treatment-experienced patients: 24-week primary efficacy and safety analysis of POWER 1. 1st European and Central Asian AIDS conference , Moscow, Russia, 2006 May 15–17. Poster. From Tibotec website ().

9. Madruga JV, Berger D, McMurchie M et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007; 370:49-58. [PubMed 17617272]

10. Ortiz R, DeJesus E, Khanlou H et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1 infected patients at week 48. AIDS. 2008; 22:1389-97. [PubMed 18614861]

12. Kowa Pharmaceuticals America. Livalo (pitavastatin) tablets prescribing information. Montgomery, AL; 2012 Feb.

13. Desbois D, Roquebert B, Peytavin G et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. 2008; 52:1545-8. [PubMed 18227188]

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179. AbbVie, Inc. Technivie (ombitasvir, paritaprevir, and ritonavir) tablets prescribing information. North Chicago, IL; 2015 Jul.

180. AbbVie, Inc. Viekira Pak (ombitasvir, paritaprevir, and ritonavir; dasabuvir) tablets prescribing information. North Chicago, IL; 2015 Mar.

181. Gilead Sciences, Inc. Harvoni (ledipasvir and sofosbuvir) tablets prescribing information. Foster City, CA; 2015 Mar.

186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23.

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188. Gilean Sciences Inc. Sovaldi (sofosbuvir) tablet prescribing information. Foster City, CA; 2013 Dec.

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201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (March 5, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

209. AbbVie Inc. Norvir (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2015 Mar.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets, chewable tablets, and for oral suspension prescribing information. Whitehouse Station, NJ; 2013 Dec.

226. Tibotec Therapeutics. Edurant (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.

237. Janssen Therapeutics. Prezcobix (darunavir/cobicistat) tablets prescribing information. Titusville, NJ; 2015 Jan.

239. Gilead Sciences Inc. Tybost (cobicistat) tablets prescribing information. Foster City, CA; 2014 Sep.

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