AHFS Class:

• HIV Protease Inhibitors 8:18.08.08

Generic Name(s):

• Darunavir

Darunavir, an antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1

Treatment of HIV Infection

Darunavir with low-dose ritonavir ( ritonavir-boosted darunavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients ≥3 years of age weighing ≥10 kg.1

Darunavir with cobicistat ( cobicistat-boosted darunavir) is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve or treatment-experienced adult and pediatric patients ≥40 kg.237,239 The manufacturer of darunavir/cobicistat states that efficacy of the fixed combination is based on efficacy demonstrated in clinical trials of ritonavir-boosted darunavir.237

Clinical Experience

Antiretroviral-naïve Adults

The comparative safety and efficacy of ritonavir-boosted darunavir and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) were evaluated in a phase 3, randomized, open-label study in 689 treatment-naïve HIV-infected adults ≥18 years of age (TMC114-C211, ARTEMIS).1,10,20 All patients had baseline plasma HIV-1 RNA levels ≥5000 copies/mL and were randomized to receive ritonavir-boosted darunavir (darunavir 800 mg once daily with ritonavir 100 mg once daily; n=343) or lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily or lopinavir 800 mg/ritonavir 200 mg once daily; n=346) in conjunction with tenofovir disoproxil fumarate (DF, 300 mg once daily) and emtricitabine (200 mg once daily).1,10,20 The primary outcome was noninferiority of darunavir/ritonavir to lopinavir/ritonavir in virologic response, defined as plasma HIV-1 RNA levels <50 copies/mL at 48 weeks.10

Mean baseline HIV-RNA level was 4.85 log₁₀ copies/mL with a median CD4⁺ T-cell count of 225 cells/mm³.10 Results at 48 weeks indicated noninferiority of ritonavir-boosted darunavir compared with lopinavir/ritonavir.10 A confirmed virologic response was seen in 84% of patients treated with ritonavir-boosted darunavir and 78% of patients treated with lopinavir/ritonavir.10 At 192 weeks, 70% of patients receiving ritonavir-boosted darunavir and 61% of those receiving lopinavir/ritonavir had plasma HIV-1 RNA levels <50 copies/mL.1 The median increase in CD4⁺ T-cell count from baseline to 192 weeks was 258 and 263 cells/mm³, respectively.1,20 In patients receiving ritonavir-boosted darunavir, 81% of those with a confirmed virologic response at week 48 remained undetectable at week 192 versus 68% of those receiving lopinavir/ritonavir.20 In the 192-week analysis, the ritonavir-boosted darunavir regimen was superior to the lopinavir/ritonavir regimen in the intent-to-treat (ITT) population.1,20

Antiretroviral-experienced Adults

The comparative efficacy of once- and twice-daily regimens of ritonavir-boosted darunavir was evaluated in a randomized, open-label, phase 3 study (TMC114-C229, ODIN) in 590 antiretroviral-experienced adults ≥18 years of age with baseline plasma HIV-1 RNA levels >1000 copies/mL and no mutations associated with darunavir resistance1,305 All patients had been receiving highly active antiretroviral therapy (HAART) for at least 12 weeks.305 A total of 590 patients were randomized to treatment with either ritonavir-boosted darunavir (darunavir 800 mg/ritonavir 100 mg) once daily or a twice-daily regimen (darunavir 600 mg with ritonavir 100 mg); all patients received an optimized background antiretroviral regimen (OBR).305 The primary outcome was confirmed virologic response (HIV-1 RNA <50 copies/mL) to establish noninferiority of the once-daily regimen.305 At 48 weeks, 69% of patients in each group had plasma HIV-1 RNA levels <50 copies/mL.1 Noninferiority of the once-daily regimen was established.305 The mean increase in CD4⁺ T-cell count from baseline was similar between groups (108 and 112 cells/mm³).1

The comparative safety and efficacy of ritonavir-boosted darunavir and lopinavir/ritonavir were evaluated in a phase 3, randomized, controlled, open-label study (TMC114-C214, TITAN) in 595 antiretroviral-experienced HIV-infected adults ≥18 years of age with baseline plasma HIV-1 RNA levels >1000 copies/mL who had been receiving HAART for at least 12 weeks.1,9 . Patients were randomized to receive ritonavir-boosted darunavir (darunavir 600 mg twice daily with ritonavir 100 twice daily; n=298) or lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily; n=297) in conjunction with an OBR consisting of at least 2 antiretrovirals1,9 The primary outcome was noninferiority of darunavir, based on the proportion of patients achieving an HIV-1 RNA level <400 copies/mL at 48 weeks.1,9

At baseline, the mean HIV-RNA level was 4.30 log₁₀ copies/mL, and median CD4⁺T-cell count was 232 cells/mm³.9 At 48 weeks, 77% of patients treated with ritonavir-boosted darunavir achieved a virologic response (<400 copies/mL) compared with 68% of patients treated with lopinavir/ritonavir, meeting criteria for noninferiority.9 At 96 weeks, 58% of patients receiving ritonavir-boosted darunavir and 52% of patients receiving lopinavir/ritonavir had plasma HIV-1 RNA levels < 50 copies/mL.1 The median increase in CD4⁺ T-cell count from baseline was 81 and 93 cells/mm³ in patients treated with ritonavir-boosted darunavir or lopinavir/ritonavir, respectively.1

Ritonavir-boosted darunavir also was evaluated in 2 randomized, controlled, phase 2b studies (TMC114-C213 [POWER-1] and TMC114-C202 [POWER-2]) in 255 adults with clinically advanced HIV infection (baseline plasma HIV-1 RNA levels >1000 copies/mL) who had received prior therapy with an antiretroviral regimen that included a protease inhibitor (PI), nucleoside reverse transcriptase inhibitor (NRTI), and non-nucleoside reverse transcriptase inhibitor (NNRTI).1,301,302 Patients also had to be receiving a stable PI-containing regimen for at least 8 weeks at study entry.1,301,302 All patients had at least 1 mutation in the HIV protease gene at baseline.1 These studies were conducted in 2 phases.1 In the initial dose-finding phase, patients received 1 of 4 doses of ritonavir-boosted darunavir or a ritonavir-boosted comparator PI regimen; all patients received an OBR.301 302 This was followed by a long-term phase in which patients were randomized to receive ritonavir-boosted darunavir (600 mg with ritonavir 100 mg twice daily) or a comparator PI, both with an OBR.301,302 The primary outcome was the proportion of patients achieving a ≥1 log₁₀ copies/mL reduction in HIV-1 RNA at 24 weeks.301,302 At baseline, patients in POWER-1 had a mean viral load of 4.48 log₁₀ and median CD4⁺ T-cell count of 179 cells/mm³; patients in POWER-2 had a mean viral load of 4.7 log₁₀and a median CD4⁺ T-cell count of 106 cells/mm³.301,302

At 24 weeks, 69-77% of patients treated with ritonavir-boosted darunavir achieved the primary outcome versus 25% of patients treated with a ritonavir-boosted comparator PI in POWER-1.301 In POWER-2, the corresponding proportions were 45-62% compared with 14%.302

At 96 weeks, 57% of those receiving ritonavir-boosted darunavir and an OBR and 10% of those receiving a comparator ritonavir-boosted PI and an OBR were virologic responders (achieved and maintained a reduction in plasma HIV-1 RNA levels of at least 1 log₁₀ copies/mL below baseline);1 39% of those receiving ritonavir-boosted darunavir and an OBR and 9% of those receiving the comparator PI-containing regimen and an OBR had plasma HIV-1 RNA levels <50 copies/mL.1

The efficacy of ritonavir-boosted darunavir was also assessed in POWER-3, an analysis of two phase 2b, open-label, nonrandomized trials (TMC114-C125 and TMC114-C208).304 A total of 327 patients were enrolled following similar inclusion/exclusion criteria as POWER-1 and -2 and were given ritonavir-boosted darunavir (600 mg with ritonavir 100 mg) twice daily with an OBR.304 All patients were treatment-experienced but naïve to darunavir.304 The primary outcome was the proportion of patients achieving a ≥1 log₁₀ copies/mL reduction in HIV-1 RNA at 24 weeks.304 The efficacy analysis included 246 patients; 65% achieved the primary outcome at 24 weeks.304 An HIV-1 RNA level <50 copies/mL was achieved by 40% of patients.304

Antiretroviral-experienced Pediatric Patients

Safety and efficacy of ritonavir-boosted darunavir in conjunction with other antiretroviral agents were evaluated in a phase 2, open-label study (TMC114-C212, DELPHI).1,308 Eighty antiretroviral-experienced HIV-infected children 6 to less than 18 years of age (median, 14 years) weighing at least 20 kg were treated with ritonavir-boosted darunavir plus an OBR consisting of at least 2 non-PI antiretroviral agents;1 79% had previously received at least 1 NNRTI and 96% had previously received at least 1 PI .1 Mean baseline plasma HIV-1 RNA level was 4.64 log₁₀ copies/mL with a median baseline CD4⁺ T-cell count of 330 cells/mm³.1 308 The primary outcome was the proportion of patients achieving a ≥1 log₁₀ HIV-1 RNA reduction from baseline.308

At 24 and 48 weeks, 74 and 65% of patients achieved the primary outcome, respectively.307 At week 24, 64 and 50% of patients had plasma HIV-1 RNA levels <400 and <50 copies/mL, respectively; the mean CD4⁺ T-cell count increase from baseline was 117 cells/mm³.1

Safety and efficacy of ritonavir-boosted darunavir were evaluated in an open-label study (TMC114-C228, ARIEL) in 21 antiretroviral-experienced HIV-infected children 3 to less than 6 years of age and weighing 10 to less than 20 kg.1,306 Patients were treated with an oral suspension of ritonavir-boosted darunavir at a twice-daily dose of 25 mg/kg darunavir and 3 mg/kg ritonavir for patients less than 15 kg and 375 mg darunavir and 50 mg ritonavir for patients 15 to less than 20 kg, with an OBR.306 Median age was 4.4 years, with mean baseline plasma HIV-1 RNA level of 4.34 log₁₀ copies/mL and a median baseline CD4⁺ T-cell count of 927 cells/mm³.1 Efficacy outcomes included a virologic response (plasma HIV-1 RNA level <50 copies/mL), viral load, and CD4⁺ T-cell count.306 At week 48, 1 patient had discontinued treatment and 71% of the remaining 20 patients had plasma HIV-1 RNA levels <50 copies/mL.1 An HIV-1 RNA level <400 copies/mL was achieved in 85.7% of patients, and 90.5% had a ≥1 log₁₀ decrease in HIV-1 RNA levels from baseline.306 The mean change in CD4⁺ T-cell count from baseline was 187 cells/mm³ and the mean increase in CD4⁺ percentage from baseline was 4%.1,306

A phase 2/3, open-label trial (GS-US-216-0128) was conducted in 7 antiretroviral-experienced adolescents >12 years of age (median age, 14 years) with HIV-1 infection to evaluate cobicistat-boosted darunavir.237 Patients on a stable ritonavir-boosted darunavir regimen were switched to cobicistat 150 mg once daily and continued darunavir and 2 NRTIs. 237 Baseline HIV-1 RNA levels were <50 copies/mL; 86% remained virologically suppressed at 48 weeks.237

Antiretroviral-naïve Pediatric Patients

Study TMC114-C230 (DIONE) was a phase 2, open-label trial evaluating the safety and efficacy of ritonavir-boosted darunavir in 12 antiretroviral-naïve pediatric patients 12 to less than 18 years of age weighing ≥40 kg.1,307 Enrolled patients (median age, 14.4 years) had a mean baseline plasma HIV-1 RNA level of 4.72 log₁₀copies/mL and a median baseline CD4⁺ T-cell count of 282 cells/mm³.1,307 Patients received the adult recommended dosage of ritonavir-boosted darunavir (darunavir 800 mg once daily with ritonavir 100 mg once daily) in addition to an OBR consisting of at least 2 non-PI antiretroviral agents.1 The primary outcome was viral response (as HIV-1 RNA <50 copies/mL) at 24 weeks.307

At 24 weeks, 92% of patients achieved the primary outcome of HIV-1 RNA <50 copies/mL.307 At 48 weeks, data from the 12 patients indicated that 91.7 and 83.3% had plasma HIV-1 RNA levels <400 and <50 copies/mL, respectively.¹ The mean increase in CD4⁺ T-cell count from baseline was 221 cells/mm³.1 307

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Darunavir, a PI, is commonly used in combination with a pharmacokinetic booster (e.g., ritonavir or cobicistat) as part of a fully suppressive antiretroviral regimen.1,237 In the 2023 HHS adult HIV treatment guideline, darunavir (boosted with ritonavir or cobicistat) is included as an option for initial therapy in regimens including either tenofovir alafenamide or tenofovir disoproxil fumarate and either emtricitabine or lamivudine when antiretroviral therapy is started in individuals who had exposure to long-acting cabotegravir as part of pre-exposure prophylaxis and if INSTI genotypic resistance test results are unavailable.200 Boosted darunavir regimens can also be used in certain clinical situations.200

In the 2023 HHS pediatric HIV treatment guideline, boosted darunavir plus a 2 NRTI backbone is included as an option in alternative PI-based regimens for children ≥3 years of age and ≥10 kg and for adolescents ≥12 years of age with sexual maturity ratings of 1-3.201 Consult HHS guidelines and the selected darunavir-containing product for information regarding pediatric populations in which the product is approved for use.201

In the 2023 HHS perinatal HIV treatment guideline, ritonavir-boosted darunavir is included in various antiretroviral regimens.202 Ritonavir-boosted darunavir with an NRTI backbone regimen is listed among preferred options in pregnant females who are antiretroviral-naïve.202 A ritonavir-boosted darunavir-containing regimen is also preferred during pregnancy in patients who are restarting antiretroviral therapy, as part of a new antiretroviral regimen if current therapy is not well-tolerated or not fully suppressive, and in nonpregnant patients who are trying to conceive.202 A ritonavir-boosted darunavir regimen can be continued if pregnancy occurs and the regimen is well tolerated and fully suppressive.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Ritonavir-boosted darunavir is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure [off-label]† (PEP) in health-care personnel and other individuals.199

Clinical Perspective

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199 These experts also state that ritonavir-boosted darunavir is one of several alternative regimens that may be used in conjunction with other antiretrovirals in PEP regimens.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious diseases specialist, clinicians with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Ritonavir-boosted darunavir is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) after sexual, injection drug use, or other nonoccupational exposures.198

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada^®).198

Consultation with an infectious diseases specialist, clinicians with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Pretreatment Screening

• In antiretroviral-experienced patients, the treatment history and genotype and/or phenotype testing is recommended prior to therapy initiation of ritonavir-boosted or cobicistat-boosted darunavir to test for drug susceptibility of the human immunodeficiency virus type 1 (HIV-1) virus.1,237
• Prior to initiation of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat), assess estimated creatinine clearance.237 If initiating cobicistat-boosted darunavir with concomitant tenofovir disoproxil fumarate (tenofovir DF), also assess urine glucose and urine protein; additional monitoring of serum phosphorus is recommended in patients with or at risk of renal impairment.237

Patient Monitoring

• In patients with underlying cirrhosis, chronic hepatitis, or baseline serum aminotransferase elevations, monitor liver serum biochemistries, particularly during the first few months of treatment with ritonavir-boosted or cobicistat-boosted darunavir.1,237
• Perform routine monitoring of estimated creatinine clearance, urine glucose, urine protein, and additional phosphorus monitoring in patients with or at risk for renal impairment when cobicistat-boosted darunavir is used concomitantly with tenofovir DF.237
• Monitor patients closely for renal safety when there is a confirmed serum creatinine increase of greater than 0.4 mg/dL from baseline while on cobicistat-boosted darunavir.237
• Monitor patients with a known sulfonamide allergy after initiation of darunavir.1,237

Dispensing and Administration Precautions

• Darunavir is commercially available as a single entity and in various fixed-combination preparations containing additional antiretroviral agents.1,237,240 Refer to the full prescribing information for specific, distinct uses of the combination products.1,237,240 Since antiretroviral agents contained in the fixed-combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.1 237,240

Administration

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

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

Darunavir should not be administered without low-dose ritonavir or cobicistat.1,200,201,237,239 Low-dose ritonavir and cobicistat are pharmacokinetic enhancers that improve the pharmacokinetic profile of darunavir.1,200,237,239

Fixed Combinations Containing Darunavir

Darunavir is also commercially available in the following fixed-combination tablets for oral use: darunavir/cobicistat (Prezcobix^®) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza^®).1,237,240 See the full prescribing information for administration of each of these combination products.1,237,240

Ritonavir-boosted Darunavir

When ritonavir-boosted darunavir is used, single-entity darunavir is administered as tablets or oral suspension at the same time as single-entity ritonavir capsules, tablets, or oral solution. 1

Oral Suspension

Darunavir oral suspension should be used in patients who have difficulty swallowing tablets.1

The oral suspension should be administered using the oral dosing syringe supplied by the manufacturer.1 If a 675- or 800-mg dose of darunavir is indicated, the dose should be given as two 3.4- or 4-mL administrations, respectively, using the oral dosing syringe.1

Store darunavir oral suspension in the original container at 25°C (excursions permitted between 15-30°C).1 The suspension should not be refrigerated or frozen and should not be exposed to excessive heat.1

The oral suspension is a white to off-white opaque suspension and should be shaken prior to each dose.1

Tablets

Darunavir tablets should be swallowed whole with a drink (e.g., water, milk).1

Children weighing 15 kg or more should be assessed for the ability to swallow darunavir tablets; darunavir oral suspension should be considered in those unable to reliably swallow tablets.1

Store darunavir tablets in the original container at 25°C (excursion permitted between 15-30°C).1

Cobicistat-boosted Darunavir

When cobicistat-boosted darunavir is used, fixed-combination tablets containing both drugs are commercially available (darunavir/cobicistat).237 Alternatively, single-entity darunavir is administered as tablets or oral suspension at the same time as single-entity cobicistat tablets.239

Store darunavir/cobicistat fixed-combination tablets between 20-25°C (excursions permitted between 15-30°C).237

Dosage

Single-entity darunavir is commercially available as an oral suspension and tablets containing darunavir ethanolate; dosage is expressed in terms of darunavir.1

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

Pediatric Dosage

Dosage of ritonavir-boosted darunavir in children 3 years to less than 18 years of age weighing at least 10 kg is based on weight.1 Pediatric dosage should not exceed the recommended dosage for adults.1

Treatment of HIV Infection in Antiretroviral-naïve Pediatric Patients

For the treatment of HIV-1 infection in antiretroviral naïve pediatric patients weighing 40 kg and greater, the recommended dosage of darunavir/cobicistat fixed-combination tablet is 1 tablet daily (800 mg of darunavir/150 mg of cobicistat).237 Administer in conjunction with other antiretroviral agents active against HIV-1.237

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

Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients

When ritonavir-boosted darunavir is used in antiretroviral-experienced pediatric patients, genotypic testing is recommended to identify mutations associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).1

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

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

For the treatment of HIV-1 infection in antiretroviral-experienced pediatric patients weighing 40 kg and greater without any mutations associated with darunavir resistance, the recommended dosage of darunavir/cobicistat fixed-combination tablet is 1 tablet daily (800 mg of darunavir/150 mg of cobicistat).237 Alternatively, single-entity darunavir 800 mg (one 800-mg darunavir tablet or 8 mL of darunavir oral suspension containing 100 mg/mL) once daily can be administered in conjunction with single-entity cobicistat (150 mg once daily).239 Both must be administered in conjunction with other antiretroviral agents active against HIV-1.237,239

Adults

Treatment of HIV Infection in Antiretroviral-naïve Adults

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

The recommended dosage of cobicistat-boosted darunavir for the treatment of HIV-1 infection in antiretroviral-naïve adults without any substitutions associated with darunavir resistance is 800 mg of darunavir once daily given in conjunction with 150 mg of cobicistat once daily.237,239 When fixed-combination darunavir/cobicistat is used, adults should receive 1 tablet (800 mg of darunavir and 150 mg of cobicistat) once daily.237 Alternatively, adults can receive 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL) once daily given in conjunction with single-entity cobicistat 150 mg once daily.239 A cobicistat-boosted darunavir regimen that contains a darunavir dosage of 600 mg twice daily is not recommended.239

Treatment of HIV Infection in Antiretroviral-experienced Adults

When ritonavir-boosted darunavir or cobicistat-boosted darunavir is used in antiretroviral-experienced patients, genotypic testing is recommended to identify substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).1,237

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

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

If genotypic testing is not feasible, a ritonavir-boosted regimen of 600 mg of single-entity darunavir (one 600- mg tablet or 6 mL of the oral suspension containing 100 mg/mL) twice daily with single-entity ritonavir 100 mg twice daily is recommended.1

For the treatment of HIV-1 infection in antiretroviral-experienced adults without any substitutions associated with darunavir resistance, the recommended dosage of cobicistat-boosted darunavir is 800 mg of darunavir once daily in conjunction with 150 mg of cobicistat once daily.237 When fixed combination darunavir/cobicistat is used, adults should receive 1 tablet (800 mg of darunavir and 150 mg of cobicistat) once daily.

Darunavir is commercially available as a single entity and in various fixed-combination preparations containing additional antiretroviral agents.1,237,239 Refer to the full prescribing information for specific, distinct uses of the combination products.1,237,239 Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.1,237,239

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the preferred dosage of ritonavir-boosted darunavir is 800 mg of darunavir once daily with ritonavir 100 mg once daily.199 Alternatively, a dosage of 600 mg of darunavir twice daily with ritonavir 100 mg twice daily may be used.199 Ritonavir-boosted darunavir usually is used in conjunction with emtricitabine and tenofovir DF.199 PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 28 days, if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP), the usual adult dosage of ritonavir-boosted darunavir is 800 mg of darunavir once daily with ritonavir 100 mg once daily.198 Ritonavir-boosted darunavir usually is used in conjunction with emtricitabine and tenofovir DF.198 The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days.198 If the exposed individual seeks care more than 72 hours after the exposure, nPEP may not be recommended.198

Special Populations

Hepatic Impairment

No dosage adjustment is necessary for cobicistat-boosted or ritonavir-boosted darunavir in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1,237,239

Cobicistat-boosted darunavir should not be used in patients with severe hepatic impairment (Child-Pugh class C).237Ritonavir-boosted darunavir has not been evaluated but is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).237

Renal Impairment

Prior to initiation of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat), estimated creatinine clearance should be assessed.237,239 The manufacturer states that cobicistat-boosted darunavir should not be used in conjunction with tenofovir DF in patients with estimated creatinine clearance less than 70 mL/minute.237,239

Geriatric Patients

The manufacturers make no specific dosage recommendations in geriatric patients; however, caution should be exercised during administration and monitoring due to decreased hepatic function, concomitant disease, or other drug therapy in this patient population.1,237

Pregnant Females

If darunavir is used during pregnancy, it should be administered as ritonavir-boosted darunavir.202

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

The manufacturer states that a once-daily regimen of 800 mg of single-entity darunavir (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL once daily) with single-entity ritonavir 100 mg once daily should be considered during pregnancy only in females already stabilized on this once-daily regimen prior to pregnancy who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) and in whom a change to a twice-daily regimen may compromise tolerability or compliance.1 However, some experts state that once-daily regimens of ritonavir-boosted darunavir are not recommended in pregnant females.202

The manufacturer states that cobicistat-boosted darunavir should not be used in pregnancy.237

Contraindications

• Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir with drugs highly dependent on cytochrome P-450 (CYP) isoenzyme CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events.1,237,239
• Concomitant use of cobicistat-boosted darunavir with drugs that are CYP3A inducers which may lead to lower darunavir and cobicistat exposures and potential loss of efficacy and the development of resistance.237
• Examples of drugs contraindicated for administration with ritonavir-boosted darunavir or cobicistat-boosted darunavir include: alfuzosin, carbamazepine, phenobarbital, phenytoin, colchicine in patients with renal or hepatic impairment, rifampin, lurasidone, pimozide, dronedarone, ivabradine, ranolazine, dihydroergotamine (DHE), ergotamine, methylergonovine, St. John's wort ( Hypericum perforatum ), the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir), lomitapide, lovastatin, simvastatin, naloxegol, orally administered midazolam and triazolam, and sildenafil [Revatio®] for treatment of pulmonary arterial hypertension.1,237,239

Warnings/Precautions

Coadministration of Single-entity Darunavir with Ritonavir

Single-entity darunavir must be coadministered with ritonavir and food to achieve the desired antiviral effect.1 Failure to administer single-entity darunavir with ritonavir and food may result in a loss of efficacy of darunavir.1

Dermatologic Reactions

Severe skin reactions, sometimes accompanied by fever and/or increases in serum aminotransferase concentrations, have occurred in patients receiving ritonavir-boosted darunavir.1,237 Stevens-Johnson syndrome has been reported rarely;1,237 toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute, generalized exanthematous pustulosis also have been reported.1,237

Rash (usually of mild to moderate intensity) has occurred in 10.3% of patients receiving ritonavir-boosted darunavir; rash usually occurs during the first 4 weeks of therapy.1,237 Ritonavir-boosted darunavir was continued without interruption in most patients.1

Although rash was reported more frequently in antiretroviral-experienced patients receiving ritonavir-boosted darunavir and raltegravir than in those receiving ritonavir-boosted darunavir without raltegravir or raltegravir without ritonavir-boosted darunavir, rash that was considered drug related occurred at similar rates in all 3 groups; rash generally was mild to moderate in severity and did not limit therapy or require discontinuance.1

Ritonavir-boosted darunavir or cobicistat-boosted darunavir should be discontinued immediately if manifestations of severe skin reactions occur (e.g., severe rash, rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).1,237

Sulfonamide Sensitivity

Darunavir contains a sulfonamide moiety, which may cause allergic-type reactions in certain susceptible individuals.1,237 In clinical studies evaluating ritonavir-boosted darunavir, the incidence of rash in patients with a history of sulfonamide sensitivity was similar to that in patients without a history of sulfonamide sensitivity.1,237

Ritonavir-boosted darunavir and cobicistat-boosted darunavir should be used with caution in patients with known hypersensitivity to sulfonamide-containing drugs.1,237

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has occurred in patients receiving ritonavir-boosted darunavir in clinical studies.1,237 Patients with preexisting liver dysfunction, including HIV-infected patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV), have an increased risk for liver function abnormalities.1,237 There have been postmarketing reports of liver injury (in some cases fatal) in patients receiving ritonavir-boosted darunavir;1,237 liver injury generally has occurred in patients with advanced HIV infection who were receiving multiple concomitant drugs, were coinfected with HBV or HCV, and/or were developing immune reconstitution syndrome.1,237

Appropriate laboratory tests should be performed to evaluate hepatic function prior to and periodically during treatment with ritonavir-boosted darunavir or cobicistat-boosted darunavir.1,237 Increased AST/ALT monitoring should be considered, especially during the first several months of therapy, in patients with hepatitis, cirrhosis, or elevated aminotransferase values prior to therapy.1,237

Renal Effects

Cobicistat decreases estimated creatinine clearance by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function; this effect should be considered when interpreting changes in estimated creatinine clearance in patients receiving cobicistat-boosted darunavir.237,239 This is particularly important in those needing creatinine clearance monitoring because of a medical condition or other concomitant drugs.237,239

Estimated creatinine clearance should be assessed prior to initiating cobicistat-boosted darunavir.237,239 Although cobicistat may cause only modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, the patient should be closely monitored for renal safety if there is an increase in serum creatinine of more than 0.4 mg/dL from baseline during cobicistat-boosted darunavir therapy.237,239

The manufacturer states that dosage recommendations are not available for drugs that require dosage adjustments in patients with renal impairment who are receiving cobicistat-boosted darunavir.237,239 Therefore, alternative drugs that do not require dosage adjustments based on renal impairment should be considered in patients receiving cobicistat-boosted darunavir.237,239

New-onset or worsening renal impairment, including acute renal failure and Fanconi syndrome, has been reported in patients receiving cobicistat in an antiretroviral regimen that also included tenofovir disoproxil fumarate (tenofovir DF).237,239 Concomitant use of cobicistat-boosted darunavir and tenofovir DF is not recommended in patients with estimated creatinine clearances less than 70 mL/minute or in patients who are receiving (or recently received) a nephrotoxic agent.237,239 Whenever cobicistat-boosted darunavir and tenofovir DF are used concomitantly, urine glucose and urine protein should be documented at baseline and estimated creatinine clearance, urine glucose, and urine protein should be routinely monitored throughout concomitant therapy.237,239 In addition, serum phosphorus should be monitored in those with or at risk for renal impairment.237,239

Interactions

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

Concomitant use of ritonavir-boosted darunavir or cobicistat-boosted darunavir with certain drugs is contraindicated or requires particular caution.1,237,239 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).1,237,239 Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted darunavir or cobicistat-boosted darunavir and possible development of resistance.1,237,239 Because ritonavir and cobicistat are inhibitors of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern.1,237,239 However, concomitant use of cobicistat-boosted darunavir with other drugs may result in different drug interactions than those observed or expected with ritonavir-boosted darunavir because of complex or unknown mechanisms of drug interactions.237,239

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

Potential drug interactions should be considered prior to and during use of ritonavir-boosted darunavir or cobicistat-boosted darunavir.1,237,239 Patients should be monitored for adverse effects associated with other drugs used concomitantly with ritonavir-boosted darunavir or cobicistat-boosted darunavir.1,237,239

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV PIs; diabetic ketoacidosis has occurred.1,237 It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents).1,237

Immune Reconstitution Syndrome

Patients receiving antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy.1,237 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]);1,237 this may necessitate further evaluation and treatment.1,237

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

Fat Redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance have been reported in patients receiving antiretroviral therapy.1,237 The mechanisms and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.1,237

Hemophilia A and B

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in patients with hemophilia A or B receiving HIV PIs.1,237 Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.1,237

HIV Resistance

Potential for cross-resistance among PIs not evaluated in patients receiving ritonavir-boosted darunavir.1 The possible effect of ritonavir-boosted darunavir therapy on subsequent therapy with other PIs is unknown.1

Use in Pediatric Patients Below 3 Years of Age

The use of single-agent darunavir in combination with ritonavir is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in animal studies.1

Specific Populations

Pregnancy

Cobicistat-boosted darunavir should not be initiated in pregnant individuals, due to significantly reduced exposures to darunavir and cobicistat in the second and third trimesters.237 An alternative regimen is recommended for individuals who become pregnant during therapy.237

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in females exposed to darunavir during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1

The overall risk of birth defects with first-trimester exposure for ritonavir-boosted darunavir and cobicistat-boosted darunavir were not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1,237 Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease.1,237 The rate of miscarriage is not reported in the APR.1,237

Lactation

It is not known whether darunavir, ritonavir, or cobicistat is distributed into human milk;1,209,237 darunavir and cobicistat are distributed into milk in rats.1,237

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.1,237

Females and Males of Reproductive Potential

Use of darunavir may reduce the efficacy of combined hormonal contraceptives and the progestin-only pill.1 Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception.1 For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.1 No data are available to make recommendations regarding coadministration with other hormonal contraceptives.237

Pediatric Use

Darunavir is not recommended in pediatric patients younger than 3 years of age since toxicity and mortality have been observed in juvenile rats given darunavir.1,237

Safety, pharmacokinetic profile, and efficacy of ritonavir-boosted darunavir have been evaluated in antiretroviral-naïve and antiretroviral-experienced pediatric patients 3 years to less than 18 years of age weighing at least 10 kg.1 Adverse effects reported in pediatric patients were similar to those reported in adults.1

Safety and efficacy of cobicistat-boosted darunavir was established in pediatric patients weighing at least 40 kg. 237,239 Use of cobicistat-boosted darunavir in this patient group is supported by evidence from studies in adults, with additional pharmacokinetic, safety, and virologic data from a study of the components of Prezcobix^® in pediatric subjects 12 to less than 18 years of age.237

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently to ritonavir-boosted darunavir or cobicistat-boosted darunavir than younger adults.1,237 Appropriate caution should be exercised in administration and monitoring because of age-related decreases in hepatic function and potential for concomitant disease and drug therapy.1,237

Pharmacokinetics of darunavir do not differ substantially over an age range of 18-75 years of age.1

Hepatic Impairment

Pharmacokinetics of ritonavir-boosted darunavir are not altered in patients with mild to moderate hepatic impairment (Child-Pugh class A or B);1 dosage adjustments are not needed in such individuals.1 Because darunavir pharmacokinetics have not been evaluated in patients with severe hepatic impairment, ritonavir-boosted darunavir is not recommended in patients with severe hepatic impairment.1

Pharmacokinetics of cobicistat-boosted darunavir have not been evaluated in patients with mild to moderate hepatic impairment (Child-Pugh class A or B);237 there were no clinically important pharmacokinetic changes when cobicistat was used alone in individuals with mild or moderate hepatic impairment.237,239 Based on recommendations for ritonavir-boosted darunavir, dosage adjustments of cobicistat-boosted darunavir are not needed in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).237 Pharmacokinetics of cobicistat-boosted darunavir or cobicistat alone have not been evaluated in patients with severe hepatic impairment (Child-Pugh class C), and cobicistat-boosted darunavir is not recommended in such patients.237

Limited data indicate that darunavir exposure is not altered in HIV-infected patients coinfected with HBV or HCV.1

The risk of liver function abnormalities, including severe hepatic adverse effects, is increased in patients with preexisting hepatic impairment (e.g., HBV or HCV infection).1,237

Liver function should be monitored during the first several months of treatment with ritonavir-boosted darunavir when the drug is used in patients with underlying chronic hepatitis or cirrhosis or in patients with pretreatment elevated liver enzymes.1

If there is evidence of new or worsening liver disease (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly, clinically important increases in hepatic enzyme concentrations), interruption or discontinuance of ritonavir-boosted darunavir or cobicistat-boosted darunavir should be considered.1,237

Renal Impairment

Pharmacokinetics of darunavir are not altered in patients with moderate renal impairment (creatinine clearance 30-60 mL/minute).1 Data are not available on darunavir pharmacokinetics in patients with severe renal impairment or end-stage renal disease.1 Because renal clearance of darunavir is limited, decreased clearance of the drug is not expected in patients with renal impairment.1

Cobicistat-boosted darunavir has not been studied in individuals with renal impairment.237 Cobicistat has been shown to decrease estimated creatinine clearance without affecting renal glomerular function.237 Prior to initiation of cobicistat-boosted darunavir (administered as fixed-combination darunavir/cobicistat or, alternatively, as single-entity darunavir and single-entity cobicistat), estimated creatinine clearance should be assessed.237,239 Cobicistat-boosted darunavir should not be used in conjunction with tenofovir DF in patients with estimated creatinine clearance less than 70 mL/minute. 237,239

Darunavir, ritonavir, and cobicistat are highly bound to plasma proteins, and the drugs are unlikely to be removed by hemodialysis or peritoneal dialysis.1,237

Common Adverse Effects

Adverse effects of at least moderate intensity (greater than or equal to Grade 2) reported in more than 5% of patients receiving ritonavir-boosted or cobicistat-boosted darunavir in conjunction with other antiretrovirals are diarrhea, nausea, vomiting, abdominal pain, headache, and rash.1,237

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

The following drug interactions are based on studies using ritonavir-boosted darunavir or studies using cobicistat alone.1,237,239 Drug interaction studies are not available to date using cobicistat-boosted darunavir administered either as the fixed combination containing darunavir and cobicistat (darunavir/cobicistat) or as single-entity darunavir given with single-entity cobicistat.237,239

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Darunavir, ritonavir, and cobicistat inhibit cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6; potential pharmacokinetic interaction with drugs metabolized by CYP3A or CYP2D6 (altered metabolism of drug metabolized by CYP3A or CYP2D6).1,237,239 Darunavir, ritonavir, and cobicistat are metabolized by CYP3A.1,237,239 Potential pharmacokinetic interactions with drugs that induce CYP3A (increased clearance of darunavir, ritonavir, or cobicistat, which may lead to loss of antiretroviral efficacy and development of resistance); potential pharmacokinetic interactions with drugs that inhibit CYP3A (increased plasma concentrations of darunavir, ritonavir, or cobicistat).1,237,239

Caution is advised if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with substrates, inhibitors, or inducers of CYP3A; such drug interactions may lead to severe, life-threatening, or fatal events due to increased exposures of certain drugs, adverse effects due to increased exposures to ritonavir-boosted or cobicistat-boosted darunavir, or loss of therapeutic effect and possible development of resistance to darunavir.1,237,239 ,

Cobicistat is metabolized by CYP2D6 to a minor extent.237,239 Based on in vitro data, cobicistat is not expected to induce CYP1A2 or 2B6; based on in vivo data, cobicistat is not expected to induce CYP3A to a clinically important extent.237,239 It is not known whether cobicistat induces CYP2C9 or 2C19, but any effect is expected to be minimal based on in vitro CYP3A induction data.237,239

Drugs Affecting or Affected by Transport Systems

Drugs Affected by P-glycoprotein Transport

Ritonavir-boosted darunavir is an inhibitor of the P-glycoprotein (P-gp) transport system;1 cobicistat also is a P- gp inhibitor.237,239 Potential pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted darunavir is used with drugs transported by P-gp (increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effects and may be associated with adverse effects).1,237,239

In vitro data suggests that darunavir may be a P-gp substrate; potential pharmacokinetic interaction if darunavir is used concomitantly with drugs that inhibit P-gp (decreased clearance of darunavir and ritonavir, leading to increased plasma concentrations).1

Drugs Affecting or Affected by Other Membrane Transporters

Cobicistat inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1 and 1B3.237,239 Potential pharmacokinetic interactions if cobicistat-boosted darunavir is used concomitantly with drugs that are substrates of BCRP, OATP1B1, or OATP1B3 (increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effects and may be associated with adverse effects).237,239

Based on in vitro data, cobicistat is not expected to induce multidrug-resistance gene (MDR) 1 to a clinically important extent.237,239 It is not known whether cobicistat induces uridine diphosphate-glucuronosyl transferase (UGT) 1A1, but any effect is expected to be minimal based on in vitro CYP3A induction data.237,239

Alfuzosin

Concomitant use of alfuzosin and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated because of the potential for serious and/or life-threatening reactions (e.g., hypotension).1,237,239

Antiarrhythmic Agents

Possible pharmacokinetic interactions if certain antiarrhythmic agents (e.g., amiodarone, disopyramide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of the antiarrhythmic agent).1,237,239

If ritonavir-boosted or cobicistat-boosted darunavir and antiarrhythmic agents are used concomitantly, clinical monitoring is recommended.1,237,239

Dronedarone

Concomitant use of dronedarone and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated due to the potential for serious and life-threatening arrhythmias.1,237,239

Anticoagulants

Apixaban

Pharmacokinetic interactions if apixaban is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased apixaban concentrations).1,237,239 Refer to the prescribing information for apixaban for dosing instructions for concomitant use of P-gp and strong CYP3A inhibitors.1,237,239

Dabigatran

Pharmacokinetic interactions if dabigatran is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased dabigatran concentrations).1,237,239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with dabigatran is based upon the indication, effects of concomitant P-gp inhibitors on dabigatran concentrations, and renal impairment.1,237,239

Refer to the prescribing information for dabigatran for specific recommendations regarding concomitant use.1,237,239 Clinical monitoring is recommended when a direct oral anticoagulant not affected by CYP3A4 but transported by P-gp like dabigatran is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237,239

Edoxaban

Possible pharmacokinetic interactions if edoxaban is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased edoxaban concentrations).1,237,239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with edoxaban is based upon the indication, effects of comcomitant P-gp inhibitors on dabigatran concentrations, and renal impairment.1,237,239

Refer to the prescribing information for edoxaban for dosing instructions for the concomitant use of ritonavir-boosted or cobicistat-boosted darunavir.1,237,239 Clinical monitoring is recommended when a direct oral anticoagulant not affected by CYP3A4 but transported by P-gp like edoxaban is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237,239

Rivaroxaban

Possible pharmacokinetic interactions if rivaroxaban is used concomitantly with ritonavir-boosted or cobicistat- boosted darunavir (increased rivaroxaban concentrations and increased risk of bleeding).1,237,239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and rivaroxaban is not recommended due to an increased risk of bleeding.1,237,239

Warfarin

Pharmacokinetic interactions if warfarin is used concomitantly with ritonavir-boosted darunavir (decreased warfarin concentrations; no change in darunavir concentrations).1 The effect of cobicistat-boosted darunavir on warfarin concentrations is not known.237,239

If warfarin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the international normalized ratio (INR) should be monitored.1,237,239

Anticonvulsants

Carbamazepine

Pharmacokinetic interactions if carbamazepine is used concomitantly with ritonavir-boosted darunavir (increased carbamazepine concentrations; no change in darunavir concentrations).1 Dosage adjustments are not needed when initiating concomitant therapy with ritonavir-boosted darunavir and carbamazepine.1 However, plasma concentrations of carbamazepine should be monitored and dosage of the anticonvulsant adjusted to achieve the desired clinical effect.1

Pharmacokinetic interactions if carbamazepine is used concomitantly with cobicistat-boosted darunavir (increased carbamazepine concentrations; decreased cobicistat concentrations; effect on darunavir concentrations unknown, but substantially decreased darunavir concentrations and loss of therapeutic effect and development of resistance are possible).237,239 Concomitant use of cobicistat-boosted darunavir and carbamazepine is contraindicated.237,239

Eslicarbazepine

Concomitant use of cobicistat-boosted darunavir and eslicarbazepine may decrease cobicistat plasma concentrations, but effects on darunavir concentrations are unknown.237,239 An alternative anticonvulsant or alternative antiretroviral therapy should be considered; if concomitant use of eslicarbazepine and cobicistat-boosted darunavir is necessary, the patient should be monitored for lack or loss of antiretroviral response.237,239

Oxcarbazepine

Pharmacokinetic interactions if oxcarbazepine is used concomitantly with cobicistat-boosted darunavir (decreased cobicistat concentrations; effect on darunavir concentrations unknown).237,239 An alternative anticonvulsant or alternative antiretroviral should be considered; if concomitant use of oxcarbazepine and cobicistat-boosted darunavir is necessary, the patient should be monitored for lack or loss of antiretroviral response.237,239

Phenobarbital and Phenytoin

Possible pharmacokinetic interactions if phenobarbital or phenytoin is used concomitantly with cobicistat-boosted darunavir (decreased cobicistat and darunavir concentrations expected and may result in loss of therapeutic effect and development of resistance).237,239 Concomitant use of cobicistat-boosted darunavir and phenobarbital or phenytoin is contraindicated.237,239

Possible pharmacokinetic interactions if phenobarbital or phenytoin is used concomitantly with ritonavir-boosted darunavir (decreased concentrations of the anticonvulsant; no change in darunavir concentrations).1 If ritonavir-boosted darunavir is used concomitantly with phenobarbital or phenytoin, plasma concentrations of the anticonvulsant should be monitored.1

Antifungal Agents

Itraconazole

Possible pharmacokinetic interactions if itraconazole is used concomitantly with ritonavir-boosted or cobicistat- boosted darunavir (increased itraconazole, darunavir, and cobicistat concentrations).1,237,239

If itraconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for itraconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects and consideration given to monitoring itraconazole plasma concentrations.1,237 High itraconazole dosage (exceeding 200 mg daily) is not recommended in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.1

Isavuconazole

Possible pharmacokinetic interactions if isavuconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased isavuconazole, darunavir, and cobicistat concentrations).1,237

If isavuconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for isavuconazole-, darunavir-, and cobicistat-associated adverse effects.1,237

Ketoconazole

Pharmacokinetic interactions if ketoconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased ketoconazole, darunavir, and cobicistat concentrations).1,237,239

If ketoconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects.1,237 Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted darunavir.1

Posaconazole

Possible pharmacokinetic interactions if posaconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased darunavir and cobicistat concentrations; posaconazole concentrations may be increased).1,237

If posaconazole and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly, patients should be monitored for increased posaconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects.1,237

Voriconazole

Possible pharmacokinetic interactions if voriconazole is used concomitantly with ritonavir-boosted darunavir (decreased voriconazole concentrations).1 Data are not available regarding concomitant use of voriconazole and cobicistat-boosted darunavir.237,239

Concomitant use of voriconazole and ritonavir-boosted or cobicistat-boosted darunavir is not recommended unless potential benefits outweigh risks. 1,237,239

Antimalarial Agents

Artemether and Lumefantrine

Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and ritonavir-boosted darunavir decreases plasma concentrations and area under the concentration-time curve (AUC) of artemether and the active metabolite of artemether (dihydroartemisinin), increases plasma concentrations and AUC of lumefantrine, and has no clinically important effect on plasma concentrations or AUC of darunavir.1 The effect of concomitant use of artemether/lumefantrine and cobicistat-boosted darunavir on lumefantrine and artemether concentrations is not known.237

If artemether/lumefantrine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the patient should be monitored for antimalarial efficacy and lumefantrine toxicity (e.g., QT interval prolongation).1,237 Although dosage adjustments are not needed when artemether/lumefantrine is used concomitantly with ritonavir-boosted darunavir, the drugs should be used concomitantly with caution.1

Antimycobacterial Agents

Rifabutin

Pharmacokinetic interactions if rifabutin is used concomitantly with ritonavir-boosted darunavir (increased rifabutin concentrations; increased darunavir concentrations).1 Possible pharmacokinetic interactions if rifabutin is used concomitantly with cobicistat-boosted darunavir (increased rifabutin concentrations expected; effects on darunavir and cobicistat concentrations unknown).237,239

If rifabutin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, dosage of the antimycobacterial agent should be reduced (e.g., 150 mg once every other day; further dosage reduction may be necessary) and increased monitoring for rifabutin-associated adverse effects (e.g., neutropenia, uveitis) is warranted.1,237,239

Rifampin

Possible pharmacokinetic interactions if rifampin is used concomitantly with ritonavir-boosted or cobicistat- boosted darunavir (substantially decreased darunavir concentrations) with possible loss of antiretroviral effects.1,237,239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and rifampin is contraindicated.1,237,239

Rifapentine

Possible pharmacokinetic interactions if rifapentine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (decreased darunavir concentrations).1,237 Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and rifapentine is not recommended.1,237

Antineoplastic Agents

Possible pharmacokinetic interactions if certain antineoplastic agents (e.g, dasatinib, irinotecan, nilotinib, vinblastine, vincristine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased antineoplastic agent concentrations).1,237,239

If dasatinib or nilotinib is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, reduction of the dosage of the antineoplastic agent may be needed.1,237,239

If irinotecan is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, ritonavir-boosted or cobicistat-boosted darunavir should be discontinued at least 1 week prior to starting irinotecan therapy.1,237 Do not use irinotecan concomitantly with ritonavir-boosted or cobicistat-boosted darunavir unless there are no therapeutic alternatives available.1,237

If vincristine or vinblastine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, consideration should be given to temporarily withholding the antiretroviral regimen in patients who develop clinically important hematologic or GI adverse effects.1,237 If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to changing to a different antiretroviral regimen that does not include a CYP3A or P-gp inhibitor.1,237

Antipsychotic Agents

Lurasidone

Potential for serious and/or life-threatening adverse effects if lurasidone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237,239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and lurasidone is contraindicated.1,237,239

Perphenazine, Risperidone, and Thioridazine

Possible pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with perphenazine, risperidone, or thioridazine (increased plasma concentrations of the antipsychotic agent).237,239

If perphenazine, risperidone, or thioridazine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, a reduced dosage of the antipsychotic may be needed.237,239

Pimozide

Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias) if pimozide is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and pimozide is contraindicated.1,237,239

Quetiapine

Pharmacokinetic interactions expected if quetiapine is used concomitantly with ritonavir-boosted or cobicistat- boosted darunavir (increased quetiapine concentrations).1,237,239

Alternative antiretroviral therapy should be considered.237,239 If ritonavir-boosted or cobicistat-boosted darunavir is necessary in a patient receiving a stable dosage of quetiapine, the quetiapine dosage should be reduced to one-sixth of the original dosage and the patient monitored for quetiapine efficacy and adverse effects.237,239

Upon initiation of quetiapine in patients taking ritonavir-boosted or cobicistat-boosted darunavir, consult quetiapine prescribing information for initial dosing and titration recommendations.237,239

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects between darunavir and enfuvirtide.1

Maraviroc

Pharmacokinetic interactions if maraviroc is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased maraviroc plasma concentrations and AUC).1,237,239 If maraviroc is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the recommended maraviroc dosage is 150 mg twice daily.1,237,239

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of dolutegravir and ritonavir-boosted darunavir does not appear to have a clinically important effect on the pharmacokinetics of either drug.1 Clinically important drug interactions are not expected if cobicistat-boosted darunavir is used with dolutegravir.237

Dosage adjustments are not needed if cobicistat-boosted darunavir is used concomitantly with dolutegravir.1

Raltegravir

No clinically important effects on pharmacokinetics of ritonavir-boosted or cobicistat-boosted darunavir when raltegravir is given concomitantly.1,237 Dosage adjustments are not necessary if raltegravir and ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly.1

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

No in vitro evidence of antagonistic antiretroviral effects between darunavir and NNRTIs, including delavirdine, efavirenz, etravirine, nevirapine, and rilpivirine.1

Efavirenz

Concomitant use of ritonavir-boosted darunavir (darunavir 300 mg and ritonavir 100 mg twice daily) and efavirenz (600 mg once daily) increased the AUC of efavirenz by 21% and decreased the AUC of darunavir by 13%.1 If efavirenz is used concomitantly with ritonavir-boosted darunavir, dosage adjustments are not necessary.1

Concomitant use of efavirenz and cobicistat-boosted darunavir is not recommended.237,239

Etravirine

Safety and efficacy of concomitant use of etravirine and ritonavir-boosted darunavir was established in phase 3 clinical studies.1 Concomitant use of etravirine and cobicistat-boosted darunavir may result in decreased cobicistat concentrations; the effects on darunavir pharmacokinetics are not known.237,239

If etravirine is used with ritonavir-boosted darunavir, dosage adjustments are not needed.1

Concomitant use of etravirine and cobicistat-boosted darunavir is not recommended due to the potential loss of therapeutic effect and resistance to darunavir.237,239

Nevirapine

Pharmacokinetic interactions if nevirapine is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of nevirapine and darunavir).1 Concomitant use of nevirapine and cobicistat-boosted darunavir may result in decreased cobicistat concentrations; the effects on darunavir pharmacokinetics are not known.237,239

If nevirapine and ritonavir-boosted darunavir are used concomitantly, dosage adjustments are not needed.1

Concomitant use of nevirapine and cobicistat-boosted darunavir is not recommended;237,239 possible loss of therapeutic effect and development of resistance to darunavir.237,239

Rilpivirine

Clinically relevant interactions have not been observed and are not expected with concomitant rilpivirine and cobicistat-boosted darunavir.237

If rilpivirine and ritonavir-boosted darunavir are used concomitantly, dosage adjustments are not needed.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

No in vitro evidence of antagonistic antiretroviral effects between darunavir and NRTIs, including abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine.1

Pharmacokinetic interactions are not expected if abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, lamivudine, or zidovudine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1 237 Dosage adjustments are not needed if ritonavir-boosted darunavir is used concomitantly with abacavir, emtricitabine, lamivudine, stavudine, or zidovudine.1

Didanosine

Concomitant use of didanosine delayed-release capsules and ritonavir-boosted or cobicistat-boosted darunavir does not affect the pharmacokinetics of didanosine or darunavir.1,237 Dosage adjustments are not necessary,1 but didanosine doses should be given (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food) or cobicistat-boosted darunavir (with food).1,237

Tenofovir Disoproxil Fumarate

Pharmacokinetic interactions if tenofovir disoproxil fumarate (tenofovir DF) is used concomitantly with ritonavir-boosted darunavir (increased tenofovir plasma concentrations and AUC; increased darunavir plasma concentrations and AUC).1

The manufacturer of darunavir states that the usual dosage of ritonavir-boosted darunavir can be used concomitantly with the usual dosage of tenofovir DF.1

If cobicistat-boosted darunavir is used concomitantly with tenofovir DF, baseline estimated creatinine clearance, urine glucose, and urine protein should be assessed and patients should be monitored for tenofovir toxicity.237,239 Concomitant use of cobicistat-boosted darunavir with tenofovir DF is not recommended in patients with estimated creatinine clearance less than 70 mL/minute.237,239

HIV Protease Inhibitors (PIs)

Concomitant use of ritonavir-boosted darunavir with other HIV PIs (except atazanavir) has not been studied.1 The manufacturer of darunavir states that concomitant use with other HIV PIs is not recommended.1

No in vitro evidence of antagonistic antiretroviral effects between darunavir and amprenavir (active metabolite of fosamprenavir), atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir.1,237

Atazanavir

Concomitant use of atazanavir 300 mg once daily with ritonavir-boosted darunavir (darunavir 400 mg and ritonavir 100 mg twice daily [dosage differs from usually recommended dosage]) results in plasma concentrations of atazanavir that are similar to those attained with ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg once daily) and plasma concentrations of darunavir similar to those attained without atazanavir.1

The manufacturer of darunavir states that concomitant use of darunavir and ritonavir-boosted atazanavir is not recommended.1

Indinavir

Concomitant use of ritonavir-boosted darunavir and indinavir results in increased peak plasma concentrations and AUCs of darunavir and indinavir.1

Appropriate dosages for concomitant use of ritonavir-boosted darunavir and indinavir are not established.1

Lopinavir

Concomitant use of ritonavir-boosted darunavir and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) results in substantially decreased concentrations of darunavir and no change in lopinavir concentrations.1

Concomitant use of lopinavir/ritonavir and ritonavir-boosted darunavir is not recommended; appropriate dosages for concomitant use with respect to safety and efficacy have not been established.1

Ritonavir

Pharmacokinetic interactions if ritonavir is used concomitant with darunavir (increased plasma concentration and AUC of darunavir).1 Low-dose ritonavir is a pharmacokinetic enhancer (pharmacokinetic booster), and is used in conjunction with darunavir for therapeutic advantage ( ritonavir-boosted darunavir).1

Saquinavir

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

Concomitant use of saquinavir and ritonavir-boosted darunavir is not recommended.1

Benzodiazepines

Possible pharmacokinetic interactions if certain benzodiazepines (e.g., diazepam, estazolam, midazolam, triazolam) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of the benzodiazepine).1,237,239

Clonazepam

Pharmacokinetic interactions if clonazepam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased clonazepam concentrations).237,239

If clonazepam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, clinical monitoring is recommended. 1,237,239

Diazepam

If diazepam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, diazepam dosage should be titrated, a lower diazepam dosage should be considered, and the patient should be monitored for adverse effects.1,237,239

Estazolam

If estazolam is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, estazolam dosage should be titrated, a lower estazolam dosage should be considered, and the patient should be monitored for adverse effects.1,237,239

Midazolam and Triazolam

Concomitant use of midazolam or triazolam with ritonavir-boosted or cobicistat-boosted darunavir potentially could result in serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1,237,239

Concomitant use of oral midazolam or triazolam with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.1,237,239

Concomitant use of parenteral midazolam and ritonavir-boosted or cobicistat-boosted darunavir should be undertaken with caution and in a monitored setting where respiratory depression and/or prolonged sedation can be managed.1,237,239 In addition, a reduced dosage of midazolam should be considered, especially if more than a single dose of midazolam is given.1,237,239

Beta-Adrenergic Blocking Agents

Possible pharmacokinetic interactions if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with carvedilol, metoprolol, or timolol (increased plasma concentrations of the β-adrenergic blocking agent).1 237

If carvedilol, metoprolol, or timolol is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, clinical monitoring of the patient is recommended and reduction of the dosage of the β-adrenergic blocking agent may be needed.1,237,239

Bosentan

Possible pharmacokinetic interactions if bosentan is used concomitantly with ritonavir-boosted darunavir (increased bosentan concentrations).1 Possible pharmacokinetic interactions if bosentan is used concomitantly with cobicistat-boosted darunavir (increased bosentan concentrations; decreased darunavir and cobicistat concentrations).237,239

In patients who have been receiving ritonavir-boosted or cobicistat-boosted darunavir for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1,237,239

In patients who have been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating ritonavir-boosted or cobicistat-boosted darunavir; after at least 10 days of ritonavir-boosted or cobicistat-boosted darunavir therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1,237,239

In patients switching from ritonavir-boosted darunavir to cobicistat-boosted darunavir, the current bosentan dosage should be maintained.237,239

Buspirone

Possible pharmacokinetic interactions if buspirone is used concomitantly with ritonavir-boosted or cobicistat- boosted darunavir (increased buspirone concentrations).1,237,239

If buspirone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, buspirone dosage should be titrated, a lower buspirone dosage should be considered, and the patient should be monitored for prolonged or adverse effects.1,237,239

Calcium-channel Blocking Agents

Possible pharmacokinetic interactions if certain calcium-channel blocking agents (e.g., amlodipine, felodipine, nicardipine, nifedipine, verapamil) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased concentrations of the calcium-channel blocking agent).1,237,239 These calcium-channel blocking agents should be used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir with caution; clinical monitoring of the patient is recommended.1

Possible pharmacokinetic interactions if diltiazem is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased diltiazem concentrations).1,237,239

Cobicistat

Pharmacokinetic interactions if cobicistat is used concomitantly with darunavir (increased plasma concentrations and AUC of darunavir).237,239 Cobicistat is a pharmacokinetic enhancer (pharmacokinetic booster) and is used in conjunction with darunavir for therapeutic advantage ( cobicistat-boosted darunavir).237,239

Colchicine

Potential pharmacokinetic interactions if colchicine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased colchicine concentrations).1,237,239

Concomitant use of colchicine and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated in patients with renal or hepatic impairment because of the potential for serious and/or life-threatening effects in such patients.1,237,239

When colchicine is used for treatment of gout flares in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, an initial colchicine dose of 0.6 mg should be given followed by 0.3 mg 1 hour later; the colchicine dose should be repeated no earlier than 3 days later.1,237,239

When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, colchicine dosage should be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1,237,239

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.1,237,239

Corticosteroids

Concomitant use of systemic dexamethasone or other systemic corticosteroids that induce CYP3A4 and ritonavir-boosted or cobicistat-boosted darunavir may result in decreased darunavir, ritonavir, or cobicistat concentrations and possible decreased antiretroviral efficacy, and alternative corticosteroids should be considered.1,237,239

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with corticosteroids that undergo CYP3A inhibition (via any route of administration) may increase exposure to the corticosteroid and the risk of Cushing's syndrome and adrenal suppression.1,237,239 Consider alternative corticosteroids whose pharmacokinetics are less affected by strong CYP3A inhibitors, which include beclomethasone, prednisone, and prednisolone, particularly for long-term use.1,237

Corticosteroids used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir that may result in increased plasma concentrations of the corticosteroid, include betamethasone, budesonide, ciclesonide, fluticasone, methylprednisolone, mometasone, and triamcinolone.1,237,239

Dextromethorphan

Pharmacokinetic interactions if dextromethorphan is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of dextromethorphan).1

Digoxin

Pharmacokinetic interactions if digoxin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased digoxin concentrations).1,237,239

If ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with digoxin, titrate the digoxin dose and monitor digoxin serum concentrations.1,237,239 The lowest dose of digoxin should be used to obtain the desired clinical effect.1

Ergot Alkaloids

Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) if ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237,239 Concomitant use of ergot alkaloids with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.1,237,239

Estrogens and Progestins

Pharmacokinetic interactions if oral contraceptives containing ethinyl estradiol and norethindrone are used concomitantly with ritonavir-boosted darunavir (decreased ethinyl estradiol and norethindrone concentrations).1 Concomitant use of darunavir may also reduce efficacy of contraceptives containing only progestins.1 Data are not available regarding concomitant use of oral contraceptives and cobicistat-boosted darunavir and possible effects on estrogen and progestin concentrations.237,239

Pharmacokinetic interactions if oral contraceptives containing drospirenone and ethinyl estradiol are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (decreased ethinyl estradiol and increased drospirenone concentrations).1,237,239 If ritonavir-boosted or cobicistat-boosted darunavir are used concomitantly with oral contraceptives containing drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.1,237,239

Additional or alternative nonhormonal methods of contraception should be used in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.1,237,239

GI Drugs

Antacids

Clinically important drug interactions are not expected if antacids are used concomitantly with cobicistat-boosted darunavir.237

Histamine H2-receptor Antagonists

No clinically important drug interactions are expected if histamine H2-receptor antagonists (e.g., famotidine) are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237

Dosage adjustments are not needed if histamine H2-receptor antagonists are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1

Proton-pump Inhibitors

Pharmacokinetic interactions if omeprazole is used concomitantly with ritonavir-boosted darunavir (decreased plasma concentrations of omeprazole; no change in plasma concentrations of darunavir).1 If ritonavir-boosted darunavir is used concomitantly with omeprazole, the patient should be monitored for decreased omeprazole efficacy; an increase in omeprazole dosage should be considered in patients whose symptoms are not well controlled, but omeprazole dosages exceeding 40 mg daily should be avoided.1

No clinically important drug interactions are expected if proton pump inhibitors (PPIs) are used concomitantly with cobicistat-boosted darunavir.237

HCV Antivirals

HCV Replication Complex Inhibitors

Elbasvir and Grazoprevir

Pharmacokinetic interactions expected if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with elbasvir/grazoprevir (resulting in increased concentrations of elbasvir and grazoprevir).1,237 Concomitant use of elbasvir/grazoprevir and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated due to the potential for increased alanine aminotransferase (ALT) levels.1,237

Glecaprevir and Pibrentasvir

Pharmacokinetic interactions expected if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with glecaprevir/pibrentasvir (resulting in increased concentrations of glecaprevir and pibrentasvir).1,237 Concomitant use of glecaprevir/pibrentasvir and ritonavir-boosted or cobicistat-boosted darunavir is not recommended.1,237

HMG-CoA Reductase Inhibitors

Pharmacokinetic interactions with HMG-CoA reductase inhibitors (statins) metabolized by CYP3A isoenzyme.1 Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and certain statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin) may increase plasma concentrations and AUC of the antilipemic agents and increase the risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.1,237,239

Atorvastatin

If atorvastatin is used concomitantly with ritonavir-boosted darunavir, atorvastatin dosage should not exceed 20 mg daily.1 Dosage of atorvastatin should be titrated carefully; the lowest necessary dosage should be used and the patient monitored for adverse effects.1

If atorvastatin is used concomitantly with cobicistat-boosted darunavir, atorvastatin should be initiated at the lowest dosage and titrated to the lowest necessary dosage, not to exceed 20 mg daily;237,239 the patient should be monitored for safety.237,239

Lovastatin

Concomitant use of lovastatin with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.,1,237,239

Pitavastatin

The effect of cobicistat-boosted darunavir on pitavastatin pharmacokinetics is not known.237 If pitavastatin is used concomitantly with cobicistat-boosted darunavir, pitavastatin should be initiated at the lowest dosage and titrated;237 the patient should be monitored for safety.237

Pravastatin

If pravastatin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, dosage of pravastatin should be titrated carefully and the lowest necessary dosage used with close monitoring for adverse effects.1,237

Rosuvastatin

If rosuvastatin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, dosage of rosuvastatin should be titrated carefully and the lowest necessary dosage used with close monitoring for adverse effects.1,237,239 If used concomitantly with cobicistat-boosted darunavir, dosage of rosuvastatin should not exceed 20 mg daily.237

Simvastatin

Concomitant use of simvastatin with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.1,237,239

Immunosuppressive Agents

Pharmacokinetic interactions with cyclosporine, everolimus, sirolimus, tacrolimus (increased concentrations of the immunosuppressive agent expected).1,237,239

If cyclosporine, sirolimus, or tacrolimus are used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, plasma concentrations of the immunosuppressive agent should be monitored.1,237,239

Concomitant use of everolimus and ritonavir-boosted or cobicistat-boosted darunavir is not recommended.1,237,239

Ivabradine

Concomitant use of ivabradine and ritonavir-boosted or cobicistat-boosted darunavir is expected to result in increased ivabradine concentrations, increasing the potential for serious or life threatening reactions.1,237

Concomitant use of ivabradine and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.1,237

Lomitapide

Concomitant use of lomitapide and ritonavir-boosted or cobicistat-boosted darunavir is expected to result in increased lomitapide concentrations, increasing the potential for marked increases in aminotransferase levels.1,237,239

Concomitant use of lomitapide and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.1,237,239

Macrolides

Clarithromycin

Pharmacokinetic interactions if clarithromycin is used concomitantly with ritonavir-boosted darunavir (increased clarithromycin concentrations).1 Modification of the usual dosage of clarithromycin is not necessary in those with normal renal function;1 however, clarithromycin dosage should be reduced by 50% in those with creatinine clearances of 30-60 mL/minute and reduced by 75% in those with creatinine clearances less than 30 mL/minute.1

Pharmacokinetic interactions if clarithromycin is used concomitantly with cobicistat-boosted darunavir (increased darunavir, cobicistat, and clarithromycin concentrations).237,239 An alternative anti-infective should be considered in patients receiving cobicistat-boosted darunavir.237,239

Erythromycin

Pharmacokinetic interactions if cobicistat-boosted darunavir is used concomitantly with erythromycin (increased darunavir, cobicistat, and erythromycin concentrations).237,239 An alternative anti-infective should be considered in patients receiving cobicistat-boosted darunavir.237,239

Opiate Agonists, Opiate Partial Agonists, and Opiate Antagonists

Buprenorphine

Pharmacokinetic interactions if buprenorphine or fixed combination of buprenorphine and naloxone is used concomitantly with ritonavir-boosted darunavir (increased norbuprenorphine concentrations and AUC).1 It is not known whether cobicistat-boosted darunavir affects the pharmacokinetics of buprenorphine or the fixed combination of buprenorphine and naloxone. 237,239

If buprenorphine or the fixed combination of buprenorphine and naloxone is used concomitantly with ritonavir-boosted darunavir, dosage adjustments are not needed but patients should be monitored.1

In patients receiving cobicistat-boosted darunavir, buprenorphine or the fixed combination of buprenorphine and naloxone should be initiated using the lowest possible dosage and carefully titrated to the desired therapeutic effect. 237,239 If initiating cobicistat-boosted darunavir in patients already receiving buprenorphine or the fixed combination of buprenorphine and naloxone, dosage adjustments of buprenorphine or the fixed combination of buprenorphine and naloxone may be needed and the patient should be clinically monitored.237,239

Fentanyl

Possible pharmacokinetic interactions if fentanyl is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased fentanyl concentrations).1,237,239

If fentanyl is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, the patient should be carefully monitored for therapeutic and adverse effects of fentanyl, including potentially fatal respiratory depression.1,237,239

Methadone

Pharmacokinetic interactions if methadone is used concomitantly with ritonavir-boosted darunavir (decreased methadone concentrations).1 Adjustment of methadone dosage is not needed when ritonavir-boosted darunavir is initiated;1 however, patients should be closely monitored for opioid withdrawal since maintenance dosage of methadone may need to be adjusted in some patients.1

It is not known whether cobicistat-boosted darunavir affects methadone pharmacokinetics.237,239 In patients receiving cobicistat-boosted darunavir, methadone should be initiated using the lowest possible dosage and carefully titrated to the desired therapeutic effect.237,239 If cobicistat-boosted darunavir is initiated in a patient already receiving methadone, dosage adjustments of methadone may be needed and the patient should be clinically monitored.237,239

Oxycodone

Possible pharmacokinetic interactions if oxycodone is used concomitantly with cobicistat-boosted or ritonavir-boosted darunavir.1,237 If the medications are used concomitantly, the patient should be carefully monitored for therapeutic and adverse effects of oxycodone, including potentially fatal respiratory depression.1,237

Naloxegol

Pharmacokinetic interactions expected, resulting in increased naloxegol concentrations if naloxegol is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237 Concomitant use of naloxegol with ritonavir-boosted or cobicistat-boosted darunavir is contraindicated due to the potential for precipitating opioid withdrawal symptoms.1,237

Tramadol

Pharmacokinetic interactions if tramadol is used concomitantly with cobicistat-boosted darunavir (increased tramadol concentrations).1,237,239 If tramadol is used concomitantly with cobicistat-boosted darunavir, decreased tramadol dosage may be needed.1,237,239

Phosphodiesterase Type 5 Inhibitors

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) is expected to result in substantially increased plasma concentrations of the PDE5 inhibitor and increase the risk of adverse effects associated with these agents (e.g., hypotension, visual disturbances, priapism, syncope).1,237,239

Avanafil

Concomitant use of avanafil and ritonavir-boosted or cobicistat-boosted darunavir is not recommended.1,237,239

Sildenafil

Concomitant use of sildenafil (Revatio^®) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated in patients receiving ritonavir-boosted or cobicistat-boosted darunavir.1,237,239 Safe and effective dosages for concomitant use of the drugs have not been established.1

If sildenafil is used for the treatment of erectile dysfunction in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, sildenafil dosage should not exceed 25 mg once every 48 hours and the patient should be closely monitored for sildenafil-related adverse effects.1 237,239

Tadalafil

If tadalafil (Adcirca^®) is indicated for the treatment of PAH in patients who have been receiving ritonavir-boosted or cobicistat-boosted darunavir for at least 1 week, tadalafil should be initiated at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1,237,239 Ritonavir-boosted or cobicistat-boosted darunavir should not be initiated in patients receiving tadalafil for the treatment of PAH; tadalafil therapy should be discontinued at least 24 hours prior to initiating ritonavir-boosted or cobicistat-boosted darunavir.1,237,239 After at least 1 week, tadalafil may be resumed at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1,237,239 In patients switching from ritonavir-boosted darunavir to cobicistat-boosted darunavir, the current tadalafil dosage should be maintained.237,239

If tadalafil is used for the treatment of erectile dysfunction in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, tadalafil dosage should not exceed 10 mg once every 72 hours and the patient should be closely monitored for tadalafil-related adverse effects.1,237,239

Vardenafil

If vardenafil is used for the treatment of erectile dysfunction in patients receiving ritonavir-boosted or cobicistat-boosted darunavir, vardenafil dosage should not exceed 2.5 mg once every 72 hours and the patient should be closely monitored for vardenafil-associated adverse effects.1,237

Platelet Aggregation Inhibitors

Clopidogrel

Pharmacokinetic interaction expected if clopidogrel is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (decreased clopidogrel active metabolite concentrations).1,237,239 Concomitant use of clopidogrel with ritonavir-boosted or cobicistat-boosted darunavir is not recommended due to potential decreases in the antiplatelet activity of clopidogrel.1,237,239

Prasugrel

The active metabolite concentrations of prasugrel are not affected when prasugrel is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237,239 No dosage adjustments are needed when prasugrel is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.1,237,239

Ticagrelor

Pharmacokinetic interaction expected if ticagrelor is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased ticagrelor concentrations expected).1,237,239 Concomitant use of ticagrelor with ritonavir-boosted or cobicistat-boosted darunavir is not recommended.1,237,239

Ranolazine

Potential for serious and/or life-threatening adverse effects if ritonavir-boosted or cobicistat-boosted darunavir is used concomitantly with ranolazine.1,237

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir and ranolazine is contraindicated.1,237,239

St. John's Wort

Potential pharmacokinetic interactions with St. John's wort (Hypericum perforatum) (decreased darunavir concentrations); potential for loss of virologic response.1,237,239 Concomitant use of St. John's wort and ritonavir-boosted or cobicistat-boosted darunavir is contraindicated.1,237,239

Salmeterol

Possible pharmacokinetic interactions if salmeterol is used concomitantly with ritonavir-boosted or cobicistat- boosted darunavir (increased salmeterol concentrations)1,237,239 and increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia.1,237,239 Concomitant use of salmeterol and ritonavir-boosted or cobicistat-boosted darunavir is not recommended.1,237,239

Selective Serotonin-reuptake Inhibitors

Pharmacokinetic interactions if paroxetine or sertraline is used concomitantly with ritonavir-boosted darunavir (decreased concentrations and AUCs of the selective serotonin-reuptake inhibitor [SSRI]; no change in darunavir concentrations).1 Dosage of the SSRI should be titrated based on clinical response.1 If ritonavir-boosted darunavir is initiated in a patient receiving a stable dosage of paroxetine or sertraline, the patient should be monitored for clinical response.1

Possible pharmacokinetic interactions if paroxetine or sertraline is used concomitantly with cobicistat-boosted darunavir (effect on SSRI concentrations not known). 237,239 Dosage of the SSRI should be carefully titrated based on clinical response using the lowest possible initial or maintenance dosage.237,239 Clinical monitoring of antidepressant response is recommended.237,239

Trazodone

Possible pharmacokinetic interactions if trazodone is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of trazodone);1,237,239 nausea, dizziness, hypotension, and syncope may occur.1 Lowest effective dosage of trazodone should be used and patients monitored for adverse CNS and cardiovascular effects.1,237,239

Tricyclic Antidepressants (TCAs)

Potential pharmacokinetic interactions if amitriptyline, desipramine, doxepin, imipramine, or nortriptyline is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of the TCA);1,237,239 possible increased risk of adverse effects (e.g., nausea, dizziness, hypotension, syncope).1

The lowest possible dosage of the TCA should be used in patients receiving ritonavir-boosted or cobicistat-boosted darunavir and dosage of the TCA titrated based on clinical assessment and/or plasma TCA concentrations.237,239

Urinary Antispasmodics

Pharmacokinetic interactions are expected if fesoterodine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of fesoterodine).1,237 When fesoterodine is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, do not exceed a fesoterodine dosage of 4 mg once daily.1,237

Pharmacokinetic interactions are expected if solifenacin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased plasma concentrations of solifenacin).1,237 When solifenacin is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, do not exceed a solifenacin dosage of 5 mg once daily.1,237

Zolpidem

Pharmacokinetic interactions expected if zolpidem is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir (increased zolpidem concentrations).1,237

If zolpidem is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir, zolpidem dosage should be titrated, a lower zolpidem dosage should be considered, and the patient should be monitored for prolonged or adverse effects.1,237

Description

Darunavir, a nonpeptidic sulfonamide derivative, inhibits replication of human immunodeficiency virus type 1 (HIV-1) by interfering with HIV protease.1,2,3 During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes.1 By interfering with the formation of these essential proteins and enzymes, darunavir blocks maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions.1

Darunavir-resistant HIV-1, including strains with decreased susceptibility to other HIV protease inhibitors (PIs), have been reported.1,3 Varying degrees of cross-resistance occurs among HIV PIs.1 Although some HIV-1 isolates resistant to atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir have remained susceptible to darunavir,1,2,3 some clinical isolates with reduced susceptibility to darunavir have been resistant to atazanavir, fosamprenavir, indinavir, lopinavir, and nelfinavir.1 Only limited cross-resistance appears to occur between tipranavir and darunavir.1

Darunavir is extensively metabolized by the hepatic cytochrome P-450 (CYP) enzyme system, principally CYP3A, and must be administered with a pharmacokinetic enhancer (pharmacokinetic booster) to improve the pharmacokinetic profile of the drug.1,200,237,239 Darunavir should be administered with low-dose ritonavir ( ritonavir-boosted darunavir) or with cobicistat ( cobicistat-boosted darunavir).1,200,201,237,239 Because ritonavir and cobicistat are potent inhibitors of CYP3A, concomitant administration with darunavir results in increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of the HIV PI.1,200,237,239 The antiretroviral activity of ritonavir-boosted darunavir or cobicistat-boosted darunavir is due to darunavir.1,237

Darunavir pharmacokinetic parameters reported with a once-daily regimen of ritonavir-boosted darunavir (darunavir 800 mg and ritonavir 100 mg) are similar to those reported with a once-daily regimen of cobicistat-boosted darunavir (darunavir 800 mg and cobicistat 150 mg).237,239 Food increases oral bioavailability of darunavir.1,237 Compared with administration in the fasting state, administration of ritonavir-boosted darunavir (given as single-entity darunavir tablets and single-entity ritonavir) with food increases peak plasma concentrations and AUC of darunavir by approximately 40%.1 Administration of cobicistat-boosted darunavir (given as fixed-combination tablets containing both drugs [darunavir/cobicistat]) with a high-fat meal increases peak plasma concentrations and AUC of darunavir by 127 and 70%, respectively.237 Darunavir has a half-life of 15 hours after administration of ritonavir-boosted darunavir1 and a half-life of 7 hours after administration of cobicistat-boosted darunavir.237 The drug is eliminated principally in feces (80%) and urine (14%).1,237

Advice to Patients

• Advise patients of the critical nature of adherence with HIV therapy and importance of remaining under the care of a clinician.1,200,237 Advise patients of the importance of taking medications as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1,237
• Advise patients on the importance of using darunavir with low-dose ritonavir ( ritonavir-boosted darunavir) or with cobicistat ( cobicistat-boosted darunavir).1,237 Advise patients on the importance of using ritonavir-boosted or cobicistat-boosted darunavir in conjunction with other antiretrovirals to make a complete regimen.1,237
• When using ritonavir-boosted darunavir, advise patients on the importance of taking single-entity darunavir with food and at the same time as single-entity ritonavir.1 Advise patients on the importance of swallowing darunavir tablets whole with a drink (e.g., water, milk).1
• When using cobicistat-boosted darunavir, advise patients on the importance of taking the fixed-combination tablet containing both drugs (darunavir/cobicistat) with food;237 alternatively, advise patients on the importance of taking single-entity darunavir with food and at the same time as single-entity cobicistat.239
• Advise patients that drug-induced hepatitis has occurred.1,237 Advise patients on the importance of notifying their clinician if manifestations of liver disease occur (e.g., jaundice of skin or eyes; dark tea-colored urine; pale stools; nausea; vomiting; loss of appetite; pain, aching, or sensitivity in right upper quadrant of abdomen).1,237
• Advise patients that mild to severe skin reactions, have occurred.1,237 Advise patients on the importance of immediately discontinuing ritonavir-boosted or cobicistat-boosted darunavir and contacting their clinician if manifestations of severe skin reactions occur (e.g., severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).1,237
• Advise patients that redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1,237
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Advise females to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected females not to breast-feed.1 Advise females to use a reliable nonhormonal (e.g., barrier) method of contraception due to potential interactions with hormonal contraceptives.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

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

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

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

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20. Orkin C, DeJesus E, Khanlou H et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2013; 14:49-59. [Web]

198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From CDC.gov website. [Web]

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [Web]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 11, 2023). Updates may be available at HIV.gov website. [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2023). Updates may be available at HIV.gov website. [Web]

209. AbbVie Inc. Norvir® (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2022 Dec.

237. Janssen Therapeutics. Prezcobix® (darunavir/cobicistat) tablets prescribing information. Titusville, NJ; 2023 Mar.

239. Gilead Sciences Inc. Tybost® (cobicistat) tablets prescribing information. Foster City, CA; 2021 Sep.

240. Janssen Products, LP. Symtuza® tablets prescribing information. Horsham, PA; 2023 Mar.

301. Katlama C, Esposito R, Gatell J, et al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER-1. AIDS . 2007;21:395-402.

302. Haubrich R, Berger D, Chiliade P, et al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS . 2007;21:F11-F18.

304. Molina J, Cohen C, Katlama C, et al. Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients. J Acquir Defic Syndr . 2007;46:k24-31.

305. Cahn P, Fourie J, Grinsztejn B, et al. Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS . 2011;25:929-939.

306. Violari A, Bolagna R, Kumarasamy N, et al. Safety and efficacy of drunavir/ritonavir in treatment-experienced pediatric patients. Pediatr Infect Dis J . 2015;34:e132-e137.

307. Flynn P, Komar S, Blanche S, et al. Efficacy and safety of darunavir/ritonavir at 48 weeks in treatment-naïve, HIV-1- infected adolescents. Pediatr Infect Dis J . 2014;33:940-945.

308. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS . 2009;23:2005-2013.