Darunavir (Monograph)
Brand name: Prezista
Drug 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
Introduction
Antiretroviral; HIV protease inhibitor (PI).
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; used in conjunction with other antiretrovirals.
Darunavir with cobicistat (cobicistat-boosted darunavir): Treatment of HIV-1 infection in adults; used in conjunction with other antiretrovirals.
Do not use darunavir without a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). Pharmacokinetic enhancer (pharmacokinetic booster) necessary to improve darunavir's pharmacokinetic profile. Low-dose ritonavir and cobicistat are not interchangeable in antiretroviral regimens; these pharmacokinetic enhancers have different dosage and administration requirements and are associated with different adverse effects, precautions, contraindications, and drug interactions.
When ritonavir-boosted darunavir used, single-entity darunavir is given with single-entity ritonavir. In antiretroviral-experienced patients, use results of genotypic and/or phenotypic viral resistance testing and individual’s prior antiretroviral treatment to guide treatment.
When cobicistat-boosted darunavir used, fixed combination containing both drugs (darunavir/cobicistat) can be used; alternatively, single-entity darunavir is given with single-entity cobicistat. Assess estimated Clcr in all patients prior to initiation of cobicistat-boosted darunavir (see Renal Effects under Cautions). 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). In antiretroviral-experienced patients, use results of genotypic viral resistance testing to guide treatment; if such testing not available, may use the fixed combination in HIV PI-naive patients, but not recommended in HIV PI-experienced patients.
For initial treatment in antiretroviral-naive adults and adolescents, experts state that ritonavir-boosted darunavir in conjunction with tenofovir alafenamide fumarate (TAF) and emtricitabine or ritonavir-boosted darunavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are recommended PI-based regimens. These experts state that cobicistat-boosted darunavir in conjunction with TAF and emtricitabine or cobicistat-boosted darunavir in conjunction with tenofovir DF and emtricitabine (or lamivudine) are alternative PI-based regimen for initial treatment in antiretroviral-naive adult and adolescents† [off-label]. Ritonavir-boosted darunavir or cobicistat-boosted darunavir in conjunction with abacavir and lamivudine (or emtricitabine) are additional alternative PI-based regimens for initial treatment, but use only in those with baseline plasma HIV RNA levels less than 100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative. Ritonavir-boosted darunavir in conjunction with raltegravir (twice daily) is another regimen option for initial treatment when TAF, TDF, or abacavir cannot be used, but use only in patients with baseline plasma HIV RNA levels <100,000 copies/mL and CD4+ T-cell count >200 cells/mm3.
For initial treatment in antiretroviral-naive pediatric patients, experts state that ritonavir-boosted darunavir (twice daily) and 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a preferred regimen in children 3 years to <12 years of age and ritonavir-boosted darunavir (once daily) in conjunction with 2 NRTIs is a preferred regimen in children ≥12 years of age. Do not use once-daily ritonavir-boosted darunavir in children <12 years of age or if darunavir resistance-associated substitutions are present.
Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)
Postexposure prophylaxis of HIV infection following occupational exposure† [off-label] (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.
USPHS recommends 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV. Ritonavir-boosted darunavir and 2 NRTIs is one of several alternative regimens. 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.
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. Do not delay initiation of PEP while waiting for expert consultation.
Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)
Postexposure prophylaxis of HIV infection following nonoccupational exposure† [off-label] (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission. Used in conjunction with other antiretrovirals.
When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada); recommended alternative regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.
Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals. Do not delay initiation of nPEP while waiting for expert consultation.
Related/similar drugs
Biktarvy, Descovy, Truvada, Atripla, Stribild, Complera, Epzicom
Darunavir Dosage and Administration
Administration
Oral Administration
Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted darunavir) once or twice daily with food.
Alternatively, administer orally in conjunction with cobicistat (cobicistat-boosted darunavir) once daily with food.
Do not administer without low-dose ritonavir or cobicistat.
Ritonavir-boosted Darunavir
Administer single-entity darunavir as tablets or oral suspension at same time as single-entity ritonavir capsules, tablets, or oral solution.
Oral suspension: Use in those who have difficulty swallowing tablets. Administer suspension using oral dosing syringe supplied by the manufacturer. If 800-mg dose is indicated, give dose as two 4-mL administrations using the oral dosing syringe. Supplied as a white to off-white opaque suspension; shake prior to each dose.
Tablets: Swallow tablets whole with a drink (e.g., water, milk). Assess ability to swallow tablets in children weighing ≥15 kg; consider darunavir oral suspension in those unable to reliably swallow tablets.
Cobicistat-boosted Darunavir
Administer fixed-combination tablets containing both drugs (darunavir/cobicistat). Alternatively, administer single-entity darunavir as tablets or oral suspension at same time as single-entity cobicistat tablets.
Dosage
Single-entity darunavir available as oral suspension or tablets containing darunavir ethanolate; dosage expressed in terms of darunavir.
Darunavir/cobicistat available as fixed-combination tablets containing darunavir ethanolate (800 mg of darunavir) and cobicistat (150 mg).
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.
Dosage of ritonavir-boosted darunavir in children and adolescents 3 years to <18 years of age weighing ≥10 kg is based on weight.
Antiretroviral-naive Pediatric Patients
OralRitonavir-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). (See Table 1 and Table 2.)
Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.
|
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.
|
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
OralGenotypic testing recommended to identify substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).
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). (See Table 3 and Table 4.)
Dosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.
|
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.
|
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). (See Table 5 and Table 6.)
|
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.
|
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
OralRitonavir-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).
Cobicistat-boosted darunavir: 1 tablet of darunavir/cobicistat (800 mg of darunavir and 150 mg of cobicistat) once daily. 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).
Antiretroviral-experienced Adults
OralGenotypic testing recommended to identify substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).
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).
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).
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).
Cobicistat-boosted darunavir: 1 tablet of darunavir/cobicistat (800 mg of darunavir and 150 mg of cobicistat) once daily. 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).
Darunavir dosage of 600 mg twice daily in conjunction with cobicistat not recommended.
Postexposure Prophylaxis following Occupational Exposure to HIV† [off-label]
Oral
Ritonavir-boosted darunavir: Single-entity darunavir 800 mg once daily in conjunction with low-dose ritonavir (100 mg once daily). Alternatively, single-entity darunavir 600 mg twice daily in conjunction with low-dose ritonavir (100 mg twice daily). Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses). Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).
Initiate PEP as soon as possible following exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.
Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)† [off-label]
Oral
800 mg once daily in conjunction with low-dose ritonavir (100 mg once daily). Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Nonoccupational Exposure to HIV [nPEP] under Uses).
Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.
nPEP not recommended if exposed individual seeks care >72 hours after exposure.
Prescribing Limits
Pediatric Patients
Treatment of HIV Infection
Oral
Do not exceed dosage recommended for antiretroviral-experienced adults.
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). Do not use in those with severe hepatic impairment (Child-Pugh class C).
Cobicistat-boosted darunavir: Dosage adjustments not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Do not use in those with severe hepatic impairment (Child-Pugh class C).
Renal Impairment
Ritonavir-boosted darunavir: Experts state dosage adjustments not necessary in patients with renal impairment.
Cobicistat-boosted darunavir: Assess estimated Clcr prior to initiation of fixed-combination darunavir/cobicistat or, alternatively, single-entity darunavir with single-entity cobicistat. Experts state dosage adjustments of cobicistat-boosted darunavir not necessary in patients with renal impairment. 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.
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.
Pregnant Women
Use ritonavir-boosted darunavir.
Ritonavir-boosted darunavir (twice-daily regimen): 600 mg of single-entity darunavir (one 600-mg tablet or 6 mL of the oral suspension containing 100 mg/mL) twice daily with single-entity ritonavir 100 mg twice daily.
Ritonavir-boosted darunavir (once-daily regimen): Manufacturer states consider 800 mg of single-entity darunavir once daily (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL once daily) with single-entity ritonavir 100 mg once daily only in women already stabilized on this once-daily regimen prior to pregnancy who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL) and in whom a change to a twice-daily regimen may compromise tolerability or compliance. Some experts state once-daily regimen of ritonavir-boosted darunavir not recommended in pregnant women.
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, lurasidone, simvastatin, oral midazolam, triazolam, ranolazine, pimozide, sildenafil [Revatio] for treatment of pulmonary arterial hypertension). (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]). (See Specific Drugs under Interactions.)
Concomitant use of cobicistat-boosted darunavir and carbamazepine, phenobarbital, phenytoin, and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir). (See Specific Drugs under Interactions.)
-
Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and colchicine in patients with renal and/or hepatic impairment. (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. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute, generalized exanthematous pustulosis reported.
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).
Sulfonamide Sensitivity
Darunavir contains a sulfonamide moiety; may cause allergic-type reaction in certain susceptible individuals.
Use ritonavir-boosted or cobicistat-boosted darunavir with caution and close monitoring in patients with known hypersensitivity to sulfonamide-containing drugs.
Hepatic Effects
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) reported in clinical studies. Patients with preexisting liver dysfunction, including HIV-infected patients coinfected with HBV or HCV, have increased risk for liver function abnormalities. Postmarketing reports of liver injury (in some cases fatal) in patients receiving ritonavir-boosted darunavir; 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.
Conduct appropriate laboratory tests to evaluate hepatic function prior to and periodically during ritonavir-boosted or cobicistat-boosted darunavir therapy. Consider increased AST/ALT monitoring in patients with hepatitis, cirrhosis, or elevated transaminase concentrations prior to therapy, especially during first several months of therapy.
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).
Renal Effects
Cobicistat decreases estimated Clcr by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function; 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.
Assess estimated Clcr prior to initiating cobicistat-boosted darunavir. 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.
Manufacturer states dosage recommendations not available for drugs requiring dosage adjustments in patients with renal impairment who are receiving cobicistat-boosted darunavir; consider alternative concomitant drugs that do not require dosage adjustments based on renal impairment.
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. 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. 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. In addition, monitor serum phosphorus in those with or at risk for renal impairment.
Interactions
Darunavir must be used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). Failure to administer darunavir with recommended dosage of ritonavir or cobicistat may result in subtherapeutic darunavir concentrations and inadequate antiviral response. When ritonavir-boosted or cobicistat-boosted darunavir used, consider cautions, precautions, contraindications, and drug interactions associated with darunavir and the pharmacokinetic enhancer.
Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with certain drugs is contraindicated or requires particular caution. Concomitant use with some drugs may result in clinically important adverse effects, including severe, life-threatening, or fatal events, due to higher exposures of the concomitant drug or higher exposures of darunavir and/or the pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat). Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted or cobicistat-boosted darunavir and possible development of resistance. Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern.
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.
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. 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.
Darunavir, ritonavir, and cobicistat are all available as single-entity preparations. In addition, fixed-combination darunavir/cobicistat is commercially available. Ensure that therapy is not duplicated; do not use darunavir/cobicistat concomitantly with any other preparations containing darunavir, cobicistat, or ritonavir.
Consider potential drug interactions prior to and during use of ritonavir-boosted or cobicistat-boosted darunavir. Monitor for adverse effects associated with drugs used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir. (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.
Initiate or adjust antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) as needed.
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.
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.
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. Mechanisms and long-term consequences unknown; causal relationship not established.
Hemophilia A and B
Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported with HIV PIs; causal relationship not established.
Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.
HIV Resistance
Possibility of cross-resistance to other HIV PIs not evaluated. Effect of ritonavir-boosted darunavir therapy on subsequent therapy with other PIs unknown.
Specific Populations
Pregnancy
Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].
Available human and animal data suggest that darunavir does not increase the risk of major birth defects overall compared to background rate.
Ritonavir-boosted darunavir: Experts state ritonavir-boosted darunavir (600 mg twice daily with ritonavir 100 mg twice daily) and 2 NRTIs is a preferred PI-based regimen for initial treatment in pregnant women. Once-daily regimens of ritonavir-boosted darunavir not recommended in pregnant women. (See Pregnant Women under Dosage and Administration.)
Cobicistat-boosted darunavir: Manufacturer states use cobicistat-boosted darunavir in pregnant women only if potential benefits to the woman justify potential risks to fetus. Experts state data insufficient to recommend routine use of cobicistat-boosted darunavir for initial treatment in pregnant women.
Lactation
Not known whether darunavir, ritonavir, or cobicistat distributed into human milk; darunavir and cobicistat distributed into milk in rats.
Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.
Pediatric Use
Ritonavir-boosted darunavir: Not recommended in children <3 years of age; toxicity and mortality reported in juvenile rats.
Ritonavir-boosted darunavir: Adverse effects in children 3 years to <18 years of age similar to those reported in adults.
Cobicistat-boosted darunavir: Safety and efficacy not established in patients <18 years of age.
Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.
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.
Hepatic Impairment
Ritonavir-boosted darunavir: Pharmacokinetics not altered in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B). Pharmacokinetics not evaluated in patients with severe hepatic impairment (Child-Pugh class C); not recommended in such patients.
Cobicistat-boosted darunavir: Pharmacokinetics not established in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B); no clinically important pharmacokinetic changes when cobicistat used alone in individuals with mild or moderate hepatic impairment. Pharmacokinetics of cobicistat-boosted darunavir or cobicistat alone not evaluated in patients with severe hepatic impairment (Child-Pugh class C); cobicistat-boosted darunavir not recommended in such patients.
Risk for liver function abnormalities, including severe adverse hepatic effects, increased in patients with preexisting hepatic impairment, including those with HBV or HCV infection.
Monitor liver function during first several months of treatment with ritonavir-boosted darunavir when the drug used in patients with underlying chronic hepatitis or cirrhosis or in patients with pretreatment elevated liver enzymes.
Consider interruption or discontinuance of ritonavir-boosted or cobicistat-boosted darunavir if there is evidence of new or worsening liver disease.
Darunavir exposure not altered in HIV-infected patients coinfected with HBV or HCV.
Renal Impairment
Ritonavir-boosted darunavir: Pharmacokinetics not altered in patients with Clcr ≥30 mL/minute. Not studied in patients with severe renal impairment or end-stage renal disease.
Cobicistat-boosted darunavir: Not studied in individuals with renal impairment. Cobicistat decreases estimated Clcr without affecting renal glomerular function. Assess estimated Clcr in all patients prior to initiation of cobicistat-boosted darunavir (see Renal Effects under Cautions). Do not use cobicistat-boosted darunavir in conjunction with tenofovir DF in patients with estimated Clcr <70 mL/minute. (See Renal Effects under Cautions.)
Common Adverse Effects
Diarrhea, nausea, vomiting, abdominal pain, headache, rash.
Drug Interactions
Darunavir, ritonavir, and cobicistat metabolized principally by CYP3A.
Darunavir, ritonavir, and cobicistat inhibit CYP3A4 and CYP2D6.
Ritonavir-boosted darunavir inhibits P-glycoprotein (P-gp) transport system; cobicistat is a P-gp inhibitor.
Cobicistat inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1 and 1B3.
Darunavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat); consider drug interactions associated with both darunavir and the pharmacokinetic enhancer. Interactions reported or expected with ritonavir-boosted darunavir may differ from those reported or expected with cobicistat-boosted darunavir.
The following drug interactions are based on studies using ritonavir-boosted darunavir or studies using cobicistat alone. Drug interaction studies 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.
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).
CYP3A inhibitors: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of darunavir, ritonavir, or cobicistat).
CYP3A substrates: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (altered metabolism of CYP3A substrates).
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).
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).
P-gp inhibitors: Potential pharmacokinetic interactions with ritonavir-boosted or cobicistat-boosted darunavir (decreased clearance of darunavir and ritonavir leading to increased plasma concentrations).
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).
Specific Drugs
|
Drug |
Interaction |
Comments |
|---|---|---|
|
Abacavir |
Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions not expected No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed |
|
Alfuzosin |
Ritonavir-boosted or cobicistat-boosted darunavir: Potential for serious and/or life-threatening reactions (e.g., hypotension) |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated |
|
Antacids |
Acid-modifying drugs not expected to alter darunavir exposures Cobicistat-boosted darunavir: Clinically important interactions not expected |
|
|
Antiarrhythmic agents (amiodarone, disopyramide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine) |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased antiarrhythmic agent concentrations |
Amiodarone: If used with ritonavir-boosted or cobicistat-boosted darunavir, experts state monitor for amiodarone toxicity and consider ECG and amiodarone concentration monitoring Dronedarone: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated Disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Use concomitantly with caution; monitor antiarrhythmic concentrations |
|
Anticoagulants, oral (apixaban, dabigatran, edoxaban rivaroxaban, warfarin) |
Apixaban, edoxaban, dabigatran, rivaroxaban: Possible increased anticoagulant concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir Warfarin: Decreased warfarin concentrations and no change in darunavir concentrations if used with ritonavir-boosted darunavir; effect of concomitant use with cobicistat-boosted darunavir unknown |
Apixaban, rivaroxaban: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended Dabigatran: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended in certain patients with renal impairment depending on indication; experts state avoid concomitant use in patients with Clcr <50 mL/minute Edoxaban: Avoid concomitant use with ritonavir-boosted or cobicistat-boosted darunavir Warfarin: Monitor INR if used with ritonavir-boosted or cobicistat-boosted darunavir (especially when initiating or discontinuing darunavir) and adjust warfarin dosage as needed; if ritonavir-boosted darunavir switched to cobicistat-boosted darunavir, effect on warfarin concentrations not expected to be equivalent |
|
Anticonvulsants (carbamazepine, eslicarbazepine, ethosuximide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin) |
Carbamazepine: If used with ritonavir-boosted darunavir, increased carbamazepine concentrations and no change in darunavir concentrations; if used with cobicistat-boosted darunavir, increased carbamazepine concentrations, decreased cobicistat concentrations, and possibility of substantially decreased darunavir concentrations, loss of therapeutic effect and development of resistance Eslicarbazepine: Possible decreased cobicistat concentrations if used with cobicistat-boosted darunavir; effect on darunavir concentrations unknown Ethosuximide: Possible increased ethosuximide concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir Lamotrigine: If used with ritonavir-boosted darunavir, possible decreased lamotrigine concentrations; data not available regarding use with cobicistat-boosted darunavir Oxcarbazepine: If used with cobicistat-boosted darunavir, decreased cobicistat concentrations, but effect on darunavir concentrations unknown Phenobarbital, phenytoin: If used with ritonavir-boosted darunavir, possible decreased phenobarbital concentrations, but no change in darunavir concentrations; if used with cobicistat-boosted darunavir, decreased cobicistat and darunavir concentrations expected and may result in loss of therapeutic effect and development of resistance, but effect on phenobarbital concentrations unknown |
Carbamazepine: If used with ritonavir-boosted darunavir, dosage adjustments not needed, but monitor carbamazepine concentrations and adjust anticonvulsant dosage to achieve appropriate clinical effect; concomitant use with cobicistat-boosted darunavir contraindicated Eslicarbazepine: Consider alternative anticonvulsant or alternative antiretroviral; if used concomitantly with cobicistat-boosted darunavir, monitor for lack or loss of antiretroviral response Ethosuximide: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for ethosuximide toxicities Lamotrigine: In patients receiving ritonavir-boosted or cobicistat-boosted darunavir, consider alternative anticonvulsant or monitor lamotrigine concentrations; if used with ritonavir-boosted darunavir increased lamotrigine dosage may be needed 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 response Phenobarbital, phenytoin: If used with ritonavir-boosted darunavir, monitor anticonvulsant concentrations or consider alternative anticonvulsant; concomitant use with cobicistat-boosted darunavir contraindicated |
|
Antifungals, azoles (isavuconazonium, itraconazole, ketoconazole, posaconazole, voriconazole) |
Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole concentrations and altered darunavir concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir Itraconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased itraconazole, darunavir, and cobicistat concentrations Ketoconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, increased ketoconazole, darunavir, and cobicistat concentrations Posaconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased posaconazole, darunavir, and cobicistat concentrations Voriconazole: If used with ritonavir-boosted darunavir, possible decreased voriconazole concentrations; data not available regarding use with cobicistat-boosted darunavir |
Isavuconazonium: Monitor for darunavir-associated adverse effects and virologic efficacy if used with ritonavir-boosted or cobicistat-boosted darunavir; consider monitoring isavuconazole concentrations 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; itraconazole dosage >200 mg daily not recommended unless itraconazole concentrations used to guide dosage Ketoconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects; ketoconazole dosage >200 mg daily not recommended in those receiving ritonavir-boosted darunavir Posaconazole: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for posaconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects; consider monitoring posaconazole concentrations Voriconazole: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended unless benefits outweigh risks; if used concomitantly, experts state consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly |
|
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; if used with cobicistat-boosted darunavir, increased lumefantrine concentrations expected, but effect on artemether concentrations unknown |
Artemether/lumefantrine: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor for antimalarial efficacy and lumefantrine toxicity (e.g., QT interval prolongation); dosage adjustments not needed if used with ritonavir-boosted darunavir, but use caution |
|
Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine) |
Bedaquiline: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased bedaquiline concentrations Rifabutin: If used with ritonavir-boosted darunavir, increased rifabutin and darunavir concentrations; if used with cobicistat-boosted darunavir, possible increased rifabutin concentrations, but effect on darunavir and cobicistat concentrations unknown Rifampin: If used with ritonavir-boosted or cobicistat-boosted darunavir, substantially decreased darunavir concentrations and possible loss of antiretroviral effects Rifapentine: If used with ritonavir-boosted or cobicistat-boosted darunavir, decreased darunavir concentrations expected |
Bedaquiline: Clinical importance unknown; 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 dysfunction 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); also monitor for antimycobacterial response and consider therapeutic drug monitoring Rifampin: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated; experts state consider rifabutin as alternative if a rifamycin indicated Rifapentine: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended |
|
Antineoplastic agents (dasatinib, nilotinib, vinblastine, vincristine) |
Dasatinib, nilotinib, vinblastine, vincristine: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased antineoplastic concentrations |
Dasatinib, nilotinib: If used with ritonavir-boosted or cobicistat-boosted darunavir, reduced dosage of the antineoplastic may be needed 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; 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 inhibitor |
|
Antipsychotics (lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine) |
Lurasidone: If used with ritonavir-boosted or cobicistat-boosted darunavir, potential for serious and/or life-threatening adverse effects Perphenazine, risperidone, thioridazine: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased antipsychotic concentrations Pimozide: If used with ritonavir-boosted or cobicistat-boosted darunavir, potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias) Quetiapine: If used with ritonavir-boosted or cobicistat-boosted darunavir, increased quetiapine concentrations expected |
Lurasidone: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated Perphenazine, risperidone, thioridazine: Decreased antipsychotic dosage may be needed if used with ritonavir-boosted or cobicistat-boosted darunavir; experts state initiate antipsychotic at lowest dosage, adjust maintenance dosage as needed, and monitor for antipsychotic-associated toxicities Perphenazine, risperidone, thioridazine: If used with cobicistat-boosted darunavir, lower antipsychotic dosage may be needed; experts state that if used concomitantly with ritonavir-boosted darunavir, use lowest initial antipsychotic dosage or adjust maintenance dosage and monitor for antipsychotic-associated adverse effects Pimozide: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated Quetiapine: Consider alternative antiretroviral; 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; if quetiapine necessary in patient receiving ritonavir-boosted or cobicistat-boosted darunavir, experts state initiate using lowest quetiapine dosage and titrate as needed |
|
Atazanavir |
Unboosted atazanavir: Depending on regimen used, no clinically important change in atazanavir or darunavir concentrations or AUC No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted atazanavir: Concomitant use with ritonavir-boosted darunavir not recommended |
|
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) |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended |
|
Benzodiazepines (alprazolam, clonazepam, diazepam, estazolam, midazolam, triazolam) |
Alprazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased alprazolam concentrations Clonazepam: If used with ritonavir-boosted or cobicistat-boosted darunavir, increased clonazepam concentrations Diazepam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased diazepam concentrations Estazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, possible increased estazolam concentrations 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) |
Alprazolam: In patients receiving ritonavir-boosted or cobicistat-boosted darunavir, consider alternative (e.g., lorazepam, oxazepam, temazepam) Clonazepam: If used with ritonavir-boosted or cobicistat-boosted darunavir, monitor patient clinically; experts state consider other benzodiazepines not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) Diazepam: If used with ritonavir-boosted or cobicistat-boosted darunavir, titrate diazepam dosage, consider lower diazepam dosage, and monitor for adverse effects; experts state consider alternative (e.g., lorazepam, oxazepam, temazepam) Estazolam: If used with ritonavir-boosted or cobicistat-boosted darunavir, titrate estazolam dosage, consider lower estazolam dosage, and monitor for adverse effects Oral midazolam or triazolam: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated 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; consider reduced midazolam dosage, especially if multiple midazolam doses are given; experts state a single parenteral midazolam dose can be used with caution in a monitored situation for procedural sedation |
|
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-blocker |
Carvedilol, metoprolol, timolol: If used with ritonavir-boosted or cobicistat-boosted darunavir, clinical monitoring recommended and reduced dosage of β-blocker may be needed; experts state consider alternative β-blocker not metabolized by CYP enzymes (e.g., atenolol, labetalol, nadolol, sotalol) |
|
Bosentan |
Ritonavir-boosted darunavir: Possible increased bosentan concentrations Cobicistat-boosted darunavir: Possible increased bosentan concentrations and decreased darunavir and cobicistat concentrations |
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 tolerability 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 tolerability If ritonavir-boosted darunavir is switched to cobicistat-boosted darunavir, maintain current bosentan dosage |
|
Buprenorphine, buprenorphine/naloxone |
Ritonavir-boosted darunavir: Increased norbuprenorphine concentrations and AUC Cobicistat-boosted darunavir: Effect on buprenorphine or buprenorphine/naloxone unknown |
Ritonavir-boosted darunavir: Dosage adjustments not needed, but monitor patient; in those with a buprenorphine subdermal implant, removal of the implant and switch to a different buprenorphine formulation that permits dosage adjustments may be needed 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; if initiating cobicistat-boosted darunavir in patient already receiving buprenorphine or buprenorphine/naloxone, monitor patient and consider that dosage adjustments may be needed; in those with a buprenorphine subdermal implant, removal of the implant and switch to a different buprenorphine formulation that permits dosage adjustments may be needed |
|
Buspirone |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased buspirone concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Titration of buspirone recommended, consider lower buspirone dosage, and monitor for adverse effects |
|
Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil) |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased calcium-channel blocking agent concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Use concomitantly with caution; clinical monitoring recommended; if used concomitantly with diltiazem, experts state adjust diltiazem dosage based on clinical response and toxicities |
|
Cisapride |
Ritonavir-boosted or cobicistat-boosted darunavir: Potential for serious and/or life-threatening effects such as cardiac arrhythmias |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated |
|
Cobicistat |
Increased darunavir concentrations and AUC; used as a pharmacokinetic enhancer (pharmacokinetic booster) for therapeutic advantage (cobicistat-boosted darunavir) |
|
|
Colchicine |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased colchicine concentrations |
Patients with renal or hepatic impairment: Concomitant use of colchicine and ritonavir-boosted or cobicistat-boosted darunavir contraindicated 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 later 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 daily 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) |
|
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; may result in adrenal insufficiency or Cushing's syndrome Beclomethasone (orally inhaled): No clinically important pharmacokinetic interactions with ritonavir-boosted darunavir; clinically important interactions with cobicistat-boosted darunavir not expected Methylprednisolone, prednisolone, or triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome Budesonide (systemic): Increased corticosteroid concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir; may result in adrenal insufficiency or Cushing's syndrome; decreased darunavir concentrations may occur Prednisone (systemic): Increased corticosteroid concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir; may result in adrenal insufficiency or Cushing's syndrome 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 efficacy |
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; consider alternative (e.g., beclomethasone), especially when long-term corticosteroid use anticipated Beclomethasone (orally inhaled): Dosage adjustments not needed Methylprednisolone, prednisolone, or triamcinolone (intra-articular or other local injections): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir; consider alternative nonsteroidal therapies; if intra-articular corticosteroid required, use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir) Budesonide or prednisone (systemic): Do not use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir unless potential benefits outweigh risks of systemic corticosteroid adverse effects Dexamethasone (systemic): Use concomitantly with ritonavir-boosted or cobicistat-boosted darunavir with caution; consider alternative corticosteroid for long-term use |
|
Daclatasvir |
Ritonavir-boosted darunavir: No clinically important effect on daclatasvir or darunavir exposures |
Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed |
|
Dasabuvir |
Ritonavir-boosted darunavir: Decreased darunavir trough concentrations if used with fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir Cobicistat-boosted darunavir: Data not available regarding pharmacokinetic interactions with ombitasvir/paritaprevir/ritonavir with dasabuvir |
Ritonavir-boosted darunavir: Concomitant use with ombitasvir/paritaprevir/ritonavir with dasabuvir not recommended Cobicistat-boosted darunavir: Do not use concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir |
|
Delavirdine |
No in vitro evidence of antagonistic antiretroviral effects with darunavir |
|
|
Didanosine |
Didanosine delayed-release capsules: No change in didanosine or darunavir concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Administer didanosine (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food) or cobicistat-boosted darunavir (with food) |
|
Digoxin |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased digoxin concentrations |
Ritonavir-boosted darunavir: Use concomitantly with caution; use lowest possible initial digoxin dosage; monitor digoxin concentrations and adjust dosage as clinically indicated Cobicistat-boosted darunavir: Use concomitantly with caution; titrate digoxin dosage and monitor digoxin concentrations |
|
Dextromethorphan |
Ritonavir-boosted darunavir: Increased dextromethorphan concentrations |
|
|
Dolutegravir |
Ritonavir-boosted darunavir: No clinically important effect on pharmacokinetics of either drug Cobicistat-boosted darunavir: Clinically important interactions not expected |
Dosage adjustments not needed if used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir |
|
Efavirenz |
Ritonavir-boosted darunavir: Decreased darunavir AUC; increased efavirenz AUC Cobicistat-boosted darunavir: Possible decreased darunavir and cobicistat concentrations; possible loss of therapeutic effect and development of darunavir resistance No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Usual dosages can be used; some experts recommend close clinical monitoring; consider monitoring plasma concentrations of darunavir and efavirenz Cobicistat-boosted darunavir: Concomitant use not recommended |
|
Elbasvir and grazoprevir |
Ritonavir-boosted darunavir: Increased elbasvir concentrations and substantially increased grazoprevir concentrations; may increase risk of elevated ALT concentrations Cobicistat-boosted darunavir: Increased grazoprevir concentrations expected; may increase risk of elevated ALT concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use with fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) contraindicated |
|
Elvitegravir |
Elvitegravir: No effect on darunavir or elvitegravir exposures if used with ritonavir-boosted darunavir; data not available regarding use with cobicistat-boosted darunavir Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/c/FTC/TDF): Altered concentrations of elvitegravir, cobicistat, and/or darunavir if used with ritonavir-boosted darunavir; possible decreased elvitegravir concentrations if cobicistat-boosted elvitegravir used with cobicistat-boosted darunavir |
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; concomitant use with cobicistat-boosted darunavir not recommended EVG/c/FTC/TDF: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended |
|
Emtricitabine |
Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions not expected No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed |
|
Enfuvirtide |
No in vitro evidence of antagonistic antiretroviral effects with darunavir |
|
|
Eplerenone |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased eplerenone concentrations expected |
Ritonavir-boosted or cobicistat-boosted darunavir: Experts state concomitant use contraindicated |
|
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) |
Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated 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 possible |
|
Estrogens/progestins |
Oral hormonal contraceptives containing ethinyl estradiol and norethindrone: Decreased ethinyl estradiol and norethindrone concentrations if used with ritonavir-boosted darunavir; data not available regarding use with cobicistat-boosted darunavir Progestin-only contraceptives: Possible reduced efficacy of contraceptive Transdermal contraceptives containing ethinyl estradiol and norelgestromin or subdermal implant contraceptives containing etonogestrel: Data not available regarding use with ritonavir-boosted or cobicistat-boosted darunavir |
Ritonavir-boosted or cobicistat-boosted darunavir: Use additional or alternative nonhormonal contraception methods |
|
Etravirine |
Ritonavir-boosted darunavir: Decreased etravirine AUC, but no change in darunavir concentrations; safety and efficacy of ritonavir-boosted darunavir and etravirine established in clinical studies Cobicistat-boosted darunavir: Possible decreased cobicistat concentrations; effect on darunavir pharmacokinetics unknown; possible loss of therapeutic effect and development of darunavir resistance No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed Cobicistat-boosted darunavir: Concomitant use not recommended |
|
Fentanyl |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased fentanyl concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Carefully monitor patient for fentanyl therapeutic and adverse effects, including potentially fatal respiratory depression |
|
Flibanserin |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased flibanserin concentrations expected |
Ritonavir-boosted or cobicistat-boosted darunavir: Experts state concomitant use contraindicated |
|
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 antagonists |
Ranitidine or other histamine H2- receptor antagonists: Dosage adjustments not needed if used with ritonavir-boosted or cobicistat-boosted darunavir |
|
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 rhabdomyolysis Pitavastatin: Decreased pitavastatin AUC and no clinically important effect on darunavir concentrations if used with ritonavir-boosted darunavir; data not available regarding use with cobicistat-boosted darunavir |
Atorvastatin: If used with ritonavir-boosted darunavir, do not exceed atorvastatin dosage of 20 mg daily; carefully titrate atorvastatin dosage; use lowest necessary dosage with close monitoring for adverse effects; if used with cobicistat-boosted darunavir, initiate atorvastatin at lowest necessary dosage and monitor patient for safety Lovastatin: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated Pitavastatin: Dosage adjustments not necessary if used with ritonavir-boosted darunavir; if used with cobicistat-boosted darunavir, initiate pitavastatin at lowest necessary dosage, titrate dosage, and monitor patient for safety; experts state dosage adjustment not necessary if used with cobicistat-boosted darunavir Pravastatin: If used with ritonavir-boosted or cobicistat-boosted darunavir, carefully titrate pravastatin dosage; use lowest necessary dosage with close monitoring for adverse effects Rosuvastatin: If used with ritonavir-boosted or cobicistat-boosted darunavir, carefully titrate rosuvastatin dosage; use lowest necessary dosage with close monitoring for adverse effects Simvastatin: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated |
|
Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus) |
Cyclosporine, everolimus, sirolimus, tacrolimus: Increased immunosuppressive agent concentrations expected if used with ritonavir-boosted or cobicistat-boosted darunavir |
Cyclosporine, sirolimus, tacrolimus: Monitor plasma concentrations of immunosuppressive agent if used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir Everolimus: Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir not recommended |
|
Indinavir |
Ritonavir-boosted darunavir: Increased concentrations and AUC of darunavir and indinavir No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Appropriate dosages for concomitant use not established |
|
Ivabradine |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased ivabradine concentrations expected |
Ritonavir-boosted or cobicistat-boosted darunavir: Experts state concomitant use contraindicated |
|
Lamivudine |
Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed |
|
Ledipasvir and sofosbuvir |
Ritonavir-boosted or cobicistat-boosted darunavir: Clinically important pharmacokinetic interactions not expected if used with fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) Ritonavir-boosted darunavir in conjunction with emtricitabine and tenofovir DF in patients receiving ledipasvir/sofosbuvir: Increased tenofovir concentrations; safety of increased tenofovir concentrations not established |
Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed if used concomitantly with ledipasvir/sofosbuvir Ritonavir-boosted darunavir in conjunction with emtricitabine and tenofovir DF in patients receiving ledipasvir/sofosbuvir: Consider alternative HCV treatment regimen or alternative antiretroviral regimen; if concomitant use necessary, monitor for tenofovir-associated adverse effects |
|
Lopinavir/ritonavir |
Ritonavir-boosted darunavir: Decreased darunavir concentrations; no change in lopinavir concentrations No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Concomitant use not recommended; appropriate dosages with respect to safety and efficacy not established |
|
Macrolides (clarithromycin, erythromycin, telithromycin) |
Clarithromycin: Increased clarithromycin concentrations if used with ritonavir-boosted darunavir; increased darunavir, cobicistat, and clarithromycin concentrations if used with cobicistat-boosted darunavir Erythromycin, telithromycin: Increased darunavir, cobicistat, and macrolide concentrations if used with cobicistat-boosted darunavir |
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; consider alternative (e.g., azithromycin) in patients receiving ritonavir-boosted or cobicistat-boosted darunavir Erythromycin, telithromycin: Consider alternative anti-infective in patients receiving cobicistat-boosted darunavir |
|
Maraviroc |
Increased maraviroc concentrations and AUC if used with ritonavir-boosted or cobicistat-boosted darunavir No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted or cobicistat-boosted darunavir: Recommended maraviroc dosage is 150 mg twice daily |
|
Methadone |
Ritonavir-boosted darunavir: Decreased methadone concentrations Cobicistat-boosted darunavir: Effect on methadone pharmacokinetics unknown |
Ritonavir-boosted darunavir: Adjustment of methadone dosage not needed when initiating ritonavir-boosted darunavir, but closely monitor for opiate withdrawal since some patients may need adjustment of methadone maintenance dosage Cobicistat-boosted darunavir: Initiate methadone using lowest possible dosage and titrate carefully to desired therapeutic effect; if initiating cobicistat-boosted darunavir in patient already receiving methadone, monitor patient and consider that adjustment of methadone dosage may be needed |
|
Nelfinavir |
No in vitro evidence of antagonistic antiretroviral effects with darunavir |
|
|
Nevirapine |
Ritonavir-boosted darunavir: Increased nevirapine and darunavir concentrations Cobicistat-boosted darunavir: Possible decreased cobicistat concentrations; effect on darunavir pharmacokinetics unknown; possible loss of therapeutic effect and development of darunavir resistance No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed Cobicistat-boosted darunavir: Concomitant use not recommended |
|
Ombitasvir |
Ritonavir-boosted darunavir: Decreased darunavir concentrations if used with fixed combination of ombitasvir/paritaprevir/ritonavir or if used with fixed combination of ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir Cobicistat-boosted darunavir: Data not available regarding use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir |
Unboosted darunavir: Manufacturer of ombitasvir/paritaprevir/ritonavir states the fixed-combination HCV drug may be used concomitantly with darunavir (800 mg) without low-dose ritonavir Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir not recommended |
|
Oxycodone |
Cobicistat-boosted darunavir: Possible increased oxycodone concentrations |
Cobicistat-boosted darunavir: Carefully monitor patient for oxycodone therapeutic and adverse effects, including potentially fatal respiratory depression |
|
Paritaprevir |
Ritonavir-boosted darunavir: Decreased darunavir trough concentrations if used with fixed combination of ombitasvir/paritaprevir/ritonavir or if used with ombitasvir/paritaprevir/ritonavir with dasabuvir Cobicistat-boosted darunavir: Data not available regarding use with ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir |
Unboosted darunavir: Manufacturer of ombitasvir/paritaprevir/ritonavir states the fixed combination HCV drug may be used concomitantly with darunavir (800 mg) without low-dose ritonavir Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use with ombitasvir/paritaprevir/ritonavir with dasabuvir not recommended |
|
Proton pump inhibitors (PPIs) |
Ritonavir-boosted darunavir: Decreased omeprazole concentrations, but no change in darunavir concentrations Cobicistat-boosted darunavir: Clinically important interactions not expected |
Ritonavir-boosted darunavir: Monitor for decreased omeprazole efficacy; consider increasing omeprazole dosage if symptoms not well controlled, but avoid omeprazole dosage >40 mg once daily Cobicistat-boosted darunavir: Dosage adjustments not needed if used with PPIs |
|
Raltegravir |
Ritonavir-boosted darunavir: No clinically important effect on pharmacokinetics of darunavir Cobicistat-boosted darunavir: Data not available, but clinically important interactions not expected |
Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed |
|
Ranolazine |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible serious and/or life-threatening adverse effects |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated |
|
Rilpivirine |
Ritonavir-boosted darunavir: Increased rilpivirine concentrations and AUC, but no clinically important effect on darunavir concentrations or AUC Cobicistat-boosted darunavir: Possible increased rilpivirine concentrations; altered darunavir concentrations not expected No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed |
|
Ritonavir |
Increased darunavir concentrations and AUC; low-dose ritonavir (100 mg once daily) used as a pharmacokinetic enhancer (pharmacokinetic booster) for therapeutic advantage (ritonavir-boosted darunavir) No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir or ritonavir-containing preparations: Concomitant use with cobicistat-boosted darunavir not recommended |
|
St. John’s wort (Hypericum perforatum) |
Ritonavir-boosted or cobicistat-boosted darunavir: Potential decreased darunavir concentrations; possible decreased antiretroviral efficacy |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use contraindicated |
|
Salmeterol |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased salmeterol concentrations and increased risk of QT interval prolongation, palpitations, and sinus tachycardia |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended |
|
Saquinavir |
Ritonavir-boosted darunavir: Decreased darunavir concentrations, but saquinavir concentrations unchanged No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Concomitant use not recommended |
|
Selective serotonin-reuptake inhibitors (SSRIs) |
Paroxetine, sertraline: Decreased SSRI concentrations and AUCs and no change in darunavir concentrations if used with ritonavir-boosted darunavir; possible pharmacokinetic interactions if used with cobicistat-boosted darunavir, but effect on SSRI concentrations unknown Fluvoxamine: Possible altered (increased or decreased) darunavir concentrations if used with ritonavir-boosted or cobicistat-boosted darunavir |
Paroxetine, sertraline: Titrate SSRI dosage based on clinical response in patients receiving ritonavir-boosted or cobicistat-boosted darunavir; if ritonavir-boosted darunavir initiated in those on stable SSRI dosage, monitor for clinical response Fluvoxamine: Experts state consider alternative to fluvoxamine in patients receiving ritonavir-boosted or cobicistat-boosted darunavir |
|
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) |
Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with ritonavir-boosted or cobicistat-boosted darunavir contraindicated; safe and effective dosage for concomitant use not established 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 effects |
|
Simeprevir |
Ritonavir-boosted darunavir: Increased concentrations and AUC of simeprevir and darunavir Cobicistat-boosted darunavir: Increased simeprevir concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Concomitant use not recommended |
|
Sofosbuvir |
Ritonavir-boosted darunavir: No clinically important pharmacokinetic interactions |
Ritonavir-boosted darunavir: Dosage adjustments not needed Cobicistat-boosted darunavir: May be used concomitantly |
|
Sofosbuvir and velpatasvir |
Ritonavir-boosted darunavir: No clinically important pharmacokinetic interactions if used with fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) HIV antiretroviral regimen of ritonavir-boosted darunavir in conjunction with emtricitabine/tenofovir DF: Increased velpatasvir and tenofovir concentrations and AUC if used with sofosbuvir/velpatasvir |
HIV antiretroviral regimens that include ritonavir-boosted darunavir and tenofovir DF: Monitor for tenofovir-associated adverse effects if used with sofosbuvir/velpatasvir |
|
Stavudine |
Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed |
|
Suvorexant |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased suvorexant concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Experts state concomitant use with suvorexant not recommended |
|
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) |
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 daily 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 daily 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 effects 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 daily |
|
Tenofovir alafenamide |
Ritonavir-boosted or cobicistat-boosted darunavir: No substantial effect on TAF exposures |
Ritonavir-boosted or cobicistat-boosted darunavir: Experts state dosage adjustments not needed |
|
Tenofovir DF |
Ritonavir-boosted darunavir: Increased tenofovir concentrations and AUC; increased darunavir concentrations and AUC Cobicistat-boosted darunavir: Possible increased tenofovir concentrations No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Experts state clinical importance unknown; monitor for tenofovir toxicity; manufacturer of darunavir states usual dosage of ritonavir-boosted darunavir and tenofovir can be used Cobicistat-boosted darunavir: Assess baseline estimated Clcr, urine glucose, and urine protein; not recommended in patients with estimated Clcr <70 mL/minute; experts state monitor for tenofovir toxicity |
|
Ticagrelor |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased ticagrelor concentrations expected |
Ritonavir-boosted or cobicistat-boosted darunavir: Avoid concomitant use |
|
Tipranavir |
No in vitro evidence of antagonistic antiretroviral effects with darunavir |
|
|
Tramadol |
Cobicistat-boosted darunavir: Increased tramadol concentrations |
Cobicistat-boosted darunavir: Decreased tramadol dosage may be needed; monitor for efficacy and tramadol-associated adverse effects |
|
Trazodone |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased trazodone concentrations and increased risk of nausea, dizziness, hypotension, syncope |
Ritonavir-boosted or cobicistat-boosted darunavir: Use lowest possible trazodone dosage and monitor for adverse CNS and cardiovascular effects |
|
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, syncope |
Ritonavir-boosted or cobicistat-boosted darunavir: Use lowest possible antidepressant dosage; titrate antidepressant dosage based on clinical assessment and/or antidepressant concentrations |
|
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) |
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 effects |
|
Vorapaxar |
Ritonavir-boosted or cobicistat-boosted darunavir: Increased vorapaxar concentrations expected |
Ritonavir-boosted or cobicistat-boosted darunavir: Avoid concomitant use |
|
Zidovudine |
Ritonavir-boosted or cobicistat-boosted darunavir: Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects with darunavir |
Ritonavir-boosted darunavir: Dosage adjustments not needed |
|
Zolpidem |
Ritonavir-boosted or cobicistat-boosted darunavir: Possible increased zolpidem concentrations |
Ritonavir-boosted or cobicistat-boosted darunavir: Use low initial zolpidem dosage; dosage reduction may be necessary |
Darunavir Pharmacokinetics
Absorption
Bioavailability
Darunavir must be administered with low-dose ritonavir (ritonavir-boosted darunavir) or cobicistat (cobicistat-boosted darunavir). Ritonavir and cobicistat are pharmacokinetic enhancers (pharmacokinetic boosters) that decrease metabolism of darunavir, resulting in increased darunavir plasma concentrations and AUC.
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).
Ritonavir-boosted darunavir: Peak plasma concentrations of darunavir attained approximately 2.5–4 hours after a dose.
Cobicistat-boosted darunavir: Peak plasma concentrations of darunavir attained approximately 4–4.5 hours after a dose.
Food
Food increases darunavir bioavailability.
Ritonavir-boosted darunavir: Administration with food increases darunavir peak plasma concentrations and AUC by approximately 40%.
Cobicistat-boosted darunavir: Administration with high-fat meal increases darunavir peak plasma concentrations and AUC by approximately 127 and 70%, respectively.
Distribution
Extent
Darunavir distributed into CSF; clinical importance unknown.
Not known whether darunavir distributed into human milk; distributed into milk in rats.
Plasma Protein Binding
Darunavir: 95%.
Binds principally to α1-acid-glycoprotein.
Elimination
Metabolism
Darunavir extensively metabolized by CYP3A.
Elimination Route
Following administration of ritonavir-boosted darunavir, darunavir eliminated principally in feces unchanged; approximately 80% of darunavir dose excreted in feces and 14% excreted in urine.
Hemodialysis or peritoneal dialysis unlikely to remove darunavir, ritonavir, or cobicistat.
Half-life
15 hours after dose of ritonavir-boosted darunavir.
7 hours after dose of cobicistat-boosted darunavir.
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.
Ritonavir-boosted darunavir in pregnant women: Darunavir and ritonavir exposures generally lower in pregnant women compared with exposures in postpartum women. Reductions in unbound darunavir and ritonavir concentrations in pregnant women are greater for once daily ritonavir-boosted darunavir regimens than twice daily regimens.
Ritonavir-boosted darunavir in renal impairment: Darunavir pharmacokinetics not affected in those with moderate renal impairment (Clcr 30–60 mL/minute). Not studied in those with severe renal impairment or end-stage renal disease.
Cobicistat-boosted darunavir in renal impairment: Pharmacokinetics not studied.
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. Not studied in those with severe hepatic impairment.
HBV or HCV coinfection: No effect on darunavir exposure in those receiving ritonavir-boosted darunavir; effect on pharmacokinetics of cobicistat-boosted darunavir not evaluated.
Higher darunavir plasma concentrations reported in females receiving ritonavir-boosted darunavir compared with males; dosage adjustments not required.
Stability
Storage
Oral
Suspension
Darunavir: 25°C (may be exposed to 15–30°C). Do not refrigerate or freeze; avoid excessive heat.
Tablets
Darunavir: 25°C (may be exposed to 15–30°C).
Darunavir/cobicistat: 20–25°C (may be exposed to 15–30°C).
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.
-
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.
-
Antiretroviral activity is due to darunavir.
-
Active against HIV-1. Also has some activity against HIV type 2 (HIV-2).
-
Darunavir inhibits replication of HIV-1 by interfering with HIV proteases.
-
Darunavir-resistant HIV-1, including strains with decreased susceptibility to other HIV PIs, has been reported.
-
Varying degrees of cross-resistance occur among HIV PIs.
-
Some clinical isolates of HIV-1 with reduced susceptibility to darunavir have been resistant to atazanavir, fosamprenavir, indinavir, lopinavir, and nelfinavir.
Advice to Patients
-
Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.
-
Importance of using darunavir with low-dose ritonavir (ritonavir-boosted darunavir) or with cobicistat (cobicistat-boosted darunavir). Importance of using ritonavir-boosted or cobicistat-boosted darunavir in conjunction with other antiretrovirals.
-
Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.
-
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. 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.
-
Importance of reading patient information provided by the manufacturer.
-
When using ritonavir-boosted darunavir, importance of taking darunavir with food and at the same time as ritonavir. Importance of swallowing darunavir tablets whole with a drink (e.g., water, milk).
-
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. 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. Do not take a double dose to make up for a missed dose.
-
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. 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. Do not take a double dose to make up for a missed dose.
-
When using cobicistat-boosted darunavir, importance of taking fixed-combination darunavir/cobicistat with food; alternatively, importance of taking single-entity darunavir with food and at the same time as single-entity cobicistat.
-
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. 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. Do not take a double dose to make up for a missed dose.
-
Advise patients that drug-induced hepatitis has occurred. 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).
-
Advise patients that mild to severe skin reactions have occurred. 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).
-
Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.
-
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.
-
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. Should not be used concomitantly with sildenafil used for treatment of PAH.
-
Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of potential interactions with hormonal contraceptives.
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
-
Importance of advising patients of other important precautionary information. (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.
|
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 |
|
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 2024, Selected Revisions May 22, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
Reload page with references included
Frequently asked questions
More about darunavir
- Check interactions
- Compare alternatives
- Pricing & coupons
- Reviews (5)
- Drug images
- Side effects
- Dosage information
- During pregnancy
- Drug class: protease inhibitors
- Breastfeeding
- En español
