AHFS Class:

• HIV Protease Inhibitors 8:18.08.08

Generic Name(s):

• Darunavir Ethanolate, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Fumarate

Darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (DRV/c/FTC/TAF) is a fixed-combination antiretrovial agent containing darunavir (human immunodeficiency virus type 1 [HIV-1] protease inhibitor), cobicistat (pharmacokinetic enhancer), emtricitabine (HIV-1 nucleoside reverse transcriptase inhibitor), and tenofovir alafenamide (HIV-1 nucleotide reverse transcriptase inhibitor).1

Treatment of HIV Infection

The fixed combination of darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (DRV/c/FTC/TAF) is used as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥40 kg who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA<50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.1,2,3,4,5,6 DRV/c/FTC/TAF is a co-formulation of a boosted protease inhibitor (DRV/COBI) and 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTI; FTC/TAF); consult guidelines for the most current information on the place in therapy for this regimen.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

Clinical Experience

Treament-naïve Adults

Efficacy of DRV/c/FTC/TAF was evaluated in a multicenter, double-blind, phase 3 trial (AMBER) in adult patients with no prior antiretroviral treatment history.1,2 Patients received either DRV/c/FTC/TAF or the combination of DRV/COBI and FTC/TDF once daily.1,2 At baseline, the median age was 34 years, 88.3% of patients were male, 83% were white, 11% were Black, and 2% were Asian.1,2 At baseline, mean plasma HIV-1 RNA was 4.5 log₁₀ copies/mL, median baseline CD4+ cell count was 453 cells/mm³, and 18% of patients had a viral load ≥100,000 copies/mL.1,2

At 48 weeks, the primary end point of HIV-1 RNA <50 copies/mL was achieved by 91% of patients treated with DRV/c/FTC/TAF compared with 88% in patients treated with DRV/COBI plus FTC/TDF (treatment difference, 2.7%; 95% CI, -1.6 to 7.1%).1,2 Virological failure occurred in 4% of patients treated with DRV/c/FTC/TAF compared with 3% of patients treated with DRV/COBI plus FTC/TDF.1,2 The mean increase in CD4+ count was 189 or 174 cells/mm³, respectively, in patients treated with DRV/c/FTC/TAF or DRV/COBI plus FTC/TDF.1 At week 96, virologic suppression (defined as viral load <50 copies/mL) occurred in 85.1% of patients treated with DRV/c/FTC/TAF compared with 83.7% of patients treated with DRV/COBI plus FTC/TDF.3 Virologic failure occurred in 5.5% compared to 4.4% of patients.3

A multicenter, open-label trial compared DRV/c/FTC/TAF to dolutegravir, abacavir, and lamivudine in 316 adult patients with a viral load ≥500 copies/mL.6 The percentage of patients achieving viral load <50 copies/mL at week 48 was 79% with DRV/c/FTC/TAF compared with 82% with dolutegravir, abacavir, and lamivudine, which did not demonstrate noninferiority of DRV/c/FTC/TAF.6

Treatment-experienced Adults

In patients who were virologically suppressed (HIV-1 RNA <50 copies/mL), the efficacy of DRV/c/FTC/TAF was evaluated in an open-label, multicenter, phase 3 study in adults with HIV-1 infection (EMERALD).1,4 Virological suppression was defined as HIV-1 RNA <50 copies/mL for at least 2 months and no more than 1 increase above 50 copies/mL in the year before enrollment.1,4 Patients were receiving a boosted protease inhibitor (DRV or atazanavir plus ritonavir or COBI or lopinavir with ritonavir) plus FTC/TDF.1,4 Patients either continued their current regimen or were switched to DRV/c/FTC/TAF.1,4

At baseline, mean age of patients was 46 years; 82% were male, 75% were white, 21% were Black, and 2% were Asian.1,4 There were 15% of patients with prior virologic failure.1,4 Tenofovir resistance-associated substitutions and emtricitabine resistance-associated substitutions were present in 5 and 53 subjects, respectively.1,4 The primary end point of percentage of patients with HIV-1 RNA <50 copies/mL at week 48 was 95% in patients treated with DRV/c/FTC/TAF compared with 94% of patients treated with a boosted PI plus FTC/TDF, indicating noninferiority of DRV/c/FTC/TAF.1,4 Among patients in AMBER or EMERALD who either continued DRV/c/FTC/TAF or switched to this regimen, virologic response was observed in 91% of patients at 96 weeks.5

Pediatric Patients

The pharmacokinetic profile, safety, and antiviral activity of DRV/c/FTC/TAF were evaluated in an open-label study in patients aged 12 to <18 years of age.1 DRV 800 mg and COBI 150 mg with 2 NRTIs were evaluated in 7 patients ≥40 kg with virologic suppression.1 Median age was 14 years, median weight was 57 kg, baseline plasma HIV-1 RNA was <50 copies per mL, and median CD4+ count was 1,117 cells/mm³.1 At week 48, all patients with available data had CD4+ counts >800 cells/mm³.1

A second study evaluated FTC 200 mg, TAF 10 mg, and COBI 150 mg with elvitegravir 150 mg in 50 treatment-naïve pediatric patients with HIV-1 who were ≥35 kg.1 Median age was 15 years, median plasma HIV-1 RNA was 4.7 log₁₀ copies/mL, median CD4+ was 456 cells/mm³, and 22% of patients had HIV-1 RNA >100,000 copies/mL.1 At week 48, the proportion of patients with HIV-1 RNA <50 copies per mL was 92% and median increase in CD4+ count from baseline was 220 cells/mm³.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) 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.200,201,202 The primary goals of ART 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.200,202 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 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial ARV 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 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

DRV/c/FTC/TAF is a co-formulation of a boosted PI (DRV and COBI) and 2 NRTIs (FTC and TAF).200 In the 2023 HHS adult and adolescent HIV treatment guideline, darunavir-containing regimens are included in various antiretroviral regimens.200 Some of these darunavir-containing regimens are listed among alternative initial regimens in certain clinical situations, and include the following regimens: DRV/COBI or DRV/ritonavir plus TAF or tenofovir disoproxil fumarate plus FTC or lamivudine for patients with concerns of INSTI resistance in the setting of past use of long-acting cabotegravir (CAB-LA) as pre-exposure prophylaxis, who received treatment prior to the results of the genotype test.200

In the 2023 HHS pediatric HIV treatment guideline, DRV/COBI is included in various antiretroviral regimens.201 DRV/COBI and a 2 NRTI-backbone is recommended as an alternative PI-based regimen for patients ≥12 years of age and weighing ≥40 kg who are not sexually mature.201

In the 2023 HHS perinatal HIV treatment guideline, DRV is included in various antiretroviral regimens.202 The combination of DRV/c/FTC/TAF is not recommended as a first-line option in pregnant people or in nonpregnant people who are trying to conceive, but in people who become pregnant on a regimen of DRV/c/FTC/TAF, the regimen may be continued with frequent viral load monitoring or be switched to another regimen.202

General

Pretreatment Screening

• Test patients for hepatitis B virus (HBV) infection.1
• Obtain baseline serum creatinine, estimated creatinine clearance, urine glucose, and urine protein.1
• Obtain baseline liver enzyme levels.1
• Check pregnancy status.1 Do not initiate in patients who are pregnant.1
• Check for patient history of sulfonamide allergy.1

Patient Monitoring

• Monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients on a clinically appropriate schedule.1
• Monitor serum phosphorus in patients with chronic kidney disease.1
• Monitor for exacerbation of HBV in patients who have concomitant HBV infection and who have discontinued treatment with the fixed combination of darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (DRV/c/FTC/TAF) for at least several months after drug discontinuation.1
• Monitor for hepatotoxicity as clinically appropriate.1 Increase frequency of monitoring liver enzymes in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of treatment.1
• Monitor patients with a known sulfonamide allergy.1
• Monitor patients for skin reactions.1

Administration

The fixed combination of DRV/c/FTC/TAF is administered orally once daily with food.1

Each fixed-combination tablet of darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate contains 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide.1

For patients who are unable to swallow the whole tablet, the tablet can be split, and the entire dose should be consumed immediately after splitting.1

Dosage

Adults

HIV-1 Infection

The recommended adult dosage of DRV/c/FTC/TAF for treatment of HIV-1 infection is 1 tablet (800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide) taken once daily with food.1

Pediatric Patients

HIV-1 Infection

The recommended dosage of DRV/c/FTC/TAF for treatment of HIV-1 infection in pediatric patients weighing ≥40 kg is 1 tablet (800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide) taken once daily with food.1

Special Populations

Hepatic Impairment

DRV/c/FTC/TAF is not recommended in patients with severe hepatic impairment.1 The manufacturer makes no specific dosage recommendations for patients with mild to moderate hepatic impairment.1

Renal Impairment

DRV/c/FTC/TAF is not recommended in patients with an estimated creatinine clearance <30 mL/minute.1 No dosage adjustment is required for patients with an estimated creatinine clearance ≥30 mL/minute.1

Geriatric Use

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• Concomitant use with drugs highly dependent on cytochrome P-450 (CYP) isoenzyme 3A (CYP3A) for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, ergot alkaloids, lovastatin, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam) is contraindicated.1
• Concomitant use with drugs that are inducers of CYP3A (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) is contraindicated, since these drugs may decrease darunavir or cobicistat concentrations resulting in possible decreased antiretroviral efficacy and development of resistance.1

Warnings/Precautions

Warnings

HIV-infected Individuals Coinfected with Hepatitis B Virus

The prescribing information for DRV/c/FTC/TAF includes a boxed warning regarding the risk of severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate; this may occur with discontinuation of DRV/c/FTC/TAF.1 Test patients with HIV-1 for the presence of chronic hepatitis B virus before initiating antiretroviral therapy.1 Closely monitor patients coinfected with HIV-1 and HBV who discontinue DRV/c/FTC/TAF with both clinical and laboratory follow-up for at least several months after stopping treatment.1 If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.1

Other Warnings and Precautions

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir.1 Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions.1

Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir.1 These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome.1 A causal relationship with darunavir therapy has not been established.1

Conduct appropriate laboratory testing prior to initiating and during therapy with DRV/c/FTC/TAF.1 Consider increased AST/ALT monitoring in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of DRV/c/FTC/TAF treatment.1

With evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly), promptly consider interruption or discontinuation of DRV/c/FTC/TAF.1

Severe Skin Reactions

In patients receiving darunavir, severe skin reactions may occur.1 These include conditions accompanied by fever and/or elevations of transaminases.1 Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%.1 During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.1 Discontinue DRV/c/FTC/TAF immediately if signs or symptoms of severe skin reactions develop.1 These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.1

Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with DRV/c/FTC/TAF in the AMBER trial.1 Rash events were mild-to-moderate, often occurring within the first 4 weeks of treatment and resolving with continued dosing.1 The discontinuation rate due to rash in subjects using DRV/c/FTC/TAF was 2%.1

Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of DRV/c/FTC/TAF and other drugs may result in known or potentially significant drug interactions, which may lead to clinically significant adverse reactions from greater exposures of concomitant drugs; clinically significant adverse reactions from greater exposures of DRV/c/FTC/TAF drugs; loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s); and loss of therapeutic effect of DRV/c/FTC/TAF and possible development of resistance from lower exposure to DRV/c/FTC/TAF.1

Consider the potential for drug interactions prior to and during DRV/c/FTC/TAF therapy; review concomitant medications during DRV/c/FTC/TAF therapy; and monitor for adverse reactions associated with concomitant medications.1

When used with concomitant medications, DRV/c/FTC/TAF, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir.1 Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain DRV/c/FTC/TAF interactions.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy.1 During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.1

Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and 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 treatment.1

New Onset or Worsening Renal Impairment

Postmarketing cases of renal impairment, including cases of acute renal failure, proximal renal tubulopathy, and Fanconi syndrome have been reported with tenofovir alafenamide-containing products.1 DRV/c/FTC/TAF is not recommended in patients with creatinine clearance <30 mL per minute.1

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory agents (NSAIAs) are at increased risk of developing renal-related adverse reactions.1

Prior to or when initiating DRV/c/FTC/TAF and during treatment, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein.1 In patients with chronic kidney disease, also assess serum phosphorus.1 Discontinue DRV/c/FTC/TAF in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.1

Cobicistat, a component of DRV/c/FTC/TAF, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration.1 This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating DRV/c/FTC/TAF, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.1 The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation.1 Closely monitor patients who experience a confirmed increase in serum creatinine of >0.4 mg/dL.1

Sulfa Allergy

Darunavir contains a sulfonamide moiety.1 Monitor patients with a known sulfonamide allergy after initiating DRV/c/FTC/TAF.1 In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.1

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of DRV/c/FTC/TAF, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals.1 Suspend treatment with DRV/c/FTC/TAF in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).1

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving HIV protease inhibitor (PI) therapy.1 Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events.1 In some cases, diabetic ketoacidosis has occurred.1 In those patients who discontinued PI therapy, hyperglycemia persisted in some cases.1 Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.1

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy.1 The mechanism and long-term consequences of these events are currently unknown.1 A causal relationship has not been established.1

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs).1 In some patients, additional factor VIII was given.1 In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued.1 A causal relationship between PI therapy and these episodes has not been established.1

Specific Populations

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DRV/c/FTC/TAF during pregnancy.1 Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 800-258-4263.1

There are insufficient prospective human data on the use of DRV/c/FTC/TAF in pregnant individuals from the APR to inform on a potential drug-associated risk of birth defects and miscarriage.1 Available data from the APR show no difference in rate of overall birth defects for darunavir, cobicistat, emtricitabine, and TAF compared with the background rate for major birth defects of 2.7% in a U.S. 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

In animal reproduction studies, no adverse developmental effects were observed.1

DRV/c/FTC/TAF is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters compared to the post-partum period, as determined in a pharmacokinetic study.1 Do not initiate DRV/c/FTC/TAF in pregnant individuals.1 An alternative regimen is recommended for individuals who become pregnant during therapy with DRV/c/FTC/TAF.1

Lactation

The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.1

Based on published data, emtricitabine has been shown to be present in human milk.1 There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production.1 Darunavir and cobicistat are present in the milk of lactating rats.1 Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF.1

Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving DRV/c/FTC/TAF.1

Pediatric Use

The safety and effectiveness of DRV/c/FTC/TAF in pediatric patients weighing ≥40 kg was established through studies with darunavir, cobicistat, emtricitabine, and tenofovir alafenamide.1 Use of DRV/c/FTC/TAF in this population is supported by evidence from studies in adults with additional pharmacokinetic, safety, and virologic data from studies of the drug's components in pediatric patients 12 to <18 years of age with HIV-1 infection.1

The safety and effectiveness of DRV/c/FTC/TAF have not been established in pediatric patients weighing <40 kg.1

Darunavir, a component of DRV/c/FTC/TAF is not recommended in pediatric patients <3 years of age because of toxicity and mortality observed in juvenile rats dosed with the drug.1

Geriatric Use

Clinical trials of DRV/c/FTC/TAF included 35 patients ≥65 years of age, of which 26 received the fixed combination preparation.1 No differences in safety or efficacy have been observed between elderly subjects and those <65 years of age.1 In general, caution should be exercised in the administration and monitoring of DRV/c/FTC/TAF in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy.1

Hepatic Impairment

No dosage adjustment of DRV/c/FTC/TAF is required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment.1 DRV/c/FTC/TAF has not been studied in patients with severe hepatic impairment (Child Pugh Class C) and there are only limited data regarding the use of DRV/c/FTC/TAF components in this population.1 Therefore, DRV/c/FTC/TAF is not recommended for use in patients with severe hepatic impairment.1

Renal Impairment

DRV/c/FTC/TAF is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/minute).1 No dosage adjustment of DRV/c/FTC/TAF is required in patients with creatinine clearance ≥30 mL/minute.1 Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function.1 Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with DRV/c/FTC/TAF.1

Common Adverse Effects

The most common adverse reactions (all grades, incidence ≥2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence.1

Drug interaction studies of co-administration of other drugs with the fixed combination of darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (DRV/c/FTC/TAF) have not been conducted.1 Information on drug interactions is based on studies evaluating components of the fixed combination, as individual agents or in combination, or are predicted interactions.1 Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs.1 The label of each drug co-administered with the fixed combination of DRV/c/FTC/TAF should be consulted to determine the potential for a drug interaction and specific actions to be taken with regard to co-administration.1

Darunavir and cobicistat are metabolized by cytochrome P-450 (CYP) 3A.1 CYP2D6 plays a minor role in cobicistat metabolism.1 Darunavir co-administered with cobicistat is a CYP3A and CYP2D6 inhibitor.1 Cobicistat inhibits the following transporters: p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein 1 (MATE1), organic anion transporter protein 1B1 (OATP1B1), and 1B3 (OATP1B3).1 In vitro and in vivo studies indicate cobicistat does not induce CYP1A2, CYP2B6, CYP3A, MDR1.1

In vitro and clinical drug interaction studies indicated that emtricitabine is not an inhibitor of CYP450 enzymes.1

In vivo, tenofovir alafenamide is not an inhibitor or inducer of CYP3A.1 Tenofovir alafenamide is also not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A or CYP2D6 Substrates

Co-administration of the fixed combination of DRV/c/FTC/TAF with drugs primarily metabolized by CYP3A and/or CYP2D6 may result in increased plasma concentrations of the substrate drug due to enzyme inhibition by darunavir and cobicistat.1 This could result in an increase or prolongation of the substrate drug's therapeutic effect or adverse events.1 Co-administration with drugs that have active metabolites formed by CYP3A may result in reduced plasma concentrations of these active metabolites, potentially leading to loss of their therapeutic effect.1

CYP3A Inducers

Co-administration of the fixed combination of DRV/c/FTC/TAF with drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance.1

CYP3A Inhibitors

Co-administration of the fixed combination of DRV/c/FTC/TAF with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat.1

Drugs Affecting P-glycoprotein Transport

P-glycoprotein (P-gp) Inducers

Drugs that induce P-gp activity are expected to decrease tenofovir alafenamide absorption, resulting in decreased plasma concentrations, possible loss of therapeutic effect of the fixed combination of DRV/c/FTC/TAF, and development of resistance.1

P-gp Inhibitors

Drugs that inhibit P-gp activity may increase tenofovir alafenamide absorption and its plasma concentrations.1

Drugs Affecting Renal Function

Co-administration of the fixed combination of DRV/c/FTC/TAF with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs, increasing the risk of adverse reactions.1 Examples of drugs eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIAs.1

Alpha1-adrenoreceptor Antagonist

Alfuzosin

Concentrations of alfuzosin can increase with co-administration.1 Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.1

Antibacterial Agents

Clarithromycin, Erythromycin

Concentrations of darunavir, cobicistat, and the antibacterial can increase with co-administration.1 Consider alternative antibiotics with concomitant use of the fixed combination of DRV/c/FTC/TAF.1

Anticancer Agents

Dasatinib, Nilotinib

Concentrations of dasatinib and nilotinib can increase with co-administration.1 A dose reduction or adjustment of the dosing interval of dasatinib or nilotinib may be necessary.1 Consult prescribing information for these agents for dosing instructions.1

Vinblastine, Vincristine

Concentrations of vinblastine or vincristine can increase with co-administration, leading to significant hematologic or GI side effects.1 Consider temporarily withholding the cobicistat-containing antiretroviral regimen if these effects occur.1 Consider initiating an alternative antiretroviral regimen that does not include a CYP3A or P-gp inhibitor if the cobicistat-containing antiretroviral regimen needs to be held for a prolonged period.1

Anticoagulants

Direct Oral Anticoagulants (DOACs)

Apixaban: Concentrations of apixaban can increase with co-administration.1 Due to the potentially increased bleeding risk, refer to apixaban prescribing information for dosing instructions for co-administration with P-gp and CYP3A inhibitors.1

Rivaroxaban: Concentrations of rivaroxaban can increase with co-administration.1 Co-administration is not recommended as it may lead to an increased bleeding risk.1

Dabigatran, Edoxaban: Concentrations of dabigatran or edoxaban can increase with co-administration.1 Refer to each DOAC's prescribing information for recommendations regarding co-administration.1 Clinically monitor when either of these agents are co-administered with the fixed combination of DRV/c/FTC/TAF.1

Other Anticoagulants

Warfarin: The effect of the fixed combination of DRV/c/FTC/TAF on warfarin concentrations is unknown.1 Monitor international normalized ratio (INR) when co-administered.1

Anticonvulsants

Carbamazepine, Phenobarbital, Phenytoin

Concentrations of cobicistat, darunavir, and tenofovir alafenamide can decrease with co-administration, leading to potential loss of therapeutic effects and development of resistance.1 Co-administration is contraindicated.1

Anticonvulsants with CYP3A Induction Effects That Are NOT Contraindicated

Eslicarbazepine, Oxcarbazepine: Concentrations of cobicistat and tenofovir alafenamide can decrease with co-administration.1 Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposure.1 If co-administration is necessary, monitor for lack or loss of virologic response.1

Anticonvulsants That Are Metabolized by CYP3A

Clonazepam: Concentrations of clonazepam can increase with co-administration.1 Clinically monitor anticonvulsants.1

Antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs)

Paroxetine, Sertraline: The effect of the fixed combination of DRV/c/FTC/TAF on SSRI concentrations is unknown.1 When co-administered, carefully titrate the antidepressant dose to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response.1

Tricyclic Antidepressants (TCAs)

Amitriptyline, Desipramine, Imipramine, Nortriptyline: Concentrations of TCAs can increase with co-administration.1 When co-administered, carefully titrate the antidepressant dose to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response.1

Other Antidepressants

Trazodone: Concentrations of trazodone can increase with co-administration.1 When co-administered, carefully titrate the antidepressant dose to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response.1

Antifungals

Itraconazole, Isavuconazole, Ketoconazole, Posaconazole

Concentrations of darunavir, cobicistat, itraconazole, isavuconazole, and ketoconazole can increase with co-administration.1 Effects on posaconazole concentrations with co-administration has not been studied.1 Monitor for increased darunavir, cobicistat, and/or antifungal adverse reactions.1 Specific dosing recommendations are not available for co-administration with these antifungals.1

Voriconazole

The effect of the fixed combination of DRV/c/FTC/TAF on voriconazole concentrations is unknown.1 Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.1

Anti-gout

Colchicine

Concentrations of colchicine can increase with co-administration.1 Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions.1

For patients without renal or hepatic impairment, colchicine dosage adjustments are dependent on indication:

Gout flare treatment: 0.6 mg for 1 dose followed by 0.3 mg 1 hour later.1 Repeat treatment course no earlier than 3 days.1

Gout flare prophylaxis: If the original regimen was 0.6 mg twice daily, reduce to 0.3 mg once a day.1 If the original regimen was 0.6 mg once a day, reduce to 0.3 mg every other day.1

Familial Mediterranean fever treatment: Maximum daily dose of 0.6 mg (can be given as 0.3 mg twice a day).1

Antimalarial

Artemether/Lumefantrine

The effect of co-administration on artemether or lumefantrine concentrations is unknown.1 Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.1

Antimycobacterials

Rifampin

Concentrations of cobicistat, darunavir, and tenofovir alafenamide can decrease with co-administration leading to potential loss of therapeutic effects and development of resistance.1 Co-administration is contraindicated.1

Rifabutin

Concentrations of tenofovir alafenamide can decrease and concentrations of rifabutin can increase with co-administration.1 Co-administration is not recommended.1 If co-administration is needed, the recommended dose of rifabutin is 150 mg every other day.1 Monitor for rifabutin-associated adverse reactions, including neutropenia and uveitis.1

Rifapentine

Concentrations of darunavir and tenofovir alafenamide can decrease with co-administration.1 Co-administration with rifapentine is not recommended.1

Antipsychotics

Lurasidone, Pimozide

Concentrations of lurasidone and pimozide can increase with co-administration.1 Co-administration is contraindicated due to potential for serious and/or life-threatening reactions including cardiac arrhythmias due to pimozide.1

Perphenazine, Risperidone, Thioridazine

Concentrations of the antipsychotic can increase with co-administration.1 A decrease in the dose of antipsychotics metabolized by CYP3A or CYP2D6 may be needed with co-administration.1

Quetiapine

Concentrations of quetiapine can increase with co-administration.1

For patients taking quetiapine, consider an alternative to the fixed combination of DRV/c/FTC/TAF.1 If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose.1 Monitor for quetiapine-associated adverse reactions based on recommendations from quetiapine's prescribing information.1

To initiate quetiapine in patients taking the fixed combination of DRV/c/FTC/TAF, refer to quetiapine's prescribing information for initial dosing and titration of quetiapine.1

Antiretroviral Medications

The fixed combination of DRV/c/FTC/TAF is a complete regimen for HIV-1 infection and co-administration with other antiretrovirals for the treatment of HIV-1 infection is not recommended.1

Beta-blockers

Carvedilol, Metoprolol, Timolol

Concentrations of β-blockers can increase with co-administration.1 Clinical monitoring is recommended for co-administration with β-blockers that are metabolized by CYP2D6.1

Calcium channel blockers

Amlodipine, Diltiazem, Felodipine, Nifedipine, Verapamil

Concentrations of calcium-channel blockers can increase with co-administration.1 Clinical monitoring is recommended for co-administration with calcium-channel blockers that are metabolized by CYP3A.1

Cardiac Disorders

Ranolazine, Ivabradine, Dronedarone

Concentrations of ranolazine and dronedarone can increase with co-administration.1 Co-administration is contraindicated due to potential for serious and/or life-threatening reactions including cardiac arrhythmias due to dronedarone.1

Other Antiarrhythmics (e.g., Amiodarone, Disopyramide, Flecainide, Lidocaine (Systemic), Mexiletine, Propafenone, Quinidine)

Concentrations of antiarrhythmics can increase with co-administration.1 Clinical monitoring is recommended with co-administration.1

Digoxin

Concentrations of digoxin can increase with co-administration.1 When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.1

Corticosteroids

Dexamethasone (Systemic)

Concentrations of darunavir and cobicistat can decrease with co-administration.1 Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to the fixed combination.1 Consider alternative corticosteroids.1

Corticosteroids Metabolized Primarily by CYP3A (e.g., Betamethasone, Budesonide, Ciclesonide, Fluticasone, Methylprednisolone, Mometasone, Triamcinolone)

Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression.1 Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (that are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.1

Endothelin Receptor Antagonists

Bosentan

Concentrations of darunavir and cobicistat can decrease and concentrations of bosentan can increase with co-administration.1

To initiate bosentan in patients taking the fixed combination of DRV/c/FTC/TAF for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.1

To initiate the fixed combination of DRV/c/FTC/TAF in patients taking bosentan, discontinue use of bosentan at least 36 hours prior to initiation.1 After at least 10 days, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.1

To switch from darunavir co-administered with ritonavir to the fixed combination of DRV/c/FTC/TAF in patients on bosentan, maintain the bosentan dose.1

Ergot Derivatives

Dihydroergotamine, Ergotamine, Methylergonovine

Concentrations of ergot derivatives can increase with co-administration.1 Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.1

Hepatitis C Virus Agents

Direct-acting Antivirals

Elbasvir/Grazoprevir: Concentrations of elbasvir/grazoprevir can increase with co-administration.1 Co-administration is contraindicated due to potential for increased risk of alanine transaminase (ALT) elevations.1

Glecaprevir/Pibrentasvir: Concentrations of glecaprevir and pibrentasvir can increase with co-administration.1 Co-administration is not recommended.1

Herbal Products

St. John's Wort ( Hypericum perforatum )

Concentrations of cobicistat, darunavir, and tenofovir alafenamide can decrease with co-administration.1 Co-administration is contraindicated.1

Hormonal Contraceptives

Drosperinone/Ethinyl Estradiol

Concentrations of drospirenone can increase and concentrations of ethinyl estradiol can decrease with co-administration.1 For co-administration with drospirenone, clinically monitor due to the potential for hyperkalemia.1 Consider additional or alternative (non-hormonal) forms of contraception when estrogen-based contraceptives are co-administered with the fixed combination of DRV/c/FTC/TAF.1

Other Progestin/Estrogen Contraceptives

The impact on concentrations of progestin or estrogen with co-administration is not known.1 No data are available to make recommendations on co-administration with oral or other hormonal contraceptives.1

Immunosuppressants

Cyclosporine, Sirolimus, Tacrolimus

Concentrations of immunosuppressants metabolized by CYP3A can increase with co-administration.1 Conduct therapeutic drug monitoring with concomitant use.1

Immunosuppressant/Neoplastic

Everolimus

Concentrations of immunosuppressants metabolized by CYP3A can increase with co-administration.1 Co-administration is not recommended.1

Irinotecan

Concentrations of immunosuppressants metabolized by CYP3A can increase with co-administration.1 Discontinue the fixed combination of DRV/c/FTC/TAF at least 1 week prior to starting irinotecan therapy.1 Do not administer these agents together unless there are no therapeutic alternatives.1

Inhaled Beta-agonist

Salmeterol

Concentrations of salmeterol can increase with co-administration.1 Co-administration with salmeterol is not recommended due to increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.1

Lipid Modifying Agents

HMG-CoA Reductase Inhibitors

Lovastatin, Simvastatin: Concentrations of lovastatin and simvastatin can increase with co-administration.1 Co-administration is contraindicated due to potential for serious reactions such as myopathy, including rhabdomyolysis.1

Atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastatin: Concentrations of these agents can increase with co-administration.1 Start with the lowest recommended dose and titrate while monitoring for safety.1 Do no exceed 20 mg daily of atorvastatin or rosuvastatin.1

Other Lipid Modifying Agents

Lomitapide: Concentrations of lomitapide can increase with co-administration.1 Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide.1

Narcotic Analgesics Metabolized by CYP3A

Fentanyl, Oxycodone, Tramadol

Concentrations of these agents can increase with co-administration.1 Monitor therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) with co-administration.1 A dose decrease may be needed for tramadol with concomitant use.1

Narcotic Analgesic for Treatment of Opioid Dependence

Buprenorpine, Buprenorphine/Naloxone, Methadone

Effects of co-administration are unknown.1

When initiating any of these agents in patients taking the fixed combination of DRV/c/FTC/TAF, carefully titrate the dose of buprenorphine, buprenorphine/naloxone, or methadone and use the lowest feasible initial or maintenance dose.1

When initiating the fixed combination of DRV/c/FTC/TAF in patients taking one of these agents for opioid dependence, a dose adjustment of the agents may be needed.1 Monitor clinical signs and symptoms.1

Opioid Antagonist

Naloxegol

Concentrations of naloxegol may increase with co-administration.1 Co-administration is contraindicated due to the potential for precipitating opioid withdrawal symptoms.1

Phosphodiesterase type 5 (PDE-5) Inhibitors

Avanafil, Sildenafil, Tadalafil, Vardenafil

Concentrations of avanafil, sildenafil, tadalafil, and vardenafil may increase with co-administration.1 Co-administration with these PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances, and priapism.1

Avanafil

Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.1

Sildenafil

For use in pulmonary arterial hypertension (PAH): co-administration is contraindicated due to the potential for sildenafil-associated adverse reactions including visual disturbances, hypotension, prolonged erection, and syncope.1

For use in erectile dysfunction: do not exceed a single dose of 25 mg in 48 hours and closely monitor for adverse reactions.1

Tadalafil

For use in pulmonary arterial hypertension (PAH):

To initiate tadalafil for patients taking the fixed combination of DRV/c/FTC/TAF, start tadalafil at 20 mg once daily for at least 1 week and increase to 40 mg once daily based on individual tolerability.1

To initiate the fixed combination of DRV/c/FTC/TAF in patients taking tadalafil, stop tadalafil at least 24 hours prior to starting the fixed combination.1 After at least 1 week, resume tadalafil at 20 mg once daily and increase to 40 mg based on individual tolerability.1

To switch from darunavir co-administered with ritonavir to the fixed combination of DRV/c/FTC/TAF in patients taking tadalafil, maintain the tadalafil dose.1

For use in erectile dysfunction: do not exceed a single dose of 10 mg in 72 hours and closely monitor for adverse reactions.1

Vardenafil

For use in erectile dysfunction: do not exceed a single dose of 2.5 mg in 72 hours and closely monitor for adverse reactions.1

Platelet Aggregation Inhibitors

Ticagrelor

Concentrations of ticagrelor can increase with co-administration.1 Co-administration is not recommended.1

Clopidogrel

Concentrations of clopidogrel active metabolite can decrease with co-administration.1 Co-administration is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel.1

Prasugrel

No effect on the concentrations of the active metabolite of prasugrel have been observed with co-administration.1 No dose adjustment is needed with co-administration.1

Sedatives/Hypnotics

Midazolam, Triazolam

Concentrations of midazolam and triazolam can increase with co-administration.1 Co-administration of orally administered midazolam or triazolam with the fixed combination of DRV/c/FTC/TAF is contraindicated due to the potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.1 Co-administration of parenteral midazolam requires close monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.1 Consider use of lower doses of midazolam especially if more than a single dose is administered.1

Buspirone, Diazepam, Estazolam, Zolpidem

Concentrations of these sedative/hypnotic agents metabolized by CYP3A can increase with co-administration.1 With concomitant use, start with lower doses and titrate carefully with close monitoring for increased and prolonged effects or adverse reactions.1

Urinary Antispasmodics

Fesoterodine

Concentrations of fesoterodine can increase with co-administration.1 When co-administered, do not exceed a fesoterodine dose of 4 mg once daily.1

Solifenacin

Concentrations of solifenacin can increase with co-administration.1 When co-administered, do not exceed a solifenacin dose of 5 mg once daily.1

Description

The fixed combination of darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (DRV/c/FTC/TAF) contains an HIV-1 protease inhibitor (darunavir), a pharmacokinetic enhancer (cobicistat), an HIV-1 nucleoside reverse transcriptase inhibitor (emtricitabine), and an HIV-1 nucleotide reverse transcriptase inhibitor (tenofovir alafenamide).1

Darunavir selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.1

Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates.1

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate.1 Emtricitabine is inactive until converted intracellularly to an active 5'-triphosphate metabolite; after conversion, the drug inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, which results in chain termination.1

Tenofovir alafenamide is a prodrug and is inactive until hydrolyzed intracellularly by cathepsin A to form tenofovir and subsequently metabolized by cellular kinases to the active metabolite (tenofovir diphosphate).1 Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination.1

HIV-1 resistance to darunavir, emtricitabine, and tenofovir alafenamide has been produced in vitro.1 In clinical trials, darunavir resistance-associated substitutions in HIV-1 protease were derived from data in protease inhibitor-experienced patients.1 Baseline International AIDS Society-USA (IAS-USA)-defined PI resistance substitutions confer reduced virologic response to darunavir.1 In the AMBER trial in subjects with no prior antiretroviral treatment history, no patients with virologic failure had detectable emergent darunavir resistance-associated substitutions or other primary protease inhibitor resistance-associated substitutions and only one patient had emergent M184M/I/V, which confers resistance to emtricitabine and lamivudine.1 In the EMERALD trial in virologically-suppressed subjects who switched to DRV/c/FTC/TAF, no patients with resistance genotypes had darunavir, primary protease inhibitor, emtricitabine, or tenofovir resistance-associated substitutions.1

Advice to Patients

• Advise patients to take the fixed combination of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (DRV/c/FTC/TAF) with food every day on a regular dosing schedule, as missed doses can result in development of resistance.1
• Inform patients not to alter the dose of DRV/c/FTC/TAF or discontinue therapy without consulting their physician.1
• Inform patients who are unable to swallow tablets whole that DRV/c/FTC/TAF may be split using a tablet-cutter, and to consume the entire dose immediately after splitting.1
• Advise patients to not discontinue DRV/c/FTC/TAF without first informing their healthcare provider as severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate.1
• Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, could potentially occur with DRV/c/FTC/TAF.1 Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop.1
• Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, could potentially occur with DRV/c/FTC/TAF.1 Advise patients to contact their healthcare provider immediately if signs or symptoms of severe skin reactions develop including severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, and/or conjunctivitis.1
• Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.1
• Advise patients that they should stop DRV/c/FTC/TAF if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.1
• Advise patients to avoid taking DRV/c/FTC/TAF with concurrent or recent use of nephrotoxic agents.1 Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs.1
• Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including DRV/c/FTC/TAF, and that the cause and long-term health effects of these conditions are not known at this time.1
• Advise patients that DRV/c/FTC/TAF is not recommended during pregnancy and to alert their healthcare provider if pregnancy occurs.1 Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to DRV/c/FTC/TAF.1
• Instruct individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.1
• DRV/c/FTC/TAF may interact with many drugs; therefore, inform patients of potential serious drug interactions with DRV/c/FTC/TAF.1 Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.1
• Inform 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.

1. Janssen. Symtuza^® (Darunavir, Cobicistat, Emtricitabine, and Tenofovir alafenamide) ORAL prescribing information. 2023 Mar [Web]

2. Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018;32(11):1431-1442.

3. Orkin C, Eron JJ, Rockstroh J, et al. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2020;34(5):707-718.

4. Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23-e34.

5. Huhn GD, Wilkin A, Mussini C, et al. Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/c/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1. HIV Res Clin Pract. 2020;21(6):151-167.

6. Podzamczer D, Micán R, Tiraboschi J, et al. Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir/Abacavir/Lamivudine in Antiretroviral-Naive Adults (SYMTRI): A Multicenter Randomized Open-Label Study (PReEC/RIS-57). Open Forum Infect Dis. 2021;9(3):ofab595.

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

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV.gov website. [Web]

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