Darunavir (Monograph)

Brand name: Prezista
Drug class: HIV Protease Inhibitors

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Antiretroviral; HIV protease inhibitor (PI).¹

Uses for Darunavir

Treatment of HIV Infection

Treatment of HIV infection with low-dose ritonavir (ritonavir-boosted darunavir) in adult and pediatric patients ≥3 years of age weighing ≥10 kg; used in conjunction with other antiretrovirals.^{1 9 10 20 200 201 301 302 304 305 306 307 308}

Treatment of HIV infection with cobicistat (cobicistat-boosted darunavir) in treatment-naïve or treatment-experienced adult and pediatric patients weighing ≥40 kg; used in conjunction with other antiretrovirals.^{200 237 239}

Boosted darunavir is commonly used as part of a fully suppressive antiretroviral regimen in conjunction with 2 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs); consult guidelines for the most current information on recommended regimens.^{200 201 202} Selection of an initial antiretroviral 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.^{200 201 202}

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Ritonavir-boosted darunavir used in conjunction with 2 NRTIs forpostexposure prophylaxis of HIV infection following occupational exposure [off-label]^{† [off-label]} (PEP) in healthcare personnel and other individuals.¹⁹⁹

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

Management of occupational exposures to HIV is complex and evolving; consult infectious diseases specialists, clinicians with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at888-448-4911) whenever possible.¹⁹⁹ Do not delay initiation of PEP while waiting for expert consultation.¹⁹⁹

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

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

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, US Centers for Disease Control and Prevention (CDC) state preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada);¹⁹⁸ recommended alternative regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.¹⁹⁸

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

Darunavir Dosage and Administration

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 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 (Cl_cr).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 Cl_cr, 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 >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 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}

• The Institute for Safe Medication Practices (ISMP) list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for antiretroviral medications (e.g., DOR, TAF, TDF) during the medication use process should be avoided as their use has been associated with serious medication errors.³⁰⁹

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted darunavir) once or twice daily with food.¹ Alternatively, administer orally in conjunction with cobicistat (cobicistat-boosted darunavir) once daily with food.^{237 239} Do not administer without low-dose ritonavir or cobicistat.^{1 200 201 237 239}

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

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

Oral suspension:Use in those who have difficulty swallowing tablets.¹ Administer suspension using oral dosing syringe supplied by the manufacturer.¹ If a 675- or 800-mg dose is indicated, give dose as two 3.4- or 4-mL administrations, respectively, using the oral dosing syringe.¹ Supplied as a white to off-white opaque suspension;¹ shake prior to each dose.¹

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

Cobicistat-boosted Darunavir

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

Dosage

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

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

Pediatric Patients

Treatment of HIV Infection in Antiretroviral-naïve Pediatric Patients

Oral

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

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

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

Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients

Oral

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

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

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

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

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

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

Cobicistat-boosted darunavir in pediatric patients weighing ≥ 40 kg without any mutations associated with darunavir resistance: 1 tablet of darunavir/cobicistat (800 mg of darunavir and 150 mg of cobicistat) once daily.²³⁷ Alternatively, single-entity darunavir 800 mg (one 800-mg darunavir tablet or 8 mL of darunavir oral suspension containing 100 mg/mL) once daily can be administered in conjunction with single-entity cobicistat (150 mg once daily).²³⁹ Both drugs must be administered in conjunction with other antiretroviral agents active against HIV-1.^{237 239}

Adults

Treatment of HIV Infection in Antiretroviral-naïve Patients

Oral

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

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

Treatment of HIV Infection in Antiretroviral-experienced Adults

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

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

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

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

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

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

Postexposure Prophylaxis following Occupational Exposure to HIV [PEP, off-label]† [off-label]

Oral

Ritonavir-boosted darunavir: Single-entity darunavir 800 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).¹⁹⁹ Alternatively, single-entity darunavir 600 mg twice daily in conjunction with low-dose ritonavir (100 mg twice daily).¹⁹⁹ Use in conjunction with 2 NRTIs.¹⁹⁹

Initiate PEP as soon as possible following exposure to HIV (preferably within hours); continue for 28 days, if tolerated.¹⁹⁹

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)† [off-label]

Oral

Ritonavir-boosted darunavir: single-entity darunavir 800 mg daily with low-dose ritonavir (100 mg once daily).¹⁹⁸ Use in conjunction with 2 NRTIs. Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.¹⁹⁸ nPEP may not be recommended if exposed individual seeks care >72 hours after exposure.¹⁹⁸

Special Populations

Hepatic Impairment

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

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

Renal Impairment

Ritonavir-boosted darunavir: No pharmacokinetic data in renal impairment; however, manufacturer states that renal clearance of darunavir is limited.¹

Cobicistat-boosted darunavir: Assess estimated Cl_cr prior to initiation of fixed-combination darunavir/cobicistat or, alternatively, single-entity darunavir with single-entity cobicistat.^{237 239} Do not usecobicistat-boosted darunavir in conjunction with tenofovir DF in patients with estimated Cl_cr <70 mL/minute.^{237 239}

Geriatric Use

Ritonavir-boosted or cobicistat-boosted darunavir: Select dosage with caution because of age-related decreases in hepatic function, concomitant disease, or other drug therapy.^{1 237}

Pregnant Females

Use ritonavir-boosted darunavir.^{1 202} Cobicistat-boosteddarunavir should not be used in pregnancy.²³⁷

Ritonavir-boosted darunavir (twice-daily regimen): 600 mg of single-entity darunavir (one 600-mg tablet or 6 mL of the oral suspension containing 100 mg/mL) twice daily with single-entity ritonavir 100 mg twice daily.¹

Ritonavir-boosted darunavir (once-daily regimen): 800 mg of single-entity darunavir once daily (one 800-mg tablet or 8 mL of the oral suspension containing 100 mg/mL once daily) with single-entity ritonavir 100 mg once daily be used only in females already stabilized on this regimen prior to pregnancy who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL) and in whom a change to a twice-daily regimen may compromise tolerability or compliance.¹

Cautions for Darunavir

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-boosteddarunavir 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

Warnings

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 increased serum aminotransferase concentrations, reported with ritonavir-boosted darunavir.^{1 237} Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute, generalized exanthematous pustulosis reported.^{1 237}

Immediately discontinue ritonavir-boosted or cobicistat-boosted darunavir if manifestations of severe skin reactions occur (e.g., severe rash, rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia).^{1 237}

Sulfonamide Sensitivity

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

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

Hepatotoxicity

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

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

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

Renal Effects

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

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

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

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

Interactions

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

Concomitant use of ritonavir-boosted or cobicistat-boosted darunavir with certain drugs is contraindicated or requires particular caution.^{1 200 237 239} Concomitant use with some drugs may result in clinically important adverse effects, 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).^{1 200 237 239} Concomitant use with other drugs may result in drug interactions leading to loss of therapeutic effect of ritonavir-boosted or cobicistat-boosted darunavir and possible development of resistance.^{1 200 237 239} Because ritonavir and cobicistat are inhibitors of CYP3A, interactions with drugs affecting or metabolized by CYP3A are of particular concern.^{1 200 237 239}

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

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

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

Hyperglycemic and Diabetogenic Effects

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

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

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.^{1 237}

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

Fat Redistribution

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

Hemophilia A and B

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

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

HIV Resistance

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

Use in Pediatric Patients Below 3 Years of Age

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

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].^{1 202 237}

Available human and animal data suggest that darunavir does not increase the risk of major birth defects overall compared to background rate.^{1 237 1}

Cobicistat-boosted darunavir: Manufacturer states to not use cobicistat-boosted darunavir in pregnancy due to reduced exposures in the second and third trimesters.²³⁷ An alternative regimen is recommended.²³⁷

Lactation

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

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

Female and Males of Reproductive Potential

Darunavir may reduce efficacy of combined hormonal contraceptives and progestin-only pill.^{1 237} Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception.^{1 237} 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

Ritonavir-boosted darunavir: Not recommended in children <3 years of age;^{1 237} toxicity and mortality reported in juvenile rats.^{1 237}

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

Cobicistat-boosted darunavir: Safety and efficacy established in patients weighing ≥ 40 kg.²³⁷

Geriatric Use

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

Ritonavir-boosted or cobicistat-boosted darunavir: Use with caution and monitor because of age-related decreases in hepatic function and concomitant disease and drug therapy.^{1 237}

Hepatic Impairment

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

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

Risk for liver function abnormalities, including severe adverse hepatic effects, increased in patients with preexisting hepatic impairment, including those with HBV or HCV infection.^{1 237}

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

Consider interruption or discontinuance of ritonavir-boosted or cobicistat-boosted darunavir if there is evidence of new or worsening liver disease.^{1 237}

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

Renal Impairment

Ritonavir-boosted darunavir: No pharmacokinetic data in renal impairment; however, manufacturer states that renal clearance of darunavir is limited.¹

Cobicistat-boosted darunavir: Assess estimated Cl_cr prior to initiation of fixed-combination darunavir/cobicistat or, alternatively, single-entity darunavir with single-entity cobicistat.^{237 239} Manufacturer states do not use cobicistat-boosted darunavir in conjunction with tenofovir DF in patients with estimated Cl_cr <70 mL/minute.,^{200 237 239}

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}

Drug Interactions

Darunavir, ritonavir, and cobicistat metabolized principally by CYP3A.^{1 237 239} Darunavir, ritonavir, and cobicistat inhibit CYP3A and CYP2D6.^{1 237 239}

Darunavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir or cobicistat); consider drug interactions associated with both darunavir and the pharmacokinetic enhancer.^{1 237 239} 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 not available to date using cobicistat-boosted darunavir administered either as fixed-combination darunavir/cobicistat or as single-entity darunavir given with single-entity cobicistat.^{237 239}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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

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

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

Drugs Affected by P-glycoprotein Transport

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

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

Drugs Affecting or Affected by Other Membrane Transporters

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

Specific Drugs

Darunavir Pharmacokinetics

Absorption

Bioavailability

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

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

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

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

Food

Food increases darunavir bioavailability.¹

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

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

Distribution

Extent

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

Plasma Protein Binding

Darunavir: 95%.¹

Binds principally to α1-acid-glycoprotein.¹

Elimination

Metabolism

Darunavir extensively metabolized by CYP3A.¹

Elimination Route

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

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

Half-life

15 hours after dose of ritonavir-boosted darunavir.¹

7 hours after dose of cobicistat-boosted darunavir.²³⁷

Special Populations

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

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

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

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

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

Stability

Storage

Oral

Suspension

Darunavir: 25°C (excursions permitted between 15–30°C).¹ Do not refrigerate or freeze; avoid excessive heat.¹

Tablets

Darunavir: 25°C (excursions permitted between 15–30°C).¹

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

Actions

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

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

• Antiretroviral activity is due to darunavir.^{1 237}

• Active against HIV-1.^{1 200}

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

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

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

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

Advice to Patients

• 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).^{1 237 239} Advise patients on the importance of using ritonavir-boosted or cobicistat-boosted darunavir in conjunction with other antiretrovirals to make a complete regimen.^{1 237 239}

• 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.

Preparations

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

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

Frequently asked questions

• What drugs are contained in the HIV treatment Symtuza?

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