Darunavir, an antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1
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
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
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
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
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 log10 copies/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
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 used in combination with a pharmacokinetic booster (e.g., ritonavir or cobicistat) as part of a fully suppressive antiretroviral regimen.1, 237 In the HHS adult HIV treatment guideline, darunavir (boosted with ritonavir or cobicistat) plus 2 NRTIs is included as an option for initial therapy in certain clinical scenarios.200 Please refer to the HHS pediatric antiretroviral and perinatal clinical guidelines for specific information on the use of boosted darunavir in these patient populations.201, 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† (PEP) in health-care personnel and other individuals.199
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
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
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 12 years of age or older is an INSTI plus 2 NRTIs.198 The alternative nPEP regimen for this patient population is a boosted PI (darunavir and cobicistat or ritonavir) plus 2 NRTIs.198 Boosted darunavir is a component of alternative nPEP regimens in pregnant women and pediatric (≥2-12 years of age) patients as well.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
Dispensing and Administration Precautions
Darunavir is administered orally in conjunction with low-dose ritonavir ( ritonavir-boosted darunavir) once or twice daily with food.1
Darunavir should not be administered without low-dose ritonavir.1, 200, 201 Low-dose ritonavir is a pharmacokinetic enhancer that improves the pharmacokinetic profile of darunavir.1, 200
Fixed Combinations Containing Darunavir
Darunavir is 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
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
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
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 at 25°C (excursion permitted between 15-30°C).1
Single-entity darunavir is commercially available as an oral suspension and tablets containing darunavir ethanolate; dosage is expressed in terms of darunavir.1
For the treatment of HIV-1 infection in pediatric patients 3 years to less than 18 years of age and weighing at least 10 kg, the recommended dosage of ritonavir-boosted darunavir 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
The weight-based dose in treatment-naïve pediatric patients weighing ≥10 but <15 kg is darunavir 35 mg/kg once daily with ritonavir 7 mg/kg once daily, using Table 1.1 For pediatric patients weighing ≥15 kg, darunavir can be dosed with either oral tablets or suspension, using Table 2.1
Body Weight | Darunavir Dosage (Oral Suspension Containing 100 mg/mL) | Ritonavir Dosage (Oral Solution Containing 80 mg/mL) |
|---|---|---|
≥10 to <11 kg | 350 mg (3.6 mLa) once daily | 64 mg (0.8 mL) once daily |
≥11 to <12 kg | 385 mg (4 mLa) once daily | 64 mg (0.8 mL) once daily |
≥12 to <13 kg | 420 mg (4.2 mLa) once daily | 80 mg (1 mL) once daily |
≥13 to <14 kg | 455 mg (4.6 mLa) once daily | 80 mg (1 mL) once daily |
≥14 to <15 kg | 490 mg (5 mLa) once daily | 96 mg (1.2 mL) once daily |
aDosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.1
Body Weight | Darunavir Dosage (Oral Suspension Containing 100 mg/mL or Tablets) | Ritonavir Dosage (Oral Solution Containing 80 mg/mL or 100-mg Capsules or Tablets) |
|---|---|---|
≥15 to <30 kg | 600 mg (6 mL) once daily | 100 mg (1.25 mL) once daily |
≥30 to <40 kg | 675 mg (6.8 mLa) once daily | 100 mg (1.25 mL) once daily |
≥40 kg | 800 mg (8 mL) once daily | 100 mg (1.25 mL) once daily |
aDosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.1
Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients
When ritonavir-boosted darunavir is used in antiretroviral-experienced pediatric patients, genotypic testing is recommended to identify mutations associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).1
For the treatment of HIV-1 infection in antiretroviral-experienced pediatric patients 3 years to less than 18 years of age without any mutations associated with darunavir resistance, the recommended dosage of ritonavir-boosted darunavir is similar to treatment-naïve patients and is presented in Table 1 (for pediatric patients weighing ≥10 but <15 kg) and Table 2 (for pediatric patients weighing ≥15 kg).1
The weight-based dose in treatment-experienced pediatric patients with at least 1 mutation associated with darunavir resistance weighing ≥10 but <15 kg is darunavir 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily, using Table 3.1 For pediatric patients weighing ≥15 kg, darunavir can be dosed with either oral tablets or suspension, using Table 4.
Body Weight | Darunavir Dosage (Oral Suspension Containing 100 mg/mL) | Ritonavir Dosage (Oral Solution Containing 80 mg/mL) |
|---|---|---|
≥10 to <11 kg | 200 mg (2 mL) twice daily | 32 mg (0.4 mL) twice daily |
≥11 to <12 kg | 220 mg (2.2 mL) twice daily | 32 mg (0.4 mL) twice daily |
≥12 to <13 kg | 240 mg (2.4 mL) twice daily | 40 mg (0.5 mL) twice daily |
≥13 to <14 kg | 260 mg (2.6 mL) twice daily | 40 mg (0.5 mL) twice daily |
≥14 to <15 kg | 280 mg (2.8 mL) twice daily | 48 mg (0.6 mL) twice daily |
Body Weight | Darunavir Dosage (Oral Suspension Containing 100 mg/mL or Tablets) | Ritonavir Dosage (Oral Solution Containing 80 mg/mL or 100-mg Capsules or Tablets) |
|---|---|---|
≥15 to <30 kg | 375 mg (3.8 mLa) twice daily | 48 mg (0.6 mL) twice daily |
≥30 to <40 kg | 450 mg (4.6 mLa) twice daily | 60 mg (0.75 mL) twice daily |
≥40 kg | 600 mg (6 mL) twice daily | 100 mg (1.25 mL) twice daily |
aDosage (in mL) rounded up for convenient measuring using oral dosing syringe provided by manufacturer.1
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
Treatment of HIV Infection in Antiretroviral-experienced Adults
When ritonavir-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
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
No dosage adjustment is necessary for ritonavir-boosted darunavir in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1
Ritonavir-boosted darunavir has not been evaluated; therefore, it is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).1
No specific dosage adjustments are recommended for ritonavir-boosted darunavir in renal impairment.1
The manufacturers make no specific dosage recommendations in geriatric patients; however, caution should be exercised due to decreased hepatic function, concomitant disease, or other drug therapy in this patient population.1
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
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
Severe skin reactions, sometimes accompanied by fever and/or increases in serum aminotransferase concentrations, have occurred in patients receiving ritonavir-boosted darunavir.1 Stevens-Johnson syndrome has been reported rarely; toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute, generalized exanthematous pustulosis also have been reported.1
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 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 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
Darunavir contains a sulfonamide moiety, which may cause allergic-type reactions in certain susceptible individuals.1 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
Ritonavir-boosted darunavir should be used with caution in patients with known hypersensitivity to sulfonamide-containing drugs.1
Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has occurred in patients receiving ritonavir-boosted darunavir in clinical studies.1 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 There have been postmarketing reports of liver injury (in some cases fatal) in patients receiving ritonavir-boosted darunavir; liver injury generally has occurred in patients with advanced HIV infection who were receiving multiple concomitant drugs, were coinfected with HBV or HCV, and/or were developing immune reconstitution syndrome.1
Appropriate laboratory tests should be performed to evaluate hepatic function prior to and periodically during treatment with ritonavir-boosted darunavir.1 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
Darunavir must be used in conjunction with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat).1 Failure to administer darunavir with the recommended dosage of ritonavir will result in subtherapeutic darunavir concentrations and inadequate antiretroviral response.1 When ritonavir-boosted darunavir is used, the cautions, precautions, contraindications, and drug interactions associated with both darunavir and the pharmacokinetic enhancer (i.e., low-dose ritonavir) should be considered.1
Concomitant use of ritonavir-boosted darunavir with certain drugs is contraindicated or requires particular caution.1 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).1 Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted darunavir and possible development of resistance.1 Because ritonavir is an inhibitor of CYP3A4, interactions with drugs affecting or metabolized by CYP3A4 are of particular concern.1
Potential drug interactions should be considered prior to and during use of ritonavir-boosted darunavir.1 Patients should be monitored for adverse effects associated with other drugs used concomitantly with ritonavir-boosted darunavir.1
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 It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents).1
Immune Reconstitution Syndrome
Patients receiving antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy.1 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1
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
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 The mechanisms and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.1
Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in patients with hemophilia A or B receiving HIV PIs.1 Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.1
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
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 was 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 Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease.1 The rate of miscarriage is not reported in the APR.1
It is not known whether darunavir or ritonavir is distributed into human milk;1, 209 darunavir is distributed into milk in rats.1
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202
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
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
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
Experience in those 65 years of age and older is insufficient to determine whether they respond differently to ritonavir-boosted darunavir than younger adults.1 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
Pharmacokinetics of darunavir do not differ substantially over an age range of 18-75 years of age.1
Pharmacokinetics of ritonavir-boosted darunavir are not altered in patients with mild to moderate hepatic impairment (Child-Pugh class A or B); dosage adjustments are not needed in such individuals.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
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
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 should be considered.1
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
Darunavir and ritonavir are highly bound to plasma proteins, and the drugs are unlikely to be removed by hemodialysis or peritoneal dialysis.1
Adverse effects of at least moderate intensity (greater than or equal to Grade 2) reported in more than 5% of patients receiving ritonavir-boosted darunavir in conjunction with other antiretrovirals are diarrhea, nausea, vomiting, abdominal pain, headache, and rash.1
Darunavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir); drug interactions associated with both darunavir and the pharmacokinetic enhancer should be considered.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Darunavir and ritonavir 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 Darunavir and ritonavir are metabolized by CYP3A.1 Potential pharmacokinetic interactions with drugs that induce CYP3A (increased clearance of darunavir or ritonavir, 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 or ritonavir).1
Caution is advised if ritonavir-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 exposure to ritonavir-boosted darunavir, or loss of therapeutic effect and possible development of resistance to darunavir.1
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 Potential pharmacokinetic interactions if ritonavir-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
In vitro data suggest 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
Concomitant use of alfuzosin and ritonavir-boosted darunavir is contraindicated because of the potential for serious and/or life-threatening reactions (e.g., hypotension).1
Possible pharmacokinetic interactions if certain antiarrhythmic agents (e.g., amiodarone, disopyramide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine) are used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of the antiarrhythmic agent).1
If ritonavir-boosted darunavir and antiarrhythmic agents are used concomitantly, clinical monitoring is recommended.1
Concomitant use of dronedarone and ritonavir-boosted darunavir is contraindicated due to the potential for serious and life-threatening arrhythmias.1
Pharmacokinetic interaction if apixaban is used concomitantly with ritonavir-boosted darunavir (increased apixaban concentrations).1 Refer to the prescribing information for apixaban for dosing instructions for concomitant use of P-gp and strong CYP3A inhibitors.1
Pharmacokinetic interaction if dabigatran is used concomitantly with ritonavir-boosted darunavir (increased dabigatran concentrations).1
Concomitant use of ritonavir-boosted darunavir with dabigatran is based upon the indication, effects of concomitant P-gp inhibitors on dabigatran concentrations, and renal impairment.1
Refer to the prescribing information for dabigatran for specific recommendations regarding concomitant use.1 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 darunavir.1
Possible pharmacokinetic interaction if edoxaban is used concomitantly with ritonavir-boosted darunavir (increased edoxaban concentrations).1
Concomitant use of ritonavir-boosted darunavir with edoxaban is based upon the indication, effects of concomitant P-gp inhibitors on dabigatran concentrations, and renal impairment.1
Refer to the prescribing information for edoxaban for dosing instructions for the concomitant use of ritonavir-boosted darunavir.1 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 darunavir.1
Possible pharmacokinetic interaction if rivaroxaban is used concomitantly with ritonavir-boosted darunavir (increased rivaroxaban concentrations and increased risk of bleeding).1
Concomitant use of ritonavir-boosted darunavir and rivaroxaban is not recommended due to an increased risk of bleeding.1
Pharmacokinetic interaction if warfarin is used concomitantly with ritonavir-boosted darunavir (decreased warfarin concentrations; no change in darunavir concentrations).1
If warfarin is used concomitantly with ritonavir-boosted darunavir, the international normalized ratio (INR) should be monitored.1
Pharmacokinetic interaction 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
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
Possible pharmacokinetic interaction if itraconazole is used concomitantly with ritonavir-boosted darunavir (increased itraconazole and darunavir concentrations).1
If itraconazole and ritonavir-boosted darunavir are used concomitantly, patients should be monitored for itraconazole-, darunavir-, and ritonavir--associated adverse effects and consideration given to monitoring itraconazole plasma concentrations.1 High itraconazole dosage (exceeding 200 mg daily) is not recommended in patients receiving ritonavir-boosted darunavir.1
Possible pharmacokinetic interaction if isavuconazole is used concomitantly with ritonavir-boosted darunavir (increased isavuconazole and darunavir concentrations).1
If isavuconazole and ritonavir-boosted darunavir are used concomitantly, patients should be monitored for isavuconazole- and darunavir--associated adverse effects.1
Pharmacokinetic interaction if ketoconazole is used concomitantly with ritonavir-boosted darunavir (increased ketoconazole and darunavir concentrations).1
If ketoconazole and ritonavir-boosted darunavir are used concomitantly, patients should be monitored for increased ketoconazole-, darunavir-, and ritonavir--associated adverse effects.1 Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted darunavir.1
Possible pharmacokinetic interaction if posaconazole is used concomitantly with ritonavir-boosted darunavir (increased darunavir concentrations; posaconazole concentrations may be increased).1
If posaconazole and ritonavir-boosted darunavir are used concomitantly, patients should be monitored for increased posaconazole-, darunavir-, and ritonavir--associated adverse effects.1
Possible pharmacokinetic interaction if voriconazole is used concomitantly with ritonavir-boosted darunavir (decreased voriconazole concentrations).1
Concomitant use of voriconazole and ritonavir-boosted darunavir is not recommended unless potential benefits outweigh risks.1
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
If artemether/lumefantrine is used concomitantly with ritonavir-boosted darunavir, the patient should be monitored for antimalarial efficacy and lumefantrine toxicity (e.g., QT interval prolongation).1 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
Pharmacokinetic interaction if rifabutin is used concomitantly with ritonavir-boosted darunavir (increased rifabutin concentrations; increased darunavir concentrations).1
If rifabutin is used concomitantly with ritonavir-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
Possible pharmacokinetic interaction if rifampin is used concomitantly with ritonavir-boosted darunavir (substantially decreased darunavir concentrations) with possible loss of antiretroviral effects.1
Concomitant use of ritonavir-boosted darunavir and rifampin is contraindicated.1
Possible pharmacokinetic interaction if rifapentine is used concomitantly with ritonavir-boosted darunavir (decreased darunavir concentrations).1 Concomitant use of ritonavir-boosted darunavir and rifapentine is not recommended.1
Possible pharmacokinetic interactions if certain antineoplastic agents (e.g, dasatinib, irinotecan, nilotinib, vinblastine, vincristine) are used concomitantly with ritonavir-boosted darunavir (increased antineoplastic agent concentrations).1
If dasatinib or nilotinib is used concomitantly with ritonavir-boosted darunavir, reduction of the dosage of the antineoplastic agent may be needed.1
If irinotecan is used concomitantly with ritonavir-boosted darunavir, ritonavir-boosted darunavir should be discontinued at least 1 week prior to starting irinotecan therapy.1 Do not use irinotecan concomitantly with ritonavir-boosted darunavir unless there are no therapeutic alternatives available.1
If vincristine or vinblastine is used concomitantly with ritonavir-boosted darunavir, consideration should be given to temporarily withholding the antiretroviral regimen in patients who develop clinically important hematologic or GI adverse effects.1 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
Potential for serious and/or life-threatening adverse effects if lurasidone is used concomitantly with ritonavir-boosted darunavir.1
Concomitant use of ritonavir-boosted darunavir and lurasidone is contraindicated.1
Perphenazine, Risperidone, and Thioridazine
Possible pharmacokinetic interactions if ritonavir-boosted darunavir is used concomitantly with perphenazine, risperidone, or thioridazine (increased plasma concentrations of the antipsychotic agent).1
If perphenazine, risperidone, or thioridazine is used concomitantly with ritonavir-boosted darunavir, a reduced dosage of the antipsychotic may be needed.1
Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias) if pimozide is used concomitantly with ritonavir-boosted darunavir.1
Concomitant use of ritonavir-boosted darunavir and pimozide is contraindicated.1
Pharmacokinetic interaction expected if quetiapine is used concomitantly with ritonavir-boosted darunavir (increased quetiapine concentrations).1
If ritonavir-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.1
Upon initiation of quetiapine in patients taking ritonavir-boosted darunavir, consult quetiapine prescribing information for initial dosing and titration recommendations.1
HIV Entry and Fusion Inhibitors
Pharmacokinetic interaction if maraviroc is used concomitantly with ritonavir-boosted darunavir (increased maraviroc plasma concentrations and AUC).1 If maraviroc is used concomitantly with ritonavir-boosted darunavir, the recommended maraviroc dosage is 150 mg twice daily.1
HIV Integrase Inhibitors (INSTIs)
Concomitant use of dolutegravir and ritonavir-boosted darunavir does not appear to have a clinically important effect on the pharmacokinetics of either drug.1
No clinically important effects on pharmacokinetics of ritonavir-boosted darunavir when raltegravir is given concomitantly.1 Dosage adjustments are not necessary if raltegravir and ritonavir-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
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
Safety and efficacy of concomitant use of etravirine and ritonavir-boosted darunavir were established in phase 3 clinical studies.1
If etravirine is used with ritonavir-boosted darunavir, dosage adjustments are not needed.1
Pharmacokinetic interaction if nevirapine is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of nevirapine and darunavir).1
If nevirapine and ritonavir-boosted darunavir are used concomitantly, dosage adjustments are not needed.1
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, tenofovir, and zidovudine.1
Pharmacokinetic interactions are not expected if abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, lamivudine, or zidovudine is used concomitantly with ritonavir-boosted darunavir.1 Dosage adjustments are not needed if ritonavir-boosted darunavir is used concomitantly with abacavir, emtricitabine, lamivudine, or zidovudine.1
Concomitant use of didanosine delayed-release capsules and ritonavir-boosted darunavir does not affect the pharmacokinetics of didanosine or darunavir.1 Dosage adjustments are not necessary, but didanosine doses should be given (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food).1
Pharmacokinetic interaction 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
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, lopinavir, nelfinavir, ritonavir, or tipranavir.1
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
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
Pharmacokinetic interaction 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
Possible pharmacokinetic interactions if certain benzodiazepines (e.g., diazepam, estazolam, midazolam, triazolam) are used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of the benzodiazepine).1
Pharmacokinetic interaction if clonazepam is used concomitantly with ritonavir-boosted darunavir (increased clonazepam concentrations).1
If clonazepam is used concomitantly with ritonavir-boosted darunavir, clinical monitoring is recommended. 1
If diazepam is used concomitantly with ritonavir-boosted darunavir, diazepam dosage should be titrated, a lower diazepam dosage should be considered, and the patient should be monitored for adverse effects.1
If estazolam is used concomitantly with ritonavir-boosted darunavir, estazolam dosage should be titrated, a lower estazolam dosage should be considered, and the patient should be monitored for adverse effects.1
Concomitant use of midazolam or triazolam with ritonavir-boosted darunavir potentially could result in serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1
Concomitant use of oral midazolam or triazolam with ritonavir-boosted darunavir is contraindicated.1
Concomitant use of parenteral midazolam and ritonavir-boosted darunavir should be undertaken with caution and in a monitored setting where respiratory depression and/or prolonged sedation can be managed.1 In addition, a reduced dosage of midazolam should be considered, especially if more than a single dose of midazolam is given.1
Beta-Adrenergic Blocking Agents
Possible pharmacokinetic interaction if ritonavir-boosted darunavir is used concomitantly with carvedilol, metoprolol, or timolol (increased plasma concentrations of the β-adrenergic blocking agent).1
If carvedilol, metoprolol, or timolol is used concomitantly with ritonavir-boosted darunavir, clinical monitoring of the patient is recommended and reduction of the dosage of the β-adrenergic blocking agent may be needed.1
Possible pharmacokinetic interaction if bosentan is used concomitantly with ritonavir-boosted darunavir (increased bosentan concentrations).1
In patients who have been receiving ritonavir-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
In patients who have been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating ritonavir-boosted darunavir; after at least 10 days of ritonavir-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
Possible pharmacokinetic interaction if buspirone is used concomitantly with ritonavir-boosted darunavir (increased buspirone concentrations).1
If buspirone is used concomitantly with ritonavir-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
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 darunavir (increased concentrations of the calcium-channel blocking agent).1 These calcium-channel blocking agents should be used concomitantly with ritonavir-boosted darunavir with caution; clinical monitoring of the patient is recommended.1
Possible pharmacokinetic interaction if diltiazem is used concomitantly with ritonavir-boosted darunavir (increased diltiazem concentrations).1
Potential pharmacokinetic interaction if colchicine is used concomitantly with ritonavir-boosted darunavir (increased colchicine concentrations).1
Concomitant use of colchicine and ritonavir-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
When colchicine is used for treatment of gout flares in patients receiving ritonavir-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
When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir-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
When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir-boosted darunavir, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.1
Concomitant use of systemic dexamethasone or other systemic corticosteroids that induce CYP3A4 and ritonavir-boosted darunavir may result in decreased darunavir or ritonavir concentrations and possible decreased antiretroviral efficacy, and alternative corticosteroids should be considered.1
Concomitant use of ritonavir-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 Consider alternative corticosteroids whose pharmacokinetics are less affected by strong CYP3A inhibitors, which include beclomethasone, prednisone, and prednisolone, particularly for long-term use.1
Corticosteroids used concomitantly with ritonavir-boosted darunavir that may result in increased plasma concentrations of the corticosteroid, include betamethasone, budesonide, ciclesonide, fluticasone, methylprednisolone, mometasone, and triamcinolone.1
Pharmacokinetic interaction if dextromethorphan is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of dextromethorphan).1
Pharmacokinetic interaction if digoxin is used concomitantly with ritonavir-boosted darunavir (increased digoxin concentrations).1
If ritonavir-boosted darunavir is used concomitantly with digoxin, titrate the digoxin dose and monitor digoxin serum concentrations.1 The lowest dose of digoxin should be used to obtain the desired clinical effect.1
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 darunavir.1 Concomitant use of ergot alkaloids with ritonavir-boosted darunavir is contraindicated.1
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
Pharmacokinetic interactions if oral contraceptives containing drospirenone and ethinyl estradiol are used concomitantly with ritonavir-boosted darunavir (decreased ethinyl estradiol and increased drospirenone concentrations).1 If ritonavir-boosted darunavir is used concomitantly with oral contraceptives containing drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.1
Additional or alternative nonhormonal methods of contraception should be used in patients receiving ritonavir-boosted darunavir.1
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 darunavir.1
Dosage adjustments are not needed if histamine H2-receptor antagonists are used concomitantly with ritonavir-boosted darunavir.1
Pharmacokinetic interaction 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
HCV Replication Complex Inhibitors
Pharmacokinetic interactions expected if ritonavir-boosted darunavir is used concomitantly with elbasvir/grazoprevir (resulting in increased concentrations of elbasvir and grazoprevir).1 Concomitant use of elbasvir/grazoprevir and ritonavir-boosted darunavir is contraindicated due to the potential for increased alanine aminotransferase (ALT) levels.1
Pharmacokinetic interactions expected if ritonavir-boosted darunavir is used concomitantly with glecaprevir/pibrentasvir (resulting in increased concentrations of glecaprevir and pibrentasvir).1 Concomitant use of glecaprevir/pibrentasvir and ritonavir-boosted darunavir is not recommended.1
Pharmacokinetic interactions with HMG-CoA reductase inhibitors (statins) metabolized by CYP3A isoenzyme.1 Concomitant use of ritonavir-boosted darunavir and certain statins (e.g., atorvastatin, 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
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
Concomitant use of lovastatin with ritonavir-boosted darunavir is contraindicated.,1
If pravastatin is used concomitantly with ritonavir-boosted darunavir, dosage of pravastatin should be titrated carefully and the lowest necessary dosage used with close monitoring for adverse effects.1
If rosuvastatin is used concomitantly with ritonavir-boosted darunavir, dosage of rosuvastatin should be titrated carefully and the lowest necessary dosage used with close monitoring for adverse effects.1
Concomitant use of simvastatin with ritonavir-boosted darunavir is contraindicated.1
Pharmacokinetic interactions with cyclosporine, everolimus, sirolimus, tacrolimus (increased concentrations of the immunosuppressive agent expected).1
If cyclosporine, sirolimus, or tacrolimus are used concomitantly with ritonavir-boosted darunavir, plasma concentrations of the immunosuppressive agent should be monitored.1
Concomitant use of everolimus and ritonavir-boosted darunavir is not recommended.1
Concomitant use of ivabradine and ritonavir-boosted darunavir is expected to result in increased ivabradine concentrations, increasing the potential for serious or life threatening reactions.1
Concomitant use of ivabradine and ritonavir-boosted darunavir is contraindicated.1
Concomitant use of lomitapide and ritonavir-boosted darunavir is expected to result in increased lomitapide concentrations, increasing the potential for marked increases in aminotransferase levels.1
Concomitant use of lomitapide and ritonavir-boosted darunavir is contraindicated.1
Pharmacokinetic interaction 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; 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
Opiate Agonists, Opiate Partial Agonists, and Opiate Antagonists
Pharmacokinetic interaction if buprenorphine or fixed combination of buprenorphine and naloxone is used concomitantly with ritonavir-boosted darunavir (increased norbuprenorphine concentrations and AUC).1
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
Possible pharmacokinetic interaction if fentanyl is used concomitantly with ritonavir-boosted darunavir (increased fentanyl concentrations).1
If fentanyl is used concomitantly with ritonavir-boosted darunavir, the patient should be carefully monitored for therapeutic and adverse effects of fentanyl, including potentially fatal respiratory depression.1
Pharmacokinetic interaction 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; however, patients should be closely monitored for opioid withdrawal since maintenance dosage of methadone may need to be adjusted in some patients.1
Pharmacokinetic interaction expected, resulting in increased naloxegol concentrations if naloxegol is used concomitantly with ritonavir-boosted darunavir.1 Concomitant use of naloxegol with ritonavir-boosted darunavir is contraindicated due to the potential for precipitating opioid withdrawal symptoms.1
Phosphodiesterase Type 5 Inhibitors
Concomitant use of ritonavir-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
Concomitant use of avanafil and ritonavir-boosted darunavir is not recommended.1
Concomitant use of sildenafil (Revatio®) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated in patients receiving ritonavir-boosted darunavir.1 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 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
If tadalafil (Adcirca®) is indicated for the treatment of PAH in patients who have been receiving ritonavir-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 Ritonavir-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 darunavir.1 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
If tadalafil is used for the treatment of erectile dysfunction in patients receiving ritonavir-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
If vardenafil is used for the treatment of erectile dysfunction in patients receiving ritonavir-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
Platelet Aggregation Inhibitors
Pharmacokinetic interaction expected if clopidogrel is used concomitantly with ritonavir-boosted darunavir (decreased clopidogrel active metabolite concentrations).1 Concomitant use of clopidogrel with ritonavir-boosted darunavir is not recommended due to potential decreases in the antiplatelet activity of clopidogrel.1
The active metabolite concentrations of prasugrel are not affected when prasugrel is used concomitantly with ritonavir-boosted darunavir.1 No dosage adjustments are needed when prasugrel is used concomitantly with ritonavir-boosted darunavir.1
Pharmacokinetic interaction expected if ticagrelor is used concomitantly with ritonavir-boosted darunavir (increased ticagrelor concentrations expected).1 Concomitant use of ticagrelor with ritonavir-boosted darunavir is not recommended.1
Potential for serious and/or life-threatening adverse effects if ritonavir-boosted darunavir is used concomitantly with ranolazine.1
Concomitant use of ritonavir-boosted darunavir and ranolazine is contraindicated.1
Potential pharmacokinetic interaction with St. John's wort ( Hypericum perforatum ) (decreased darunavir concentrations); potential for loss of virologic response.1 Concomitant use of St. John's wort and ritonavir-boosted darunavir is contraindicated.1
Possible pharmacokinetic interaction if salmeterol is used concomitantly with ritonavir-boosted darunavir (increased salmeterol concentrations) and increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia.1 Concomitant use of salmeterol and ritonavir-boosted darunavir is not recommended.1
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 interaction if trazodone is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of trazodone); 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
Tricyclic Antidepressants (TCAs)
Potential pharmacokinetic interactions if amitriptyline, desipramine, doxepin, imipramine, or nortriptyline is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of the TCA); possible increased risk of adverse effects (e.g., nausea, dizziness, hypotension, syncope).1
Pharmacokinetic interaction expected if fesoterodine is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of fesoterodine).1 When fesoterodine is used concomitantly with ritonavir-boosted darunavir, do not exceed a fesoterodine dosage of 4 mg once daily.1
Pharmacokinetic interaction expected if solifenacin is used concomitantly with ritonavir-boosted darunavir (increased plasma concentrations of solifenacin).1 When solifenacin is used concomitantly with ritonavir-boosted darunavir, do not exceed a solifenacin dosage of 5 mg once daily.1
Pharmacokinetic interaction expected if zolpidem is used concomitantly with ritonavir-boosted darunavir (increased zolpidem concentrations).1
If zolpidem is used concomitantly with ritonavir-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
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 Darunavir should be administered with low-dose ritonavir ( ritonavir-boosted darunavir).1, 200, 201 Because ritonavir is a strong inhibitor 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 The antiretroviral activity of ritonavir-boosted darunavir is due to darunavir.1
Food increases oral bioavailability of darunavir.1 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 Darunavir has a half-life of 15 hours after administration of ritonavir-boosted darunavir.1 The drug is eliminated principally in feces (80%) and urine (14%).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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Suspension | 100 mg (of darunavir) per mL | Janssen Products LP | |
Tablets, Film-Coated | 75 mg* | Prezista® | Janssen Products LP | |
Darunavir Tablets | ||||
150 mg* | Prezista® | Janssen Products LP | ||
Darunavir Tablets | ||||
300 mg* | Darunavir Tablets | |||
400 mg* | Darunavir Tablets | |||
600 mg* | Prezista® | Janssen Products LP | ||
Darunavir Tablets | ||||
800 mg* | Prezista® | Janssen Products LP | ||
Darunavir Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
1. Janssen Therapeutics. Prezista® (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2023 Mar.
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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13. Desbois D, Roquebert B, Peytavin G et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother. 2008; 52:1545-8. [Web]
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. Antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - CDC recommendations, United States, 2025. MMWR Morbid Mortal Wkly Rep . 2025;74(1):1-57.
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 (September 25, 2025). 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 (September 30, 2025). 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 (June 12, 2025). 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; 2025 Mar.
239. Gilead Sciences Inc. Tybost® (cobicistat) tablets prescribing information. Foster City, CA; 2025 June.
240. Janssen Products, LP. Symtuza® (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) 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.
309. Institute for Safe Medication Practices. ISMP list of error-prone abbreviations, symbols, and dose designations. 2024.