Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (Monograph)

Brand name: Symtuza
Drug class: HIV Protease Inhibitors

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

Introduction

Antiretroviral; fixed combination of darunavir, cobicistat, emtricitabine and tenofovir alafenamide (DRV/c/FTC/TAF). Darunavir is an HIV-1 protease inhibitor, cobicistat is a CYP3A inhibitor, emtricitabine is an HIV-1 nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir alafenamide is an HIV-1 nucleotide reverse transcriptase inhibitor.

Uses for Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Treatment of HIV Infection

Used as a complete regimen for 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 ≥6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

DRV/c/FTC/TAF is a co-formulation of a boosted protease inhibitor (DRV/c) and 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; FTC/TAF); consult guidelines for the most current information on the place in therapy for this regimen.

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.

Related/similar drugs

Biktarvy, Descovy, Truvada, Atripla, Stribild, Complera, Epzicom

Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Dosage and Administration

General

Pretreatment Screening

• Test patients for HBV infection.

• Obtain baseline serum creatinine, estimated creatinine clearance, urine glucose, and urine protein.

• Obtain baseline liver enzyme levels.

• Check pregnancy status. Do not initiate in patients who are pregnant.

• Check for patient history of sulfonamide allergy.

Patient Monitoring

• Monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients on a clinically appropriate schedule.

• Monitor serum phosphorus in patients with chronic kidney disease.

• Monitor for exacerbation of HBV in patients who have concomitant HBV infection and who have discontinued treatment with DRV/c/FTC/TAF for at least several months after drug discontinuation.

• Monitor for hepatotoxicity as clinically appropriate. 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.

• Monitor patients with a known sulfonamide allergy.

• Monitor patients for skin reactions.

Administration

Oral Administration

Adminster orally once daily with food. Available as an oral tablet containing darunavir ethanolate, cobicistat, emtricitabine, and tenofovir alafenamide fumarate; each tablet contains 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide.

Tablets can be split; take full dose immediately after splitting.

Dosage

Pediatric Patients

HIV-1 Infection

Oral

Pediatric patients weighing ≥40 kg: Recommended dosage is 1 tablet (800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide) once daily with food.

Adults

HIV-1 Infection

Oral

Recommended dosage is 1 tablet (800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide) once daily with food.

Special Populations

Hepatic Impairment

Not recommended in patients with severe hepatic impairment. No specific dosage recommendations for patients with mild to moderate hepatic impairment.

Renal Impairment

Not recommended in patients with Cl_cr<30 mL/minute. No dosage adjustment required for patients with Cl_cr ≥30 mL/minute.

Geriatric Use

No specific dosage recommendations.

Cautions for Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Contraindications

• Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, ergot alkaloids, lovastatin, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam).

• Concomitant use with drugs that are inducers of CYP3A (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort [Hypericum perforatum]).

Warnings/Precautions

Warnings

HIV-infected Individuals Coinfected with HBV

Test all patients for presence of chronic HBV before initiating the fixed combination of DRV/c/FTC/TAF.

Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after treatment is discontinued. If appropriate, resumption of HBV treatment may be warranted, especially in patients with cirrhosis or advanced liver disease, since posttreatment exacerbation of HBV infection may lead to hepatic decompensation and liver failure. (See Boxed Warning).

Other Warnings and Precautions

Hepatotoxicity

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, reported with darunavir, a component of DRV/c/FTC/TAF.

Conduct appropriate laboratory testing prior to initiating and during therapy with DRV/c/FTC/TAF. 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.

Promptly consider interruption or discontinuation of DRV/c/FTC/TAF if 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) occurs.

Severe Skin Reactions

Severe skin reactions, accompanied by fever and transaminase elevations, may occur in patients receiving darunavir. Rash events were mild-to-moderate, often occurring within the first 4 weeks of treatment and resolving with continued dosing.

Discontinue DRV/c/FTC/TAF 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, conjunctivitis, hepatitis, and/or eosinophilia.

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

Concomitant use with certain drugs may result in drug interactions. May lead to loss of therapeutic effect and possible development of resistance or possible adverse effects from increased exposures of concomitant drugs.

Consider potential for drug interactions prior to and during treatment with DRV/c/FTC/TAF and monitor for adverse effects associated with concomitant drugs.

Immune Reconstitution Syndrome

Immune reconstitution syndrome reported in patients treated with combination antiretroviral therapy. 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.

Other autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) can occur many months after initiation of antiretroviral treatment.

New Onset or Worsening Renal Impairment

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

Assess serum creatinine, estimated Cl_cr, urine glucose, and urine protein in all patients prior to and during treatment. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DRV/c/FTC/TAF in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Consider cobicistat-induced elevations of serum creatinine when interpreting changes in estimated Cl_cr in patients initiating DRV/c/FTC/TAF. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Closely monitor patients who experience a confirmed increase in serum creatinine of >0.4 mg/dL.

Sulfa Allergy

Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating DRV/c/FTC/TAF.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with use of nucleoside analogs, including emtricitabine and TDF, alone or in combination with other antiretrovirals.

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).

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia reported during postmarketing surveillance in patients receiving HIV PI therapy; may require initiation or dose adjustments of insulin or oral hypoglycemic agents.

Fat Redristibution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" observed in patients receiving antiretroviral therapy.

Hemophilia

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, reported in patients with hemophilia type A and B treated with HIV PIs. A causal relationship has not been established.

Specific Populations

Pregnancy

Healthcare providers are encouraged to register pregnant patients at the Antiretroviral Pregnancy Registry (APR) at 800-258-4263.

Insufficient data in pregnant women to inform a drug-associated risk of birth defects and miscarriage. Available data from the APR show no difference in rate of overall birth defects for darunavir and emtricitabine compared with the background rate for major birth defects in a U.S. reference population.

DRV/c/FTC/TAF is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy. Do not initiate in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy.

Lactation

The Centers for Disease Control and Prevention (CDC) recommend that mothers with HIV not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Emtricitabine has been shown to be present in human milk. Darunavir, cobicistat, and tenofovir are present in the milk of lactating rats and monkeys.

Pediatric Use

Safety and effectiveness in pediatric patients weighing <40 kg not established. 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 darunavir.

Geriatric Use

No differences in safety or efficacy observed between geriatric patients and those ≤65 years of age. Exercise caution when used in elderly patients, considering greater frequency of decreased hepatic function and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment; not studied in patients with severe hepatic impairment (Child Pugh Class C).

Not recommended for use in patients with severe hepatic impairment.

Renal Impairment

Not recommended in patients with severe renal impairment (Cl_cr <30 mL per minute).

No dosage adjustment required in patients with Cl_cr ≥30 mL per minute.

Common Adverse Effects

Most common adverse reactions (≥2%): diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, flatulence.

Drug Interactions

Darunavir and cobicistat are metabolized by CYP3A. CYP2D6 plays a minor role in cobicistat metabolism.

Darunavir co-administered with cobicistat is a CYP3A and CYP2D6 inhibitor.

Cobicistat inhibits 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). In vitro and in vivo studies indicate cobicistat does not induce CYP1A2, CYP2B6, CYP3A, MDR1.

Emtricitabine is not an inhibitor of CYP enzymes.

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A or CYP2D6 Substrates

Co-administration 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. May increase or prolong substrate drug’s therapeutic effect or adverse events.

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.

CYP3A Inducers

Co-administration with drugs that induce CYP3A 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.

CYP3A Inhibitors

Co-administration with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat.

Drugs Affecting P-glycoprotein Transport

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.

P-gp Inhibitors

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

Drugs Affecting Renal Function

Co-administration 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. 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.

Specific Drugs

Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Pharmacokinetics

Absorption

Bioavailability

Not affected when administered as a split tablet compared to whole tablet.

T_max: darunavir (3 hours), cobicistat (3 hours), emtricitabine (1.5 hours), tenofovir alafenamide (0.5 hours).

Distribution

Plasma Protein Binding

Darunavir: 95%.

Cobicistat: 97–98%.

Emtricitabine: <4%.

Tenofovir alafenamide: approximately 80%.

Elimination

Metabolism

Darunavir: CYP3A.

Cobicistat: CYP3A (major), CYP2D6 (minor).

Emtricitabine: not significantly metabolized.

Tenofovir alafenamide: hydrolyzed intracellularly (peripheral blood mononuclear cells, hepatocytes) to active metabolite – tenofovir diphosphate, minimal CYP3A metabolism.

Elimination Route

Darunavir: metabolism; Cobicistat: metabolism; Emtricitabine: glomerular filtration/active tubular secretion; Tenofovir alafenamide: metabolism.

Half-life

Darunavir: 9.4 hours.

Cobicistat: 3.2 hours.

Emtricitabine: 7.5 hours.

Tenofovir alafenamide: 0.5 hours.

Special Populations

No substantial changes in pharmacokinetics based on gender or race.

Impact of severe hepatic impairment on pharmacokinetics of individual components not evaluated.

Severe renal impairment (Cl_cr <30 mL/minute) results in increased mean systemic emtricitabine exposure.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C). Dispense in original container; keep container tightly closed.

Actions

• DRV/c/FTC/TAF is a fixed-dose combination antiretroviral containing darunavir (a protease inhibitor), cobicistat (a pharmacokinetic enhancer), emtricitabine (a nucleoside analog reverse transcriptase inhibitor; NRTI), and tenofovir alafenamide (an NRTI).

• Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2. Cobicistat has no detectable antiviral activity in cell culture against HIV-1. Emtricitabine has antiviral activity in cell culture against HIV-1 classes A, B, C, D, E, F, and G and shows strain specific activity against HIV-2. TAF has antiviral activity against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G and strain specific activity against HIV-2.

• HIV-1 resistance to darunavir, emtricitabine, and tenofovir alafenamide has been produced in vitro.

• Cross-resistance among PIs has been observed. Cross-resistance between darunavir and NRTIs, non-nucleoside reverse transcriptase inhibitors, gp41 fusion inhibitors, CCR5 co-receptor antagonists, or integrase strand transfer inhibitors is unlikely. Cross-resistance also occurs among HIV NRTIs.

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.

• Inform patients not to alter the dose of DRV/c/FTC/TAF or discontinue therapy without consulting their physician.

• 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.

• 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.

• 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. Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop.

• 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. 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.

• 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.

• Advise patients that they should stop DRV/c/FTC/TAF if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.

• Advise patients to avoid taking DRV/c/FTC/TAF with concurrent or recent use of nephrotoxic agents. Renal impairment, including cases of acute renal failure, has been reported in association with the use of tenofovir prodrugs.

• 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.

• Advise patients that DRV/c/FTC/TAF is not recommended during pregnancy and to alert their healthcare provider if pregnancy occurs. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to DRV/c/FTC/TAF.

• Instruct individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

• DRV/c/FTC/TAF may interact with many drugs; therefore, inform patients of potential serious drug interactions with DRV/c/FTC/TAF. 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.

• Inform patients of other important precautionary information.

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.

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Frequently asked questions

• What drugs are contained in the HIV treatment Symtuza?

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